CN117897158A

CN117897158A - ERK1/2 and SHP2 inhibitor combination therapies

Info

Publication number: CN117897158A
Application number: CN202280057190.3A
Authority: CN
Inventors: 罗伯特·菲尔德·舒梅克; 艾琳·丹尼斯·卢; 林卫; 莱斯利·哈里斯·布雷尔; 莱努斯·马丁; 张京川; 乔安妮·吴
Original assignee: Yirui Shikang Pharmaceutical Research And Development Co
Current assignee: Yirui Shikang Pharmaceutical Research And Development Co
Priority date: 2021-06-24
Filing date: 2022-06-23
Publication date: 2024-04-16

Abstract

The present disclosure relates generally to the use of ERK1/2 inhibitors in combination with SHP2 inhibitors for the treatment of cancer, in particular solid tumors.

Description

ERK1/2 and SHP2 inhibitor combination therapies

Cross reference

The present application claims the benefit of U.S. provisional application Ser. No. 63/214,769, U.S. provisional application Ser. No. 63/277,550, U.S. provisional application Ser. No. 63/280,521, and U.S. provisional application Ser. No. 63/321,615, U.S. provisional application Ser. No. 63/521, and U.S. Ser. No. 3/18, 2022, filed on 24, 2021, 11, and 9, 2021, respectively, both of which are incorporated herein by reference in their entirety.

Background

ERK1 and ERK2 (collectively, "ERK 1/2") are related protein-serine/threonine kinases that are involved in the Ras-Raf-MEK-ERK signal transduction pathway, and the like, sometimes referred to as the mitogen-activated protein kinase (MAPK) pathway. This pathway is thought to play an important role in regulating many basic cellular processes including one or more of cell proliferation, survival, adhesion, cyclical progression, migration, differentiation, metabolism and transcription. Activation of the MAPK pathway has been reported in many tumor types, including lung, colon, pancreas, kidney, and ovary. Thus, substances that can reduce activation may be of interest for possible treatments.

Disclosure of Invention

MEK appears to activate ERK1/2 through phosphorylation of both threonine and tyrosine residues (i.e., at Tyr204/187 and Thr 202/185). Once activated, ERK1/2 catalyzes the phosphorylation of serine/threonine residues of over 100 substrates, and activates both cytoplasmic and nuclear proteins associated with cell growth, proliferation, survival, angiogenesis, and differentiation (all markers of the cancer phenotype). Thus, it may be beneficial to target ERK1 and ERK 2 to develop and use ERK1/2 inhibitors as a way to inhibit tumor growth.

In addition, ERK inhibitors may have utility in combination with other kinase (e.g., MAPK) inhibitors. Recently, researchers have reported that small molecule inhibitors have a synergistic effect on the dual inhibition of MEK and ERK and act to overcome acquired resistance to MEK inhibitors. See Hatzivessiliou et al ERK Inhibition Overcomes Acquired Resistance to MEK Inhibition mol. Cancer Ther.2012,11,1143-1154.

In addition to ERK1/2, SHP2 also acts upstream of the RAS pathway. SHP2 is a protein tyrosine phosphatase and is a key upregulating factor for growth signaling from RTK growth factor receptors to intracellular signaling pathways that promote growth and survival of normal and cancer cells, including RAS/MAPK and PI 3K. Thus, SHP2 is a convergent node of upstream RTK signaling: activated SHP2 up-regulates ("up") the positive signal in the signaling cascade and down-regulates ("down") the negative signal in the signaling cascade. SHP2 also serves as a central node for relaying growth and survival signals from RTKs (such as EGFR and FLT 3) to RAS/MAPK and other intracellular pathways. SHP2 is an attractive target because SHP2 inhibition generally blocks growth signals from multiple RTKs, thereby preventing cancer cells from bypassing the blocking of specific RTKs (e.g., EGFR inhibitors) by activating other RTK growth factor receptors (e.g., MET).

The opportunity to target the signal transduction pathway from multiple angles and potentially improve the feedback loop upstream of Ras through ERK1/2 and SHP2 provides an opportunity to develop methods employing combination therapies.

The present embodiments disclosed herein relate generally to compositions and methods related to combination therapies that utilize an ERK1/2 inhibitor in combination with an SHP2 inhibitor to treat cancer while providing an unexpected degree of synergy.

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof; and

(ii) SHP2 inhibitors.

In some embodiments, the SHP2 inhibitor is sodium antimonate gluconate, RMC-4550, NSC87877, SPI-112, TN0155, IACS-13909, SHP099 HCl, or Compound 2:or a pharmaceutically acceptable salt thereof.

Also disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof; and

(ii) Compound 2:or a pharmaceutically acceptable salt thereof.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Octreotide (osiert inib).

In some embodiments, the octreotide is administered in an amount of about 80 mg/day.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Cetuximab (cetuximab).

In some embodiments, cetuximab is at 500mg/m ² Once every two weeks, 400mg/m ² Once every two weeks or 300mg/m ² Once every two weeks.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) Kang Naifei Ni (encorafenib); and

(iv) Ornitinib.

In some embodiments, kang Naifei Ni is administered in an amount of about 100 mg/day to about 500 mg/day.

In some embodiments, kang Naifei Ni is administered in an amount of about 450 mg/day, 300 mg/day, 225 mg/day, or 150 mg/day.

In some embodiments, the octreotide is administered at about 80 mg/day.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) Kang Naifei Ni; and

(iv) Cetuximab.

In some embodiments, kang Naifei Ni is administered in an amount of about 450 mg/day, about 300 mg/day, about 225 mg/day, or about 150 mg/day.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Geranitinib (gilsteritinib).

In some embodiments, ji Ruiti Ni is administered in an amount of about 120 mg/day.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Sotoracib (sotoraib).

In some embodiments, the sotoracicada is administered in an amount of about 960 mg/day.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Adaglazeb (adagarasib).

In some embodiments, adaglazeb is administered in an amount of about 1200 mg/day.

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Palbociclib (palbociclib).

In some embodiments, palbociclib is administered in an amount from about 50 mg/day to about 500 mg/day.

In some embodiments, palbociclib is administered in an amount of about 75 mg/day, about 100 mg/day, about 125 mg/day, or about 150 mg/day.

In some embodiments, palbociclib is administered in an amount from about 50mg once per week to about 650mg once per week.

In some embodiments, palbociclib is administered in an amount of about 200mg once per week, 300mg once per week, 400mg once per week, 500mg once per week, or 600mg once per week.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg/day to about 500 mg/day.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg/day to about 400 mg/day.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 30 mg/day to about 300 mg/day.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered QD or BID for 2 weeks and discontinued for 1 week (21 day schedule).

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered QD or BID for 3 weeks and discontinued for 1 week (28 day schedule).

In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered as QD or BID for three days per week (D1D 3D5 TIW), e.g., day 1, day 3, and day 5.

In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily/two days a week, e.g., day 1 and day 2 (BID-D1D 2-BIW).

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered once daily (QD) at a dose of 20 mg/day to 60 mg/day, 40 mg/day, or 60 mg/day.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of 20 mg/day to 80 mg/day for continuous dosing.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg/day to 100 mg/day twice daily (BID) for continuous dosing.

In some embodiments, the pharmaceutically acceptable salt of compound 1 is mandelate.

In some embodiments, the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

In some embodiments, the cancer is a BRAF-driven cancer, HRAS-driven cancer, or NRAS-driven cancer.

In some embodiments, the cancer comprises at least one cancer cell driven by deregulated ERK.

In some embodiments, the cancer has at least one mutation in the RAS. In some embodiments, the cancer has at least one mutation in RAF. In some embodiments, the cancer has at least one mutation in MEK.

In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G13D KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q16KKRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation.

In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is pancreatic cancer or PDAC that does not receive MAPKm/MAPKi.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of: increased EGFR gene copy, EGFR gene amplification, chromosome 7 polyhedra, L858R, exon 19 deletion/insertion, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, vvi and Vii), A289D, A289T, A289V, G598A, G598V, T790M and C797S.

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

In some embodiments, the cancer is a liquid tumor.

In some embodiments, the liquid tumor is leukemia.

In some embodiments, the leukemia is Acute Myelogenous Leukemia (AML).

In some embodiments, AML is relapsed and/or refractory AML.

In some embodiments, AML is FLT3 mutant AML.

In some embodiments, the cancer is a solid tumor.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an EGFR mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12C mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12D mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12S mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12V mutant NSCLC. In some embodiments, the NSCLC is KRAS G12A mutant NSCLC. In some embodiments, the NSCLC is a KRAS G13D mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61H mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61K mutant NSCLC. In some embodiments, the NSCLC is an NRAS Q61R mutant NSCLC. In some embodiments, the cancer is NSCLC that does not receive MAPKm/MAPKi. In some embodiments, the cancer is BRAFi treated V600 NSCLC. In some embodiments, the cancer is KRAS treated G12C NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated G12SNSCLC. In some embodiments, the cancer is KRAS treated G12V NSCLC. In some embodiments, the cancer is KRAS treated G13D NSCLC. In some embodiments, the cancer is KRAS treated Q61H NSCLC. In some embodiments, the cancer is KRAS treated Q61K NSCLC. In some embodiments, the cancer is NRAS treated Q61R NSCLC.

In some embodiments, the cancer is pancreatic cancer.

In some embodiments, the cancer is pancreatic cancer that does not receive MAPKm/MAPKi.

In some embodiments, the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC).

In some embodiments, the cancer is melanoma.

In some embodiments, the melanoma has a NF1 loss of function (NF 1-LoF) mutation.

In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer is BRAFi treated V600 melanoma.

In some embodiments, the cancer is a salivary gland tumor.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is a BRAF V600E CRC. In some embodiments, the CRC is a KRAS mutant CRC. In some embodiments, the CRC is a KRAS G12C mutant CRC. In some embodiments, the CRC is a KRAS G12D mutant CRC. In some embodiments, the CRC is a KRAS G12S mutant CRC. In some embodiments, the CRC is a KRAS G12V mutant CRC. In some embodiments, the CRC is a KRAS G13D mutant CRC. In some embodiments, the CRC is a KRAS Q61H mutant CRC. In some embodiments, the CRC is a KRAS Q61K mutant CRC. In some embodiments, the CRC is an NRAS mutant CRC. In some embodiments, the CRC is an NRAS Q61R mutant CRC.

In some embodiments, the cancer is esophageal cancer.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day to about 300 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 25 mg/day to 150 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250 mg/day.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once daily (QD).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered three times per day (TID).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered once a week.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered twice weekly.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, or about 250mg, twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 100mg, about 125mg, or about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 125mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28 day period.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered on days 1, 8, 15, and 22 of a 28 day cycle.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered on day 1, day 8, day 15 of the 28 day cycle.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

In some embodiments, the method further comprises administering an additional MAPK pathway inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor. In some embodiments, the additional MAPK pathway inhibitor is a BRAF inhibitor. In some embodiments, the additional MAPK pathway inhibitor is an EGFR inhibitor. In some embodiments, the additional MAPK pathway inhibitor is CDK4/6.

In some embodiments, the additional MAPK pathway inhibitor is a FLT3 inhibitor. In some embodiments, the additional MAPK pathway inhibitor is adaglabra, afatinib (afatinib), ASTX029, bimetanib (binimeinib), cetuximab, cobimanib (cobimanib), dabrafeninib (dabrafeniib), dactinonib (dacomitinib), kang Naifei, erlotinib (erlotinib), gefitinib (gefitinib), ji Ruiti, lapatinib (lapatinib), LTT462, LY3214996, cetuximab (necitumumab), lenvatinib (nepatinib), nimotuzumab (nimotuzumab), octuzumab, panitumumab (panitunib), semetinib (sumetetinib), sotomitinib, trametinib (trametinib), ulitinib (ulitinib), vantine (vantivantivanb) or vanadm Mo Feini. In some embodiments, the additional MAPK pathway inhibitor is adaglazeb. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is Kang Naifei ni. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is palbociclib (palbociclib). In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is sotorubin.

