WO2023230429A1

WO2023230429A1 - Methods of treating colorectal cancer with tucatinib in combination with an anti-her2 antibody

Info

Publication number: WO2023230429A1
Application number: PCT/US2023/067249
Authority: WO
Inventors: Michael David STECHER
Original assignee: Seagen Inc.
Priority date: 2022-05-22
Filing date: 2023-05-19
Publication date: 2023-11-30

Abstract

The invention provides methods of treating cancers, such as metastatic colorectal cancer, with a combination of tucatinib, or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab.

Description

METHODS OF TREATING COLORECTAL CANCER WITH TUCATINIB IN COMBINATION WITH AN ANTI-HER2 ANTIBODY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 63/344,628, filed on May 22, 2022, the disclosure of which is incorporated by reference for all purposes.

REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The contents of the electronic sequence listing (761682009540SEQLIST.xml;

Size: 3,195 bytes; and Date of Creation: May 15, 2023) is herein incorporated by reference in its entirety.

TECHNICAL FIELD

[0003] The present invention relates to methods of treating cancers, such as metastatic colorectal cancer, with a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab.

BACKGROUND

[0004] Tucatinib ((N⁴ -(4-([l,2,4]triazolo[l,5-a]pyridin-7-yloxy)-3-methylphenyl)-N ⁶- (4,4-dimethyl-4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine) (TUKYSA™; formerly known as ARRY-380 and ONT-380) is an orally (PO) administered, potent, highly selective, small-molecule tyrosine kinase inhibitor (TKI) of HER2. Tucatinib is a potent inhibitor of HER2 in vitro, and in cellular signaling assays is >1000-fold more selective for HER2 compared to the closely related kinase EGFR. The selectivity of tucatinib for HER2 reduces the potential for EGFR-related toxicities that can be seen with dual HER2/EGFR inhibitors. Tucatinib inhibits the HER2-driven mitogen-activated protein and PI3 kinase signaling pathways, resulting in inhibition of tumor cell proliferation, survival, and metastasis.

[0005] Tucatinib, combined with trastuzumab and capecitabine, is approved for use in previously treated patients with advanced unresectable or metastatic HER2+ breast cancer in Australia, Canada, Singapore, Switzerland, and the US. [0006] Trastuzumab, a humanized anti-HER2 antibody that binds to the HER2 extracellular domain, is approved for use in the treatment of HER2+ breast cancer and remains the backbone of treatment in the perioperative and metastatic setting, usually in combination with a taxane. Pertuzumab is another approved anti-HER2 monoclonal antibody, which binds to the HER2 receptor at a site different from trastuzumab.

[0007] Encoded by the ERBB2 gene, human epidermal growth factor receptor 2 (HER2) is part of a family of 4 related receptor tyrosine kinases, which include HER1 (also known as epidermal growth factor receptor [EGFR]), HER2, HER3, and HER4. HER1-4 are singlepass transmembrane glycoprotein receptors containing an extracellular ligand binding region and an intracellular signaling domain. HER2 has no known ligand, but it is the preferred dimerization partner for the other HER family receptors. When overexpressed in tumors, HER2 forms ligand-independent homodimeric complexes that autophosphorylate. HER2 homo- or heterodimerization results in the activation of multiple signaling cascades, including the Ras/Raf/MEK/MAPK, PI3K/AKT, Src, and STAT pathways. These signaling pathways lead to cell proliferation, inhibition of apoptosis, and metastasis.

[0008] HER2 is a validated target in multiple cancers, with anti-HER2 biologies and small molecule-drugs approved for patients with HER2 overexpressing/amplified breast and gastric cancers. Amplification of the HER2 gene or overexpression of its protein occurs in approximately 15% to 20% of breast cancers.

[0009] In typical HER2+ cancers, including breast cancer, gastric cancer, and colorectal cancer, the amplification of HER2 leads to strong signal transduction through either homodimerization or heterodimerization with another ErbB-family member. This results in downstream activation of both the MAP kinase and phosphatidyl-inositol-3 (PI3) kinase pathways, which in turn enhances mitogenicity and survival.

[0010] In some cancers, however, HER2 expression is not amplified, but rather HER2 may contain an activating mutation in the kinase domain that also leads to increased signaling and mitogenicity. See WO 2018/200505. HER2 activating mutations may act as oncogenic drivers in various cancer types. See WO 2018/200505. The majority of these HER2-mutant cancers have not been associated with concurrent HER2 gene amplification, with the result that an important subgroup of HER2-altered cancers are not detected by immunohistochemistry (IHC) or in situ hybridization (ISH) methods. In the clinic, they can be identified by next generation sequencing (NGS) in either tumor biopsies or circulating cell-free DNA (cfDNA). Annals of Oncol 28: 136-141 (2017). Preclinical data indicate that HER2 “hot spot” mutations may be constitutively active, have transforming capacity in vitro and in vivo and may show variable sensitivity to anti-HER2 based therapies. J Mol Diagn, 17(5):487-495 (2015), Nat Gen 51, 207-216 (2019). Recent clinical trials also revealed potential activity of HER2 -targeted drugs against a variety of tumors harboring HER2 mutations. HER2 -targeted agents could potentially be useful for the treatment of cancers harboring these activating mutations. ESMO Open 2017; 2: e000279. However, efforts to target cancers with HER2 mutations have met with limited clinical success, possibly because of their low frequency, inadequate understanding of the biological activity of these mutations, and difficulty in separating the drivers from the passenger mutations. The Oncologist 24(12):el303-el314 (2019). The role of HER2-directed therapy in these HER2-mutated cancers is the subject of active exploration.

[0011] Targeted therapy of multiple non-redundant molecular pathways regulating immune responses can enhance antitumor immunotherapy. However, not all combinations have acceptable safety and/or efficacy. There remains a need for combination therapies with an acceptable safety profile and high efficacy for the treatment of cancer, in particular for the treatment of advanced (such as metastatic) colorectal cancer. Targeted therapy of multiple non-redundant molecular pathways regulating immune responses can enhance antitumor immunotherapy. However, not all combinations have acceptable safety and/or efficacy. There remains a need for combination therapies with an acceptable safety profile and high efficacy for the treatment of cancer, in particular for the treatment of HER2+ cancers.

[0012] All references cited herein, including patent applications, patent publications, and scientific literature, are herein incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference.

SUMMARY

[0013] Provided herein is a method for treating colorectal cancer in a subject comprising administering a combination of tucatinib, or a salt or solvate thereof, and at least one anti- HER2 antibody to the subject. In some embodiments, administering such treatment results in a confirmed objective response rate that is at least about 30%. In some embodiments, administering such treatment results in a confirmed objective response rate that is about 30% to about 60%. In some embodiments, administering such treatment results in a confirmed objective response rate that is about 30% to about 40%. In some embodiments, administering such treatment results in a confirmed objective response rate that is about 35% to about 40%. In some embodiments, administering such treatment results in a median duration of response that is about 10.4 months to about 15 months. In some embodiments, administering such treatment results in a median duration of response that is about 11 months to about 14 months. In some embodiments, administering such treatment results in a median duration of response that is about 12 months to about 13 months. In some embodiments, administering such treatment results in a median duration of response that is about 12.4 months. In some embodiments, administering such treatment results in a median progression free survival (PFS) of about 8.1 months to about 10 months. In some embodiments, administering such treatment results in a median PFS of about 8.1 months to about 9 months. In some embodiments, administering such treatment results in a median PFS of about 8.2 months. In some embodiments, administering such treatment results in a median overall survival of about 15 months to about 30 months. In some embodiments, administering such treatment results in a median overall survival of about 20 months to about 28 months. In some embodiments, administering such treatment results in a median overall survival of about 23 months to about 25 months. In some embodiments, administering such treatment results in a median overall survival of about 24.1 months. In some embodiments, administering such treatment results in complete response in at least 1% of the subjects. In some embodiments, administering such treatment results in complete response in at least 3% of the subjects. In some embodiments, administering such treatment results in complete response in about 3.6% of subjects.

[0014] In some embodiments, the subject is at least 65 years old. In some embodiments, the cancer is HER2+. In some embodiments, the cancer is metastatic colorectal cancer. In some embodiments, the cancer is wild-type RAS. In some embodiments, the RAS is determined to be wild-type based on expanded RAS testing. In some embodiments, the RAS is determined to be wild-type based on expanded RAS testing comprising sequencing of known cancer-associated codons in KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.

[0015] In some embodiments, the subject has completed at least one prior line of treatment for the cancer. In some embodiments, the prior line of treatment for the cancer is selected from the list consisting of systemic therapy with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) antibody. In some embodiments, the at least one prior line of treatment for the cancer comprises an anti-PD-Ll antibody. In some embodiments, the subject has relapsed from standard of care treatment. In some embodiments, the subject is refractory to standard of care treatment.

[0016] In some embodiments, the tucatinib, or salt or solvate thereof, and the at least one anti-HER.2 antibody are administered to the subject on a 21 -day treatment cycle. In some embodiments, the at least one anti-HER2 antibody is administered to the subject on day 1 of the 21 -day treatment cycle. In some embodiments, the at least one anti-HER2 antibody is administered once about every 3 weeks. In some embodiments, the tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 150 mg to about 650 mg. In some embodiments, the tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 300 mg. In some embodiments, the tucatinib, or salt or solvate thereof, is administered to the subject orally. In some embodiments, the at least one anti-HER.2 antibody is administered to the subject at a dose of about 4 mg/kg to about 10 mg/kg. In some embodiments, the at least one anti-HER2 antibody is administered to the subject at a dose of about 6 mg/kg of the subject’s body weight. In some embodiments, the at least one anti- HER2 antibody is administered to the subject at a dose of about 8 mg/kg of the subject’s body weight. In some embodiments, the at least one anti-HER2 antibody is administered to the subject at a dose of about an initial dose of about 8 mg/kg followed by subsequent doses of about 6 mg/kg. In some embodiments, the dose of the at least one anti-HER2 antibody administered during the first 21 -day treatment cycle is 8 mg/kg of the subject’s body weight and the dose administered during the subsequent 21 -day treatment cycles is 6 mg/kg of the subject’s bodyweight. In some embodiments, the at least one anti-HER2 antibody is administered intravenously. In some embodiments, the at least one anti-HER2 antibody comprises one anti-HER.2 antibody. In some embodiments, the at least one anti-HER2 antibody is trastuzumab, or a biosimilar thereof. In some embodiments, the at least one anti- HER2 antibody is trastuzumab. In some embodiments, the subject is a human.

[0017] Further provided herein is a kit comprising: (a) tucatinib, or a salt or solvate thereof; (b) at least one anti-HER.2 antibody; and (c) instructions for using the kit in any of the methods described above. In some embodiments, the at least one anti-HER2 antibody comprises trastuzumab.

[0018] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1A shows a schematic of a clinical trial design evaluating the efficacy and safety of tucatinib in combination with trastuzumab and tucatinib monotherapy in patients with HER2+ metastatic colorectal cancer. FIG. IB shows an updated schematic of the clinical trial design evaluating the efficacy and safety of tucatinib in combination with trastuzumab and tucatinib monotherapy in patients with HER2+ metastatic colorectal cancer.

[0020] FIG. 2 shows confirmed objective response rate (cORR) for Cohorts A + B of the clinical trial, including for defined subgroups of age, Eastern Cooperative Oncology Group (ECOG) performance score, primary site of disease, and geographic region.

[0021] FIG. 3 shows duration of response per blinded independent central review (BICR) for Cohorts A + B.

[0022] FIG. 4 shows progression-free survival per BICR for Cohorts A + B.

[0023] FIG. 5 shows overall survival for Cohorts A + B.

DETAILED DESCRIPTION

I. Definitions

[0024] In order that the present disclosure can be more readily understood, certain terms are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[0025] The terms “a,” “an,” or “the” as used herein not only include aspects with one member, but also include aspects with more than one member. For instance, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells and reference to “the agent” includes reference to one or more agents known to those skilled in the art, and so forth.

[0026] The term “or” as used herein should in general be construed non-exclusively. For example, a claim to “a composition comprising A or B” would typically present an aspect with a composition comprising both A and B. “Or” should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a composition pH that is between 9 and 10 or between 7 and 8).

[0027] The group “A or B” is typically equivalent to the group “selected from the group consisting of A and B.”

[0028] The term "and/or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and/or" as used in a phrase such as "A and/or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and/or" as used in a phrase such as "A, B, and/or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0029] It is understood that aspects and embodiments of the invention described herein include “comprising,” “consisting,” and “consisting essentially of’ aspects and embodiments.

[0030] The terms “about” and “approximately” as used herein shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Typical, exemplary degrees of error are within 20 percent (%), preferably within 10%, and more preferably within 5% of a given value or range of values. Any reference to “about X” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, “about X” is intended to teach and provide written description support for a claim limitation of, e.g., “0.98X.” The terms “about” and “approximately,” particularly in reference to a given quantity, encompass and describe the given quantity itself.

[0031] Alternatively, in biological systems, the terms “about” and “approximately” may mean values that are within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold of a given value. Numerical quantities given herein are approximate unless stated otherwise, meaning that the term “about” or “approximately” can be inferred when not expressly stated.

[0032] When “about” is applied to the beginning of a numerical range, it applies to both ends of the range. Thus, “from about 5 to 20%” is equivalent to “from about 5% to about 20%. ” When “about” is applied to the first value of a set of values, it applies to all values in that set. Thus, “about 7, 9, or 11 mg/kg” is equivalent to “about 7, about 9, or about 11 mg/kg.”

[0033] The term “comprising” as used herein should in general be construed as not excluding additional ingredients. For example, a claim to “a composition comprising A” would cover compositions that include A and B; A, B, and C; A, B, C, and D; A, B, C, D, and E; and the like.

[0034] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0035] Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects of the disclosure, which can be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0036] As used herein, the term “co-administering” includes sequential or simultaneous administration of two or more structurally different compounds. For example, two or more structurally different pharmaceutically active compounds can be co-administered by administering a pharmaceutical composition adapted for oral administration that contains two or more structurally different active pharmaceutically active compounds. As another example, two or more structurally different compounds can be co-administered by administering one compound and then administering the other compound. The two or more structurally different compounds can be comprised of an anti-HER2 antibody and tucatinib. In some instances, the co-administered compounds are administered by the same route. In other instances, the co-administered compounds are administered via different routes. For example, one compound can be administered orally, and the other compound can be administered, e.g., sequentially or simultaneously, via intravenous, intramuscular, subcutaneous, or intraperitoneal injection. The simultaneously or sequentially administered compounds or compositions can be administered such that an anti-HER2 antibody and tucatinib are simultaneously present in a subject or in a cell at an effective concentration.

[0037] A "cancer" refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. A "cancer" or "cancer tissue" can include a tumor. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and can also metastasize to distant parts of the body through the lymphatic system or bloodstream. Following metastasis, the distal tumors can be said to be "derived from" the pre-metastasis tumor. For example, a "tumor derived from" a colorectal cancer refers to a tumor that is the result of a metastasized colorectal cancer.

[0038] In the context of cancer, the term “stage” refers to a classification of the extent of cancer. Factors that are considered when staging a cancer include but are not limited to tumor size, tumor invasion of nearby tissues, and whether the tumor has metastasized to other sites. The specific criteria and parameters for differentiating one stage from another can vary depending on the type of cancer. Cancer staging is used, for example, to assist in determining a prognosis or identifying the most appropriate treatment option(s).

[0039] One non-limiting example of a cancer staging system is referred to as the “TNM” system. In the TNM system, “T” refers to the size and extent of the main tumor, “N” refers to the number of nearby lymph nodes to which the cancer has spread, and “M” refers to whether the cancer has metastasized. “TX” denotes that the main tumor cannot be measured, “TO” denotes that the main tumor cannot be found, and “Tl,” “T2,” “T3,” and “T4” denote the size or extent of the main tumor, wherein a larger number corresponds to a larger tumor or a tumor that has grown into nearby tissues. “NX” denotes that cancer in nearby lymph nodes cannot be measured, “NO” denotes that there is no cancer in nearby lymph nodes, and “Nl,” “N2,” “N3,” and “N4” denote the number and location of lymph nodes to which the cancer has spread, wherein a larger number corresponds to a greater number of lymph nodes containing the cancer. “MX” denotes that metastasis cannot be measured, “M0” denotes that no metastasis has occurred, and “Ml” denotes that the cancer has metastasized to other parts of the body.

[0040] As another non-limiting example of a cancer staging system, cancers are classified or graded as having one of five stages: “Stage 0,” “Stage I,” “Stage II,” “Stage III,” or “Stage IV.” Stage 0 denotes that abnormal cells are present, but have not spread to nearby tissue. This is also commonly called carcinoma in situ (CIS). CIS is not cancer, but may subsequently develop into cancer. Stages I, II, and III denote that cancer is present. Higher numbers correspond to larger tumor sizes or tumors that have spread to nearby tissues. Stage IV denotes that the cancer has metastasized. One of skill in the art will be familiar with the different cancer staging systems and readily be able to apply or interpret them.

