TW201302792A - Dosage and administration of anti-ErbB3 antibodies in combination with tyrosine kinase inhibitors - Google Patents

Abstract

Provided are methods and compositions for clinical treatment of NSCLC using anti-ErbB3 antibodies combined with use of TKIs such as erlotinib or gefitinib.

Description

Dosage and administration of anti-ERBB3 antibody and tyrosine kinase inhibitor

The present invention relates to methods and compositions for the clinical treatment of NSCLC using an anti-ErbB3 antibody in combination with a TKI such as erlotinib or gefitinib.

Related application cross reference

This application claims US Provisional Application No. 61/497,834 filed on June 16, 2011, US Provisional Application No. 61/555,141 filed on November 3, 2011, and filed on February 7, 2012. US Provisional Application No. 596,097, US Provisional Application No. 61/602,365, filed on February 23, 2012, and US Provisional Application No. 61/616,912, filed on March 28, 2012 (all applications are referred to by reference) Priority rights included in this article).

background

Despite improvements in lung cancer therapy and advanced treatment options, more people die from lung cancer than any other type of cancer. The number of people dying from lung cancer is greater than the number of breast cancer, prostate cancer and colon cancer. There is an urgent need to optimize existing therapies and develop promising new therapies to sustain their lives while maintaining a high quality of life.

The ErbB3 receptor is a 148 kilodalton (kD) transmembrane receptor tyrosine kinase belonging to the ErbB/EGFR family and inactivating kinases. Transmembrane receptor tyrosine kinase of the ErbB family, which triggers multiple signals Ligand-dependent activation of the transduction pathway affects the physiological functions of cells and organs. However, it has been shown that heterodimers containing ErbB3 in tumor cells (such as ErbB2/ErbB3) are the most mitogenic and carcinogenic receptor complexes in the ErbB family. Upon binding to the physiological ligand-modulating protein (HRG) of the ErbB3 receptor, ErbB3 forms a dimer with other ErbB family members, preferably ErbB2. ErbB3/ErbB2 dimerization results in transphosphorylation of ErbB3 in the tyrosine residues contained in the cytoplasmic tail of the protein. Phosphorylation of these sites establishes an SH2 junction site for SH2 containing proteins, including PI3 kinase. Since ErbB3 has six tyrosine phosphorylation sites and YXXM sequences, these sites serve as excellent binding sites for phosphoinositide-3-kinase (PI3K) after phosphorylation, and binding will cause subsequent AKT pathways. Downstream activation, so the dimer complex containing ErbB3 is a potent activator of AKT. These six PI3K sites serve as powerful amplifiers for ErbB3 signal transmission. Activation of this pathway further induces several important biological processes involved in tumorigenesis, such as cell growth and survival.

There is evidence that the ErbB2/ErbB3 heterodimeric homologue ligands are found in several different types of cancer, including breast, ovarian, endometrial, colon, stomach, lung, thyroid, Glioma, medulloblastoma, melanoma, and head and neck squamous cell carcinoma. In most of these tumor types, HRG controls growth, invasion, and angiogenesis by overexpressing or activating autocrine or paracrine loops. Controls specific cancer by blocking HRG binding to disrupt the autocrine loop of the regulatory protein or disrupting the ErbB2/ErbB3 dimer The growth of the disease provides important treatments.

Summary

Compositions and methods for treating non-small cell lung cancer (NSCLC) in a human patient comprising administering an anti-ErbB3 antibody to a small molecule tyrosine kinase inhibitor (TKI) in combination with a patient, wherein the combination will be according to a particular clinical dosing regimen (ie, A particular dose is administered and administered according to the particular dosage regimen.

Exemplary anti-ErbB3 antibodies belong to antibody A (including antigen-binding fragments and variants thereof). In one embodiment, the anti-ErbB3 antibody comprises a heavy chain variable (VH) and/or a light chain variable (VL) region, encoded by the nucleic acid sequences set forth in SEQ ID NOs 1 and 3, respectively. In another embodiment, the antibody comprises a VH and/or VL region, and wherein the amino acid sequences set forth in SEQ ID NOs 2 and 4, respectively, are included. In another embodiment, the antibody comprises CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) And/or CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3). In another embodiment, an antibody that is directed to bind to and/or incorporate the same epitope on human ErbB3 is used as the antibody described above. In a specific embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 11). In another embodiment, the antibody is Antibody A competes for binding to human ErbB3, and at least 90% of the variable region amino acid sequences are identical to the anti-ErbB3 antibodies described above.