Incorporation by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features of the disclosure are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings of which:

FIG. 1A shows in vivo data for Compound 1+Compound 2 in the mutant RAS CDX model (NCI-H441).

Fig. 1B shows in vivo data of compound 1+compound 2 in mutant RAS CDX model (NCI-H2009).

Figure 2A shows the in vitro combined benefit of compound 1+ compound 2 in KRAS G12V mutant NSCLC cell line NCI-H441 in a 14 day clonogenic assay.

Figure 2B shows the in vitro combined benefit of compound 1+ compound 2 in KRAS G12D mutant NSCLC cell line Gp2D in a 14 day clonogenic assay.

Figure 3A shows the in vitro combined benefit of compound 1+ compound 2 in KRAS G12D mutant pancreatic cell line Panc 04.03 in a 14 day clonogenic assay.

Figure 3B shows the in vitro combined benefit of compound 1+ compound 2 in KRAS G12D mutant PDAC cell line HPAC in a 14 day clonogenic assay.

Figure 4 shows the in vivo combined benefit of compound 1+ compound 2 in KRAS G12D mutant PDAC PDX model PAN 092.

Figure 5 shows the in vivo combined benefit of compound 1+ compound 2 in KRAS G12D mutant PDAC PDX model PAN 026.

Figure 6 shows the in vivo combined benefit of compound 1+ compound 2 in NF1 LoF mutant melanoma CDX model MeWo.

Figure 7 shows the in vivo combined benefit of compound 1+ compound 2 in KRAS G13D mutant CRC CDX model LoVo.

Figure 8 shows the in vitro combined benefits of compound 1+ compound 2 in KRAS G12V mutant PDAC cell line cap-2 in a 14 day clonogenic assay.

Figure 9 shows the in vitro combined benefit of compound 1+ compound 2 in KRAS G12D mutant PDAC cell line Panc 10.05 in a 14 day clonogenic assay.

Figure 10 shows the in vitro combined benefits of compound 1+ compound 2 in KRAS G12V mutant PDAC cell line Panc 1 in a 14 day clonogenic assay.

Detailed Description

As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties (e.g., molecular weight) or chemical properties (e.g., formula), it is intended to include all combinations and subcombinations of the ranges and specific embodiments therein. When referring to a number or range of values, the term "about" means that the number or range of values referred to is an approximation within experimental variability (or within statistical experimental error), and thus in some cases the number or range of values will vary from 1% to 15% of the number or range of values. The term "comprising" (and related terms such as "having" or "including") is not intended to exclude "consisting of" or "consisting essentially of" any of the other embodiments, e.g., embodiments of any of the compositions of matter, compositions, methods, or processes described herein, etc.

As used in the specification and the appended claims, the following terms have the meanings indicated below, unless otherwise indicated.

As used herein, the term "therapeutic agent" refers to an agent for treating, combating, ameliorating, preventing or ameliorating an undesired condition or disease in a patient. In some embodiments, a therapeutic agent such as compound 1 is involved in the treatment and/or amelioration of cancer.

When used in combination with a therapeutic agent, "administering" refers to the systemic or local administration of the therapeutic agent directly into or onto the target tissue, or to the patient, whereby the therapeutic agent positively affects the tissue to which it is targeted. Thus, as used herein, the term "administering" when used in conjunction with the compositions described herein can include, but is not limited to, providing the composition into or onto a target tissue; the composition is provided systemically to the patient, for example, by oral administration, whereby the therapeutic agent reaches the target tissue or cells. "administration" of the composition may be accomplished by injection, topical administration, and oral administration, or by other methods alone or in combination with other known techniques.

The term "animal" as used herein includes, but is not limited to, human and non-human vertebrates, such as wild, domestic and farm animals. As used herein, the terms "patient," "subject," and "individual" are intended to include living organisms in which certain conditions as described herein may occur. Examples include humans, monkeys, cows, sheep, goats, dogs, cats, mice, rats and transgenic species thereof. In a preferred embodiment, the patient is a primate. In certain embodiments, the primate or subject is a human. In some cases, the person is an adult. In some cases, the person is a child. In other cases, the person is less than 12 years old. In some cases, the person is an elderly person. In other cases, the age of the person is 60 years or older. Other examples of subjects include laboratory animals such as mice, rats, dogs, cats, goats, sheep, pigs, and cattle. The experimental animal may be an animal model of a disorder, such as a transgenic mouse with hypertensive pathology.

By "pharmaceutically acceptable" is meant that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The term "pharmaceutical composition" shall mean a composition comprising at least one active ingredient, whereby the composition is suitable for studying specific effective results in mammals (e.g. but not limited to humans). Those of ordinary skill in the art will understand and appreciate techniques suitable for determining whether an active ingredient has a desired effective result based on the needs of the skilled artisan.

As used herein, "therapeutically effective amount" or "effective amount" refers to the amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, subject, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) prevention of disease; for example, preventing a disease, condition, or disorder in an individual who may be susceptible to the disease, condition, or disorder but who has not yet experienced or displayed the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., arresting further development of the pathology and/or symptom), and (3) ameliorating the disease; for example, a disease, condition, or disorder (i.e., reversing pathology and/or symptoms) is ameliorated in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder.

The term "treatment" as used herein refers in some embodiments to therapeutic treatment, and in other embodiments to prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain a beneficial or desired clinical result. For purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; reducing the extent of a condition, disorder or disease; stabilization (i.e., not worsening) of the condition, disorder or disease state; delay onset of or slow progression of the condition, disorder or disease; improving a condition, disorder or disease state; and either detectable or undetectable remission (whether partial or complete) of a condition, disorder or disease, or enhancement or amelioration of a condition, disorder or disease. Treatment involves eliciting a clinically significant response without undue levels of side effects. Treatment also includes prolonging survival compared to the expected survival without treatment. The prophylactic benefit of treatment includes preventing the condition, slowing the progression of the condition, stabilizing the condition, or reducing the likelihood of the condition developing. As used herein, in some embodiments, "treating" includes prophylaxis.

The term "substantially identical" as used herein means that the powder X-ray diffraction pattern or differential scanning calorimetry pattern is different from those depicted herein, but falls within the limits of experimental error when considered by one of ordinary skill in the art.

Compound 1

Disclosed herein are (S) -N- (2-amino-1- (3-chloro-5-fluorophenyl) ethyl) -1- (5-methyl-2- ((tetrahydro-2H-pyran-4-yl) amino) pyrimidin-4-yl) -1H-imidazole-4-carboxamide:or a pharmaceutically acceptable salt thereof.

In some embodiments, the salt of compound 1 is a mandelate salt. In some embodiments, the salt of compound 1 is a benzenesulfonate salt. In some embodiments, the salt of compound 1 is the hydrochloride salt. In some embodiments, the salt of compound 1 is p-toluenesulfonate.

In some embodiments, the salt of compound 1 is a benzenesulfonate salt.

SHP2 inhibitors

SHP2 plays an important role in basic cellular functions including proliferation, differentiation, cell cycle maintenance and motility, and regulates a variety of intracellular signaling pathways in response to a wide range of growth factors, cytokines and hormones. The cellular signaling processes involved in SHP2 include MAPK, PI3K and JAK pathways. SHP2 inhibitors have the potential to attenuate upstream RTK signaling (which generally globally drives oncogenic signaling and adaptive tumor escape) and become broad-spectrum anticancer agents.

In some embodiments, the SHP2 inhibitor is sodium antimonate gluconate, RMC-4550, NSC87877, SPI-112, TNO155, IACS-13909, GDC01971, or SHP099HCl.

In some embodiments, the SHP2 inhibitor is compound 2.

Compound 2

Disclosed herein are (3- ((3S, 4S) -4-amino-3-methyl-2-oxa-8-azaspiro [ 4.5)]Dec-8-yl) -6- (((6 aS, 8S) -8- ((methoxymethoxy) methyl) -6a,7,8, 9-tetrahydro-6H-pyrido [3, 2-b)]Pyrrolo [1,2-d][1,4]Oxazin-4-yl) thio) pyrazin-2-yl) methanol:or a pharmaceutically acceptable salt thereof.

EGFR inhibitors

EGFR inhibitors are agents that bind to EGFR and slow or stop cell growth, and can be classified as Tyrosine Kinase Inhibitors (TKIs) or monoclonal antibodies.

TKIs are inhibitors that bind to tyrosine kinase domains in the epidermal growth factor receptor and stop EGFR activity. Examples include, but are not limited to, afatinib, dactinib, erlotinib, gefitinib, lapatinib, lanetinib (lazertinib), lififenib (lifarafenib), mo Bo tinib (mobocertinib), nazatinib (nazartinib), lenatinib, octtinib, and vandetanib.

Monoclonal antibody inhibitors are agents that bind to the extracellular component of EGFR and prevent binding of epidermal growth factor to its own receptor, thereby preventing cell division. Examples include, but are not limited to, anti-angstrom Mo Tuoshan, cetuximab, clozotocet, nituzumab, and cetuximab.

In some embodiments, the EGFR inhibitor is afatinib, el Mo Tuo mab (amivantmaab), canetinib (canertinib), cetuximab, dactyltinib, daphnetin (daphnetin), erlotinib, gefitinib, icotinib (icotinib), lapatinib, lasatinib, lifenifenib, crizotinib (mirzotamab clezutoclax), mo Bo tinib, natatinib, cetuximab, lenatinib, octreotide, panitumumab (panitumab), pelitinib, wave Ji Tini (poziotinib), tivozanib, luo Xiti (rociletinib), sapitinib (sapitinib), vande or valatinib (vaitinib).

In some embodiments, the EGFR inhibitor is AC480, AEE788, AG-1478, AG-18, AG-490, AST-1306, AV-412, AZ5104, AZD3759, BIBX 1382, CGP-52411, CL-387785, CNX-2006, CUDC-101, OSI-420, PD153035HC1, PD168393, TAK-285, tyrosine phosphorylation inhibitor (Tyrphostin) 9, tyrosine phosphorylation inhibitor AG 183, WHI-P154, WHI-P180, WZ3146, or WZ4002.

In some embodiments, the EGFR inhibitor is a small molecule inhibitor. In some embodiments, the EGFR inhibitor is octreotide. In some embodiments, the EGFR inhibitor is cetuximab. In some embodiments, the EGFR inhibitor is afatinib. In some embodiments, the EGFR inhibitor is dactinib.

In some embodiments, the EGFR inhibitor is erlotinib. In some embodiments, the EGFR inhibitor is gefitinib. In some embodiments, the EGFR inhibitor is lapatinib. In some embodiments, the EGFR inhibitor is lanitinib. In some embodiments, the EGFR inhibitor is lififensil. In some embodiments, the EGFR inhibitor is Mo Bo tinib. In some embodiments, the EGFR inhibitor is azatinib. In some embodiments, the EGFR inhibitor is lenatinib. In some embodiments, the EGFR inhibitor is vandetanib.

In some embodiments, the EGFR inhibitor is not an anti-EGFR antibody inhibitor.

Oritinib

OritinibAre small molecule EGFR tyrosine kinase inhibitors and are useful in the treatment of locally advanced or metastatic NSCLC. It was approved by the FDA at 11 months 2015 for specific treatment of metastatic NSCLC with EGFR exon 19 deletion or exon 21L858R mutation and EGFR T790M mutation positive NSCLC. Ornitinib is described by AstraZeneca as +.>And (5) selling.

Cetuximab

Cetuximab is a chimeric monoclonal antibody EGFR inhibitor for use in the treatment of metastatic CRC and head and neck cancer. Cetuximab was FDA approved for the treatment of colon cancer with wild-type KRAS in month 7 of 2009. Cetuximab is taken as Eli Lilly and Company And (5) selling.