[0041] The term “HER2” (also known as also known as HER2/neu, ERBB2, CD340, receptor tyrosine-protein kinase erbB-2, proto-oncogene Neu, and human epidermal growth factor receptor 2) refers to a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family of receptor tyrosine kinases. Amplification or overexpression of HER2 plays a significant role in the development and progression of certain aggressive types of cancer, including cancer, lung cancer (e.g., non-small cell lung

cancer (NSCLC)), biliary cancers (e.g., cholangiocarcinoma, gallbladder cancer), bladder cancer, esophageal cancer, melanoma, ovarian cancer, liver cancer, prostate cancer, pancreatic cancer, small intestine cancer, head and neck cancer, uterine cancer, cervical cancer, and breast cancer. Non-limiting examples of HER2 nucleotide sequences are set forth in GenBank reference numbers NP_001005862, NP_001289936, NP_001289937, NP_001289938, and NP_004448. Non-limiting examples of HER2 peptide sequences are set forth in GenBank reference numbers NP_001005862, NP_001276865, NP_001276866, NP_001276867, and NP_004439.

[0042] When HER2 is amplified or overexpressed in or on a cell, the cell is referred to as being “HER2 positive.” The level of HER2 amplification or overexpression in HER2 positive cells is commonly expressed as a score ranging from 0 to 3 (i.e., HER2 0, HER2 1+, HER2 2+, or HER2 3+), with higher scores corresponding to greater degrees of expression. Mol Biol Int. 2014:852748 (2014). The scoring method may be based on the cell membrane staining pattern as determined by immunohistochemistry and is as follows: i. 3+: positive HER2 expression, uniform intense membrane staining of more than 30% of invasive tumor cells; ii. 2+: equivocal for HER2 protein expression, complete membrane staining that is either nonuniform or weak in intensity but has circumferential distribution in at least 10% of cells; iii. 0 or 1+: negative for HER2 protein expression. [0043] The term “tucatinib,” also known as ONT-380 and ARRY-380, refers to the small molecule tyrosine kinase inhibitor that suppresses or blocks HER2 activation. Tucatinib has the following structure:

[0044] The term “anti-HER2 antibody” refers to an antibody that binds to the HER2 protein. Anti-HER2 antibodies used for the treatment of cancer are typically monoclonal, although polyclonal antibodies are not excluded by the term. Anti-HER2 antibodies inhibit HER2 activation or downstream signaling by various mechanisms. As non-limiting examples, anti-HER2 antibodies can prevent ligand binding, receptor activation or receptor signal propagation, result in reduced HER2 expression or localization to the cell surface, inhibit HER2 cleavage, or induce antibody-mediated cytotoxicity. Non-limiting examples of anti-HER2 antibodies that are suitable for use in the methods and compositions of the present invention include trastuzumab, pertuzumab, ado-trastuzumab emtansine (also known as T- DM1), margetuximab, and combinations thereof.

[0045] T he term "chemotherapeutic agent" refers to a group of compounds useful in treating or ameliorating cancer or its symptoms. In some embodiments, chemotherapeutic agents include alkylating antineoplastic agents (e.g., nitrogen mustards, such as mechiorathamine, isfosfamide, melphalan, chlorambucil, and cyclophosphamide; alkyl sufonates, such as busulfan; nitrosoureas, such as streptozocin, carmustine, and lomustine; triazines, such as dacarbazine and temozolomide; and ethyleneimines, such as thiotepa and altretamine), antimetabolites (see below), antitumor antibiotics (e.g. , the anthracycins, such as daunorubicin, doxorubicin, epirubicin, idarubicin, and valrubicin; the bleomycins; mitomycin C, mitoxantrone, and actinomycin), aromatase inhibitors (e.g. , steroidal inhibitors, such as exemestane, and non-steroidal inhibitors, such as anastrozole and letrozole), kinase inhibitors (e.g., tyrosine kinase inhibitors, such as imatinib, gefitinib, erlotinib, lapatinib, nilotinib, sunitibnib, and sorafenib, and, e.g. , bosunitinib, neratinib, vatalanib, and toceranib), mTor inhibitors (e.g. , rapamycin and its analogs, such as temsiroiimus, everolimus, and ridaforolimus; dual PIcK/mTOR inhibitors; and ATP- competitive mTOR inhibitors, such as sapanisertib), retinoids (e.g., tretinoin, alitretinoin, bexarotene, and isotretinoin), topoisomerase inhibitors (e.g. , doxorubicin, etoposide, teniposide, niitoxantrone, novobiocin, merbaron, aclatubicin, camptothecin, and camptothecin prodrugs or derivatives, such as irinotecan and topothecan), and plant alkaloids (e.g., the Vinca alkaloids vinblastine, vinorelbine, vincristine, and vindesine; the taxanes, such as docetaxel and paclitaxel).

[0046] The term “tumor growth inhibition (TGI) index” refers to a value used to represent the degree to which an agent (e.g., tucatinib described herein, an anti-HER2 antibody described herein, or a combination thereof) inhibits the growth of a tumor when compared to an untreated control. The TGI index is calculated for a particular time point (e.g., a specific number of days into an experiment or clinical trial) according to the following formula:

where “Tx Day 0” denotes the first day that treatment is administered (i.e., the first day that an experimental therapy or a control therapy (e.g., vehicle only) is administered) and “Tx Day X” denotes X number of days after Day 0. Typically, mean volumes for treated and control groups are used. As a non-limiting example, in an experiment where study day 0 corresponds to “Tx Day 0” and the TGI index is calculated on study day 28 (i.e., “Tx Day 28”), if the mean tumor volume in both groups on study day 0 is 250 mm³ and the mean tumor volumes in the experimental and control groups are 125 mm³ and 750 mm³, respectively, then the TGI index on day 28 is 125%.

[0047] As used herein, the term “synergistic” or “synergy” refers to a result that is observed when administering a combination of components or agents (e.g., a combination of tucatinib and at least one anti-HER2 antibody) produces an effect (e.g., inhibition of tumor

growth, prolongation of survival time) that is greater than the effect that would be expected based on the additive properties or effects of the individual components. In some embodiments, synergism is determined by performing a Bliss analysis (see, e.g., Foucquier et al. Pharmacol. Res. Perspect. (2015) 3(3):e00149; hereby incorporated by reference in its entirety for all purposes). The Bliss Independence model assumes that drug effects are outcomes of probabilistic processes, and asumes that the drugs act completely independently (i.e., the drugs do not interfere with one another (e.g., the drugs have different sites of action) but each contributes to a common result). According to the Bliss Independence model, the predicted effect of a combination of two drugs is calculated using the formula:

E_AB = E_A + E_B - E_A X E_B, where EA and EB represent the effects of drugs A and B, respectively, and EAB represents the effect of a combination of drugs A and B. When the observed effect of the combination is greater than the predicted effect EAB, then the combination of the two drugs is considered to be synergistic. When the observed effect of the combination is equal to EAB, then the effect of the combination of the two drugs is considered to be additive. Alternatively, when the observed effect of the combination is less than EAB, then the combination of the two drugs is considered to be antagonistic.

[0048] The observed effect of a combination of drugs can be based on, for example, the TGI index, tumor size (e.g., volume, mass), an absolute change in tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day a treatment is adminstered and a particular number of days after treatment is first administered), the rate of change of tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day a treatment is adminstered and a particular number of days after treatment is first administered), or the survival time of a subject or a population of subjects. When the TGI index is taken as a measure of the observed effect of a combination of drugs, the TGI index can be determined at one or more time points. When the TGI index is determined at two or more time points, in some instances the mean or median value of the multiple TGI indices can be used as a measure of the observed effect. Furthermore, the TGI index can be determined in a single subject or a population of subjects. When the TGI index is determined in a population, the mean or median TGI index in the population (e.g., at one or more time points) can be used as a measure of the observed effect. When tumor size or the rate of tumor growth is used as a measure of the observed effect, the tumor size or rate of tumor growth can be measured in a subject or a population of subjects. In some instances, the mean or median tumor size or rate of tumor growth is determined for a subject at two or more time points, or among a population of subjects at one or more time points. When survival time is measured in a population, the mean or median survival time can be used as a measure of the observed effect.

[0049] The predicted combination effect EAB can be calculated using either a single dose or multiple doses of the drugs that make up the combination (e.g., tucatinib and at least one anti-HER2 antibody). In some embodiments, the predicted combination effect EAB is calculated using only a single dose of each drug A and B (e.g., tucatinib and at least one anti- HER2 antibody), and the values EA and EB are based on the observed effect of each drug when administered as a single agent. When the values for EA and EB are based on the observed effects of administering drugs A and B as single agents, EA and EB can be based on, for example, TGI indices, tumor sizes (e.g., volume, mass) measured at one or more time points, absolute changes in tumor size (e.g., volume, mass) between two or more time points (e.g., between the first day a treatment is adminstered and a particular number of days after treatment is first administered), the rates of change of tumor sizes (e.g., volume, mass) between two or more time points (e.g., between the first day a treatment is adminstered and a particular number of days after treatment is first administered), or the survival time of a subject or a population of subjects in each treatment group.

[0050] When TGI indices are taken as a measure of the observed effects, the TGI indices can be determined at one or more time points. When TGI indices are determined at two or more time points, in some instances the mean or median values can be used as measures of the observed effects. Furthermore, the TGI indices can be determined in a single subject or a population of subjects in each treatment group. When the TGI indices are determined in populations of subjects, the mean or median TGI indices in each population (e.g., at one or more time points) can be used as measures of the observed effects. When tumor sizes or the rates of tumor growth are used as measures of the observed effects, the tumor sizes or rates of tumor growth can be measured in a subject or a population of subjects in each treatment group. In some instances, the mean or median tumor sizes or rates of tumor growth are determined for subjects at two or more time points, or among populations of subjects at one or more time points. When survival time is measured in a population, mean or median survival times can be used as measures of the observed effects.

[0051] In some embodiments, the predicted combination effect EAB is calculated using a range of doses (i.e., the effects of each drug, when administered as a single agent, are observed at multiple doses and the observed effects at the multiple doses are used to determine the predicted combination effect at a specific dose). As a non-limiting example, EAB can be calculated using values for EA and EB that are calculated according to the following formulae:

where EAmax and Enmax are the maximum effects of drugs A and B, respectively, A₅₀ and B₅₀ are the half maximum effective doses of drugs A and B, respectively, a and b are administered doses of drugs A and B, respectively, and p and q are coefficients that are derived from the shapes of the dose-response curves for drugs A and B, respectively (see, e.g., Foucquier et al. Pharmacol. Res. Perspect. (2015) 3(3):e00149).

[0052] In some embodiments, a combination of two or more drugs is considered to be synergistic when the combination produces an observed TGI index that is greater than the predicted TGI index for the combination of drugs (e.g., when the predicted TGI index is based upon the assumption that the drugs produced a combined effect that is additive). In some instances, the combination is considered to be synergistic when the observed TGI index is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% greater than the predicted TGI index for the combination of drugs.

[0053] In some embodiments, the rate of tumor growth (e.g., the rate of change of the size (e.g., volume, mass) of the tumor) is used to determine whether a combination of drugs is synergistic (e.g., the combination of drugs is synergistic when the rate of tumor growth is slower than would be expected if the combination of drugs produced an additive effect). In other embodiments, survival time is used to determine whether a combination of drugs is synergistic (e.g., a combination of drugs is synergistic when the survival time of a subject or population of subjects is longer than would be expected if the combination of drugs produced an additive effect).

[0054] Treatment" or "therapy" of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down, or preventing the onset, progression, development, severity, or recurrence of a symptom, complication, condition, or biochemical indicia associated with a disease. In some embodiments, the disease is cancer.

[0055] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In some embodiments, the subject is a human. The terms "subject" and "patient" and “individual” are used interchangeably herein. [0056] An “effective amount” or "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0057] By way of example for the treatment of tumors, a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth by at least about 10%, by at least about 20%, by at least about 30%, by at least about 40%, by at least about 50%, by at least about 60%, by at least about 70%, or by at least about 80%, by at least about 90%, by at least about 95%, by at least about 96%, by at least about 97%, by at least about 98%, or by at least about 99% in a treated subject(s) (e.g., one or more treated subjects) relative to an untreated subject(s) (e.g., one or more untreated subjects). In some embodiments, a therapeutically effective amount of an anti-cancer agent inhibits cell growth or tumor growth by 100% in a treated subject(s) (e.g., one or more treated subjects) relative to an untreated subject(s) (e.g., one or more untreated subjects).

[0058] In other embodiments of the disclosure, tumor regression can be observed and continue for a period of at least about 20 days, at least about 30 days, at least about 40 days, at least about 50 days, or at least about 60 days.

[0059] A therapeutically effective amount of a drug (e.g., tucatinib) includes a "prophylactically effective amount," which is any amount of the drug that, when administered alone or in combination with an anti-cancer agent to a subject at risk of developing a cancer (e.g., a subject having a pre-malignant condition) or of suffering a recurrence of cancer, inhibits the development or recurrence of the cancer. In some embodiments, the prophylactically effective amount prevents the development or recurrence of the cancer entirely. "Inhibiting" the development or recurrence of a cancer means either lessening the likelihood of the cancer’s development or recurrence, or preventing the development or recurrence of the cancer entirely. [0060] As used herein, "subtherapeutic dose" means a dose of a therapeutic compound (e.g., tucatinib) that is lower than the usual or typical dose of the therapeutic compound when administered alone for the treatment of a hyperproliferative disease (e.g., cancer).

[0061] By way of example, an "anti-cancer agent" promotes cancer regression in a subject. In some embodiments, a therapeutically effective amount of the drug promotes cancer regression to the point of eliminating the cancer. "Promoting cancer regression" means that administering an effective amount of the drug, alone or in combination with an anticancer agent, results in a reduction in tumor growth or size, necrosis of the tumor, a decrease in severity of at least one disease symptom, an increase in frequency and duration of disease symptom-free periods, or a prevention of impairment or disability due to the disease affliction. In addition, the terms "effective" and "effectiveness" with regard to a treatment includes both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of the drug to promote cancer regression in the patient. Physiological safety refers to the level of toxicity or other adverse physiological effects at the cellular, organ and/or organism level (adverse effects) resulting from administration of the drug.

[0062] Sustained response" refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration that is at least the same as the treatment duration, or at least 1.5, 2.0, 2.5, or 3 times longer than the treatment duration.

[0063] As used herein, "complete response" or "CR" refers to disappearance of all target lesions; "partial response" or "PR" refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD; and "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.

[0064] As used herein, "progression free survival" or “PFS” is defined as the time from start of treatment to first documentation of tumor progression (clinical progression or PD per RECIST 1.1), or to death due to any cause, whichever comes first. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease. [0065] As used herein, "confirmed objective response rate" or “cORR” is defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR), per RECIST 1.1. Subjects who do not have at least 2 (initial response and confirmation scan) post-baseline response assessments will be counted as non-responders.

[0066] As used herein, "overall survival" or “OS” is defined as the time from start of treatment to date of death due to any cause.

[0067] As used herein, “duration of response” or “DOR” is defined as the time from first documentation of objective response (CR or PR that is subsequently confirmed) to the first documentation of progressive disease (PD) (per RECIST 1.1) or to death due to any cause, whichever comes first.

[0068] The term "weight-based dose", as referred to herein, means that a dose administered to a subject is calculated based on the weight of the subject. For example, when a subject with 60 kg body weight requires 6.0 mg/kg of an agent, such as trastuzumab, one can calculate and use the appropriate amount of the agent (i.e., 360 mg) for administration to said subject.

[0069] The use of the term "fixed dose" with regard to a method of the disclosure means that two or more different agents (e.g., tucatinb and anti-HER2 antibody) are administered to a subject in particular (fixed) ratios with each other. In some embodiments, the fixed dose is based on the amount (e.g., mg) of the agents. In certain embodiments, the fixed dose is based on the concentration (e.g., mg/ml) of the agents. For example, a 1 :2 ratio of tucatinib to an anti-HER2 antibody administered to a subject can mean about 300 mg of tucatinib and about 600 mg of the at least one anti-HER2 antibody or about 3 mg/ml of tucatinib and about 6 mg/ml of the at least one anti-HER2 antibody are administered to the subject.

[0070] The use of the term "flat dose" with regard to the methods and dosages of the disclosure means a dose that is administered to a subject without regard for the weight or body surface area (BSA) of the subject. The flat dose is therefore not provided as a mg/kg dose, but rather as an absolute amount of the agent (e.g., tucatinib or anti-HER2 antibody). For example, a subject with 60 kg body weight and a subject with 100 kg body weight would receive the same dose of tucatinb (e.g., 300 mg).

[0071] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. [0072] As used herein, the term “pharmaceutically acceptable carrier” refers to a substance that aids the administration of an active agent to a cell, an organism, or a subject. “Pharmaceutically acceptable carrier” refers to a carrier or excipient that can be included in the compositions of the invention and that causes no significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable carriers include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, liposomes, dispersion media, microcapsules, cationic lipid carriers, isotonic and absorption delaying agents, and the like. The carrier may also be substances for providing the formulation with stability, sterility and isotonicity (e.g., antimicrobial preservatives, antioxidants, chelating agents and buffers), for preventing the action of microorganisms (e.g. antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid and the like) or for providing the formulation with an edible flavor etc. In some instances, the carrier is an agent that facilitates the delivery of a small molecule drug or antibody to a target cell or tissue. One of skill in the art will recognize that other pharmaceutical carriers are useful in the present invention.