Small molecule TKI useful in the methods disclosed herein include erlotinib, gefitinib, vandetanib, lapatinib, afatinib, and neratinib.

Accordingly, in one aspect, compositions and methods are provided for treating non-small cell lung cancer (NSCLC) in a human patient, wherein the method comprises administering a composition in combination with erlotinib, the composition comprising: an anti-ErbB3 antibody comprising CDRH1, CDRH2, and CDRH3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the sequences of CDRL1, CDRL2 and CDRL3, and these sequences comprise The amino acid sequences of SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3) are listed and treated in combination with erlotinib, and the following dosing schedule according to Table 1 One or more of 1, 2, 3, 3a, 4a, 4b or 4c. In one embodiment, the anti-ErbB3 antibody is Antibody A.

Table 1

In one embodiment, the dosing regimen is dosing regimen 1, wherein the antibody is administered intravenously (or administered) once a week at a dose of 6 mg/kg while oral erlotinib is administered at a dose of 100 per day. Mg.

In another embodiment, the dosing regimen is Dosage 2, wherein the antibody is administered intravenously (or administered) once a week at a dose of 6 mg/kg while oral erlotinib is administered at a daily dose 150 mg.

In another embodiment, the dosing regimen is Dosage 3, wherein the antibody is administered intravenously (or administered) once a week at a dose of 12 mg/kg while oral erlotinib is administered at a daily dose. 150 mg.

In another embodiment, the dosing regimen is dosing regimen 3a wherein the antibody is administered intravenously (or administered) once a week at a dose of 12 mg/kg while oral erlotinib is administered at a daily dose 100 mg.

In another embodiment, the dosing regimen is Dosage 4a, wherein the antibody is administered intravenously (or administered) once a week at a dose of 20 mg/kg while oral erlotinib is administered at a daily dose 100 or 150 mg.

In another embodiment, the dosing regimen is Dosage 4b, wherein the antibody is administered intravenously (or administered) once every two weeks at a dose of 20 mg/kg while oral erlotinib is administered at a dose of 100 or 150 mg per day.

In another embodiment, the dosing regimen is dosing regimen 4c wherein the antibody is administered intravenously (or administered) once every three weeks at a dose of 20 mg/kg while oral erlotinib is administered at a dose of 100 or 150 mg per day.