BRAF inhibitors

BRAF inhibitors selectively target BRAF kinase, thereby interfering with MAPK signaling pathways that regulate melanoma cell proliferation and survival. BRAF inhibitors also have beneficial effects on the tumor microenvironment and anti-tumor immune response in BRAF mutant melanoma, thereby exerting an immunomodulatory effect on the MAPK pathway and promoting recognition of tumor cells by the immune system and enhancing anti-tumor T cell responses.

In some embodiments, the BRAF inhibitor is Kang Naifei ni.

In some embodiments, the BRAF inhibitor is dabrafenib.

Kang Naifei Ni

Kang Naifei NiIs a medicine for treating some melanoma. It is a small molecule BRAF inhibitor targeting a key enzyme in the MAPK signaling pathway. This pathway occurs in many different cancers, including melanoma and colorectal cancer. At month 6 of 2018, the FDA approved it for use in combination with bimatinib in treating patients with unresectable or metastatic BRAF V600E or V600K mutation positive melanoma. Kang Naifei Nile is taken as PfizerAnd (5) selling.

Darafenib

DarafenibIs a medicament for treating cancer associated with a mutated form of the gene BRAF. Darafenib acts as an inhibitor of the related enzyme B-Raf, which plays a role in regulating cell growth. Dabrafenib has clinical activity with a manageable safety profile in phase 1 and phase 2 clinical trials in patients with BRAF (V600) mutated metastatic melanoma. Darafenib is expressed by Novartis as +. >And (5) selling.

CDK4/6 inhibitors

CDK4/6 inhibitors at G ₁ To the S cell cycle checkpoint, which is tightly controlled by D-type cyclin CDK4 and CDK6, functions. When CDK4 and CDK6 are activated by D-cyclin they phosphorylate retinoblastoma-related proteins (pRb), which release pRb's inhibition of the E2F transcription factor family and allow the cell to undergo a cell cycle. In hr+ cancers, cyclin D overexpression is common, and loss of pRb is rare, such that G ₁ Checkpoints to S are ideal therapeutic agents.

In some embodiments, the CDK4/6 inhibitor is palbociclib, rebabociclib, abbe cilib, FCN-437c, or A Fu Xini (alvociclib).

In some embodiments, the CDK4/6 inhibitor is palbociclib.

Parbosini (Pabosini)

Parbosini (Pabosini)Is a kinase inhibitor for the treatment of hr+/HER 2-advanced or metastatic breast cancer. Pabociclib was expressed as +.>And (5) selling.

FLT3 inhibitors

FLT3 inhibitors are tyrosine kinase inhibitors that compete for ATP binding sites in the kinase active domain, thereby preventing phosphorylation of proteins and reducing the activity of proteins.

The type I inhibitor binds to the ATP binding site when the receptor is active, while the type II inhibitor interacts with a hydrophobic region immediately adjacent to the ATP binding site, which is accessible when the receptor is in its inactive configuration. Type I inhibitors include sunitinib, letatinib, midostaurin, clavulanin, crinolanib and giritinib, while type II inhibitors include sorafenib, quezatinib and ponatinib.

In some embodiments, the FLT3 inhibitor is clarithromycin, ji Ruiti, ibrutinib, rituximab, midostaurin, ponatinib, quinizarinib, sorafenib, sunitinib, or tandutinib (tandutinib). In some embodiments, the FLT3 inhibitor is clarithromycin. In some embodiments, the FLT3 inhibitor is gefitinib. Gerittinib is known by the trade name Astellas Pharma US, incAnd (5) selling. In some embodiments, the FLT3 inhibitor is ibrutinib. In some embodiments, the FLT3 inhibitor is rituximab. In some embodiments, the FLT3 inhibitor is midostaurin. In some embodiments, the FLT3 inhibitor is ponatinib. In some embodiments, the FLT3 inhibitor is quinacrine. In some embodiments, the FLT3 inhibitor is sorafenib. In some embodiments, the FLT3 inhibitor is sunitinib. In some embodiments, the FLT3 inhibitor is tandutinib. In some embodiments, the FLT3 inhibitor is ibrutinib, ponatinib, quezatinib, cladribine, or gefitinib. In some embodiments, the FLT3 inhibitor is sorafenib, rituximab, midostaurin, sunitinib, or tanditinib. In some embodiments, a combination of two or more FLT3 inhibitors listed above may be used in combination, for example, a type I FLT3 inhibitor in combination with a type II FLT3 inhibitor. For example, gefitinib may be combined with quezatinib.

KRAS G12C inhibitors

KRAS is a key regulator of signaling pathways responsible for cell proliferation, differentiation and survival. KRAS is the most frequently mutated oncogene in human cancers, and mutations in KRAS can lead to sustained cell proliferation and cancer progression. The G12C mutation is a single point mutation with a glycine to cysteine substitution at codon 12. This substitution favors the activation state of KRAS, amplifying the signaling pathways leading to tumorigenesis.

Soto-la sibutra

Soto-la sibutraIn trade name->And->The next market, marketed by Amgen, is an anticancer drug for the treatment of non-small cell lung cancer (NSCLC). It targets a specific mutation G12C in the protein K-Ras encoded by the gene KRAS, which triggers various forms of cancer. Sotorubin is an inhibitor of the RAS gtpase family.

Sotoprazole is the first approved targeted therapy for tumors with any KRAS mutation that accounts for about 25% of mutations in non-small cell lung cancer. KRAS G12C mutations occur in about 13% of non-small cell lung cancer patients.

At month 5 of 2021, the FDA approved sotoracicb for the treatment of KRAS G12C mutated NSCLC.

Combination of two or more kinds of materials

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1: Or a pharmaceutically acceptable salt thereof; and

(ii) SHP2 inhibitors.

In some embodiments, the SHP2 inhibitor is compound 2:or a pharmaceutically acceptable salt thereof.

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1:or a pharmaceutically acceptable salt thereof; and

(ii) Compound 2:or a pharmaceutically acceptable salt thereof.

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) EGFR inhibitors.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Ornitinib;

(iii) EGFR inhibitors.

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1: Or a pharmaceutically acceptable salt thereof;

(ii) Compounds of formula (I)2：Or a pharmaceutically acceptable salt thereof; and

(iii) Cetuximab.

Disclosed herein is a method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1:or a pharmaceutically acceptable salt thereof; />

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) BRAF inhibitors; and

(iv) EGFR inhibitors.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) Kang Naifei Ni; and

(iv) Ornitinib.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) Kang Naifei Ni; and

(iv) Cetuximab.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) FLT3 inhibitors.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and->

(iii) Geranitinib.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) KRAS G12C inhibitors.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Sotoracicb.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Adaglazeb.

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) CDK4/6 inhibitors.

Disclosed herein is aA method of treating cancer in a subject in need thereof, the method comprising: administering to a subject in need thereof a therapeutically effective amount of (i) compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Palbociclib.

Further combination of

In some embodiments, the method comprises administering an additional MAPK pathway inhibitor. Without being bound by theory, inhibition of MAPK signaling in cancer cells may lead to down-regulation of PD-L1 expression and increase the likelihood that cancer cells will be detected by the immune system. Such a third MAPK pathway inhibitor may be based on other mutations in the protein in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits a protein in the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor inhibits a protein other than the MAPK pathway. In some embodiments, the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor. Exemplary MAPK pathway inhibitors include, but are not limited to, adaglazeb, afatinib, ASTX029, bimatinib, cetuximab, cobratinib, dabrafenib, dactyltinib, kang Naifei, erlotinib, gefitinib, ji Ruiti, lapatinib, LTT462, LY3214996, rituximab, lenatinib, nimodib, octreotide, panitumumab, sematinib, sotoldine, trim, ulitinib, vandetanib, and vitamin Mo Feini.

In some embodiments, the additional MAPK pathway inhibitor is adaglazeb. In some embodiments, the additional MAPK pathway inhibitor is afatinib. In some embodiments, the additional MAPK pathway EPO inhibitor is bimetanib. In some embodiments, the additional MAPK pathway inhibitor is cetuximab. In some embodiments, the additional MAPK pathway inhibitor is cobicitinib. In some embodiments, the additional MAPK pathway inhibitor is dabrafenib. In some embodiments, the additional MAPK pathway inhibitor is dactinib. In some embodiments, the additional MAPK pathway inhibitor is Kang Naifei ni. In some embodiments, the additional MAPK pathway inhibitor is erlotinib. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is gefitinib. In some embodiments, the additional MAPK pathway inhibitor is lapatinib. In some embodiments, the additional MAPK pathway inhibitor is LTT462. In some embodiments, the additional MAPK pathway inhibitor is LY3214996. In some embodiments, the additional MAPK pathway inhibitor is rituximab. In some embodiments, the additional MAPK pathway inhibitor is lenatinib. In some embodiments, the additional MAPK pathway inhibitor is nituzumab. In some embodiments, the additional MAPK pathway inhibitor is octreotide. In some embodiments, the additional MAPK pathway inhibitor is palbociclib. In some embodiments, the additional MAPK pathway inhibitor is panitumumab. In some embodiments, the additional MAPK pathway inhibitor is semantenib. In some embodiments, the additional MAPK pathway inhibitor is sotorubin. In some embodiments, the additional MAPK pathway inhibitor is trametinib. In some embodiments, the additional MAPK pathway inhibitor is ulitinib. In some embodiments, the additional MAPK pathway inhibitor is vandetanib.

Cancer of the human body

Disclosed herein are methods of treating cancer using the combinations disclosed herein.

"cancer" refers to all types of cancers, neoplasms, or malignant tumors found in mammals (e.g., humans), including, but not limited to, leukemia, lymphoma, myeloma, carcinoma, and sarcoma. Exemplary cancers that may be treated with the compounds or methods provided herein include brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer (such as pancreatic adenocarcinoma, PDAC), medulloblastoma, melanoma, cervical cancer, gastric cancer, ovarian cancer, lung cancer, head cancer, hodgkin's disease, and non-hodgkin's lymphoma. Exemplary cancers that may be treated with the compounds or methods provided herein include blood cancer, thyroid cancer, cancer of the endocrine system, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, ovarian cancer, pancreatic cancer, rectal cancer, stomach cancer, and uterine cancer. Further examples include thyroid cancer, cholangiocarcinoma, pancreatic adenocarcinoma, skin melanoma, colon adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, breast invasive carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, non-small cell lung cancer, mesothelioma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocythemia, primary macroglobulinemia, primary brain tumor, malignant insulinoma (malignant pancreatic insulanoma), malignant carcinoid, bladder cancer, premalignant skin lesions, testicular cancer, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical carcinoma, endocrine or exocrine pancreatic tumor, medullary thyroid cancer (medullary thyroid cancer), medullary thyroid cancer (medullary thyroid carcinoma), melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma or prostate cancer.

In some embodiments, the cancer has a class 1B-Raf mutation.

In some embodiments, the cancer has at least one of EGFR, KRAS, BRAF (e.g., BRAF class III) and/or NF1 (e.g., loss of function) mutation.

In some embodiments, the mutant B-Raf comprises a V600 mutation. In some embodiments, the mutant of B-Raf comprises the mutation V600E. In some embodiments, the mutation is V600K. In some embodiments, the mutation is V600D. In some embodiments, the mutation is V600L. In some embodiments, the mutation is V600R. In some embodiments, the cancer is a BRAF V600E or V600K mutant tumor.