[0073] The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 4,4’ -methyl ene-bis -(2-hydroxy-3 -naphthoate)) salts, alkali metal (e.g, sodium and potassium) salts, alkaline earth metal (e.g, magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part, of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion. [0074] "Administering" or “administration” refer to the physical introduction of a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Exemplary routes of administration include oral, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion (e.g., intravenous infusion). The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intralymphatic, intralesional, intracap sul ar, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion, as well as in vivo electroporation. A therapeutic agent can be administered via a non-parenteral route, or orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administration can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

[0075] The terms "baseline" or "baseline value" used interchangeably herein can refer to a measurement or characterization of a symptom before the administration of the therapy or at the beginning of administration of the therapy. The baseline value can be compared to a reference value in order to determine the reduction or improvement of a symptom of a disease contemplated herein (e.g., cancer). The terms "reference" or "reference value" used interchangeably herein can refer to a measurement or characterization of a symptom after administration of the therapy. The reference value can be measured one or more times during a dosage regimen or treatment cycle or at the completion of the dosage regimen or treatment cycle. A "reference value" can be an absolute value; a relative value; a value that has an upper and/or lower limit; a range of values; an average value; a median value: a mean value; or a value as compared to a baseline value.

[0076] Similarly, a "baseline value" can be an absolute value; a relative value; a value that has an upper and/or lower limit; a range of values; an average value; a median value; a mean value; or a value as compared to a reference value. The reference value and/or baseline value can be obtained from one individual, from two different individuals or from a group of individuals (e.g., a group of two, three, four, five or more individuals).

[0077] The term “monotherapy” as used herein means that the tucatinib, or salt or solvate thereof, is the only anti-cancer agent administered to the subject during the treatment cycle. Other therapeutic agents, however, can be administered to the subject. For example, antiinflammatory agents or other agents administered to a subject with cancer to treat symptoms associated with cancer, but not the underlying cancer itself, including, for example inflammation, pain, weight loss, and general malaise, can be administered during the period of monotherapy.

[0078] An "adverse event" (AE) as used herein is any unfavorable and generally unintended or undesirable sign (including an abnormal laboratory finding), symptom, or disease associated with the use of a medical treatment. A medical treatment can have one or more associated AEs and each AE can have the same or different level of severity. Reference to methods capable of "altering adverse events" means a treatment regime that decreases the incidence and/or severity of one or more AEs associated with the use of a different treatment regime.

[0079] A “serious adverse event” or “SAE” as used herein is an adverse event that meets one of the following criteria:

• Is fatal or life-threatening (as used in the definition of a serious adverse event, “lifethreatening” refers to an event in which the patient was at risk of death at the time of the event; it does not refer to an event which hypothetically might have caused death if it was more severe.

• Results in persistent or significant disability/incapacity

• Constitutes a congenital anomaly/birth defect

• Is medically significant, z.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes listed above. Medical and scientific judgment must be exercised in deciding whether an AE is “medically significant”

• Requires inpatient hospitalization or prolongation of existing hospitalization, excluding the following: 1) routine treatment or monitoring of the underlying disease, not associated with any deterioration in condition; 2) elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent; and 3) social reasons and respite care in the absence of any deterioration in the patient’s general condition. [0080] The terms "once about every week," "once about every two weeks," or any other similar dosing interval terms as used herein mean approximate numbers. "Once about every week" can include every seven days ± one day, z.e., every six days to every eight days. "Once about every two weeks" can include every fourteen days ± two days, z.e., every twelve days to every sixteen days. "Once about every three weeks" can include every twenty-one days ± three days, z.e., every eighteen days to every twenty-four days. Similar approximations apply, for example, to once about every four weeks, once about every five weeks, once about every six weeks, and once about every twelve weeks. In some embodiments, a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose can be administered any day in the first week, and then the next dose can be administered any day in the sixth or twelfth week, respectively. In other embodiments, a dosing interval of once about every six weeks or once about every twelve weeks means that the first dose is administered on a particular day of the first week (e.g., Monday) and then the next dose is administered on the same day of the sixth or twelfth weeks (ie., Monday), respectively.

[0081] As described herein, any concentration range, percentage range, ratio range, or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.

[0082] Various aspects of the disclosure are described in further detail in the following subsections.

II. Methods for Treating a Cancer with Tucatinib and at least one anti-HER2 antibody

[0083] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib, or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject.

[0084] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib or a salt or solvate thereof, and at least one anti-HER.2 antibody, such as trastuzumab, to the subject, wherein administering such treatment results in a confirmed objective response rate that is at least about 30%. In some embodiments, the confirmed objective response rate is at least about 35%. In some embodiments, the confirmed objective response rate is at least about 40%. In some embodiments, the confirmed objective response rate is at least about 45%. In some embodiments, the confirmed objective response rate is at least about 50%. In some embodiments, the confirmed objective response rate is at least about 55%. In some embodiments, the confirmed objective response rate is at least about 60%. In some embodiments, the confirmed objective response is about 30% to about 60%, such as any of about 30% to about 55%, about 30% to about 50%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 60%, about 40% to about 60%, about 45% to about 60%, about 50% to about 60%, about 35% to about 45%, about 35% to about 40%, about 40% to about 45%, and values and ranges therebetween. In some embodiments, the confirmed objective response rate is about 30% to about 40%. In some embodiments, the confirmed objective response rate is about 35% to about 40%. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0085] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administering such treatment to a plurality of subjects results in a confirmed objective response rate that is at least about 30%. In some embodiments, the confirmed objective response rate is at least about 35%. In some embodiments, the confirmed objective response rate is at least about 40%. In some embodiments, the confirmed objective response rate is at least about 45%. In some embodiments, the confirmed objective response rate is at least about 50%. In some embodiments, the confirmed objective response rate is at least about 55%. In some embodiments, the confirmed objective response rate is at least about 60%. In some embodiments, the confirmed objective response is about 30% to about 60%, such as any of about 30% to about 55%, about 30% to about 50%, about 30% to about 45%, about 30% to about 40%, about 30% to about 35%, about 35% to about 60%, about 40% to about 60%, about 45% to about 60%, about 50% to about 60%, about 35% to about 45%, about 35% to about 40%, about 40% to about 45%, and values and ranges therebetween. In some embodiments, the confirmed objective response rate is about 30% to about 40%. In some embodiments, the confirmed objective response rate is about 35% to about 40%. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0086] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administering such treatment results in a median duration of response that is about 10.4 months to about 15 months. In some embodiments, the median duration of response is about 10.4 months to about 15 months, such as any of about 10.4 months to about 14 months, about 10.4 months to about 13 months, about 11 months to about 15 months, about 11 months to about 14 months, about 11 months to about 13 months, about 12 months to about 13 months, and values and ranges therebetween. In some embodiments, the median duration of response is about 11 months to about 14 months. In some embodiments, the median duration of response is about 12 months to about 13 months. In some embodiments, the median duration of response is about 12.4 months. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0087] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administering such treatment to a plurality of subjects results in a median duration of response that is about 10.4 months to about 15 months. In some embodiments, the median duration of response is about 10.4 months to about 15 months, such as any of about 10.4 months to about 14 months, about 10.4 months to about 13 months, about 11 months to about 15 months, about 11 months to about 14 months, about 11 months to about 13 months, about 12 months to about 13 months, and values and ranges therebetween. In some embodiments, the median duration of response is about 11 months to about 14 months. In some embodiments, the median duration of response is about 12 months to about 13 months. In some embodiments, the median duration of response is about 12.4 months. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0088] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administration of such treatment results in a median progression free survival (PFS) of about 8.1 months to about 10 months. In some embodiments, the median PFS is about 8.1 months to about 10 months, such as any of about 8.1 months to about 9 months, about 9 months to about 10 months, and values and ranges therebetween. In some embodiments, the median PFS is at least 8.1 months. In some embodiments, the median PFS is at least 8.2 months. In some embodiments, the median PFS is about 8.2 months. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0089] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib or a salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administration of such treatment to a plurality of subjects results in a median progression free survival (PFS) of about 8.1 months to about 10 months. In some embodiments, the median PFS is about 8.1 months to about 10 months, such as any of about 8.1 months to about 9 months, about 9 months to about 10 months, and values and ranges therebetween. In some embodiments, the median PFS is at least 8.1 months. In some embodiments, the median PFS is at least 8.2 months. In some embodiments, the median PFS is about 8.2 months. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0090] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administration of such treatment results in a median overall survival of about 15 months to about 30 months. In some embodiments, the median overall survival is about 15 months to about 30 months, such as any of about 15 months to about 28 months, about 15 months to about 26 months, about 15 months to about 24 months, about 15 months to about 22 months, about 15 months to about 20 months, about 17 months to about 30 months, about 17 months to about 28 months, about 17 months to about 26 months, about 17 months to about 24 months, about 19 months to about 30 months, about 19 months to about 28 months, about 19 months to about 26 months, about 21 months to about 30 months, about 21 months to about 28 months, about 21 months to about 26 months, about 22 months to about 30 months, about 22 months to about 28 months, about 22 months to about 26 months, about 24 months to about 30 months, about 24 months to about 28 months, about 24 months to about 26 months, about 23 months to about 25 months, and values and ranges therebetween. In some embodiments, the median overall survival is about 20 months to about 28 months. In some embodiments, the median overall survival is about 23 months to about 25 months. In some embodiments, the median overall survival is about 24.1 months. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0091] In one aspect, the present invention provides a method for treating a cancer, such as metastatic colorectal cancer, in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administration of such treatment to a plurality of subjects results in a median overall survival of about 15 months to about 30 months. In some embodiments, the median overall survival is about 15 months to about 30 months, such as any of about 15 months to about 28 months, about 15 months to about 26 months, about 15 months to about 24 months, about 15 months to about 22 months, about 15 months to about 20 months, about 17 months to about 30 months, about 17 months to about 28 months, about 17 months to about 26 months, about 17 months to about 24 months, about 19 months to about 30 months, about 19 months to about 28 months, about 19 months to about 26 months, about 21 months to about 30 months, about 21 months to about 28 months, about 21 months to about 26 months, about 22 months to about 30 months, about 22 months to about 28 months, about 22 months to about 26 months, about 24 months to about 30 months, about 24 months to about 28 months, about 24 months to about 26 months, about 23 months to about 25 months, and values and ranges therebetween. In some embodiments, the median overall survival is about 20 months to about 28 months. In some embodiments, the median overall survival is about 23 months to about 25 months. In some embodiments, the median overall survival is about 24.1 months. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0092] In one aspect, the present invention provides a method for treating a cancer in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein the subject is at least 65 years old. In one aspect, the present invention provides a method for treating a cancer in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein the subject is less than 65 years old. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the cancer is HER2+ and is wildtype RAS. In some embodiments, the treatment is a second line therapy.

[0093] In one aspect, the present invention provides a method for treating a cancer in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administering such treatment results in complete response in at least 1% of subjects, such as at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5%, at least 5.5%, at least 6%, at least 6.5%, at least 7%, at least 7.5%, at least 8%, at least 8.5%, at least 9%, at least 9.5%, or at least 10% of subjects. In some embodiments, administering such treatment results in complete response in at least 1.5% of subjects. In some embodiments, administering such treatment results in complete response in at least 2% of subjects. In some embodiments, administering such treatment results in complete response in at least 2.5% of subjects. In some embodiments, administering such treatment results in complete response in at least 2.5% of subjects. In some embodiments, administering such treatment results in complete response in at least 3% of subjects. In some embodiments, administering such treatment results in complete response in at least 3.5% of subjects. In some embodiments, administering such treatment results in complete response in about 3.6% of subjects. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS.

[0094] In one aspect, the present invention provides a method for treating a cancer in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein administering such treatment to a plurality of subjects results in complete response in at least 1% of subjects, such as at least 1.5%, at least 2%, at least 2.5%, at least 3%, at least 3.5%, at least 4%, at least 4.5%, at least 5%, at least 5.5%, at least 6%, at least 6.5%, at least 7%, at least 7.5%, at least 8%, at least 8.5%, at least 9%, at least 9.5%, or at least 10% of subjects. In some embodiments, administering such treatment results in complete response in at least 1.5% of subjects. In some embodiments, administering such treatment results in complete response in at least 2% of subjects. In some embodiments, administering such treatment results in complete response in at least 2.5% of subjects. In some embodiments, administering such treatment results in complete response in at least 2.5% of subjects. In some embodiments, administering such treatment results in complete response in at least 3% of subjects. In some embodiments, administering such treatment results in complete response in at least 3.5% of subjects. In some embodiments, administering such treatment results in complete response in about 3.6% of subjects. In some embodiments, the subject is at least 65 years old. In some embodiments, the subject is less than 65 years old. In some embodiments, the subject is male. In some embodiments, the subject is female. In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy. In some embodiments, the cancer is HER2+ and is wild-type RAS. [0095] In one aspect, the present invention provides a method for treating a cancer in a subject comprising administering a combination of tucatinib, or salt or solvate thereof, and at least one anti-HER2 antibody, such as trastuzumab, to the subject, wherein the cancer is RAS wild-type. In some embodiments, RAS wild-type is determined based on expanded RAS testing. Expanded RAS testing is a method sequencing cancer-associated codons in KRAS and NRAS. In some embodiments, expanded RAS testing comprises sequencing cancer- associated codons in KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4. In some embodiments, expanded RAS testing comprises sequencing cancer-associated codons in KRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146) and NRAS exons 2 (codons 12 and 13), 3 (codons 59 and 61), and 4 (codons 117 and 146). In some embodiments, the cancer is wild-type RAS. In some embodiments, the cancer is HER2+. In some embodiments, the treatment is a second line therapy.

[0096] In some embodiments, the cancer has one or more HER2 alterations. In some embodiments, the one or more HER2 alterations is a HER2 mutation. In some embodiments, the HER2 mutation is at least one amino acid substitution, insertion, or deletion compared to the human wild-type HER2 amino acid sequence. In some embodiments, human wild-type HER2 comprises the amino acid sequence of: MELAALCRWGLLLALLPPGAASTQVCTGTDMKLRLPASPETHLDMLRHLYQGCQV VQGNLELTYLPTNASLSFLQDIQEVQGYVLIAHNQVRQVPLQRLRIVRGTQLFEDNY ALAVLDNGDPLNNTTPVTGASPGGLRELQLRSLTEILKGGVLIQRNPQLCYQDTILW KDIFHKNNQLALTLIDTNRSRACHPCSPMCKGSRCWGESSEDCQSLTRTVCAGGCAR CKGPLPTDCCHEQCAAGCTGPKHSDCLACLHFNHSGICELHCPALVTYNTDTFESMP NPEGRYTFGASCVTACPYNYLSTDVGSCTLVCPLHNQEVTAEDGTQRCEKCSKPCA RVCYGLGMEHLREVRAVTSANIQEFAGCKKIFGSLAFLPESFDGDPASNTAPLQPEQL QVFETLEEITGYLYISAWPDSLPDLSVFQNLQVIRGRILHNGAYSLTLQGLGISWLGLR SLRELGSGLALIHHNTHLCFVHTVPWDQLFRNPHQALLHTANRPEDECVGEGLACH QLCARGHCWGPGPTQCVNCSQFLRGQECVEECRVLQGLPREYVNARHCLPCHPECQ PQNGSVTCFGPEADQCVACAHYKDPPFCVARCPSGVKPDLSYMPIWKFPDEEGACQ PCPINCTHSCVDLDDKGCPAEQRASPLTSIISAVVGILLVVVLGVVFGILIKRRQQKIR KYTMRRLLQETELVEPLTPSGAMPNQAQMRILKETELRKVKVLGSGAFGTVYKGIW IPDGENVKIPVAIKVLRENTSPKANKEILDEAYVMAGVGSPYVSRLLGICLTSTVQLV TQLMPYGCLLDHVRENRGRLGSQDLLNWCMQIAKGMSYLEDVRLVHRDLAARNV LVKSPNHVKITDFGLARLLDIDETEYHADGGKVPIKWMALESILRRRFTHQSDVWSY GVTVWELMTFGAKPYDGIPAREIPDLLEKGERLPQPPICTIDVYMIMVKCWMIDSEC RPRFRELVSEFSRMARDPQRFVVIQNEDLGPASPLDSTFYRSLLEDDDMGDLVDAEE YLVPQQGFFCPDPAPGAGGMVHHRHRSSSTRSGGGDLTLGLEPSEEEAPRSPLAPSE GAGSDVFDGDLGMGAAKGLQSLPTHDPSPLQRYSEDPTVPLPSETDGYVAPLTCSPQ PEYVNQPDVRPQPPSPREGPLPAARPAGATLERPKTLSPGKNGVVKDVFAFGGAVEN PEYLTPQGGAAPQPHPPPAFSPAFDNLYYWDQDPPERGAPPSTFKGTPTAENPEYLGL DVPV (SEQ ID NO: 1).