In another aspect, a method for treating non-small cell lung cancer (NSCLC) in a human patient is provided, wherein the method comprises: administering to the patient a combination therapy comprising an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences comprise Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are included in SEQ ID NO: 8 (CDRL1) the amino acid sequences of SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), in combination with gefitinib, and according to the following dosing schedules 5, 6, 7, 7a of Table 2, One or more of 8a, 8b or 8c. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another aspect, a method for treating non-small cell lung cancer (NSCLC) in a human patient is provided, wherein the method comprises: administering to the patient a combination therapy comprising an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences comprise Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are included in SEQ ID NO: 8 (CDRL1) the amino acid sequences of SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), in combination with vandetanib, and according to Table 3 below, the following dosing schedules 9, 10, 11, 11a, One or more of 12a, 12b or 12c. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another aspect, a method for treating non-small cell lung cancer (NSCLC) in a human patient is provided, wherein the method comprises: administering to the patient a combination therapy comprising an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences comprise Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are included in SEQ ID NO: 8 (CDRL1) the amino acid sequences of SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), in combination with neratinib, and according to the following dosing schedules 13, 14, 15, 15a of Table 4, One or more of 16a, 16b or 16c. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another aspect, a method for treating non-small cell lung cancer (NSCLC) in a human patient is provided, wherein the method comprises: administering to the patient a combination therapy comprising an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences comprise Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are included in SEQ ID NO: 8 (CDRL1) the amino acid sequences of SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), in combination with lapatinib, and according to the following dosing schedules 17, 18, 19, 19a of Table 5, 20a, 20b Or one or more of the schemes of 20c. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In other embodiments, including embodiments comprising the above related items in Tables 1-5, the patient (ie, the human subject) has locally advanced or metastatic NSCLC. In another embodiment, the patient has an NSCLC tumor, wherein the EGFR tyrosine kinase domain is wild-type, and the subject has previously experienced at least one regimen containing chemotherapy. In another embodiment, the patient has an NSCLC tumor that has been shown to develop acquired resistance to EGFR TKI. In another embodiment, the patient has an NSCLC tumor, wherein the EGFR tyrosine kinase domain comprises an activating mutation and the subject has never received any EGFR TKI therapy before. In another embodiment, the patient's NSCLC is characterized by a mutation in the EGFR tyrosine kinase domain that makes NSCLC sensitive to TKI therapy. In another In the examples, the patient's NSCLC is characterized by a mutation in the EGFR tyrosine kinase domain (SEQ ID NO: 15), ie, a deletion of exon 19 of less than 10 contiguous amino acids, including amino acids in the EGFR tyrosine kinase domain. Deletion of R748 and E749 (SEQ ID NO: 15). The patient may be tested or selected for one or more of the above clinical attributes before, during, and after treatment.

In another aspect, there is provided a method of selecting a therapy for a patient with NSCLC, wherein the method comprises: (a) determining whether the cancer of the patient comprises an activating mutation of the EGFR tyrosine kinase domain; and (b) if included, to the patient An effective amount of the following items is administered: (1) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprising SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) amino acid sequence, and CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3) , and (2) erlotinib. In one embodiment, the activating mutation of the EGFR tyrosine kinase domain is a deletion of the residue E746-A750 of the EGFR tyrosine kinase domain (SEQ ID NO: 15). In another embodiment, the anti-ErbB3 antibody is Antibody A.

In another aspect, there is provided a composition for treating a human patient diagnosed with NSCLC (non-small cell lung cancer) and with a TKI (such as erlotinib, gefitinib, vandetanib or neratinib) Combination therapy wherein the composition comprises an anti-ErbB3 antibody, which comprises CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, Whereas these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), administered intravenously at a dose of 6 mg/kg per dose. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another aspect, there is provided a composition for treating a human patient diagnosed with NSCLC and a combination therapy with a TKI such as erlotinib, gefitinib, vandetanib or neratinib, wherein The composition comprises an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise amino acids set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) Sequences, and CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), administered intravenously , 12 mg / kg per dose. In one embodiment, the anti-ErbB3 antibody is Antibody A.

In another aspect, there is provided a composition for treating (eg, effective treatment) a human patient diagnosed with NSCLC and with a TKI (eg, erlotinib, gefitinib, vandetanib or neratinib) Combined treatment, and the composition comprises an anti-ErbB3 antibody, which comprises CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, Whereas these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), administered intravenously at a dose of 20 mg/kg per dose.

In one embodiment, the antibody is administered by intravenous injection, 6 mg/kg per week, and the TKI is erlotinib, orally administered daily at a dose of 100 mg per day, or the TKI is gefitinib, orally daily. The dose is 125 mg per day, or vandetaxan, orally daily, at a dose of 150 mg per day, or neratinib, orally daily at a dose of 120 mg per day.

In another embodiment, the antibody is administered by intravenous injection, 6 mg/kg per week, and is administered erlotinib daily, at a dose of 150 mg per day, or in combination with gefitinib, orally daily. 250 mg per day, or with vandetanib, daily orally, at a dose of 300 mg per day, or in combination with natinib, orally daily at a dose of 240 mg per day.

In another embodiment, the antibody is administered by intravenous injection, once daily at a dose of 12 mg/kg, and is administered erlotinib daily, at a dose of 150 mg per day, or in combination with gefitinib, orally daily. 250 mg per day, or with vandetanib, orally daily, at a dose of 300 mg per day, or in combination with natinib, daily orally The amount is 240 mg per day.