In some embodiments, the cancer has a G12C KRAS mutation. In some embodiments, the cancer has a G12D KRAS mutation. In some embodiments, the cancer has a G12R KRAS mutation. In some embodiments, the cancer has a G12S KRAS mutation. In some embodiments, the cancer has a G12V KRAS mutation. In some embodiments, the cancer has a G12W KRAS mutation. In some embodiments, the cancer has a G13DKRAS mutation. In some embodiments, the cancer has an H95D KRAS mutation. In some embodiments, the cancer has an H95Q KRAS mutation. In some embodiments, the cancer has an H95R KRAS mutation. In some embodiments, the cancer has a Q16H KRAS mutation. In some embodiments, the cancer has a Q61H KRAS mutation. In some embodiments, the cancer has a Q16K KRAS mutation. In some embodiments, the cancer has a Q61R NRAS mutation. In some embodiments, the cancer has an R68S KRAS mutation.

In some embodiments, the cancer is pancreatic cancer that does not receive MAPKm/MAPKi. In some embodiments, the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC).

In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of: increased EGFR gene copy, EGFR gene amplification, chromosome 7 multimerity, L858R, exon 19 deletion/insertion, L718Q, L861 719S, G724S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, vvi and Vii), A289D, A289T, A289V, G598 458 598V, T790M, S768 6279X and C797S. In some embodiments, the cancer comprises one or more EGFR mutations selected from the group consisting of L858R, exon 19 deletion, and T790M.

In some embodiments, the cancer is a liquid tumor. In some embodiments, the cancer that is a liquid tumor is leukemia. In some embodiments, the cancer that is leukemia is Acute Myelogenous Leukemia (AML). In some embodiments, the cancer that is AML is relapsed and/or refractory AML. In some embodiments, the cancer that is AML is FLT3 mutant AML.

In some embodiments, the cancer is a solid tumor. In some embodiments, the solid tumor is an advanced or metastatic solid tumor.

In some embodiments, the cancer is colorectal cancer (CRC), pancreatic Ductal Adenocarcinoma (PDAC), cholangiocarcinoma, appendiceal carcinoma, gastric cancer, esophageal cancer, non-small cell lung cancer (NSCLC), head and neck cancer, ovarian cancer, uterine cancer, acute Myelogenous Leukemia (AML), or melanoma.

In some embodiments, the cancer is gastrointestinal cancer. In some embodiments, the gastrointestinal cancer is anal cancer, cholangiocarcinoma, colon cancer, rectal cancer, esophageal cancer, gallbladder cancer, liver cancer, pancreatic cancer, small intestine cancer, or stomach cancer.

In some embodiments, the cancer is non-small cell lung cancer (NSCLC). In some embodiments, the NSCLC is an EGFR mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12C mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12D mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12S mutant NSCLC. In some embodiments, the NSCLC is a KRAS G12V mutant NSCLC. In some embodiments, the NSCLC is a KRAS G13D mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61H mutant NSCLC. In some embodiments, the NSCLC is a KRAS Q61K mutant NSCLC. In some embodiments, the EGFR mutation is an acquired EGFR mutation. In some embodiments, the acquired EGFR mutation is C797X. In some embodiments, the acquired EGFR mutation is L718Q. In some embodiments, the acquired EGFR mutation is EGFR gene amplification. In some embodiments, the acquired EGFR mutation is G724S. In some embodiments, the acquired EGFR mutation is S768I.

In some embodiments, the NSCLC is an NRAS Q61R mutant NSCLC. In some embodiments, the cancer is NSCLC that does not receive MAPKm/MAPKi. In some embodiments, the cancer is BRAFi treated V600 NSCLC. In some embodiments, the cancer is KRAS treated G12C NSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated G12S NSCLC. In some embodiments, the cancer is KRAS treated G12V NSCLC. In some embodiments, the cancer is KRAS treated G13DNSCLC. In some embodiments, the cancer is KRAS treated Q61H NSCLC. In some embodiments, the cancer is KRAS treated Q61K NSCLC. In some embodiments, the cancer is NRAS treated Q61R NSCLC. In some embodiments, the cancer is KRAS treated G12R NSCLC. In some embodiments, the cancer is KRAS treated G12W NSCLC. In some embodiments, the cancer is KRAS treated H95D NSCLC. In some embodiments, the cancer is KRAS treated H95Q NSCLC. In some embodiments, the cancer is KRAS treated H95RNSCLC. In some embodiments, the cancer is KRAS treated G12D NSCLC. In some embodiments, the cancer is KRAS treated R68S NSCLC.

In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is pancreatic cancer that does not receive MAPKm/MAPKi. In some embodiments, the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC).

In some embodiments, the cancer is melanoma. In some embodiments, the melanoma is a BRAF V600E or V600K mutant tumor. In some embodiments, the cancer is BRAFi treated V600 melanoma.

In some embodiments, the cancer is a salivary gland tumor.

In some embodiments, the cancer is thyroid cancer.

In some embodiments, the cancer is colorectal cancer (CRC). In some embodiments, the CRC is a BRAF V600E CRC. In some embodiments, the CRC is a KRAS mutant CRC.

In some embodiments, the CRC is a KRAS G12C mutant CRC. In some embodiments, the CRC is a KRAS G12D mutant CRC. In some embodiments, the CRC is a KRAS G12R mutant CRC. In some embodiments, the CRC is a KRAS G12S mutant CRC. In some embodiments, the CRC is a KRAS G12V mutant CRC. In some embodiments, the CRC is a KRAS G12W mutant CRC. In some embodiments, the CRC is a KRAS G13D mutant CRC. In some embodiments, the CRC has an H95D KRAS mutation. In some embodiments, the CRC has an H95QKRAS mutation. In some embodiments, the CRC has an H95R KRAS mutation. In some embodiments, the CRC is a KRAS Q61H mutant CRC. In some embodiments, the CRC is a KRAS Q61K mutant CRC. In some embodiments, the CRC is an NRAS mutant CRC. In some embodiments, the CRC is an NRAS Q61R mutant CRC. In some embodiments, the CRC has an R68S KRAS mutation.

In some embodiments, the cancer is esophageal cancer.

In some embodiments, the cancer has one or more acquired mutations. In some embodiments, the acquired mutation results from first line therapy. In some embodiments, the first line treatment is an EGFR inhibitor. In some embodiments, the EGFR inhibitor is octreotide. In some embodiments, the first line treatment is a KRAS inhibitor. In some embodiments, the KRAS inhibitor is a KRAS G12C inhibitor. In some embodiments, the KRAS G12C inhibitor is adaglazeb. In some embodiments, the KRAS G12C inhibitor is sotorubin. In some embodiments, the cancer is a solid tumor cancer. In some embodiments, the cancer is NSCLC.

In some embodiments, the acquired mutation is an acquired EGFR mutation. In some embodiments, the acquired EGFR mutation is C797X. In some embodiments, the acquired EGFR mutation is L718Q. In some embodiments, the acquired EGFR mutation is EGFR amplification. In some embodiments, the acquired EGFR mutation is G724S. In some embodiments, the acquired mutation is S768I.

In some embodiments, the acquired mutation is an acquired amplification mutation. In some embodiments, the acquired mutation is MET gene amplification. In some embodiments, the acquired mutation is HER2 gene amplification.

In some embodiments, the acquired mutation is an acquired oncogenic fusion. In some embodiments, the acquired oncogenic fusion is SPTBN1-ALK. In some embodiments, the acquired oncogenic fusion is a RET fusion. In some embodiments, the acquired oncogenic fusion is a BRAF fusion.

In some embodiments, the acquired mutation is an acquired MAPK-PI3K mutation. In some embodiments, the acquired MAPK-PI3K mutation is BRAF-V600E. In some embodiments, the acquired MAPK-PI3K mutation is PI3KCA. In some embodiments, the acquired MAPK-PI3K mutation is KRAS. In some embodiments, the acquired MAPK-PI3K mutation is HER2.

In some embodiments, the acquired mutation is an acquired KRAS mutation. In some embodiments, the acquired mutation is KRAS G12C. In some embodiments, the acquired mutation is KRAS G12D. In some embodiments, the acquired mutation is KRAS G12R. In some embodiments, the acquired mutation is KRAS G12V. In some embodiments, the acquired mutation is KRAS G12W. In some embodiments, the acquired mutation is KRAS G13D. In some embodiments, the acquired mutation is KRAS H95D. In some embodiments, the acquired mutation is KRAS H95D. In some embodiments, the acquired mutation is KRAS H95Q. In some embodiments, the acquired mutation is KRAS H95R. In some embodiments, the acquired mutation is KRAS Q61H. In some embodiments, the acquired mutation is KRAS R68S.

In some embodiments, the acquired mutation is an acquired MAPK pathway mutation. In some embodiments, the acquired MAPK pathway mutation is MAP2K 1K 57N. In some embodiments, the acquired MAPK pathway mutation is MAP2K 1K 57T. In some embodiments, the acquired MAPK pathway mutation is CCDC6-RET. In some embodiments, the acquired MAPK pathway mutation is rib 128L. In some embodiments, the acquired MAPK pathway mutation is PTEN G209V. In some embodiments, the acquired MAPK pathway mutation is BRAF V600E. In some embodiments, the acquired MAPK pathway mutation is MAP2K1 199_k104del. In some embodiments, the acquired MAPK pathway mutation is MAP2K 1K 57N. In some embodiments, the acquired MAPK pathway mutation is EML4-ALK. In some embodiments, the acquired MAPK pathway mutation is EGFR a289A. In some embodiments, the acquired MAPK pathway mutation is FGFR3-TACC3. In some embodiments, the acquired MAPK pathway mutation is AKAP9-BRAF. In some embodiments, the acquired MAPK pathway mutation is RAF1-CCDC176. In some embodiments, the acquired MAPK pathway mutation is RAF1-TRAK1. In some embodiments, the acquired MAPK pathway mutation is NRAS Q61K. In some embodiments, the acquired MAPK pathway mutation is MAP2 k1e102_1103 DEL. In some embodiments, the acquired MAPK pathway mutation is NRF1-BRAF.

In some embodiments, the acquired mutation is a KRAS G12C reactivation mutation. In some embodiments, the KRAS G12C reactivation mutation is RKRAS G12C gene amplification. In some embodiments, the KRAS G12C reactivation mutation is NF 1R 22637 (LoF).

In some embodiments, the acquired mutation is a non-G12C activating KRAS mutation. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12D. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12R. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12V. In some embodiments, the non-G12C activating KRAS mutation is KRAS G12W. In some embodiments, the non-G12C activating KRAS mutation is KRAS G13D. In some embodiments, the non-G12C activating KRAS mutation is KRAS Q61H. In some embodiments, the non-G12C activating KRAS mutation is KRAS Q61K.

In some embodiments, the acquired mutation is a sterically hindered KRAS G12C mutation. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS R68S. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS H95D. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS H95Q. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS H95R. In some embodiments, the sterically hindered KRAS G12C mutation is KRAS Y96C.

In some embodiments, the acquired mutation is an RTK activating mutation. In some embodiments, the RTK activating mutation is EGFR a289V. In some embodiments, the RTK activating mutation is RET M918T. In some embodiments, the RTK activating mutation is MET gene amplification. In some embodiments, the RTK activating mutation is EML-ALK. In some embodiments, the RTK activating mutation is CCDC6-RET. In some embodiments, the RTK activating mutation is FGFR3-TACC3.

In some embodiments, the acquired mutation is a downstream RAS/MAPK activation mutation. In some embodiments, the downstream RAS/MAPK activation mutation is BRAF V600E. In some embodiments, the downstream RAS/MAPK activation mutation is MAP2K I99_k104del. In some embodiments, the downstream RAS/MAPK activation mutation is MAP2k1i99_k104del. In some embodiments, the downstream RAS/MAPK activation mutation is MAP2 k1e102_i103del. In some embodiments, the downstream RAS/MAPK activation mutation is a RAF fusion.