[0097] In some embodiments of any of the methods described herein, the cancer is a HER2+ cancer. In some embodiments of any of the methods described herein, the cancer is a metastatic cancer. In some embodiments of any of the methods described herein, the cancer is locally-advanced. In some embodiments of any of the methods described herein, the cancer is unresetable. In some embodiments of any of the methods described herein, the subject has been previously treated with one or more additional therapeutic agents for the cancer. In some embodiments of any of the methods described herein, the subject has been previously treated with one or more additional therapeutic agents for the cancer and did not respond to the treatment. In some embodiments of any of the methods described herein, the subject has been previously treated with one or more additional therapeutic agents for the cancer and relapsed after the treatment. In some embodiments of any of the methods described herein, the subject has been previously treated with one or more additional therapeutic agents for the cancer and experienced disease progression during the treatment. In some embodiments of any of the described methods, the subject has previously received a prior line of treatment for the cancer selected from the list consisting of systemic therapy with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) antibody. In some embodiments of any of the described methods, the subject has previously received a prior line of treatment for the cancer comprising an anti-PD-Ll antibody. In some embodiments of any of the described methods, the cancer is colorectal cancer. In some embodiments of any of the described methods, the cancer is metastatic colorectal cancer. In some embodiments of any of the described methods, the cancer is HER2+, RAS wild-type, metastatic colorectal cancer. In some embodiments, the prior line of treatment is selected from the group consisting of chemotherapy, endocrine therapy, and targeted therapy.

[0098] In some embodiments, ther HER2 status of a sample cell is determined. The determination can be made before treatment (i.e., administration of tucatinib) begins, during treatment, or after treatment has been completed. In some instances, determination of the HER2 status results in a decision to change therapy (e.g., adding an anti-HER2 antibody to the treatment regimen, discontinuing the use of tucatinib, discontinuing therapy altogether, or switching from another treatment method to a method of the present invention). In some embodiments, the sample cell is a cancer cell. In some instances, the sample cell is obtained from a subject who has cancer. The sample cell can be obtained as a biopsy specimen, by surgical resection, or as a fine needle aspirate (FNA). In some embodiments, the sample cell is a circulating tumor cell (CTC). HER2 expression can be compared to a reference cell. In some embodiments, the reference cell is a non-cancer cell obtained from the same subject as the sample cell. In other embodiments, the reference cell is a non-cancer cell obtained from a different subject or a population of subjects. In some embodiments, measuring expression of HER2 comprises, for example, determining HER2 gene copy number or amplification, nucleic acid sequencing (e.g., sequencing of genomic DNA or cDNA or RNA sequencing), measuring mRNA expression, measuring protein abundance, or a combination thereof.

HER2 testing methods include immunohistochemistry (IHC), in situ hybridization, fluorescence in situ hybridization (FISH), chromogenic in situ hybridization (CISH), ELISAs, and RNA quantification (e.g., of HER2 expression) using techniques such as RT- PCR and microarray analysis.

III. Tucatinib Dose and Administration

[0099] In some embodiments, a dose of tucatinib is between about 0.1 mg and 10 mg per kg of the subject’s body weight (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg per kg of the subject’s body weight). In other embodiments, a dose of tucatinib is between about 10 mg and 100 mg per kg of the subject’s body weight (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg per kg of the subject’s body weight). In some embodiments, a dose of tucatinib is at least about 100 mg to 500 mg per kg of the subject’s body weight (e.g., at least about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg per kg of the subject’s body weight). In particular embodiments, a dose of tucatinib is between about 1 mg and 50 mg per kg of the subject’s body weight (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg per kg of the subject’s body weight). In some instances, a dose of tucatinib is about 50 mg per kg of the subject’s body weight. [0100] In some embodiments, a dose of tucatinib comprises between about 1 mg and 100 mg (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40,

45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg) of tucatinib. In other embodiments, a dose of tucatinib comprises between about 100 mg and 1,000 mg (e.g., about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200,

205, 210, 215, 220, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550,

575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000 mg) of tucatinib. In particular embodiments, a dose of tucatinib is about 300 mg (e.g., when administered twice per day). In particular embodiments, a dose of tucatinib is 300 mg administered twice per day.

[0101] In some embodiments, a dose of tucatinib comprises at least about 1,000 mg to 10,000 mg (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100,

3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400,

4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700,

5,800, 5,900, 6,000, 6,100, 6,200, 6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000,

7,100, 7,200, 7,300, 7,400, 7,500, 7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300,

8,400, 8,500, 8,600, 8,700, 8,800, 8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600,

9,700, 9,800, 9,900, 10,000 or more mg) of tucatinib.

[0102] In some embodiments, a dose of tucatinib, or salt or solvate thereof, contains a therapeutically effective amount of tucatinib, or salt or solvate thereof. In other embodiments, a dose of tucatinib, or salt or solvate thereof, contains less than a therapeutically effective amount of tucatinib, or salt or solvate thereof, (e.g., when multiple doses are given in order to achieve the desired clinical or therapeutic effect).

[0103] Tucatinib, or salt or solvate thereof, can be administered by any suitable route and mode. Suitable routes of administering antibodies and/or antibody-drug conjugate of the present invention are well known in the art and may be selected by those of ordinary skill in the art. In one embodiment, tucatinib, or salt or solvate thereof, administered parenterally. Parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrastemal injection and infusion. In some embodiments, the route of administration of tucatinib, or salt or solvate thereof, is intravenous injection or infusion. In some embodiments, the route of administration of tucatinib, or salt or solvate thereof, is intravenous infusion. In some embodiments, the route of administration of tucatinib, or salt or solvate thereof, is intravenous injection or infusion. In some embodiments, the tucatinib, or salt or solvate thereof, is intravenous infusion. In some embodiments, the route of administration of tucatinib, or salt or solvate thereof, is oral.

[0104] In one embodiment of the methods or uses or product for uses provided herein, tucatinib, or salt or solvate thereof, is administered to the subject daily, twice daily, three times daily or four times daily. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject every other day, once about every week or once about every three weeks. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject once per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject twice per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 300 mg twice per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of 300 mg twice per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 600 mg once per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of 600 mg once per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject twice per day on each day of a 21 -day treatment cycle. In some embodiments, the tucatinib, or salt or solvate thereof, is administered to the subject orally.

IV. Anti-HER2 Antibody Dose and Administration

[0105] In some embodiments, a dose of the anti-HER2 antibody is between about 0.1 mg and 10 mg per kg of the subject’s body weight (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg per kg of the subject’s body weight). In some embodiments, a dose of the anti-HER.2 antibody is between about 4 mg and 10 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER2 antibody is between 4 mg and 10 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER.2 antibody is about 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER2 antibody is about 8 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER2 antibody is about 8 mg per kg of the subject’s body weight for the first dose of the anti-HER2 antibody administered to the subject followed by subsequent doses of about 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER2 antibody is 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER.2 antibody is 8 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER2 antibody is 8 mg per kg of the subject’s body weight for the first dose of the anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg per kg of the subject’s body weight. In other embodiments, a dose of the anti-HER2 antibody is between about 10 mg and 100 mg per kg of the subject’s body weight (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg per kg of the subject’s body weight). In some embodiments, a dose of the anti-HER.2 antibody is at least about 100 mg to 500 mg per kg of the subject’s body weight (e.g., at least about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more mg per kg of the subject’s body weight). In some instances, a dose of the anti-HER.2 antibody is about 6 mg per kg of the subject’s body weight. In other instances, a dose of the anti-HER2 antibody is about 8 mg per kg of the subject’s body weight. In some other instances, a dose of the anti-HER2 antibody is about 20 mg per kg of the subject’s body weight. In some embodiments, a dose of the anti-HER.2 antibody comprises between about 1 mg and 100 mg (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg) of the anti-HER2 antibody. In other embodiments, a dose of the anti-HER.2 antibody comprises between about 100 mg and 1,000 mg (e.g., about 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000 mg) of the anti-HER.2 antibody. In particular embodiments, a dose of the anti-HER.2 antibody comprises between about 100 mg and 400 mg (e.g., about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg) of the anti-HER.2 antibody. In some embodiments, a dose of the anti-HER.2 antibody is between about 400 mg and 800 mg. In some embodiments, a dose of the anti-HER.2 antibody is between 400 mg and 800 mg. In some embodiments, a dose of the anti-HER2 antibody is about 600 mg. In some embodiments, a dose of the anti-HER2 antibody is 600 mg. As a non-limiting example, when using a dose of 6 mg/kg, a dose for a 50 kg subject will be about 300 mg. As another non-limiting example, when using a dose of 8 mg/kg, a dose for a 50 kg subject will be about 400 mg. In some embodiments, a dose of the anti-HER2 antibody comprises at least about 1,000 mg to 10,000 mg (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500,

2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700, 3,800,

3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000, 5,100,

5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000, 6,100, 6,200, 6,300, 6,400,

6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300, 7,400, 7,500, 7,600, 7,700,

7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600, 8,700, 8,800, 8,900, 9,000,

9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000 or more mg) of the anti- HER2 antibody. In some embodiments, a dose of the anti-HER2 antibody contains a therapeutically effective amount of the anti-HER2 antibody. In other embodiments, a dose of the anti-HER2 antibody contains less than a therapeutically effective amount of the anti- HER2 antibody (e.g., when multiple doses are given in order to achieve the desired clinical or therapeutic effect). In some embodiments, the anti-HER2 antibody is administered to the subject once about every 1 to 4 weeks. In certain embodiments, an anti-HER2 antibody is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks or once about every 4 weeks. In one embodiment, an anti-HER2 antibody is administered once about every 3 weeks. In some embodiments, the anti-HER2 antibody is administered to the subject once every 1 to 4 weeks. In certain embodiments, an anti-HER2 antibody is administered once every 1 week, once about every 2 weeks, once about every 3 weeks or once about every 4 weeks. In one embodiment, an anti-HER2 antibody is administered once every 3 weeks. In some embodiments, the anti-HER2 antibody is administered to the subject subcutaneously. In some embodiments, the anti-HER2 antibody is administered to the subject intraperitoneally. In some embodiments, the anti-HER2 antibody is administered to the subject intravenously. In some embodiments, the at least one anti-HER2 antibody is one anti- HER2 antibody. In some embodiments, the at least one anti-HER.2 antibody is a combination of two anti-HER2 antibodies. In some embodiments, the at least one anti-HER.2 antibody is a combination of three anti-HER2 antibodies. In some embodiments, the at least one anti- HER2 antibody is a combination of four anti-HER.2 antibodies. In some embodiments, the anti-HER.2 antibody is selected from the group consisting of trastuzumab, pertuzumab, ado- trastuzumab emtansine, margetuximab, and a combination thereof. In some instances, the anti-HER.2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the anti-HER2 antibody is trastuzumab. In some embodiments, the anti-HER2 antibody is pertuzumab. In some embodiments, the anti-HER2 antibody is administered at a dose of about 600 mg once about every 3 weeks and the anti-HER2 antibody is administered subcutaneously. In some embodiments, the anti-HER.2 antibody is administered at a dose of 600 mg once every 3 weeks and the anti-HER2 antibody is administered subcutaneously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of about 600 mg once about every 3 weeks and the trastuzumab is administered subcutaneously. In some embodiments, the anti-HER.2 antibody is trastuzumab and is administered at a dose of 600 mg once every 3 weeks and the trastuzumab is administered subcutaneously. In some embodiments, the anti-HER2 antibody is administered at a dose of about 6 mg/kg once about every 3 weeks and the anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered at a dose of about 8 mg/kg once about every 3 weeks and the anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the anti-HER2 antibody administered to the subject followed by subsequent doses of about 6 mg/kg, wherein anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER.2 antibody is administered at a dose of 6 mg/kg once every 3 weeks and the anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER.2 antibody is administered at a dose of 8 mg/kg once every 3 weeks and the anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of the anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg/kg, wherein anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of about 6 mg/kg once about every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER.2 antibody is trastuzumab and is administered at a dose of about 8 mg/kg once about every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER.2 antibody is trastuzumab and is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the trastuzumab administered to the subject followed by subsequent doses of about 6 mg/kg, wherein the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of 6 mg/kg once every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of 8 mg/kg once every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of trastuzumab administered to the subject followed by subsequent doses of 6 mg/kg, wherein the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered to the subject on a 21 -day treatment cycle and is administered to the subject once per treatment cycle. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered to the subject on day one of a 21 -day treatment cycle and is administered to the subject once per treatment cycle.

[0106] In some embodiments, the at least one anti-HER2 antibody comprises a first anti- HER2 antibody and a second anti-HER.2 antibody. In some embodiments, a dose of the first anti-HER.2 antibody is between about 0.1 mg and 10 mg per kg of the subject’s body weight (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg per kg of the subject’s body weight). In some embodiments, a dose of the first anti-HER.2 antibody is between about 4 mg and 10 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody is between 4 mg and 10 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti- HER2 antibody is about 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody is about 8 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody is about 8 mg per kg of the subject’s body weight for the first dose of the first anti-HER2 antibody administered to the subject followed by subsequent doses of about 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody is 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody is 8 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody is 8 mg per kg of the subject’s body weight for the first dose of the first anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg per kg of the subject’s body weight. In other embodiments, a dose of the first anti-HER2 antibody is between about 10 mg and 100 mg per kg of the subject’s body weight (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg per kg of the subject’s body weight). In some embodiments, a dose of the first anti-HER2 antibody is at least about 100 mg to 500 mg per kg of the subject’s body weight (e.g., at least about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more mg per kg of the subject’s body weight). In some instances, a dose of the first anti-HER2 antibody is about 6 mg per kg of the subject’s body weight. In other instances, a dose of the first anti-HER2 antibody is about 8 mg per kg of the subject’s body weight. In some other instances, a dose of the first anti-HER.2 antibody is about 20 mg per kg of the subject’s body weight. In some embodiments, a dose of the first anti-HER2 antibody comprises between about 1 mg and 100 mg (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg) of the first anti- HER2 antibody. In other embodiments, a dose of the first anti-HER2 antibody comprises between about 100 mg and 1,000 mg (e.g., about 100, 105, 110, 115, 120, 125, 130, 135, 140,

145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 250,

275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700,

725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000 mg) of the first anti-HER2 antibody. In particular embodiments, a dose of the first anti-HER.2 antibody comprises between about 100 mg and 400 mg (e.g., about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg) of the first anti-HER2 antibody. In some embodiments, a dose of the first anti-HER2 antibody is between about 400 mg and 800 mg. In some embodiments, a dose of the first anti-HER2 antibody is between 400 mg and 800 mg. In some embodiments, a dose of the first anti-HER2 antibody is about 600 mg. In some embodiments, a dose of the first anti-HER2 antibody is 600 mg. In some embodiments, a dose of the first anti-HER2 antibody comprises at least about 1,000 mg to 10,000 mg (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400,

2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600, 3,700,

3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900, 5,000,

5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000, 6,100, 6,200, 6,300,

6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300, 7,400, 7,500, 7,600,

7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600, 8,700, 8,800, 8,900,

9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000 or more mg) of the first anti-HER2 antibody. In some embodiments, a dose of the first anti-HER2 antibody contains a therapeutically effective amount of the first anti-HER2 antibody. In other embodiments, a dose of the first anti-HER2 antibody contains less than a therapeutically effective amount of the first anti-HER2 antibody (e.g., when multiple doses are given in order to achieve the desired clinical or therapeutic effect). In some embodiments, the first anti- HER2 antibody is administered to the subject once about every 1 to 4 weeks. In certain embodiments, the first anti-HER2 antibody is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks or once about every 4 weeks. In one embodiment, the first anti-HER2 antibody is administered once about every 3 weeks. In some embodiments, the first anti-HER.2 antibody is administered to the subject once every 1 to 4 weeks. In certain embodiments, the first anti-HER2 antibody is administered once every 1 week, once about every 2 weeks, once about every 3 weeks or once about every 4 weeks. In one embodiment, the first anti-HER2 antibody is administered once every 3 weeks. In some embodiments, the first anti-HER.2 antibody is administered to the subject subcutaneously. In some embodiments, the first anti-HER2 antibody is administered to the subject intraperitoneally. In some embodiments, the first anti-HER.2 antibody is administered to the subject intravenously. In some embodiments, the first anti-HER.2 antibody is selected from the group consisting of trastuzumab, pertuzumab, ado-trastuzumab emtansine, and margetuximab. In some embodiments, the first anti-HER2 antibody is trastuzumab. In some embodiments, the first anti-HER.2 antibody is administered at a dose of about 600 mg once about every 3 weeks and the first anti-HER2 antibody is administered subcutaneously. In some embodiments, the first anti-HER.2 antibody is administered at a dose of 600 mg once every 3 weeks and the first anti-HER.2 antibody is administered subcutaneously. In some embodiments, the first anti-HER.2 antibody is trastuzumab and is administered at a dose of about 600 mg once about every 3 weeks and the trastuzumab is administered subcutaneously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered at a dose of 600 mg once every 3 weeks and the trastuzumab is administered subcutaneously. In some embodiments, the first anti-HER.2 antibody is administered at a dose of about 6 mg/kg once about every 3 weeks and the first anti-HER2 antibody is administered intravenously. In some embodiments, the first anti-HER.2 antibody is administered at a dose of about 8 mg/kg once about every 3 weeks and the first anti-HER2 antibody is administered intravenously. In some embodiments, the first anti-HER.2 antibody is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the first anti-HER.2 antibody administered to the subject followed by subsequent doses of about 6 mg/kg, wherein first anti-HER.2 antibody is administered intravenously. In some embodiments, the first anti-HER2 antibody is administered at a dose of 6 mg/kg once every 3 weeks and the first anti-HER2 antibody is administered intravenously. In some embodiments, the first anti-HER2 antibody is administered at a dose of 8 mg/kg once every 3 weeks and the first anti-HER2 antibody is administered intravenously. In some embodiments, the first anti-HER2 antibody is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of the first anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg/kg, wherein first anti-HER2 antibody is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered at a dose of about 6 mg/kg once about every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered at a dose of about 8 mg/kg once about every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the trastuzumab administered to the subject followed by subsequent doses of about 6 mg/kg, wherein the trastuzumab is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered at a dose of 6 mg/kg once every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered at a dose of 8 mg/kg once every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of trastuzumab administered to the subject followed by subsequent doses of 6 mg/kg, wherein the trastuzumab is administered intravenously. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered to the subject on a 21 -day treatment cycle and is administered to the subject once per treatment cycle. In some embodiments, the first anti-HER2 antibody is trastuzumab and is administered to the subject on day one of a 21 -day treatment cycle and is administered to the subject once per treatment cycle.