Detailed description First, the definition

The words "subject" or "patient" as used herein refer to a human cancer patient.

As used herein, "effective treatment" refers to a treatment that produces a beneficial effect, such as at least one symptom improvement of a disease or disorder. The beneficial effect is an improvement above the baseline, ie an improvement over the measurements or observations made prior to the initiation of treatment according to the relevant method. The beneficial effects are also reflected in the suppression, slowing, slowing or stabilization of harmful developments in NSCLC markers. Effective treatment can mean at least one symptom of non-small cell lung cancer. For example, such effective treatment can reduce the patient's illness, reduce the size and/or number of lesions, and reduce or prevent tumor metastasis, and/or slow tumor growth.

The term "effective amount" refers to an amount of a drug that has been clinically proven to provide the desired biological, therapeutic, and/or prophylactic effect. This effect can be a reduction, amelioration, mitigation, mitigation, delay and/or alleviation of one or more signs, symptoms or causes, or any other desired change in the biological system. In the case of cancer, an effective amount comprises an amount sufficient to promote cancer atrophy and/or reduce tumor growth rate (e.g., inhibit tumor growth), or to prevent or delay other undesirable cell proliferation. In some embodiments, the effective amount is an amount sufficient to delay tumor progression. In some embodiments, the effective amount is an amount sufficient to prevent or delay tumor recurrence. An effective amount can be administered in one or more administrations. An effective amount of a drug or composition can: (i) reduce cancer Number of cells; (ii) shrinking tumors; (iii) inhibiting, delaying, slowing down and preventing cancer cells from infiltrating into peripheral organs to a certain extent; (iv) inhibiting (ie, slowing down and preventing to some extent) tumor metastasis; v) inhibiting tumor growth; (vi) preventing or delaying the appearance and/or recurrence of the tumor; and/or (vii) alleviating to some extent one or more of the symptoms involved in the cancer. For example, the "effective amount" for therapeutic use is that antibody A and erlotinib, gefitinib, neratinib, lapatinib or vandetanib can clinically significantly improve or slow NSCLC. The amount required for NSCLC to progress.

The term "antibody" includes antibodies and antibody variants comprising at least one antibody-derived antigen binding site (such as the VH/VL region or Fv) that specifically binds to ErbB3. Antibodies include antibodies in known forms. For example, the antibody can be a human antibody, a humanized antibody, a bispecific antibody, or a chimeric antibody. The antibody may also be a Fab, Fab'2, ScFv, SMIP, AFFIBODY®, Nanobody or domain antibody. The antibody may also be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgA1, IgA2, IgAsec, IgD, and IgE.

The term antibody variant as used herein includes naturally occurring antibodies which, upon alteration (e.g., by mutation, deletion, substitution or binding to a non-antibody portion), comprise at least one variant amino acid that alters the properties of the antibody. For example, numerous such changes known in the art can affect, for example, half-life, effector function, and/or subject's immune response to antibodies. The term antibody variant also encompasses an artificial polypeptide construct comprising at least one antibody-derived antigen binding site.

The term "tyrosine kinase inhibitor" or "TKI" refers to a small molecule (below 900 AMU) compound that selectively inhibits one or more receptor tyrosine kinase-regulated kinase activities. Examples of TKI include erlotinib, gefitinib, imatinib, lapatinib, neratinib, nilotinib, sunitinib, and vandetanib.