In some embodiments, the acquired mutation is a parallel pathway activation mutation. In some embodiments, the parallel pathway activation mutation is PIK3CA H1047R. In some embodiments, the parallel pathway activation mutation is PIK3R 1S 361fs. In some embodiments, the parallel pathway activation mutation is PTEN N48K. In some embodiments, the parallel pathway activation mutation is PTEN G209V. In some embodiments, the parallel pathway activation mutation is RIT1P128L.

Administration of drugs

In one aspect, the compositions described herein are used to treat diseases and conditions described herein. Furthermore, a method for treating any disease or condition described herein in a subject in need of such treatment comprises administering to the subject a therapeutically effective amount of the composition.

The dosage of the compositions described herein may be determined by any suitable method. The Maximum Tolerated Dose (MTD) and the Maximum Response Dose (MRD) of compound 1 or a pharmaceutically acceptable salt thereof can be determined by established animal and human protocols and examples described herein. For example, toxicity and therapeutic efficacy of compound 1 or a pharmaceutically acceptable salt thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals including, but not limited to, for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio between LD50 and ED50. The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds is preferably within a circulating concentration range, including the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration employed. Additional relative doses expressed as a percentage of the maximum response or maximum tolerated dose are readily obtained via the protocol.

In some embodiments, the amount of a given formulation comprising compound 1 or a pharmaceutically acceptable salt thereof corresponding to such amount varies depending on factors such as the molecular weight of the particular salt or form, the disease condition and severity thereof, the identity (e.g., age, weight, sex) of the subject or host in need of treatment, and the like, but may be determined according to the particular circumstances surrounding the case, including, for example, the particular agent administered, the type of liquid formulation, the condition being treated, and the subject or host being treated.

In some embodiments, the amount of compound 1, or a pharmaceutically acceptable salt thereof, as described herein is relative to the free base equivalent of compound 1.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 100mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 50mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 100mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 150mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 175mg to about 200mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 225mg to about 300mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 225mg to about 250mg twice daily, one day per week (BID-QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 300mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 50mg to about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 300mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg to about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 300mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg to about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 100mg, once per week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 150mg, once per week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200mg, once per week (QW). In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250mg, once per week (QW).

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250mg, once a day, one day a week.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 30mg, 40mg, 50mg, about 60mg, about 70mg, about 75mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 175mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 225mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, or about 300 mg.

In some embodiments, each of the above amounts may be administered as QD, QW, BID, BID-QD or BID-QW.

In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day, about 275 mg/day, about 300 mg/day, about 325 mg/day, about 350 mg/day, or about 400 mg/day.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered QD or BID for 2 weeks and discontinued for 1 week (21 day schedule). In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered QD or BID for 3 weeks and discontinued for 1 week (28 day schedule). In some embodiments, compound 2 or a pharmaceutically acceptable salt thereof is administered as QD or BID three days a week (D1D 3D5 TIW), e.g., day 1, day 3, and day 5. In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily/two days per week, e.g., day 1 and day 2 (BID-D1D 2-BIW).

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered once daily (QD) at a dose of 20 mg/day to 60 mg/day, 40 mg/day, or 60 mg/day. In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID) at a dose of 20 mg/day to 80 mg/day for continuous dosing. In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered at a dose of 10 mg/day to 100 mg/day twice daily (BID) for continuous dosing.

In some embodiments, the octreotide is administered in an amount of about 50 mg/day to about 300 mg/day. In some embodiments, the octreotide is administered in an amount of about 20 mg/day. In some embodiments, the octreotide is administered in an amount of about 40 mg/day. In some embodiments, the octreotide is administered in an amount of about 60 mg/day. In some embodiments, the octreotide is administered in an amount of about 80 mg/day. In some embodiments, the octreotide is administered in an amount of about 100 mg/day. In some embodiments, the octreotide is administered in an amount of about 120 mg/day. In some embodiments, the octreotide is administered in an amount of about 140 mg/day.

In some embodiments, cetuximab is administered at 400mg/m once a week ² Administration was for 120 minutes followed by 250mg/m ² Applied over a period of 60 minutes. In some embodiments, cetuximab is administered at 500mg/m once every two weeks ² And (3) application. In some embodiments, cetuximab is administered at 400mg/m once every two weeks ² And (3) application. In some embodiments, cetuximab is administered at 300mg/m once every two weeks ² And (3) application.

In some embodiments, kang Naifei Ni is administered in an amount of about 100 mg/day to about 500 mg/day. In some embodiments, kang Naifei Ni is administered in an amount of about 450 mg/day. In some embodiments, kang Naifei Ni is administered in an amount of about 300 mg/day. In some embodiments, kang Naifei Ni is administered in an amount of about 225 mg/day. In some embodiments, kang Naifei Ni is administered in an amount of about 150 mg/day.

In some embodiments, dabrafenib is administered in an amount of from about 100 mg/day to about 500 mg/day. In some embodiments, dabrafenib is administered in an amount of about 450 mg/day. In some embodiments, dabrafenib is administered in an amount of about 300 mg/day. In some embodiments, dabrafenib is administered in an amount of about 225 mg/day. In some embodiments, dabrafenib is administered in an amount of about 150 mg/day. In some embodiments, dabrafenib is administered in an amount of about 100 mg/day.

In some embodiments, ji Ruiti Ni is administered in an amount of about 100 mg/day to about 500 mg/day. In some embodiments, ji Ruiti Ni is administered in an amount of about 450 mg/day. In some embodiments, ji Ruiti Ni is administered in an amount of about 300 mg/day. In some embodiments, ji Ruiti Ni is administered in an amount of about 225 mg/day. In some embodiments, ji Ruiti Ni is administered in an amount of about 150 mg/day. In some embodiments, ji Ruiti Ni is administered in an amount of about 120 mg/day. In some embodiments, ji Ruiti Ni is administered in an amount of about 100 mg/day.

In some embodiments, the sotoracicada is administered in an amount of about 500 mg/day to about 1500 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 1000 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 960 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 900 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 800 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 700 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 600 mg/day. In some embodiments, the sotoracicada is administered in an amount of about 500 mg/day.

In some embodiments, adaglazeb is administered in an amount of about 500 mg/day to about 1500 mg/day. In some embodiments, adaglazeb is administered in an amount of about 1200 mg/day. In some embodiments, adaglazeb is administered in an amount of about 1000 mg/day. In some embodiments, adaglazeb is administered in an amount of about 800 mg/day. In some embodiments, adaglazeb is administered in an amount of about 600 mg/day. In some embodiments, adaglazeb is administered in an amount of about 400 mg/day.

In some embodiments, palbociclib is administered in an amount from about 50 mg/day to about 500 mg/day. In some embodiments, palbociclib is administered in an amount of about 150 mg/day. In some embodiments, palbociclib is administered in an amount of about 125 mg/day. In some embodiments, palbociclib is administered in an amount of about 100 mg/day. In some embodiments, palbociclib is administered in an amount of about 75 mg/day. In some embodiments, palbociclib is administered in an amount of about 50 mg/day.

In some embodiments, palbociclib is administered from about 50mg once per week to about 650mg once per week. In some embodiments, palbociclib is administered in an amount of about 600mg once a week. In some embodiments, palbociclib is administered in an amount of about 500mg once a week. In some embodiments, palbociclib is administered in an amount of about 400mg once a week. In some embodiments, the palbociclib is administered in an amount of about 300mg once a week. In some embodiments, the palbociclib is administered in an amount of about 200mg once a week.

Application of

Compound 1 or a pharmaceutically acceptable salt thereof and a combination partner (partner) described herein are administered at the dosages described herein or at other dosage levels and compositions determined and considered by the medical practitioner. In certain embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered for prophylactic and/or therapeutic treatment. In certain therapeutic applications, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a patient already suffering from a disease in an amount sufficient to cure the disease or at least partially prevent or ameliorate symptoms. The amount effective for this use will depend on the age of the patient, the severity of the disease, the previous treatment, the health of the patient, the weight and response to the composition, and the judgment of the treating physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, up-dosing clinical trials.

In prophylactic applications, the compositions described herein are administered to a patient susceptible to or otherwise at risk of a particular disease (e.g., cancer). Such an amount is defined as a "prophylactically effective amount or dose". In this use, the precise amount will also depend on the age, health, weight, etc. of the patient. When used in a patient, the effective amount for such use will depend on the risk or susceptibility to developing the particular disease, the previous treatment, the patient's health and response to the composition, and the discretion of the treating physician.

In certain embodiments, wherein the condition of the patient is not improved, the compositions described herein are administered chronically (i.e., for an extended period of time, including throughout the life of the patient) at the discretion of the physician, in order to improve or otherwise control or limit the symptoms of the patient's disease. In other embodiments, the administration of the composition is continued until a complete or partial response to the disease.

In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and a combination partner described herein, are administered once daily. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and a combination partner described herein, are administered twice daily. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, and a combination partner described herein, are administered three times daily.

In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, compound 2, or a pharmaceutically acceptable salt thereof, is administered three times per day.

In some embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fasted state. Fasted state refers to a subject that is not fed or fasted for a period of time. Typical fasted periods include no feeding for at least 4 hours, at least 6 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 14 hours, and at least 16 hours. In some embodiments, compound 1, or a pharmaceutically acceptable salt thereof, is administered to a subject in a fasted state for at least 8 hours. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fasted state for at least 10 hours. In still other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fasted state for at least 12 hours. In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject who has fasted overnight.

In other embodiments, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fed state. Fed state refers to a subject that has been fed or has been fed. In certain embodiments, the composition is administered to a subject in a fed state at 5 minutes post-meal, 10 minutes post-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutes post-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal, or 2 hours post-meal. In certain instances, compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in a fed state 30 minutes after a meal. In other cases, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered to a subject in a fed state 1 hour after a meal. In a further embodiment, compound 1 or a pharmaceutically acceptable salt thereof is administered to a subject in combination with food.

The length of the treatment period depends on the treatment administered. In some embodiments, the length of the treatment period ranges from 2 to 6 weeks. In some embodiments, the length of the treatment period ranges from 3 to 6 weeks. In some embodiments, the length of the treatment period ranges from 3 to 4 weeks. In some embodiments, the length of the treatment period is 3 weeks (or 21 days). In some embodiments, the length of the treatment period is 4 weeks (28 days). In some embodiments, the length of the treatment period is 5 weeks (35 days). In some embodiments, the length of the treatment period is 56 days. In some embodiments, the treatment period lasts for 1, 2, 3, 4, or 5 weeks. In some embodiments, the treatment period lasts for 3 weeks. In some embodiments, the treatment period lasts for 4 weeks. In some embodiments, the treatment period lasts for 5 weeks. The number of therapeutic doses scheduled in each cycle also varies depending on the drug administered.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered at a 28 day period. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in a plurality of 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least one 28-day cycle. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least two 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least three 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least four 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least five 28-day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least six 28-day cycles.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-7 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-21 of each 28-day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-28 of each 28-day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 1 of a 28 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 8 of the 28 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 15 of a 28 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 22 of the 28 day cycle. In some embodiments of the method of treating cancer, compound 1, or a pharmaceutically acceptable salt thereof, is not administered twice a day on day 22 of the 28 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily on days 1, 8 and 15 of a 28 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, 23-28 of the 28 day cycle.

In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in a 35 day period. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in a plurality of 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered at least one 35 day period. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least two 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least three 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least four 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least five 35 day cycles. In some embodiments of the methods of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof and a combination partner described herein are administered in at least six 35 day cycles.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-7 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-14 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-21 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-28 of each 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1-35 of each 35 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 1 of a 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 8 of the 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 15 of a 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 22 of the 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice a day on day 29 of the 35 day cycle. In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is not administered twice a day on day 29 of the 35 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is administered twice daily on days 1, 8, 15 and 22 of a 35 day cycle.

In some embodiments of the method of treating cancer, compound 1 or a pharmaceutically acceptable salt thereof is not administered on days 2-7, 9-14, 16-21, 23-28, and 30-35 of the 28 day cycle.