[0107] In some embodiments, the at least one anti-HER2 antibody comprises a first anti- HER2 antibody and a second anti-HER2 antibody. In some embodiments, a dose of the second anti-HER2 antibody is between about 0.1 mg and 10 mg per kg of the subject’s body weight (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 mg per kg of the subject’s body weight). In some embodiments, a dose of the second anti-HER2 antibody is between about 4 mg and 10 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER2 antibody is between 4 mg and 10 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER2 antibody is about 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER2 antibody is about 8 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER.2 antibody is about 8 mg per kg of the subject’s body weight for the first dose of the second anti-HER.2 antibody administered to the subject followed by subsequent doses of about 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER.2 antibody is 6 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER2 antibody is 8 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER2 antibody is 8 mg per kg of the subject’s body weight for the first dose of the second anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg per kg of the subject’s body weight. In other embodiments, a dose of the second anti-HER2 antibody is between about 10 mg and 100 mg per kg of the subject’s body weight (e.g., about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg per kg of the subject’s body weight). In some embodiments, a dose of the second anti-HER.2 antibody is at least about 100 mg to 500 mg per kg of the subject’s body weight (e.g., at least about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, or more mg per kg of the subject’s body weight). In some instances, a dose of the second anti-HER2 antibody is about 6 mg per kg of the subject’s body weight. In other instances, a dose of the second anti-HER2 antibody is about 8 mg per kg of the subject’s body weight. In some other instances, a dose of the second anti-HER.2 antibody is about 20 mg per kg of the subject’s body weight. In some embodiments, a dose of the second anti-HER.2 antibody comprises between about 1 mg and 100 mg (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 mg) of the second anti-HER2 antibody. In other embodiments, a dose of the second anti-HER.2 antibody comprises between about 100 mg and 1,000 mg (e.g., about 100, 105, 110, 115, 120, 125, 130, 135, 140,

725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or 1,000 mg) of the second anti-HER.2 antibody. In particular embodiments, a dose of the second anti-HER2 antibody comprises between about 100 mg and 400 mg (e.g., about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, or 400 mg) of the second anti-HER2 antibody. In some embodiments, a dose of the second anti-HER.2 antibody is between about 400 mg and 800 mg. In some embodiments, a dose of the second anti-HER2 antibody is between 400 mg and 800 mg. In some embodiments, a dose of the second anti-HER2 antibody is about 600 mg. In some embodiments, a dose of the second anti-HER2 antibody is 600 mg. In some embodiments, a dose of the second anti-HER.2 antibody comprises at least about 1,000 mg to 10,000 mg (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000,

2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300,

3,400, 3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600,

4,700, 4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900,

6,000, 6,100, 6,200, 6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200,

7,300, 7,400, 7,500, 7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500,

8,600, 8,700, 8,800, 8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800,

9,900, 10,000 or more mg) of the second anti-HER.2 antibody. In some embodiments, a dose of the second anti-HER.2 antibody contains a therapeutically effective amount of the second anti-HER.2 antibody. In other embodiments, a dose of the second anti-HER2 antibody contains less than a therapeutically effective amount of the second anti-HER2 antibody (e.g., when multiple doses are given in order to achieve the desired clinical or therapeutic effect). In some embodiments, the second anti-HER2 antibody is administered to the subject once about every 1 to 4 weeks. In certain embodiments, the second anti-HER2 antibody is administered once about every 1 week, once about every 2 weeks, once about every 3 weeks or once about every 4 weeks. In one embodiment, the second anti-HER2 antibody is administered once about every 3 weeks. In some embodiments, the second anti-HER.2 antibody is administered to the subject once every 1 to 4 weeks. In certain embodiments, the second anti-HER2 antibody is administered once every 1 week, once about every 2 weeks, once about every 3 weeks or once about every 4 weeks. In one embodiment, the second anti- HER2 antibody is administered once every 3 weeks. In some embodiments, the second anti- HER2 antibody is administered to the subject subcutaneously. In some embodiments, the second anti-HER2 antibody is administered to the subject intraperitoneally. In some embodiments, the second anti-HER2 antibody is administered to the subject intravenously. In some embodiments, the second anti-HER2 antibody is selected from the group consisting of trastuzumab, pertuzumab, ado-trastuzumab emtansine, and margetuximab. In some embodiments, the second anti-HER2 antibody is pertuzumab. In some embodiments, the second anti-HER2 antibody is administered at a dose of about 600 mg once about every 3 weeks and the second anti-HER.2 antibody is administered subcutaneously. In some embodiments, the second anti-HER2 antibody is administered at a dose of 600 mg once every 3 weeks and the second anti-HER2 antibody is administered subcutaneously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered at a dose of about 600 mg once about every 3 weeks and the pertuzumab is administered subcutaneously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered at a dose of 600 mg once every 3 weeks and the pertuzumab is administered subcutaneously. In some embodiments, the second anti-HER2 antibody is administered at a dose of about 6 mg/kg once about every 3 weeks and the second anti-HER.2 antibody is administered intravenously. In some embodiments, the second anti-HER2 antibody is administered at a dose of about 8 mg/kg once about every 3 weeks and the second anti-HER2 antibody is administered intravenously. In some embodiments, the second anti-HER2 antibody is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the second anti-HER2 antibody administered to the subject followed by subsequent doses of about 6 mg/kg, wherein second anti-HER2 antibody is administered intravenously. In some embodiments, the second anti-HER2 antibody is administered at a dose of 6 mg/kg once every 3 weeks and the second anti-HER2 antibody is administered intravenously. In some embodiments, the second anti-HER2 antibody is administered at a dose of 8 mg/kg once every 3 weeks and the second anti-HER2 antibody is administered intravenously. In some embodiments, the second anti-HER2 antibody is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of the second anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg/kg, wherein second anti-HER2 antibody is administered intravenously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered at a dose of about 6 mg/kg once about every 3 weeks and the pertuzumab is administered intravenously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered at a dose of about 8 mg/kg once about every 3 weeks and the pertuzumab is administered intravenously. In some embodiments, the second anti-HER.2 antibody is pertuzumab and is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the pertuzumab administered to the subject followed by subsequent doses of about 6 mg/kg, wherein the pertuzumab is administered intravenously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered at a dose of 6 mg/kg once every 3 weeks and the pertuzumab is administered intravenously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered at a dose of 8 mg/kg once every 3 weeks and the pertuzumab is administered intravenously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of pertuzumab administered to the subject followed by subsequent doses of 6 mg/kg, wherein the pertuzumab is administered intravenously. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered to the subject on a 21 -day treatment cycle and is administered to the subject once per treatment cycle. In some embodiments, the second anti-HER2 antibody is pertuzumab and is administered to the subject on day one of a 21 -day treatment cycle and is administered to the subject once per treatment cycle.

[0108] In some embodiments, a method of treatment described herein comprises administering to the subject tucatinib, or salt or solvate thereof, and trastuzumab. In some embodiments, the tucatinib, or salt or solvate thereof, and trastuzumab are administered to the subject on a 21-day treatment cycle. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 300 mg twice per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of 300 mg twice per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 600 mg once per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject at a dose of 600 mg once per day. In some embodiments, tucatinib, or salt or solvate thereof, is administered to the subject twice per day on each day of a 21-day treatment cycle. In some embodiments, the tucatinib, or salt or solvate thereof, is administered to the subject orally. In some embodiments, the anti-HER2 antibody is administered at a dose of about 6 mg/kg once about every 3 weeks and the anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered at a dose of about 8 mg/kg once about every 3 weeks and the anti-HER.2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the anti-HER2 antibody administered to the subject followed by subsequent doses of about 6 mg/kg, wherein anti-HER2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered at a dose of 6 mg/kg once every 3 weeks and the anti-HER2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered at a dose of 8 mg/kg once every 3 weeks and the anti-HER2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of the anti-HER2 antibody administered to the subject followed by subsequent doses of 6 mg/kg, wherein anti-HER2 antibody is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of about 6 mg/kg once about every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER.2 antibody is trastuzumab and is administered at a dose of about 8 mg/kg once about every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER.2 antibody is trastuzumab and is administered once about every 3 weeks at a dose of about 8 mg/kg for the first dose of the trastuzumab administered to the subject followed by subsequent doses of about 6 mg/kg, wherein the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of 6 mg/kg once every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered at a dose of 8 mg/kg once every 3 weeks and the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered once every 3 weeks at a dose of 8 mg/kg for the first dose of trastuzumab administered to the subject followed by subsequent doses of 6 mg/kg, wherein the trastuzumab is administered intravenously. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered to the subject on a 21 -day treatment cycle and is administered to the subject once per treatment cycle. In some embodiments, the anti-HER2 antibody is trastuzumab and is administered to the subject on day one of a 21 -day treatment cycle and is administered to the subject once per treatment cycle.

[0109] In an exemplary embodiment, a method of treatment described herein comprises administering trastuzumab at a dose of about 8 mg/kg intravenously followed by a dose of 6 mg/kg intravenously about once every 3 weeks.

V. Treatment Outcome

[0110] In some embodiments, treating the subject comprises inhibiting cancer cell growth, inhibiting cancer cell proliferation, inhibiting cancer cell migration, inhibiting cancer cell invasion, decreasing or eliminating one or more signs or symptoms of cancer, reducing the size (e.g., volume) of a cancer tumor, reducing the number of cancer tumors, reducing the number of cancer cells, inducing cancer cell necrosis, pyroptosis, oncosis, apoptosis, autophagy, or other cell death, increasing survival time of the subject, or enhancing the therapeutic effects of another drug or therapy. [OHl] In some embodiments, treating the subject as described herein results in a tumor growth inhibition (TGI) index that is between about 10% and 70% (e.g., about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, or 70%). Preferably, treating the subject results in a TGI index that is at least about 70% (e.g., about 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%). More preferably, treating the subject results in a TGI index that is at least about 85% (e.g., about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%). Even more preferably, treating the subject results in a TGI index that is at least about 95% (e.g., about 95%, 96%, 97%, 98%, 99%, or 100%). Most preferably, treating the subject results in a TGI index that is about 100% or more (e.g, about 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 125%, 130%, 135%, 140%, 145%, 150%, or more).

[0112] In particular embodiments, treating the subject with tucatinib and trastuzumab results in a TGI index that is greater than the TGI index that is observed when tucatinib or trastuzumab is used alone. In some instances, treating the subject results in a TGI index that is greater than the TGI index that is observed when tucatinib is used alone. In other instances, treating the subject results in a TGI index that is greater than the TGI index that is observed when trastuzumab is used alone. In some embodiments, treating the subject results in a TGI index that is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% greater than the TGI index that is observed when tucatinib or trastuzumab is used alone.

[0113] In some embodiments, the combination of the tucatinib and trastuzumab is synergistic. In particular embodiments, with respect to the synergistic combination, treating the subject results in a TGI index that is greater than the TGI index that would be expected if the combination of tucatinib and trastuzumab produced an additive effect. In some instances, the TGI index observed when a combination of tucatinib and trastuzumab is administered is at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% greater than the TGI index that would be expected if the combination of tucatinib and trastuzumab produced an additive effect. [0114] In some embodiments, treating the subject as described herein results in an increase in the overall amount of HER2 in the cancer. In some embodiments, the amount of HER2 in the cancer is determined by western blot analysis. In some embodiments, the amount of HER2 in the cancer is determined by immunohistochemistry. In some embodiments, the amount of HER2 in the cancer is determined by mass spectrometry. In some embodiments, the amount of HER2 in the cancer is determined by ELISA. In some embodiments, the amount of HER2 in the cancer is determined by real-time quantitative PCR (qRT-PCR). In some embodiments, the amount of HER2 in the cancer is determined by microarray analysis. In some embodiments, treating the subject as described herein results in an increase in the amount of plasma membrane-bound HER2 in the cancer. In some embodiments, the amount of plasma membrane-bound HER2 in the cancer is determined by quantitative fluorescence activated cell sorting (qFACS). In some embodiments, treating the subject as described herein results in an increase in the dwell time of HER2 at the cell surface. In some embodiments, treating the subject as described herein results in an increase in the internalization of plasma membrane-bound HER2. In some embodiments, treating the subject as described herein results in an increase in the lysosomal degradation of HER2.

[0115] In one aspect, a method of treating cancer with tucatinib as described herein and at least one anti-HER2 antibody as described herein results in an improvement in one or more therapeutic effects in the subject after administration of tucatinib as described herein and the at least one anti-HER2 antibody as described herein relative to a baseline. In some embodiments, the one or more therapeutic effects is the size of the tumor derived from the cancer, the objective response rate, the duration of response, the time to response, progression free survival, overall survival, or any combination thereof. In one embodiment, the one or more therapeutic effects is the size of the tumor derived from the cancer. In one embodiment, the one or more therapeutic effects is decreased tumor size. In one embodiment, the one or more therapeutic effects is stable disease. In one embodiment, the one or more therapeutic effects is partial response. In one embodiment, the one or more therapeutic effects is complete response. In one embodiment, the one or more therapeutic effects is the objective response rate. In one embodiment, the one or more therapeutic effects is the duration of response. In one embodiment, the one or more therapeutic effects is the time to response. In one embodiment, the one or more therapeutic effects is progression free survival. In one embodiment, the one or more therapeutic effects is overall survival. In one embodiment, the one or more therapeutic effects is cancer regression. [0116] In one embodiment of the methods or uses or product for uses provided herein, response to treatment with tucatinib as described herein and at least one anti-HER2 antibody as described herein may include the following criteria (RECIST Criteria 1.1):

[0117] In one embodiment of the methods or uses or product for uses provided herein, the effectiveness of treatment with tucatinib described herein and at least one anti-HER2 antibody described herein is assessed by measuring the confirmed objective response rate. In some embodiments, the confirmed objective response rate is the proportion of patients with tumor size reduction of a predefined amount and for a minimum period of time. In some embodiments the confirmed objective response rate is based upon RECIST vl .1. In one embodiment, the confirmed objective response rate is at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, or at least about 60%. In one embodiment, the objective response rate is at least about 30%-60%. In one embodiment, the confirmed objective response rate is at least about 30%-40%. In one embodiment, the confirmed objective response rate is at least about 35%-40%. In one embodiment, the confirmed objective response rate is at least about 30%. In one embodiment, the confirmed objective response rate is at least about 35%. In one embodiment, the confirmed objective response rate is at least about 38%. In one embodiment, the objective response rate is about 38.1%.

[0118] In one embodiment of the methods or uses or product for uses provided herein, response to treatment with tucatinib described herein and at least one anti-HER2 antibody described herein is assessed by measuring the size of a tumor derived from the cancer described herein (e.g., cancer). In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer before administration of tucatinib described herein and/or the at least one anti-HER.2 antibody described herein. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 10%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 20%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 30%- 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 40%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 50%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 60%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 70%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 85%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 95%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least about 99%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, or at least 80% relative to the size of the tumor derived from the cancer before administration of tucatinib described herein and/or the at least one anti-HER.2 antibody described herein. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 10%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 20%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 30%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 40%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 50%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 60%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 70%-80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 80%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 85%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 90%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 95%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 98%. In one embodiment, the size of a tumor derived from the cancer is reduced by at least 99%. In one embodiment, the size of a tumor derived from the cancer is reduced by 100%. In one embodiment, the size of a tumor derived from the cancer is measured by magnetic resonance imaging (MRI). In one embodiment, the size of a tumor derived from the cancer is measured by computed tomography (CT). In one embodiment, the size of a tumor derived from the cancer is measured by positron emission tomography (PET). In one embodiment, the size of a tumor derived from the cancer is measured by mammography. In one embodiment, the size of a tumor derived from the cancer is measured by sonography. See Gruber et. al., 2013, BMC Cancer. 13:328.