Second, anti-ErbB3 antibody

Useful anti-ErbB3 antibodies (or VH/VL domains derived therefrom) can be made using methods known in the art. Alternatively, a technically recognized anti-ErbB3 antibody can also be used. For example, Ab #3, Ab #14, Ab #17, and Ab # 19 described in U.S. 7,846,440 can be used. Antibodies that compete with any such antibody for binding to ErbB3 can also be used. Other technology-approved anti-ErbB3 antibodies that can be used include the antibodies disclosed in US 7,285,649, US20200310557 and US20100255010, as well as antibodies IB4C3 and 2D1D12 (U3 Pharma Ag), both of which are described in US 2004/0197332; referred to as AMG888 (U3- 1287-U3 Pharma Ag and Amgen) anti-ErbB3 antibodies; and monoclonal antibody 8B8 as described in US 5,968,511. Other useful anti-ErbB3 antibodies are disclosed in the technical field of bispecific antibodies (see, for example, B2B3-1 or B2B3-2 in WO/2009/126920), and in US 7,846,440 and US 2010/0266584, all of which are The content is incorporated herein by reference. An example of such an antibody is antibody A having a heavy chain and a light chain, which contain the amino acid sequences listed in SEQ ID NOs 12 and 13, respectively. Antibody A in US 7,846,440 is called "Ab #6".

In one embodiment, the anti-ErbB3 antibody comprises a heavy chain variable (VH) and/or a light chain variable (VL) region, encoded by the nucleic acid sequences set forth in SEQ ID NOs 1 and 3, respectively. In another embodiment, the antibody comprises a VH and/or VL region, and wherein the amino acid sequences set forth in SEQ ID NOs 2 and 4, respectively, are included.

In another embodiment, the antibody comprises CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) And/or CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3). In another embodiment, an antibody that seeks to bind and/or incorporate the same epitope on human ErbB3 is used as the antibody described above. In a specific embodiment, the epitope comprises residues 92-104 of human ErbB3 (SEQ ID NO: 11). In another embodiment, the antibody binds to human ErbB3 and at least 90% of the variable region sequences are identical to the antibodies described above.

In other embodiments, the antibody is a fully human monoclonal antibody, such as IgG2 that binds to ErbB3 and prevents HRG and EGF-like ligand-induced phosphorylation of ErbB3.

An anti-ErbB3 antibody, such as antibody A, can be produced in prokaryotic or eukaryotic cells using methods known in the art. In one embodiment, the antibody is in a cell line capable of glycosylating a protein (eg, CHO fine) Produced in cells).

Third, TKI

For example, a TKI for an intracellular ErbB signal transmission pathway includes erlotinib, gefitinib, neratinib, lapatinib or vandetanib.

In one embodiment, the TKI is specifically directed against the epidermal growth factor receptor (EGFR) tyrosine kinase, which is highly expressed and mutated in a variety of cancers. Such TKIs include neratinib, afatinib, dacomitinb, vandetanib, lapatinib, erlotinib, and gefitinib. Some TKIs bind to the receptor's adenosine triphosphate (ATP) binding site in a reversible manner.

As for the signal transmitted by the ErbB receptor, two EGFR family member molecules need to be joined together to form a homodimer (except ErbB3/ErbB3 homodimer) or a heterodimer. The associated dimeric molecule is then autophosphorylated or phosphorylated using an ATP molecule. Phosphorylation exposes binding sites on the cytoplasmic domain of the receptor for binding to cellular proteins, and when cellular proteins bind to phosphorylated receptors, a signal cascade that transmits mitogenic stimuli is emitted to the nucleus. In one embodiment, the TKI acts by inhibiting phosphorylation to reduce or prevent signal transduction of the nucleus.

Fourth, pharmaceutical composition

Pharmaceutical compositions suitable for administration to a patient may be in the form of a troche, capsule, pill, diamond, powder, granule, solution or dispersion.

In general, the compositions typically comprise a pharmaceutically acceptable carrier. body. The term "pharmaceutically acceptable" as used herein refers to other generally recognized pharmacopeia approved by a government regulatory agency or listed in the US Pharmacopoeia or related animals, especially humans. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids such as water and oil including petroleum, animal, vegetable or synthetic products such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Aqueous solutions of water or saline, dextrose and glycerol can be used as carriers, especially for injectable solutions (for example comprising an anti-ErbB3 antibody). Liquid compositions for parenteral administration (e.g., comprising antibodies) can be administered by injection or continuous infusion. Routes of administration for injection or infusion include intravenous, intraperitoneal, intramuscular, intrathecal and subcutaneous.

In the case of oral administration (e.g., oral TKI), compositions in the form of lozenges can be prepared for this purpose using pharmaceutical excipients known in the art, and excipients are conventionally employed in the preparation of solid pharmaceutical compositions.