Examples

Example 1: in vivo assays

Vehicle/control preparations were prepared, 0.5% methylcellulose and 0.1% tween 80 or 100mM acetic acid in deionized water, pH adjusted to 4.8-5.0, and stored at ambient conditions throughout the study period.

Formulation of test articles

Test article compound 1 was freshly prepared weekly in a vehicle of 0.5% methylcellulose and 0.1% tween 80 and stored under ambient conditions. The combination agent compound 2 was freshly prepared weekly in 100mM acetate buffer vehicle and stored under ambient conditions.

Animals

Female Balb/c nude mice were purchased from beijing velarihua laboratory animal technologies limited (Beijing Vital River Laboratory Animal Technology co., ltd.). Mice were housed in a pathogen free (SPF) environment of an animal feeding facility and allowed to adapt to their new environment for at least 3 days before any experiments were initiated. Mice were 6-8 weeks of age at implantation.

All procedures related to animal handling, care and treatment in this study were performed according to protocols and guidelines approved by the institutional animal care and use committee (Institutional Animal Care and Use Committee, IACUC) of GenenDesign and WuXi AppTec. Animal facilities and procedures operate under the standards of the laboratory animal care and use guidelines (Guide for the Care and Use of Laboratory Animals) (NRC, 2011) and are certified by the laboratory animal care assessment and certification association (Association for Assessment and Accreditation of Laboratory Animal Care, AAALAC). Specifically, all parts of the study conducted in GenenDesign and WuXi AppTec followed the study protocol reviewed and approved by IACUC and the Standard Operating Program (SOP) applicable.

Preparation of xenograft models

NCI-H441 is KRAS-carrying ^G12V A mutant human NSCLC cell line. NCI-H441 cell line was purchased from American type culture Collection (American Type Culture Collection) (. Times.HTB-174 ^TM ). NCI-H441 cells were cultured in a medium containing RPMI-1640 plus 10% Fetal Bovine Serum (FBS) at 37℃under a culture atmosphere of 5% CO ₂ Is a gas in the air chamber. Will contain 5X 10 mixed with 50% matrigel ⁶ NCI-H441 cells in 200. Mu.L cell suspension of individual cells were subcutaneously implanted in mice. When the tumor volume reached an average of 200mm ³ At this time, tumor-bearing mice were randomized into different groups of 8 mice each and treatment was started on the day of randomization.

NCI-H2009 is carrying KRAS ^G12A A mutant human NSCLC cell line. The NCI-H2009 cell line was purchased from the American type culture Collection @CRL-5911). NCI-H2009 cells were cultured in a medium supplemented with Glutamax and pyruvate at 37deg.C with RPMI-1640 plus 10% Fetal Bovine Serum (FBS) under a culture atmosphere of 5% CO ₂ Is a gas in the air chamber. Will contain 5X 10 mixed with 50% matrigel ⁶ NCI-H2009 cells in 100 μl of cell suspension of individual cells were subcutaneously implanted in mice. When the tumor volume reached an average of 200mm ³ At this time, tumor-bearing mice were randomized into different groups of 8 mice each and treatment was started on the day of randomization. />

Treatment of

Mice were dosed in the monotherapy treatment groups by oral administration of vehicle control solution, compound 1 or compound 2. Mice were dosed by oral administration comprising a combination of compound 1 and compound 2. The dosing volume of each compound was 5mL/kg and the BID protocol was 8 hours apart. In the combination of compound 1 and compound 2, compound 1 is administered 1 hour after compound 2QD or the first dose of BID. In addition to the conventional food and water supply, at least two mice therein showed >Dietgel (ClearH 2O, US) was added to the 10% BWL cage. Tumor volume reached 2,000mm at the end of 4 weeks of treatment or in vehicle control group ³ The study was terminated at that time.

Results

In KRAS G12V NSCLC CDX model NCI-H441, as shown in fig. 1A, the combination of compound 1 at 30mg/kg QD and compound 2 at 15mg/kg QD achieved a statistically significant TGI of 113% (p-value < 0.001), demonstrating statistically significant benefits (p-value < 0.01) relative to the respective monotherapy doses of compound 1 at 30mg/kg QD and compound 2 at 15mg/kg QD. Compound 1 as monotherapy at doses of 30mg/kg BID and 30mg/kg QD achieved statistically significant TGI of 115% (p-value < 0.001) and 94% (p-value < 0.001), respectively. Compound 2 as monotherapy at doses of 30mg/kg QD and 15mg/kg QD achieved statistically significant TGI of 101% (p-value < 0.001) and 87% (p-value < 0.001), respectively. Fig. 1A shows the tumor growth curve of this study.

In KRAS G12A NSCLC CDX model NCI-H2009, as shown in fig. 1B, the combination of compound 1 at 30mg/kg QD and compound 2 at 15mg/kg QD achieved a statistically significant TGI of 107% (p value < 0.001). The combination of compound 1 and compound 2 achieved a statistically significant combined benefit (p-value < 0.01) relative to the respective monotherapy doses of compound 1 and compound 2 of 30mg/kg QD. The combination also showed statistically significantly superior TGI relative to compound 1 monotherapy (p-value < 0.05) and compound 2 monotherapy (p-value < 0.01) with 30mg/kg BID. These doses represent the maximum monotherapy non-clinically effective doses of compound 1 and compound 2. Compound 1 as monotherapy, 30mg/kg BID achieved 93% statistically significant TGI. Compound 2 as monotherapy at doses of 30mg/kg QD and 15mg/kg QD achieved statistically significant TGI of 90% (p-value < 0.001) and 73% (p-value < 0.001), respectively. Fig. 1B shows the tumor growth curve of this study.

Compound 1 and compound 2 exhibited in vivo combined benefits on the mutant RAS CDX model.

Example 2: in vitro study of Compound 1 alone, compound 2 alone and Compound 1+Compound 2 in NSCLC cell lines

Cells (8000 cells per well) were seeded onto 6-well plates in 2mL of cell culture medium. Cells were incubated overnight and treated with the concentrations of compound 1 and compound 2. After 7 days of incubation, the medium was replaced with fresh medium, the cells were again treated with the same concentrations of compound 1 and compound 2, and incubated for an additional 7 days. After 14 days of total incubation, cells were washed twice with PBS and fixed with 4% formaldehyde for 30 min. Cells were washed twice with PBS and incubated with 0.1% crystal violet for 60 minutes. After crystal violet staining, the cells were washed 5 times with water and dried at room temperature. After drying the plates, the crystals were stained decolorized with 1ml of 10% acetic acid and absorbance was measured at 560 nM.

As shown in fig. 2A, compound 1 and compound 2 showed combined benefits in KRAS G12V mutant NSCLC cell line NCI-H441. As shown in fig. 2B, compound 1 and compound 2 showed combined benefits in KRAS G12D mutant NSCLC cell line Gp 2D.

Example 3: in vitro studies of compound 1 alone, compound 2 alone, and compound 1+ compound 2 in combination in mutated pancreatic and pancreatic cancer cell lines

Cells were seeded in 12-well plates and allowed to adhere overnight. The next day, vehicle or compound is added to the wells in 1mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing the vehicle or compound. After 14 days of incubation, cells were washed twice in 1xPBS, fixed in 4% formaldehyde for 30 min, and then washed twice with 1 xPBS. Cells were stained with 0.1% crystal violet for 60 min and then washed five times with 1 xPBS. The plates were dried at room temperature for 2 hours and imaged. Subsequently, the cells were decolorized with 10% acetic acid and absorbance was measured using BCA protocol or absorbance at 560 nm.

As shown in fig. 3A, compound 1 and compound 2 showed combined benefits in the KRAS G12D mutant pancreatic cell line Panc 04.03. As shown in fig. 3B, compound 1 and compound 2 showed combined benefits in KRAS G12D mutant PDAC cell line HPAC.

Example 4: in vivo study of Compound 1 alone, compound 2 alone, and Compound 1+Compound 2 in KRAS G12D mutant PDAC PDX model PAN092

Vehicle/control preparations were prepared, 100mM acetic acid in deionized water, pH adjusted to 4.8-5.0, and stored at ambient conditions throughout 28 days of administration in mice.

Test article compound 2 was prepared weekly in a vehicle of 100mM acetate buffer and stored under ambient conditions. Test article compound 1 was prepared weekly in vehicle of 0.5% mc and 0.1% tween 80 solution and stored at ambient conditions throughout 28 days of administration in mice.

Female Balb/c nude mice were purchased from Beijing Vietnam Lihua laboratory animal technologies Co. Mice were housed in a pathogen free (SPF) environment of an animal feeding facility and allowed to adapt to their new environment for at least 3 days before any experiments were initiated. Mice were 6-8 weeks of age at implantation. All procedures related to animal handling, care and treatment in this study were performed according to protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of genedesign. Animal facilities and procedures operate under the standards of the laboratory animal care and use guidelines (national institutes of sciences (National Research Council), 2011) and are certified by the laboratory animal care evaluation and certification association (AAALAC). Specifically, all parts of the study conducted at genedesign followed the study protocol reviewed and approved by IACUC and the applicable Standard Operating Program (SOP).

Preparation of PDX

The PAN092 model was established in genedesign (Shanghai, china) for non-clinical efficacy studies. The PDX model was derived from 65 year old chinese male PDAC patients carrying KRAS G12D mutations. KRAS G12D mutations in PDX model PAN092 were confirmed by whole-exome sequencing and PCR sequencing. Tumor fragments harvested from the PDX model were subcutaneously implanted into the right flank of female Balb/c nude mice. Mice were anesthetized with isoflurane and anesthesia was maintained throughout the implantation procedure. The right flank of the mice was sterilized with appropriate surgical scrubs and alcohol and a sterile surgical procedure was used. A small skin incision was made using the tip of the trocar and a 1.5cm subcutaneous pocket along the right chest wall was formed by blunt dissection with a 10-12g trocar. Tumor fragments (15-30 mm) ³ ) Placed into a trocar and advanced into a subcutaneous pocket in the right abdomen. The trocar incision is closed with a suture or wound clip, which is removed one week after closure. When the tumor size reaches 200mm ³ Tumor-bearing mice were randomly divided into study groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

Treatment was started on the day of randomization. The day of treatment initiation is indicated as day 0 of treatment. Mice were dosed as monotherapy by oral administration of vehicle control solution, 15mg/kg QD compound 2 and 30mg/kg QD compound 1. Compound 1+Compound 2 treatment group received 30mg/kg QD of Compound 1 and 15mg/kg QD of Compound 2. The dosing volume of each compound was 5mL/kg. In the compound 1+ compound 2 treatment group, compound 1 was administered 1 hour after compound 2 administration. The study was terminated on day 28 of treatment as defined in the study protocol.

As shown in fig. 4, compound 1 and compound 2 showed in vivo combined benefits in KRAS G12D mutant PDAC PDX model PAN 092. No significant weight change was observed in the control and treatment groups.

Example 5: in vivo study of Compound 1 alone, compound 2 alone, and Compound 1+Compound 2 in KRAS G12D mutant PDAC PDX model PAN026

Female Balb/c nude mice were purchased from Beijing Vietnam Lihua laboratory animal technologies Co. Mice were housed in a pathogen free (SPF) environment of an animal feeding facility and allowed to adapt to their new environment for at least 3 days before any experiments were initiated. Mice were 6-8 weeks of age at implantation. All procedures related to animal handling, care and treatment in this study were performed according to protocols and guidelines approved by the Institutional Animal Care and Use Committee (IACUC) of genedesign. Animal facilities and procedures operate under the standards of the laboratory animal care and use guidelines (national institutes of sciences, 2011) and are certified by the laboratory animal care evaluation and certification association (AAALAC). Specifically, all parts of the study conducted at genedesign followed the study protocol reviewed and approved by IACUC and the applicable Standard Operating Program (SOP).