[0119] In one embodiment of the methods or uses or product for uses provided described herein, response to treatment with tucatinib described herein and at least one anti-HER2 antibody described herein, promotes regression of a tumor derived from the cancer described herein (e.g., cancer). In one embodiment, a tumor derived from the cancer regresses by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80% relative to the size of the tumor derived from the cancer before administration of the tucatinib described herein and/or anti-HER2 antibody described herein. In one embodiment, a tumor derived from the cancer regresses by at least about 10% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 20% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 30% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 40% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 50% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 60% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 70% to about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 80%. In one embodiment, a tumor derived from the cancer regresses by at least about 85%. In one embodiment, a tumor derived from the cancer regresses by at least about 90%. In one embodiment, a tumor derived from the cancer regresses by at least about 95%. In one embodiment, a tumor derived from the cancer regresses by at least about 98%. In one embodiment, a tumor derived from the cancer regresses by at least about 99%. In one embodiment, a tumor derived from the cancer regresses by at least 10%, at least 15%, at least

20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least

60%, at least 70%, or at least 80% relative to the size of the tumor derived from the cancer before administration of tucatinib described herein and/or at least one anti-HER.2 antibody described herein. In one embodiment, a tumor derived from the cancer regresses by at least 10% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 20% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 30% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 40% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 50% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 60% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 70% to 80%. In one embodiment, a tumor derived from the cancer regresses by at least 80%. In one embodiment, a tumor derived from the cancer regresses by at least 85%. In one embodiment, a tumor derived from the cancer regresses by at least 90%. In one embodiment, a tumor derived from the cancer regresses by at least 95%. In one embodiment, a tumor derived from the cancer regresses by at least 98%. In one embodiment, a tumor derived from the cancer regresses by at least 99%. In one embodiment, a tumor derived from the cancer regresses by 100%. In one embodiment, regression of a tumor is determined by magnetic resonance imaging (MRI). In one embodiment, regression of a tumor is determined by computed tomography (CT). In one embodiment, regression of a tumor is determined by positron emission tomography (PET). In one embodiment, regression of a tumor is determined by mammography. In one embodiment, regression of a tumor is determined by sonography. See Gruber et. al., 2013, BMC Cancer. 13:328.

[0120] In one embodiment of the methods or uses or product for uses described herein, response to treatment with tucatinib described and at least one anti-HER2 antibody described herein is assessed by measuring the median time of progression free survival after administration of tucatinib described herein and/or at least one anti-HER2 antibody described herein. In some embodiments, the median progression-free survival is at least about 8.1 months, at least about 8.2 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 13 months, at least about 14 months, or at least about 15 months after administration of tucatinib described herein and/or at least one anti-HER2 antibody described herein. In some embodiments, the subject exhibits progression-free survival of at least about 8.1 months after administration of tucatinib described herein and/or at least one anti-HER2 antibody described herein. In some embodiments, the subject exhibits progression-free survival of at least about 8.2 months after administration of tucatinib described herein and/or at least one anti-HER.2 antibody described herein.

[0121] In one embodiment of the methods or uses or product for uses described herein, response to treatment with tucatinib described herein and at least one anti-HER2 antibody described herein is assessed by measuring the median time of overall survival after administration of tucatinib described herein and/or at least one anti-HER.2 antibody described herein. In some embodiments, the subjects exhibits median overall survival of at least about 15 month, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, at least about 20 months, at least about 21 months, at least about 22 months, at least about 23 months, at least about 24 months, at least about 25 months, at least about 26 months, at least about 27 months, at least about 28 months, at least about 29 months, or at least about 30 months after administration of tucatinib described herein and the at least one anti-HER2 antibody described herein. In some embodiments, the subjects exhibit median overall survival of at least about 15 months after administration of tucatinib described herein and the at least one anti-HER2 antibody described herein. In some embodiments, the subjects exhibit overall survival of at least about 20 months after administration of tucatinib described herein and the at least one anti-HER2 antibody described herein. In some embodiments, the subjects exhibit median overall survival of at least about two years after administration of tucatinib described herein and/or at least one anti-HER2 antibody described herein. In some embodiments, the subjects exhibit median overall survival of about 24.1 months after administration of tucatinib described herein and/or at least one anti-HER2 antibody described herein. [0122] In one embodiment of the methods or uses or product for uses described herein, response to treatment with tucatinib described herein and at least one anti-HER2 antibody described herein is assessed by measuring the median duration of response to tucatinib described herein and the at least one anti-HER2 antibody described herein after administration of tucatinib described herein and the anti-HER2 antibody described herein. In some embodiments, the median duration of response to tucatinib described herein and the at least one anti-HER2 antibody described herein is at least about 10 months, at least about 10.4 months, at least about 11 months, at least about 12 months, at least about 12.4 months, at least about 13 months, at least about 14 months, at least about 15 months, at least about 16 months, at least about 17 months, at least about 18 months, at least about 19 months, or at least about 20 months after administration of tucatinib described herein and the at least one anti-HER2 antibody described herein. In some embodiments, the median duration of response to tucatinib described herein and the at least one anti-HER2 antibody described herein is at least about 12 months after administration of tucatinib described herein and the at least one anti-HER2 antibody described herein. In some embodiments, the median duration of response to tucatinib described herein and the at least one anti-HER2 antibody described herein is about 12.4 months after administration of tucatinib and the at least one anti-HER2 antibody.

VI. Compositions

[0123] In another aspect, the present invention provides a pharmaceutical composition comprising tucatinib described herein and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising at least one anti-HER2 antibody, such as trastuzumab, described herein and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a pharmaceutical composition comprising tucatinib described herein, at least one anti-HER2 antibody described herein, and a pharmaceutically acceptable carrier. In some embodiments, the at least one anti-HER2 antibody is a member selected from the group consisting of trastuzumab, pertuzumab, ado-trastuzumab emtansine, margetuximab, and a combination thereof. In some instances, the at least one anti-HER2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the at least one anti-HER2 antibody is trastuzumab.

[0124] In some embodiments, tucatinib described herein is present at a concentration between about 0.1 nM and 10 nM (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM). In other embodiments, tucatinib described herein is present at a concentration between about 10 nM and 100 nM (e.g, about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nM). In some other embodiments, tucatinib described herein is present at a concentration between about 100 nM and 1,000 nM (e.g., about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 nM). In yet other embodiments, tucatinib described herein is present at a concentration at least about 1,000 nM to 10,000 nM (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300, 2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400,

3,500, 3,600, 3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700,

4,800, 4,900, 5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000,

6.100, 6,200, 6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300,

7.400, 7,500, 7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600,

8.700, 8,800, 8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900,

10,000, or more nM).

[0125] In some embodiments, the at least one anti-HER.2 antibody described herein is present at a concentration between about 0.1 nM and 10 nM (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM). In other embodiments, the at least one anti-HER.2 antibody described herein is present at a concentration between about 10 nM and 100 nM (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nM). In some other embodiments, the at least one anti-HER2 antibody is present at a concentration between about 100 nM and 1,000 nM (e.g., about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 nM). In yet other embodiments, the at least one anti-HER.2 antibody is present at a concentration of at least about 1,000 nM to 10,000 nM (e.g., at least about 1,000,

1.100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300,

2.400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600,

3.700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900,

5,000, 5,100, 5,200, 5,300, 5,400, 5,500, 5,600, 5,700, 5,800, 5,900, 6,000, 6,100, 6,200,

6,300, 6,400, 6,500, 6,600, 6,700, 6,800, 6,900, 7,000, 7,100, 7,200, 7,300, 7,400, 7,500,

7,600, 7,700, 7,800, 7,900, 8,000, 8,100, 8,200, 8,300, 8,400, 8,500, 8,600, 8,700, 8,800,

8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000, or more nM). [0126] In some embodiments, there is a pharmaceutical composition comprising at least one anti-HER2 antibody described herein, wherein the at least one anti-HER2 antibody comprises a first anti-HER2 antibody and a second anti-HER2 antibody, wherein each of the first anti-HER2 antibody and the second anti-HER2 antibody are present at a concentration between about 0.1 nM and 10 nM (e.g., about 0.1, 0.2, 0.3, 0.4, 0.5 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10 nM). In other embodiments, each of the first anti-HER2 antibody and the second anti-HER2 antibody described herein are present at a concentration between about 10 nM and 100 nM (e.g., about 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 nM). In some other embodiments, each of the first anti-HER2 antibody and the second anti-HER2 antibody are present at a concentration between about 100 nM and 1,000 nM (e.g., about 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1,000 nM). In yet other embodiments, each of the first anti-HER2 antibody and the second anti-HER2 antibody are present at a concentration of at least about 1,000 nM to 10,000 nM (e.g., at least about 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,100, 2,200, 2,300,

2,400, 2,500, 2,600, 2,700, 2,800, 2,900, 3,000, 3,100, 3,200, 3,300, 3,400, 3,500, 3,600,

3,700, 3,800, 3,900, 4,000, 4,100, 4,200, 4,300, 4,400, 4,500, 4,600, 4,700, 4,800, 4,900,

8,900, 9,000, 9,100, 9,200, 9,300, 9,400, 9,500, 9,600, 9,700, 9,800, 9,900, 10,000, or more nM). In some embodiments, the pharmaceutical composition is for subcutaneous administration. In some embodiments, the pharmaceutical composition comprises hyaluronidase.

[0127] The pharmaceutical compositions of the present invention may be prepared by any of the methods well-known in the art of pharmacy. Pharmaceutically acceptable carriers suitable for use with the present invention include any of the standard pharmaceutical carriers, buffers and excipients, including phosphate-buffered saline solution, water, and emulsions (such as an oil/water or water/oil emulsion), and various types of wetting agents or adjuvants. Suitable pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, 19th ed. 1995). Preferred pharmaceutical carriers depend upon the intended mode of administration of the active agent. [0128] The pharmaceutical compositions of the present invention can include a combination of drugs (e.g., tucatinib described herein and at least one anti-HER2 antibody described herein), or any pharmaceutically acceptable salts thereof, as active ingredients and a pharmaceutically acceptable carrier or excipient or diluent. A pharmaceutical composition may optionally contain other therapeutic ingredients.

[0129] The compositions (e.g., comprising tucatinib described herein, at least one anti- HER2 antibody described herein, or a combination thereof) can be combined as the active ingredients in intimate admixture with a suitable phrmaceutical carrier or excipient according to conventional pharmaceutical compounding techniques. Any carrier or excipient suitable for the form of preparation desired for administration is contemplated for use with the compounds disclosed herein.

[0130] The pharmaceutical compositions include those suitable for oral, topical, parenteral, pulmonary, nasal, or rectal administration. The most suitable route of administration in any given case will depend in part on the nature and severity of the cancer condition and also optionally the HER2 status or stage of the cancer.

[0131] Other pharmaceutical compositions include those suitable for systemic (e.g., enteral or parenteral) administration. Systemic administration includes oral, rectal, sublingual, or sublabial administration. Parenteral administration includes, e.g., intravenous, intramuscular, intra-arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc. In particular embodiments, pharmaceutical compositions of the present invention may be administered intratum orally.

[0132] Compositions for pulmonary administration include, but are not limited to, dry powder compositions consisting of the powder of a compound described herein (e.g., tucatinib described herein, at least one anti-HER2 antibody described herein, or a combination thereof), or a salt thereof, and the powder of a suitable carrier or lubricant. The compositions for pulmonary administration can be inhaled from any suitable dry powder inhaler device known to a person skilled in the art.

[0133] Compositions for systemic administration include, but are not limited to, dry powder compositions consisting of the composition as set forth herein (e.g., tucatinib described herein, at least one anti-HER2 anibody described herein, or a combination thereof) and the powder of a suitable carrier or excipient. The compositions for systemic administration can be represented by, but not limited to, tablets, capsules, pills, syrups, solutions, and suspensions.

[0134] In some embodiments, the compositions (e.g., tucatinib described herein, at least one anti-HER2 anibody described herein, or a combination thereof) further include a pharmaceutical surfactant. In other embodiments, the compositions further include a cryoprotectant. In some embodiments, the cryoprotectant is selected from the group consisting of glucose, sucrose, trehalose, lactose, sodium glutamate, PVP, HPpCD, CD, glycerol, maltose, mannitol, and saccharose.

[0135] Pharmaceutical compositions or medicaments for use in the present invention can be formulated by standard techniques using one or more physiologically acceptable carriers or excipients. Suitable pharmaceutical carriers are described herein and in Remington: The Science and Practice of Pharmacy, 21st Ed., University of the Sciences in Philadelphia, Lippencott Williams & Wilkins (2005).

[0136] Controlled-release parenteral formulations of the compositions (e.g., tucatinib described herein, at least one anti-HER2 anibody described herein, or a combination thereof) can be made as implants, oily injections, or as particulate systems. For a broad overview of delivery systems see Banga, A. J., Therapeutic Peptides and Proteins: Formulation, Processing, and Delivery Systems, Technomic Publishing Company, Inc., Lancaster, PA, (1995), which is incorporated herein by reference. Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles.

[0137] Polymers can be used for ion-controlled release of compositions of the present invention. Various degradable and nondegradable polymeric matrices for use in controlled drug delivery are known in the art (Langer R., Accounts Chem. Res., 26:537-542 (1993)). For example, the block copolymer, polaxamer 407 exists as a viscous yet mobile liquid at low temperatures but forms a semisolid gel at body temperature. It has been shown to be an effective vehicle for formulation and sustained delivery of recombinant interleukin 2 and urease (Johnston et al., Pharm. Res., 9:425-434 (1992); and Pec et al., J. Parent. Sci. Tech., 44(2):58 65 (1990)). Alternatively, hydroxyapatite has been used as a microcarrier for controlled release of proteins (Ijntema et al., Int. J. Pharm., 112:215-224 (1994)). In yet another aspect, liposomes are used for controlled release as well as drug targeting of the lipid- capsulated drug (Betageri et al., LIPOSOME DRUG DELIVERY SYSTEMS, Technomic Publishing Co., Inc., Lancaster, PA (1993)). Numerous additional systems for controlled delivery of therapeutic proteins are known. See, e.g., U.S. Pat. No. 5,055,303, 5,188,837, 4,235,871, 4,501,728, 4,837,028 4,957,735 and 5,019,369, 5,055,303; 5,514,670; 5,413,797; 5,268,164; 5,004,697; 4,902,505; 5,506,206, 5,271,961; 5,254,342 and 5,534,496, each of which is incorporated herein by reference.

[0138] For oral administration of a combination of tucatinib described herein and/or at least one anti-HER2 anibody described herein, a pharmaceutical composition or a medicament can take the form of, for example, a tablet or a capsule prepared by conventional means with a pharmaceutically acceptable excipient. The present invention provides tablets and gelatin capsules comprising tucatinib described herein, at least one anti-HER2 anibody described herein, or a combination thereof, or a dried solid powder of these drugs, together with (a) diluents or fillers, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose (e.g., ethyl cellulose, microcrystalline cellulose), glycine, pectin, polyacrylates or calcium hydrogen phosphate, calcium sulfate, (b) lubricants, e.g., silica, talcum, stearic acid, magnesium or calcium salt, metallic stearates, colloidal silicon dioxide, hydrogenated vegetable oil, corn starch, sodium benzoate, sodium acetate or polyethyleneglycol; for tablets also (c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone or hydroxypropyl methylcellulose; if desired (d) disintegrants, e.g., starches (e.g., potato starch or sodium starch), glycolate, agar, alginic acid or its sodium salt, or effervescent mixtures; (e) wetting agents, e.g., sodium lauryl sulphate, or (f) absorbents, colorants, flavors and sweeteners.

[0139] Tablets may be either film coated or enteric coated according to methods known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups, or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives, for example, suspending agents, for example, sorbitol syrup, cellulose derivatives, or hydrogenated edible fats; emulsifying agents, for example, lecithin or acacia; non-aqueous vehicles, for example, almond oil, oily esters, ethyl alcohol, or fractionated vegetable oils; and preservatives, for example, methyl or propyl-p-hydroxybenzoates or sorbic acid. The preparations can also contain buffer salts, flavoring, coloring, or sweetening agents as appropriate. If desired, preparations for oral administration can be suitably formulated to give controlled release of the active compound(s). [0140] Typical formulations for topical administration of tucatinib described herein, at least one anti-HER2 anibody described herein, or a combination thereof include creams, ointments, sprays, lotions, and patches. The pharmaceutical composition can, however, be formulated for any type of administration, e.g, intradermal, subdermal, intravenous, intramuscular, subcutaneous, intranasal, intracerebral, intratracheal, intraarterial, intraperitoneal, intravesical, intrapleural, intracoronary or intratumoral injection, with a syringe or other devices. Formulation for administration by inhalation (e.g, aerosol), or for oral or rectal administration is also contemplated.

[0141] Suitable formulations for transdermal application include an effective amount of one or more compounds described herein, optionally with a carrier. Preferred carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound to the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin. Matrix transdermal formulations may also be used.

[0142] The compositions and formulations set forth herein (e.g., tucatinib described herein, at least one anti-HER2 anibody described herein, or a combination thereof) can be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection can be presented in unit dosage form, for example, in ampules or in multi-dose containers, with an added preservative. Injectable compositions are preferably aqueous isotonic solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or buffers. Alternatively, the active ingredient(s) can be in powder form for constitution with a suitable vehicle, for example, sterile pyrogen-free water, before use. In addition, they may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively.

[0143] For administration by inhalation, the compositions (e.g., comprising tucatinib described herein, at least one anti-HER2 anibody described herein, or a combiation thereof) may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, di chlorotetrafluoroethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator can be formulated containing a powder mix of the compound(s) and a suitable powder base, for example, lactose or starch.

[0144] The compositions (e.g., comprising tucatinib described herein, at least one anti- HER2 anibody described herein, or a combiation thereof) can also be formulated in rectal compositions, for example, suppositories or retention enemas, for example, containing conventional suppository bases, for example, cocoa butter or other glycerides.

[0145] Furthermore, the active ingredient(s) can be formulated as a depot preparation. Such long-acting formulations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, one or more of the compounds described herein can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

VII. Articles of Manufacture and Kits

[0146] In another aspect, the present invention provides an article of manufacture or kit for treating or ameliorating the effects of metastatic colorectal cancer in a subject, the article of manufacture or kit comprising a pharmaceutical composition of the present invention (e.g., a pharmaceutical composition comprising tucatinib described herein, at least one anti-HER2 antibody described herein, or a combination thereof). In some embodiments, the at least one anti-HER.2 antibody is trastuzumab, pertuzumab, ado-trastuzumab emtansine, margetuximab, or a combination thereof. In some instances, the at least one anti-HER2 antibody is a combination of trastuzumab and pertuzumab. In some embodiments, the at least one anti- HER2 antibody is trastuzumab.

[0147] The articles of manufacture or kits are suitable for treating or ameliorating the effects of cancers, particularly cancers that have been determined to express a mutant form of HER2. In some embodiments, the cancer is an advanced cancer.

[0148] Materials and reagents to carry out the various methods of the present invention can be provided in articles of manufacture or kits to facilitate execution of the methods. As used herein, the term “kit” includes a combination of articles that facilitates a process, assay, analysis, or manipulation. In particular, kits of the present invention find utility in a wide range of applications including, for example, diagnostics, prognostics, therapy, and the like.

[0149] Articles of manufacture or kits can contain chemical reagents as well as other components. In addition, the articles of manufacture or kits of the present invention can include, without limitation, instructions to the user, apparatus and reagents for administering combinations of tucatinib described herein and anti-HER2 antibodies described herein or pharmaceutical compositions thereof, sample tubes, holders, trays, racks, dishes, plates, solutions, buffers, or other chemical reagents. In some embodiments, the articles of manufacture or kits contain instructions, apparatus, or reagents for determining the genotype of a gene (e.g., KRAS, NRAS, BRAF) or determining the expression of HER2 in a sample. Articles of manufacture or kits of the present invention can also be packaged for convenient storage and safe shipping, for example, in a box having a lid.

[0150] The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims.

EXAMPLES

Example 1: A phase II, Open Label Study of Tucatinib Combined with Trastuzumab in Patients with HER2+ Metastatic Colorectal Cancer.

[0151] Study design. This multicenter, randomized, open-label, Phase 2 study administered tucatinib as monotherapy and in combination with trastuzumab in patients with HER2-positive, RAS wild-type, unresectable or metastatic CRC. Eligible patients were required to have previously received and failed, unless contraindicated, systemic therapy with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-VEGF mAb; patients with dMMR or MSI-H disease must also have received an anti-PD-(L)l mAb, if indicated. The study consisted of Cohorts A and B, which were treated with tucatinib and trastuzumab, and Cohort C, which were treated with tucatinib monotherapy.

[0152] Treatment is administered in cycles of 21 days each. All subjects enrolled in the expansion portion of the trial (Cohorts B and C) were randomized in a 4:3 ratio to receive tucatinib given in combination with trastuzumab (Cohort B) or tucatinib monotherapy (Cohort C). Subjects in Cohorts A and B were treated with tucatinib at a dose of 300 mg orally twice daily (PO BID) and trastuzumab at a loading dose of 8 mg/kg intravenous (IV) followed by a dose of 6 mg/kg IV every 3 weeks. Subjects randomized to Cohort C were treated with tucatinib at a dose of 300 mg PO BID.

[0153] Subjects enrolled in Cohort A and those randomized to Cohort B continued on therapy until evidence of radiographic or clinical progression, unacceptable toxicity, withdrawal of consent, or study closure. Subjects randomized to Cohort C were allowed to crossover and receive doublet tucatinib + trastuzumab therapy if they experienced radiographic progression at any time point, or if they had not achieved a partial response (PR) or complete response (CR) by the Week 12 assessment. Subjects in Cohort C must have a new baseline RECIST assessment prior to crossover from monotherapy to doublet therapy using the Week 12 scans or the first progressive disease (PD) scans as applicable.

[0154] The primary analysis set comprised all treated subjects in Cohorts A+B.

[0155] The primary endpoint of the study was the confirmed objective response rate

(cORR). Radiographic response was assessed by a blinded independent central review (BICR), according to RECIST 1.1, with confirmation of response required >4 weeks from the first documentation of response.

[0156] Secondary efficacy endpoints include duration of confirmed response, PFS, and OS for all subjects enrolled on the doublet regimen (Cohort A+B). In addition, in order to assess the contribution of tucatinib to the doublet regimen, ORR by 12 weeks is assessed in Cohorts A+B, as well as in Cohort C.

[0157] The study will be closed 5 years after enrollment of the last subject, or when no subjects remain in long-term follow-up, whichever occurs first.

[0158] A schematic of the study design is shown in FIG. 1.

[0159] Cohorts A and B and subjects from Cohort C who crossover to doublet therapy. Trastuzumab 8 mg/kg is administered by IV infusion over 90 minutes on Day 1 of Cycle 1. In subsequent cycles, trastuzumab 6 mg/kg is administered IV over 30 minutes on Day 1 of each cycle, except in specific circumstances where 2 mg/kg may be given weekly or 4 mg/kg every 2 weeks to compensate for modifications in treatment schedule. Subjects who are crossing over from Cohort C are able to start doublet combination therapy as soon as the formal crossover process occurs, even if it entails abruption in a previous cycle. On days when trastuzumab is administered, the tucatinib dose may be taken before, during, or after the trastuzumab infusion.

[0160] Treatments administered. Subjects in the study will receive doublet combination therapy of tucatinib with trastuzumab (Cohorts A and B) or tucatinib monotherapy (Cohort C). For Cohorts A and B, tucatinib will be given on a 21-day cycle, with trastuzumab on day 1 of each cycle. For Cohort C, tucatinib will be given on a 21-day cycle. Subjects in Cohort C are allowed to crossover to start doublet combination therapy with Medical Monitor’s approval, if, by investigator assessment (per RECIST 1.1), they experience radiographic progression at any time point, or if they have not achieved PR or CR by the 12-week assessment, at which point the monotherapy-cycle will be abrupted and the combination therapy-cycle will start. The treatment schedule is summarized in the table, below.

[0161] Trastuzumab may also be given on a weekly basis at 2 mg/kg IV or Q2 week basis at 4 mg/kg IV, but only in circumstances where the trastuzumab infusion schedule has been interrupted or suspended, and these infusions are required to resynchronize the cycle length to 21 days.

[0162] Dose modification (tucatinib). Up to 3 dose reductions of tucatinib are allowed, but dose reductions to below 150 mg BID are not allowed. Patients who would require a dose reduction to <150 mg BID, or who would require a potential fourth dose reduction of tucatinib, will discontinue study treatment. The dose of tucatinib will not be re-escalated after a dose reduction is made.

[0163] Dose modification (trastuzumab). No dose reductions for trastuzumab are allowed. Trastuzumab may also be given on a weekly basis at 2 mg/kg IV q 7 days or biweekly at 4mg/kg IV, but only in the circumstance that trastuzumab infusion has been delayed, and these infusions are required to resynchronize the cycle length to 21 days. If trastuzumab cannot be restarted at the same dose after being held for an AE, it must be discontinued. If dosing of trastuzumab has been held for >4 weeks, the IV loading dose of 8 mg/kg will be given per approved dosing instructions.

[0164] Duration of treatment. Subjects in Cohorts A or B may continue on study treatment until progressive disease (PD), death, AEs that are considered intolerable and unmanageable, lost to follow-up, treatment-related adverse events which do not resolve to Grade <2 within 6 weeks, request by regulatory agencies, dosing delay greater than 6 weeks, investigator decision, protocol noncompliance, withdrawal of consent, start of a subsequent anticancer therapy, pregnancy or breastfeeding, or study termination by the sponsor. Subjects randomized to Cohort C, who have experienced radiographic progression at any time point, or if they have not achieved a PR or CR by the Week 12 assessment, may crossover to receive doublet therapy. Subjects in Cohort C must have a new baseline RECIST assessment prior to crossover from monotherapy to doublet therapy using the Week 12 scans or the first PD scans as applicable. Subjects with signs of clinical benefit (e.g., mixed response, symptom improvement, demonstrable slowing of progression, progression rate of <20% over 6 months) who are tolerating treatment may be allowed to continue treatment past formal radiologic progression (per RECIST 1.1) if such treatment is considered in the subject's best interest by the subject, the treating physician, and the Medical Monitor. In this scenario, subjects may continue until clinical progression.

[0165] Efficacy assessments. Radiological disease assessments (computerized tomography [CT] or magnetic resonance imaging [MRI] scans of chest, abdomen, and pelvis) and carcinoembryonic antigen (CEA) tumor marker assays are undertaken on the following schedule: [0166] 1. Cohort A: at screening/baseline, every 9 weeks (±14 days) during treatment

(every 12 weeks [±7 days] after 12 months of treatment, if the subject is clinically stable), and at the end of treatment (EOT) visit. Subjects who discontinue for reasons other than documented PD will continue to have disease assessments approximately every 9 weeks until PD, death, withdrawal of consent, study closure, or alternative therapy.

[0167] 2 Cohorts B and C: at screening/baseline, every 6 weeks (±7 days) during treatment (every 12 weeks [±7 days] after 12 months of treatment, if the subject is clinically stable), and at the EOT visit. Subjects who discontinue for reasons other than documented PD will continue to have disease assessments approximately every 9 weeks until PD, death, withdrawal of consent, study closure, or alternative therapy.

[0168] The determination of antitumor activity will be based on confirmed objective response assessments as defined by RECIST 1.1. Disease assessments will be evaluated by both the BICR and investigators. The investigator will make treatment decisions based on site assessments of scans. For Cohort A, confirmation of response was initially not required per protocol. For the purposes of the primary analysis, the disease assessment timepoint after the first response documented by the BICR will be used to determine confirmed response. For Cohort A, responses (CR or PR) will be confirmed at the next re-staging timepoint, 9 weeks (±14 days) after first documentation of response. For Cohorts B and C, responses (CR or PR) will be confirmed at the next re-staging timepoint, 6 weeks (±7 days) after first documentation of response. Subjects will be followed for survival every 12 weeks (±14 days) up to 5 years from treatment initiation in a long-term follow-up phase of the study.

[0169] Pharmacokinetic assessments. PK assessments of trough levels of tucatinib drug levels will be performed on Day 1 of Cycles 2 to 6 prior to administration of tucatinib in both Cohorts B and Cohort C. On Day 1 of Cycle 3, PK assessments of peak levels of tucatinib drug levels will be performed 1 to 4 hours after administration of tucatinib in both Cohort B and Cohort C. Subjects in Cohort C who crossover to the tucatinib + trastuzumab regimen should continue PK assessments, if crossover occurs prior to Cycle 6. If the crossover happens after Cycle 6, no PK collections are required.

[0170] Biomarker assessments. Biomarker assessments may include the confirmation of HER2 status by IHC, FISH, and NGS as well as an exploratory assessment of HER2 mutations or other mutations as potential biomarkers of response. HER2 status will be verified by central laboratory analysis using IHC by an FDA-approved or CE-marked IHC test following the package insert’s interpretational manual for breast cancer. NGS analysis may be performed to interrogate the mutation status of a panel of oncogenes and tumor suppressor genes that are associated with tumor growth, survival and resistance to targeted therapeutics. This assessment may enable the correlation of treatment outcome to either preexisting or acquired cancer gene mutations and may ultimately guide or refine patient selection strategies to better match tucatinib regimens with tumor genotype in the future.

[0171] Patient-reported outcomes and health economic assessments. PRO measures will be completed at protocol-specified time points using the EORTC QLQ-C30. Health economic assessments will be explored with the EQ-5D-5L instrument and health resource utilization. EQ-5D-5L and EORTC QLQ-C30 questionnaires will be administered for Cohorts B and C at: pre-dose Cycle 1 Day 1 (C1D1), C1D8, C1D15, C2D1, C3D1, C4D1, every 3 cycles thereafter, until treatment discontinuation, PD, death, toxicity, withdrawal of consent or study closure, and at the EOT.

[0172] Safety assessments. Safety assessments will include the surveillance and recording of AEs, including SAEs, physical examination findings, vital signs, concomitant medications, pregnancy testing, and laboratory tests. Assessment of cardiac ejection fraction will be performed by MUGA scan or ECHO.

[0173] Concomitant therapies. Use of investigational drugs and devices, anticancer (including but not limited to chemotherapy and hormonal therapy) and radiation therapy (except for palliative radiotherapy at focal non-CNS sites which are not considered target lesions per RECIST 1.1) are prohibited during the study. Tucatinib is held 7 days prior to and 7 days post radiation therapy. Strong CYP2C8 inhibitors and strong CYP2C8 or CYP3 A4 inducers are prohibited as concomitant medications during study treatment and within 1 week of discontinuation of tucatinib treatment. Concomitant use of a sensitive CYP3 A substrate is avoided 1 week prior to the first dose of study treatment and during the study. Use of moderate or weak inhibitors of CYP2C8 are permitted but used with caution.

[0174] Statistical methods. Safety and efficacy endpoints will be summarized with descriptive statistics. Data collected in this study will be presented using summary tables, subject data listings, and figures. Continuous variables will be summarized using descriptive statistics, specifically the mean, median, standard deviation, minimum, and maximum. Categorical variables will be summarized by frequencies and percentages. Confidence intervals (CI), 95% 2-sided, will be presented where needed to gauge the strength of evidence for a corresponding estimated treatment effect. For time-to-event endpoints, the median survival time will be estimated using the Kaplan Meier method; the associated 95% CI will be calculated based on the complementary log-log transformation. Subjects from the initial, non-randomized Cohort A and those randomized to Cohort B during the expansion will be analyzed together (Cohorts A+B). Demographic and baseline characteristics will be summarized separately by cohort. The primary analysis of efficacy endpoints will be performed per BICR assessment using RECIST 1.1 criteria. Supportive analysis per investigator assessments will also be performed. Discordance between the BICR and investigator’s assessment will be evaluated.

[0175] Efficacy analyses. The primary endpoint of this study is the confirmed cORR per RECIST 1.1 according to BICR assessment. The cORR is defined as the proportion of subjects with confirmed CR or PR. The cORR and its exact 2-sided 95% CI, using the Clopper-Pearson method, will be calculated. The timing of the primary analysis will be based on the time to confirmed ORR per BICR (cORR). DOR according to BICR assessment will also be analyzed at this time. PFS and OS will also be analyzed at the time of the primary cORR and DOR analyses; additional analysis of these time-to-event endpoints may be undertaken when mature progression and survival data become available. ORR, DOR, and PFS according to investigator assessment will also be analyzed; discordance between the BICR and investigator’s assessment will be summarized descriptively.

[0176] Interim futility efficacy analyses of the Cohort A will be undertaken after the first 10 subjects have undergone disease assessment (first stage of Fleming design), and after the first 25 subjects have undergone disease assessment (second stage of Fleming design).

[0177] Pharmacokinetic analyses. Individual (subject) plasma tucatinib concentrations at each sampling time will be listed and summarized with descriptive statistics. Additional exploratory PK analyses may be conducted, including exploratory analyses investigating the relationship between tucatinib exposure and efficacy and safety endpoints.

[0178] Patient-reported outcomes and health resource utilization analyses. PRO assessments based on the EQ-5D-3L and EORTC QLQ-C30 will be summarized using descriptive statistics. PRO scores will be analyzed descriptively. All subscales and individual item scores will be tabulated. Descriptive summaries of observed data at each scheduled assessment time point may be presented. [0179] Safety analyses. Safety will be assessed through summaries of AEs, changes in laboratory test results, changes in vital signs, physical examination findings, changes in ECOG PS, and changes in cardiac ejection fraction results. AEs will be classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA); AE severities will be classified using the CTCAE v4.03 criteria. Separately, all SAEs and AEs of special interest (e.g., any drug-induced liver injury, and asymptomatic left ventricular systolic dysfunction) will also be listed.