Preparation of PDX

The PAN026 model was established in genedesign (Shanghai, china) for non-clinical efficacy studies. The PDX model was derived from 58 year old chinese male PDAC patients carrying KRAS G12D mutations. KRAS G12D mutations in PDX model PAN026 were confirmed by whole-exome sequencing and PCR sequencing. Tumor fragments harvested from the PDX model were subcutaneously implanted into the right flank of female Balb/c nude mice. Mice were anesthetized with isoflurane and anesthesia was maintained throughout the implantation procedure. The right flank of the mice was sterilized with appropriate surgical scrubs and alcohol and a sterile surgical procedure was used. A small skin incision was made using the tip of the trocar and a 1.5cm subcutaneous pocket along the right chest wall was formed by blunt dissection with a 10-12g trocar. Tumor fragments (15-30 mm) ³ ) Placed into a trocar and advanced into a subcutaneous pocket in the right abdomen. The trocar incision is closed with a suture or wound clip, which is removed one week after closure. When the tumor size reaches 190mm ³ Tumor-bearing mice were randomly divided into study groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

Treatment was started on the day of randomization. The day of treatment initiation is indicated as day 0 of treatment. Mice were dosed as monotherapy by oral administration of vehicle control solution, 15mg/kg QD compound 2 and 30mg/kg QD compound 1. Compound 1+Compound 2 combination treatment groups received 30mg/kg QD of Compound 1 and 15mg/kg QD of Compound 2. The dosing volume of each compound was 5mL/kg. In the compound 1+compound 2 combination treatment group, compound 1 was administered 1 hour after compound 2 administration. The study was terminated on day 28 of treatment as defined in the study protocol.

As shown in fig. 5, compound 1 and compound 2 showed in vivo combined benefits in KRAS G12D mutant PDAC PDX model PAN 026. No significant weight change was observed in the control and treatment groups.

Example 6: in vivo study of combination of Compound 1 alone, compound 2 alone and Compound 1+Compound 2 in the NF1 LoF mutant melanoma CDX model MeWo

Preparation of CDX

MeWo is a human melanoma cell line carrying the NF1LOF mutation (NF 1Q 1336 x). MeWo cell line was purchased from american type culture collection @HTB-65 ^TM ). Culturing MeWo cells in medium containing Minimum Essential Medium (MEM) and 10% Fetal Bovine Serum (FBS) at 37deg.C under 5% CO ₂ Is a gas in the air chamber. Every 2 to 3The medium was refreshed daily and tumor cells were routinely subcultured to 80-90% confluency by trypsin-EDTA. Cells grown in exponential growth phase were harvested and counted for seeding. MeWo tumor cells were implanted subcutaneously into mice. 5X 10 containing a mixture with 50% matrigel was injected using a syringe ⁶ 200 μl of cell suspension of individual tumor cells was subcutaneously implanted in the right flank of mice. Animals were monitored daily for health and tumor growth. Tumor volumes were measured twice a week by calipers when tumors were palpable and measurable. When the tumor volume reached an average of 195mm ³ At this time, tumor-bearing mice were randomly divided into different groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

Treatment was started on the day of randomization. The day of treatment initiation is indicated as day 0 of treatment. Mice were dosed as monotherapy by oral administration of vehicle control solution, 15mg/kg QD compound 2, and 30mg/kg QD compound l. Compound 1+Compound 2 combination treatment groups received 30mg/kg QD of Compound 1 and 15mg/kg QD of Compound 2. The dosing volume of each compound was 5mL/kg. In the compound 1+compound 2 combination treatment group, compound 1 was administered 1 hour after compound 2 administration. The study was terminated on day 28 of treatment as defined in the study protocol.

As shown in fig. 6, compound 1 and compound 2 showed in vivo combined benefits in NF1 LoF mutant melanoma CDX model MeWo. No significant weight change was observed in the control and treatment groups.

Example 7: in vivo study of combination of Compound 1 alone, compound 2 alone and Compound 1+ Compound 2 in KRAS G13D mutant CRC CDX model LoVo

Preparation of CDX

LoVo is a human CRC cell line harboring KRAS G13D mutations. LoVo cell line was purchased from the American type culture Collection @CCL-229 ^TM ). LoVo cells were cultured in F12K medium containing 10% Fetal Bovine Serum (FBS) at 37deg.C under a culture atmosphere of 5% CO ₂ Is a gas in the air chamber. The medium was updated every 2 to 3 days and tumor cells were routinely subcultured to 80-90% confluency. Cells grown in exponential growth phase were harvested using trypsin-EDTA, counted for inoculation, and subsequently subcutaneously implanted into mice. Using a syringe, a syringe containing 2X 10 gel mixed with 50% matrigel was used ⁶ 200 μl of cell suspension of individual tumor cells was subcutaneously implanted in the right flank of mice. Animals were monitored daily for health and tumor growth. Tumor volumes were measured twice a week by calipers when tumors were palpable and measurable. When the tumor volume reached an average of 190mm ³ At this time, tumor-bearing mice were randomly divided into different groups of 8 mice each. Randomization date is expressed as day 0 of treatment.

Treatment of

As shown in fig. 7, compound 1 and compound 2 showed in vivo combined benefits in KRAS G13D mutant CRC CDX model LoVo. No significant weight change was observed in the control and treatment groups.

Example 8-in vitro study of Compound 1 alone, compound 2 alone, and Compound 1+ Compound 2 in combination in the KRAS G12V mutant PDAC cell line Capan-2 in a 14 day clonogenic assay

Capan-2 cells were seeded at 4000 cells/well density in 12-well plates and allowed to adhere overnight (see Table below). The next day, the compound was added to the wells in 1mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing the vehicle or compound. After 14 days of incubation, cells were washed twice in 1xPBS, fixed in 4% formaldehyde for 30 min, and then washed twice with 1 xPBS. Cells were stained with 0.1% crystal violet for 60 min and then washed five times with 1 xPBS. The plates were dried at room temperature for 2 hours and imaged. Subsequently, the cells were decolorized with 10% acetic acid and absorbance was measured using BCA protocol or absorbance at 560 nm.

As shown in fig. 8, compound 1 and compound 2 showed combined benefits in KRAS G12V mutant PDAC cell line cap-2.

Example 9-in vitro study of Compound 1 alone, compound 2 alone, and Compound 1+ Compound 2 in combination in the KRAS G12V mutant PDAC cell line Panc10.05 in a 14 day clonogenic assay

Panc10.05 cells were seeded at 2000 cells/well density in 12-well plates and allowed to adhere overnight (see table below). The next day, the compound was added to the wells in 1mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing the vehicle or compound. After 14 days of incubation, cells were washed twice in 1xPBS, fixed in 4% formaldehyde for 30 min, and then washed twice with 1 xPBS. Cells were stained with 0.1% crystal violet for 60 min and then washed five times with 1 xPBS. The plates were dried at room temperature for 2 hours and imaged. Subsequently, the cells were decolorized with 10% acetic acid and absorbance was measured using BCA protocol or absorbance at 560 nm.

As shown in fig. 9, compound 1 and compound 2 showed combined benefits in KRAS G12V mutant PDAC cell line Panc 10.05.

Example 10-in vitro study of Compound 1 alone, compound 2 alone, and Compound 1+ Compound 2 in combination in the KRAS G12V mutant PDAC cell line Panc1 in a 14 day clonogenic assay

Panc-1 cells were seeded at 4000 cells/well density in 12-well plates and allowed to adhere overnight (see Table below). The next day, the compound was added to the wells in 1mL of medium. After 7 days of incubation, the medium was replaced with fresh medium containing the vehicle or compound. After 14 days of incubation, cells were washed twice in 1xPBS, fixed in 4% formaldehyde for 30 min, and then washed twice with 1 xPBS. Cells were stained with 0.1% crystal violet for 60 min and then washed five times with 1 xPBS. The plates were dried at room temperature for 2 hours and imaged. Subsequently, the cells were decolorized with 10% acetic acid and absorbance was measured using BCA protocol or absorbance at 560 nm.

As shown in fig. 10, compound 1 and compound 2 showed combined benefits in KRAS G12V mutant PDAC cell line Panc 1.

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof; and

(ii) SHP2 inhibitors.

2. The method of claim 1, wherein the SHP2 inhibitor is sodium antimonate, RMC-4550, NSC87877, SPI-112, TNO155, IACS-13909, SHP099 HCl, or compound 2: Or a pharmaceutically acceptable salt thereof.

3. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof; and

(ii) Compound 2:or a pharmaceutically acceptable salt thereof.

4. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Ornitinib.

5. The method of claim 4, wherein the octreotide is administered in an amount of about 80 mg/day.

6. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Cetuximab.

7. The method of claim 6, wherein cetuximab is at 500mg/m ² Once every two weeks, 400mg/m ² Once every two weeks or 300mg/m ² Once every two weeks.

8. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) Kang Naifei Ni; and

(iv) Ornitinib.

9. The method of claim 8, wherein Kang Naifei ni is administered in an amount of about 100 mg/day to about 500 mg/day.

10. The method of claim 8 or 9, wherein Kang Naifei ni is administered in an amount of about 450 mg/day, 300 mg/day, 225 mg/day, or 150 mg/day.

11. The method of any one of claims 8 to 10, wherein the octreotide is administered at about 80 mg/day.

12. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof;

(iii) Kang Naifei Ni; and

(iv) Cetuximab.

13. The method of claim 12, wherein Kang Naifei ni is administered in an amount of about 100 mg/day to about 500 mg/day.

14. The method of claim 12 or 13, wherein Kang Naifei ni is administered in an amount of about 450 mg/day, about 300 mg/day, about 225 mg/day, or about 150 mg/day.

15. The method of any one of claims 12 to 14, wherein cetuximab is at 500mg/m ² Once every two weeks, 400mg/m ² Once every two weeks or 300mg/m ² Once every two weeks.

16. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Geranitinib.

17. The method of claim 16, wherein Ji Ruiti ni is administered in an amount of about 120 mg/day.

18. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Sotoracicb.

19. The method of claim 18, wherein the sotoracicada is administered in an amount of about 960 mg/day.

20. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Adaglazeb.

21. The method of claim 20, wherein adaglazeb is administered in an amount of about 1200 mg/day.

22. A method of treating cancer in a subject in need thereof, the method comprising: administering to said subject in need thereof a therapeutically effective amount of

(i) Compound 1:or a pharmaceutically acceptable salt thereof;

(ii) Compound 2:or a pharmaceutically acceptable salt thereof; and

(iii) Palbociclib.

23. The method of claim 22, wherein palbociclib is administered in an amount of about 50 mg/day to about 500 mg/day.

24. The method of claim 22 or 23, wherein palbociclib is administered in an amount of about 75 mg/day, about 100 mg/day, about 125 mg/day, or about 150 mg/day.

25. The method of claim 22, wherein palbociclib is administered in an amount of about 50mg once per week to about 650mg once per week.

26. The method of claim 22 or 23, wherein palbociclib is administered in an amount of about 200mg once per week, 300mg once per week, 400mg once per week, 500mg once per week, or 600mg once per week.

27. The method of any one of claims 2-26, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered orally.

28. The method of any one of claims 2-27, wherein compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1 mg/day to about 500 mg/day.

29. The method of any one of claims 2-27, wherein compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 20 mg/day to about 400 mg/day.

30. The method of any one of claims 2-27, wherein compound 2, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 30 mg/day to about 300 mg/day.

31. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered QD or BID for 2 weeks and discontinued for 1 week (21 day schedule).

32. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered QD or BID for 3 weeks and discontinued for 1 week (28 day schedule).

33. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered as QD or BID three days a week (D1D 3D5 TIW), such as day 1, day 3, and day 5.

34. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily/two days a week, such as day 1 and day 2 (BID-D1D 2-BIW).

35. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered once daily (QD) at a dose of 20 mg/day to 60 mg/day, 40 mg/day, or 60 mg/day.

36. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily (BID) at a dose of 20 mg/day to 80 mg/day for continuous administration.

37. The method of any one of claims 2-27, wherein compound 2 or a pharmaceutically acceptable salt thereof is administered twice daily (BID) at a dose of 10 mg/day to 100 mg/day for continuous administration.

38. The method of any one of claims 1-37, wherein the pharmaceutically acceptable salt of compound 1 is mandelate.

39. The method of any one of claims 1-38, wherein the cancer is a mitogen-activated protein kinase (MAPK) pathway-driven cancer.

40. The method according to any one of claims 1-38, wherein the cancer is a BRAF-driven cancer, HRAS-driven cancer, or NRAS-driven cancer.

41. The method of any one of claims 1-38, wherein the cancer comprises at least one cancer cell driven by deregulated ERK.

42. The method of any one of claims 1-38, wherein the cancer has at least one mutation in the RAS.

43. The method of any one of claims 1-38, wherein the cancer has at least one mutation in RAF.

44. The method of any one of claims 1-38, wherein the cancer has at least one mutation in MEK.

45. The method of any one of claims 1-38, wherein the cancer has a G12C KRAS mutation.

46. The method of any one of claims 1-38, wherein the cancer has a G12D KRAS mutation.

47. The method of any one of claims 1-38, wherein the cancer has a G12S KRAS mutation.

48. The method of any one of claims 1-38, wherein the cancer has a G12V KRAS mutation.

49. The method of any one of claims 1-38, wherein the cancer has a G13D KRAS mutation.

50. The method of any one of claims 1-38, wherein the cancer has a Q16H KRAS mutation.

51. The method of any one of claims 1-38, wherein the cancer has a Q16K KRAS mutation.

52. The method of any one of claims 1-38, wherein the cancer has a Q61R NRAS mutation.

53. The method according to any one of claims 1-38, wherein the cancer is a BRAF V600E or V600K mutant tumor.

54. The method of any one of claims 1-38, wherein the cancer is pancreatic cancer or PDAC that does not receive MAPKm/MAPKi.

55. The method of any one of claims 1-38, wherein the cancer comprises one or more EGFR mutations selected from the group consisting of: increased EGFR gene copy, EGFR gene amplification, chromosome 7 polyhedra, L858R, exon 19 deletion/insertion, L861Q, G719C, G719S, G719A, V765A, T783A, exon 20 insertion, EGFR splice variants (Viii, vvi and Vii), A289D, A289T, A289V, G598A, G598V, T790M and C797S.

56. The method of any one of claims 1-38, wherein the cancer comprises one or more EGFR mutations selected from L858R, exon 19 deletion, and T790M.

57. The method of any one of claims 1-56, wherein the cancer is a liquid tumor.

58. The method of claim 57, wherein the liquid tumor is leukemia.

59. The method of claim 57, wherein the leukemia is Acute Myelogenous Leukemia (AML).

60. The method according to claim 59, wherein the AML is relapsed and/or refractory AML.

61. The method according to claim 59, wherein the AML is FLT3 mutant AML.

62. The method of any one of claims 1-56, wherein the cancer is a solid tumor.

63. The method of any one of claims 1-56 or 62, wherein the cancer is non-small cell lung cancer (NSCLC), melanoma, pancreatic cancer, salivary gland tumor, thyroid cancer, colorectal cancer (CRC), or esophageal cancer.

64. The method of any one of claims 1-56 or 62, wherein the cancer is non-small cell lung cancer (NSCLC).

65. The method of claim 64, wherein the NSCLC is an EGFR mutant NSCLC.

66. The method of claim 64, wherein the NSCLC is KRAS G12C mutant NSCLC.

67. The method of claim 64, wherein the NSCLC is KRAS G12D mutant NSCLC.

68. The method of claim 64, wherein the NSCLC is KRAS G12S mutant NSCLC.

69. The method of claim 64, wherein the NSCLC is KRAS G12V mutant NSCLC.

70. The method of claim 64, wherein the NSCLC is KRAS G12A mutant NSCLC.

71. The method of claim 64, wherein the NSCLC is KRAS G13D mutant NSCLC.

72. The method of claim 64, wherein the NSCLC is KRAS Q61H mutant NSCLC.

73. The method of claim 64, wherein the NSCLC is KRAS Q61K mutant NSCLC.

74. The method of claim 64, wherein the NSCLC is NRAS Q61R mutant NSCLC.

75. The method of claim 64, wherein the cancer is NSCLC that does not receive MAPKm/MAPKi.

76. The method of claim 64, wherein the cancer is BRAFi treated V600 NSCLC.

77. The method of claim 64, wherein the cancer is KRAS-treated G12C NSCLC.

78. The method of claim 64, wherein the cancer is KRAS-treated G12D NSCLC.

79. The method of claim 64, wherein the cancer is KRAS-treated G12S NSCLC.

80. The method of claim 64, wherein the cancer is KRAS-treated G12V NSCLC.

81. The method of claim 64, wherein the cancer is KRAS-treated G13D NSCLC.

82. The method of claim 64, wherein the cancer is KRAS treated Q61H NSCLC.

83. The method of claim 64, wherein the cancer is KRAS treated Q61K NSCLC.

84. The method of claim 64, wherein the cancer is NRAS treated Q61R NSCLC.

85. The method of any one of claims 1-56 or 62, wherein the cancer is pancreatic cancer.

86. The method of any one of claims 1-56 or 62, wherein the cancer is pancreatic cancer that does not receive MAPKm/MAPKi.

87. The method of any one of claims 85, wherein the pancreatic cancer is Pancreatic Ductal Adenocarcinoma (PDAC).

88. The method of any one of claims 1-56 or 62, wherein the cancer is melanoma.

89. The method of claim 88, wherein the melanoma has NF1 loss of function (NF 1-LoF) mutations.

90. The method of claim 88, wherein the melanoma is BRAF V600E or V600K mutant tumor.

91. The method of claim 88, wherein the cancer is BRAFi treated V600 melanoma.

92. The method of any one of claims 1-56 or 62, wherein the cancer is a salivary gland tumor.

93. The method of any one of claims 1-56 or 62, wherein the cancer is thyroid cancer.

94. The method of any one of claims 1-56 or 62, wherein the cancer is colorectal cancer (CRC).

95. The method of claim 94, wherein the CRC is BRAF V600ECRC.

96. The method of claim 94, wherein the CRC is a KRAS mutant CRC.

97. The method of claim 94, wherein the CRC is a KRAS G12C mutant CRC.

98. The method of claim 94, wherein the CRC is a KRAS G12D mutant CRC.

99. The method of claim 94, wherein the CRC is a KRAS G12S mutant CRC.

100. The method of claim 94, wherein the CRC is a KRAS G12V mutant CRC.

101. The method of claim 94, wherein the CRC is a KRAS G13D mutant CRC.

102. The method of claim 94, wherein the CRC is a KRAS Q61H mutant CRC.

103. The method of claim 94, wherein the CRC is a KRAS Q61K mutant CRC.

104. The method of claim 94, wherein the CRC is an NRAS mutant CRC.

105. The method of claim 94, wherein the CRC is an NRAS Q61R mutant CRC.

106. The method of any one of claims 1-56 or 62, wherein the cancer is esophageal cancer.

107. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25 mg/day to about 300 mg/day.

108. The method of any one of claims 1-107, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of 25 mg/day to 150 mg/day.

109. The method of any one of claims 1-108, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg/day, about 50 mg/day, about 75 mg/day, about 100 mg/day, about 150 mg/day, about 175 mg/day, about 200 mg/day, about 225 mg/day, or about 250 mg/day.

110. The method of any one of claims 1-109, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered in an amount of about 25 mg/day, about 50 mg/day, about 100 mg/day, or about 150 mg/day.

111. The method of any one of claims 1-109, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 250 mg/day.

112. The method of any one of claims 1-111, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered once daily (QD).

113. The method of any one of claims 1-111, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered twice daily (BID).

114. The method of any one of claims 1-111, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered three times per day (TID).

115. The method of any one of claims 1-114, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered weekly.

116. The method of any one of claims 1-114, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered twice weekly.

117. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 300mg twice daily, one day per week (BID-QW).

118. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 250mg twice daily, one day per week (BID-QW).

119. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg to about 150mg twice daily, one day per week (BID-QW).

120. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 75mg, about 100mg, about 125mg, about 150mg, about 175mg, about 200mg, about 225mg, or about 250mg twice daily, one day per week (BID-QW).

121. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 25mg, 50mg, about 100mg, about 125mg, or about 150mg twice daily, one day per week (BID-QW).

122. The method of any one of claims 1-106, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 125mg twice daily, one day per week (BID-QW).

123. The method of any one of claims 1-122, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered for at least one 28-day period.

124. The method of any one of claims 1-123, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on days 1, 8, 15, and 22 of a 28 day cycle.

125. The method of any one of claims 1-123, wherein compound 1 or a pharmaceutically acceptable salt thereof is administered on day 1, day 8, day 15 of a 28 day cycle.

126. The method of any one of claims 1-125, wherein compound 1, or a pharmaceutically acceptable salt thereof, is administered orally.

127. The method of any one of claims 1-126, wherein the method further comprises administering an additional MAPK pathway inhibitor.

128. The method of claim 127, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor, NRAS inhibitor, HRAS inhibitor, PDGFRA inhibitor, PDGFRB inhibitor, MET inhibitor, FGFR inhibitor, ALK inhibitor, ROS1 inhibitor, TRKA inhibitor, TRKB inhibitor, TRKC inhibitor, EGFR inhibitor, IGFR1R inhibitor, GRB2 inhibitor, SOS inhibitor, ARAF inhibitor, BRAF inhibitor, RAF1 inhibitor, MEK2 inhibitor, c-Mycv, CDK4/6, inhibitor CDK2 inhibitor, FLT3 inhibitor, or ERK1/2 inhibitor.

129. The method of claim 127, wherein the additional MAPK pathway inhibitor is a KRAS inhibitor.

130. The method of claim 127, wherein the additional MAPK pathway inhibitor is a BRAF inhibitor.

131. The method of claim 127, wherein the additional MAPK pathway inhibitor is an EGFR inhibitor.

132. The method of claim 127, wherein the additional MAPK pathway inhibitor is CDK4/6.

133. The method of claim 127, wherein the additional MAPK pathway inhibitor is a FLT3 inhibitor.

134. The method of claim 127, wherein the additional MAPK pathway inhibitor is adaglazeb, afatinib, ASTX029, bimatinib, cetuximab, cobratinib, dabrafenib, dacatinib, kang Naifei ni, erlotinib, gefitinib, ji Ruiti ni, lapatinib, LTT462, LY3214996, rituximab, lenatinib, nimotuzumab, octtinib, panitumumab, sematinib, sotoracetib, trimetinib, ulitinib, vandetanib, or vitamin Mo Feini.

135. The method of claim 127, wherein the additional MAPK pathway inhibitor is adaglazeb.

136. The method of claim 127, wherein the additional MAPK pathway inhibitor is cetuximab.

137. The method of claim 127, wherein the additional MAPK pathway inhibitor is dabrafenib.

138. The method of claim 127, wherein the additional MAPK pathway inhibitor is Kang Naifei ni.

139. The method of claim 127, wherein the additional MAPK pathway inhibitor is gefitinib.

140. The method of claim 127, wherein the additional MAPK pathway inhibitor is palbociclib.

141. The method of claim 127, wherein the additional MAPK pathway inhibitor is panitumumab.

142. The method of claim 127, wherein the additional MAPK pathway inhibitor is sotoraciclovir.