[0180] Objectives and endpoints. The study evaluates the efficacy and safety of tucatinib given in combination with trastuzumab in patients with human epidermal growth factor receptor 2 positive (HER2+), RAS wild-type, unresectable or metastatic CRC who have previously received and failed, unless contraindicated, systemic therapy with fluoropyrimidines, oxaliplatin, irinotecan, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb); patients whose disease has deficient mismatch repair (dMMR) proteins or is Microsatellite instability-High (MSI-H) must also have received an antiprogrammed death ligand 1 (anti-PD-Ll) mAb, if indicated. Specific objectives and corresponding endpoints for the study are summarized in the table, below.

[0181] Study population. Patients with HER2 -positive, RAS wild-type, unresectable or metastatic CRC who, unless contraindicated, have previously received systemic therapy with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-VEGF mAh; patients whose disease has dMMR proteins or is MSI-H must also have received an anti-PD-(L)l mAh, if indicated. Patients must meet all of the enrollment criteria to be eligible for this study.

[0182] Inclusion criteria. Subjects must met the following criteria to be eligible for the study:

1. Have histologically and/or cytologically documented adenocarcinoma of the colon or rectum, which is metastatic and/or unresectable.

2. Unless otherwise contraindicated, subjects must have received and failed regimens containing the following agents: fluoropyrimidine (e.g., 5 -fluorouracil or capecitabine), oxaliplatin, irinotecan, an anti-VEGF mAb (bevacizumab, ramucirumab, or ziv- aflibercept), and an anti-PD-(L)l therapy (nivolumab or pembrolizumab) if the tumor has dMMR proteins or is MSI-H.

3. Have progression of unresectable or metastatic CRC after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy

4. Have RAS wild-type in primary or metastatic tumor tissue, based on expanded RAS testing including KRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146), and NRAS exon 2 (codons 12 and 13), exon 3 (codons 59 and 61), and exon 4 (codons 117 and 146)

5. Subjects must be willing and able to provide the most recently available tissue blocks (or slides, with Medical Monitor’s approval), obtained prior to treatment initiation, to a sponsor-designated central laboratory for biomarker analysis. If archival tissue is not available, then a newly-obtained baseline biopsy of an accessible tumor lesion is required.

6. Have confirmed HER2-positive mCRC, as defined by having tumor tissue tested at a Clinical Laboratory Improvement Amendments (CLIA)-certified or International Organization for Standardization (ISO)-accredited laboratory, meeting at least one of the following criteria: a. HER2+ overexpression (3+ immunohistochemistry [IHC]) by an FDA-approved or Conformite Europeenne (CE)-marked HER2 IHC test following the package insert’s interpretational manual for breast cancer b. HER2 2+ IHC is eligible if the tumor is amplified by an FDA-approved or CE-marked HER2 in situ hybridization assay (FISH or chromogenic in situ hybridization [CISH]) following the package insert’s interpretational manual for breast cancer c. HER2 (ERBB2') amplification by CLIA-certified or ISO-accredited Next Generation Sequencing (NGS) sequencing assay.

7. Age >18 years at time of consent

8. Have radiographically measurable disease assessable by RECIST 1.1, with at least one site of disease that is measurable and that has not been previously irradiated; or, if the subject has had previous radiation to the target lesion(s), there must be evidence of progression since the radiation Have an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0, 1, or 2. Life expectancy greater than 3 months in the opinion of the investigator Have adequate hematological, hepatic, renal, coagulation, and cardiac function as defined below, obtained <7 days prior to the first study treatment: a. Absolute neutrophil count (ANC) >1.0 * 10³/pL b. Platelet count >75 x 10³/pL c. Hemoglobin >8.0 g/dL d. Total bilirubin <1.5 x upper limit of normal (ULN). Subjects with known history of Gilbert’s Syndrome and normal direct bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) are eligible e. AST and ALT <2.5 x ULN (<5 x ULN if liver metastases are present) f. Calculated creatinine clearance >50 mL/min using the Cockcroft-Gault formula g. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) <1.5 x ULN unless on medication known to alter INR and/or aPTT h. Left ventricular ejection fraction (LVEF) >50% as assessed by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan documented <28 days prior to study treatment For subjects of childbearing potential, as defined in Section 4.3, the following stipulations apply: a. Must have a negative serum pregnancy test (minimum sensitivity of 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [P-hCG]) result within 7 days prior to the first dose of study treatment. A subject with a false positive result and documented verification that the subject is not pregnant is eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 7 months after the final dose of study drug administration c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 7 months after the final dose of study drug administration d. May choose to practice complete abstinence, if consistent with the subject’s preferred lifestyle, as an acceptable form of contraception e. If sexually active in a way that could lead to pregnancy, must consistently use

2 highly effective methods of birth control, starting at the time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug. For subjects who can father children, the following stipulations apply: a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 7 months after the final study drug administration b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use 2 highly effective methods of birth control, starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug c. If sexually active with a person who is pregnant or breastfeeding, must consistently use one of 2 contraception options, starting at time of informed consent and continuing throughout the study and for at least 7 months after the final dose of any study drug.

14. Subject must provide signed informed consent document that has been approved by an institutional review board/independent ethics committee (IRB/IEC) prior to initiation of any study-related tests or procedures that are not part of standard-of-care for the subject’s disease

Subject must be willing and able to comply with study procedures

[0183] Exclusion criteria. Subjects were excluded from the study for any of the following reasons:

1. Have previously been treated with anti-HER2 targeting therapy

2. Have received treatment with any systemic anticancer therapy (including hormonal and biologic therapy), non-central nervous system (CNS) radiation, or experimental agent <3 weeks of first dose of study treatment or are currently participating in another interventional clinical trial

3. Have any toxicity related to prior cancer therapies that has not resolved to < Grade 1, with the following exceptions:

• Alopecia and neuropathy, which must have resolved to < Grade 2

• Congestive heart failure (CHF), which must have been < Grade 1 in severity at the time of occurrence, and must have resolved completely

• Anemia, which must have resolved to < Grade 2

• Decreased ANC, which must have resolved to < Grade 2

4. Have clinically significant cardiopulmonary disease such as:

• Ventricular arrhythmia requiring therapy

• Symptomatic hypertension or uncontrolled asymptomatic hypertension, as determined by the investigator

• Any history of symptomatic CHF, left ventricular systolic dysfunction or decrease in ejection fraction

• Severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced malignancy or hypoxia requiring supplementary oxygen therapy

• Presence of > Grade 2 QTc prolongation on screening ECG

5. Have known myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or cardiac surgery within 6 months prior to first dose of study treatment 6. Major surgical procedure, open biopsy, or significant traumatic injury <28 days prior to enrollment (<56 days for hepatectomy, open thoracotomy, or major neurosurgery) or anticipation of need for major surgical procedure during the course of the study

7. Serious, non-healing wound, ulcer, or bone fracture

8. Known to be positive for hepatitis B by surface antigen expression

9. Known to have active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Subjects who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks

10. Known to be positive for human immunodeficiency virus (HIV)

11. Subjects who are pregnant, breastfeeding, or planning a pregnancy

12. Inability to swallow pills or any significant gastrointestinal disease which would preclude the adequate oral absorption of medications

13. Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP2C8 or CYP3 A4 inducer within 5 days prior to first dose of study treatment.

14. Have any other medical, social, or psychosocial factors that, in the opinion of the investigator, could impact safety or compliance with study procedures

15. History of another malignancy within 3 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year OS >90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer)

16. Subjects with known active CNS metastasis (irradiated or resected lesions are permitted, provided the lesions are fully treated and inactive, subject is asymptomatic, and no steroids have been administered for at least 30 days)

17. Have a hypersensitivity to tucatinib or any of its excipients, to trastuzumab or any of its excipients, or to murine proteins

[0184] Discontinuation of study treatment. A subject’s study treatment may be discontinued for any of the following reasons:

• PD (per RECIST 1.1), as assessed by investigator

• Clinical disease progression

• AE

• Pregnancy or begins breastfeeding while on trial

• Subject decision, non-AE.

[0185] Subjects with signs of clinical benefit (e.g., mixed response, symptom improvement, demonstrable slowing of progression, progression rate of <20% over 6 months) who are tolerating treatment may be allowed to continue treatment past formal radiologic progression (i.e., RECIST 1.1) if such treatment is considered in the subject's best interest by the subject, the treating physician, and the Medical Monitor. In this scenario, subjects may continue on treatment, with radiographic assessments performed per the protocol defined assessment schedule until clinical progression.

[0186] Subjects who discontinue from study treatment will remain on study for follow-up unless they withdraw consent.

Example 2. Outcomes of a phase II, Open Label Study of Tucatinib Combined with Trastuzumab in Patients with HER2+ Metastatic Colorectal Cancer.

[0187] The clinical trial was carried out as described in Example 1, above. An updated schematic of the clinical trial is shown in FIG. IB.

[0188] Demographics. Summary of the patient demographics for cohorts A, B, and C are summarized in the Table, below.

[0189] Baseline disease characteristics. Patient baseline disease characteristics are summarized in the Table, below.

[0190] Disposition.

[0191] Results. Safety results were consistent with known safety when administering tucatinib and/or trastuzumab (data not shown). The primary endpoint in the study was confirmed ORR per BICR. The confirmed ORR was defined as the proportion of subjects with confirmed complete response (CR) or partial response (PR), per RECIST 1.1. Subjects who did not have at least 2 (initial response and confirmation scan) post-baseline response assessments of the protocol were counted as non-responders. The duration of response (DOR) was defined as the time from first documentation of objective response (CR or PR that was subsequently confirmed) to the first documentation of progressive disease (PD) per RECIST 1.1, or to death due to any cause, whichever comes first. The PFS was defined as the time from start of study treatment (Cohort A) or randomization (Cohorts B and C) to first documentation of tumor progression (clinical progression or PD per RECIST 1.1), as determined by BICR assessment, or to death due to any cause, whichever comes first. The OS was defined as the time from start of study treatment (Cohort A) or randomization (Cohorts B and C) to date of death due to any cause.

[0192] The confirmed objective response rate for cohorts A and B of the trial are summarized in the Table, below. Best overall response is based on confirmed overall response assessed per RECIST 1.1. Stable disease includes stable disease and non-CR/non- PD. Not available includes subjects with no post-baseline response assessment and subjects whose disease assessments were not evaluable. The 95% confidence interval is the two-sided 95% exact confidence interval computed using the Clopper-Pearson method. The overall confirmed objective response rate was 38.1% (FIG. 2).

[0193] The confirmed objective response rate in Cohorts A + B across pre-specified subgroups (age less than 65 years, age of at least 65 years, ECOG performance of 0, ECOG performance of 1-2, primary site of disease, and geographic region) are summarized in FIG.

2.

[0194] The confirmed duration of response in Cohorts A + B is summarized in FIG. 3. The median duration of response was 12.4 months.

[0195] The confirmed progression-free survival in Cohorts A + B is summarized in FIG. 4. The median PFS was 8.2 months. [0196] In summary, administration of tucatinib and trastuzumab in this trial showed a 38.1% confirmed objective response rate (cORR) (95% CI: 27.7%, 49.3%) per blinded independent central review. The median duration of response (DoR) per BICR was 12.4 months (95% CI: 8.5, 20.5). The combination of tucatinib and trastuzumab was well- tolerated, and the most common (> 20%) treatment-emergent adverse events were diarrhea (64.0%), fatigue (44.2%), nausea (34.9%), and infusion-related reaction (20.9%), which were primarily low-grade.

Claims

CLAIMS What is claimed is:

1. A method for treating colorectal cancer in a subject comprising administering a combination of tucatinib, or a salt or solvate thereof, and at least one anti-HER2 antibody to the subject.

2. The method of claim 1, wherein administering such treatment results in a confirmed objective response rate that is at least about 30%.

3. The method of claim 2, wherein administering such treatment results in a confirmed objective response rate that is about 30% to about 60%.

4. The method of claim 2 or claim 3, wherein administering such treatment results in a confirmed objective response rate that is about 30% to about 40%.

5. The method of any one of claims 2-4, wherein administering such treatment results in a confirmed objective response rate that is about 35% to about 40%.

6. The method of any one of claims 1-5, wherein administering such treatment results in a median duration of response that is about 10.4 months to about 15 months.

7. The method of claim 6, wherein administering such treatment results in a median duration of response that is about 11 months to about 14 months.

8. The method of claim 6 or claim 7, wherein administering such treatment results in a median duration of response that is about 12 months to about 13 months.

9. The method of any one of claims 6-8, wherein administering such treatment results in a median duration of response that is about 12.4 months.

10. The method of any one of claims 1-9, wherein administering such treatment results in a median progression free survival (PFS) of about 8.1 months to about 10 months.

11. The method of claim 10, wherein administering such treatment results in a median PFS of about 8.1 months to about 9 months.

12. The method of claim 10 or claim 11, wherein administering such treatment results in a median PFS of about 8.2 months.

13. The method of any one of claims 1-12, wherein administering such treatment results in a median overall survival of about 15 months to about 30 months.

14. The method of claim 13, wherein administering such treatment results in a median overall survival of about 20 months to about 28 months.

15. The method of claim 13 or claim 14, wherein administering such treatment results in a median overall survival of about 23 months to about 25 months.

16. The method of any one of claims 13-15, wherein administering such treatment results in a median overall survival of about 24.1 months.

17. The method of any one of claims 1-16, wherein administering such treatment results in complete response in at least 1% of the subjects.

18. The method of any one of claims 1-17, wherein administering such treatment results in complete response in at least 3% of the subjects.

19. The method of any one of claims 1-18, wherein administering such treatment results in complete response in about 3.6% of subjects.

20. The method of any one of claims 1-19, wherein the subject is at least 65 years old.

21. The method of any one of claims 1-20, wherein the cancer is HER2+.

22. The method of any one of claims 1-21, wherein the cancer is metastatic colorectal cancer.

23. The method of any one of claims 1-22, wherein the cancer is wild-type RAS.

24. The method of claim 23, wherein the RAS is determined to be wild-type based on expanded RAS testing.

25. The method of claim 23 or claim 24, wherein the RAS is determined to be wild-type based on expanded RAS testing comprising sequencing of known cancer-associated codons in KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4.

26. The method of any one of claims 1-25, wherein the subject has completed at least one prior line of treatment for the cancer.

27. The method of claim 26, wherein the prior line of treatment for the cancer is selected from the list consisting of systemic therapy with fluoropyrimidines, oxaliplatin, irinotecan, and an anti-vascular endothelial growth factor (VEGF) antibody.

28. The method of claim 26 or claim 27, wherein the at least one prior line of treatment for the cancer comprises an anti-PD-Ll antibody.

29. The method of any one of claims 26-28, wherein the subject has relapsed from standard of care treatment.

30. The method of claim 29, wherein the subject is refractory to standard of care treatment.

31. The method of anyone of claims 1-30, wherein the tucatinib, or salt or solvate thereof, and the at least one anti-HER2 antibody are administered to the subject on a 21 -day treatment cycle.

32. The method of claim 31, wherein the at least one anti-HER2 antibody is administered to the subject on day 1 of the 21 -day treatment cycle.

33. The method of any one of claims 1-32, wherein the at least one anti-HER2 antibody is administered once about every 3 weeks.

34. The method of any one of claims 1-33, wherein the tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 150 mg to about 650 mg.

35. The method of claim 34, wherein the tucatinib, or salt or solvate thereof, is administered to the subject at a dose of about 300 mg.

36. The method of any one of claims 1-35, wherein the tucatinib, or salt or solvate thereof, is administered to the subject orally.

37. The method of any one of claims 1-36, wherein the at least one anti-HER2 antibody is administered to the subject at a dose of about 4 mg/kg to about 10 mg/kg.

38. The method of claim 37, wherein the at least one anti-HER2 antibody is administered to the subject at a dose of about 6 mg/kg of the subject’s body weight.

39. The method of claim 37, wherein the at least one anti-HER2 antibody is administered to the subject at a dose of about 8 mg/kg of the subject’s body weight.

40. The method of claim 37, wherein the at least one anti-HER2 antibody is administered to the subject at a dose of about an initial dose of about 8 mg/kg followed by subsequent doses of about 6 mg/kg.

41. The method of claim 37, wherein the dose of the at least one anti-HER2 antibody administered during the first 21 -day treatment cycle is 8 mg/kg of the subject’s body weight and the dose administered during the subsequent 21 -day treatment cycles is 6 mg/kg of the subject’s body weight.

42. The method of any one of claims 1-41, wherein the at least one anti-HER2 antibody is administered intravenously.

43. The method of any one of claims 1-42, wherein the at least one anti-HER2 antibody comprises one anti-HER2 antibody.

44. The method of any one of claims 1-43, wherein the at least one anti-HER2 antibody is trastuzumab, or a biosimilar thereof.

45. The method of any one of claims 1-44, wherein the at least one anti-HER2 antibody is trastuzumab.

46. The method of any one of claims 1-45, wherein the subject is a human.

47. A kit comprising:

(a) tucatinib, or a salt or solvate thereof;

(b) at least one anti-HER2 antibody; and

(c) instructions for using the kit in the method of any one of claims 1-42.

48. The kit of claim 47, wherein the at least one anti-HER2 antibody comprises trastuzumab.