Erlotinib (TARCEVA®) oral lozenges are commercially available in three dose strengths (27.3 mg, 109.3 mg, and 163.9 mg) of erlotinib HCl, equivalent to 25 mg, 100 mg, and 150 mg erlotinib, and The following inactive ingredients are lactose monohydrate, hypromellose, hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate and titanium dioxide. Tablets also contain trace amounts of colorants for product identification, including (for 25 mg only) FD&C Yellow No. 6. The chemical formula of erlotinib is as follows:

An oral dose of gefitinib (IRESSA®) is commercially available in a dose strength (250 mg) containing the inner layer of the tablet containing gefitinib, lactose monohydrate, microcrystalline cellulose, croscarmellose Sodium, povidone, sodium lauryl sulfate and magnesium stearate, while the inner layer is coated with a film coat comprising hypromellose, polyethylene glycol 300, titanium dioxide, red iron oxide and yellow iron oxide. . The chemical formula of gefitinib is as follows:

CAPRELSA® Oral Lozenges are commercially available in 100 and 300 mg dose strength lozenges, the inner layer of which contains vandetanib (dibasic calcium phosphate dihydrate, microcrystalline cellulose, cross-linked polyv. Ketones, povidones and magnesium stearate; and film coats comprising hypromellose 2910, polyethylene glycol 300 and titanium dioxide E171. The chemical formula of vandetanib is as follows:

TYKERB® Oral Lozenges are commercially available in a dosage strength (250 mg) containing 405 mg of lapatinib ditosylate monohydrate in the inner layer of the tablet. 398 mg lapatinib ditosylate or 250 mg lapatinib free radical, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and FD&C Yellow No. 6 / An orange film coat of sunset yellow FCF aluminum thioglycol, hypromellose, polyethylene glycol/PEG 400, polysorbate 80 and titanium dioxide.

The chemical formula of lapatinib is as follows:

The chemical formula of afatinib is as follows:

The chemical formula of neratinib is as follows:

Antibody A for intravenous infusion (eg, one hour of infusion) is in the form of a clear liquid solution placed in a sterile single-use vial containing 10.1 ml of Antibody A in 20 mmol of histidine, 150 mmol of chlorine The concentration in sodium is 25 mg / ml, the pH is 6.5, and the storage temperature should be 2-8 ° C

Five, patient group

An effective method for treating NSCLC patients with anti-ErbB3 antibodies and TKI is provided herein. In a specific embodiment, the subject has a locally advanced or metastatic NSCLC that is histologically or cytologically confirmed.

In one embodiment, the mutated state of the patient's NSCLC tumor EGFR tyrosine kinase domain is determined, for example, using techniques recognized by the relevant art. For example, tumors can be biopsied and PCR or plus known primers or hybridization plus known probes to determine the mutated state of the EGFR tyrosine kinase domain. In one embodiment, the mutated state of the EGFR tyrosine kinase domain is wild-type, ie, non-mutated.

In another embodiment, the patient's cancer relapses or progresses after undergoing at least one chemotherapy regimen that is considered a metastatic treatment of NSCLC standard care.

In another embodiment, the patient is tested or selected prior to treatment with respect to one or more of the above features. For example, a patient can be tested to ascertain the following aspects: histologically or cytologically confirmed locally advanced or metastatic NSCLC; the mutated state of the EGFR tyrosine kinase domain of the tumor is wild-type; and/or the cancer is at least once Recurrence or progression after treatment with a chemotherapy regimen that is considered a metastatic treatment of NSCLC standard care.

In a specific embodiment, the patient is tested or selected to have a tumor and the tumor is after one or more prior standard chemotherapy regimens Characterized by EGFR wild type.

In another embodiment, the patient is tested or selected to have a tumor in which a known activating mutation occurs in the EGFR tyrosine kinase domain.

In another embodiment, the patient is tested or selected to have not received any EGFR TKI therapy prior to treatment of metastatic NSCLC.

In another embodiment, the patient is tested or selected to have a tumor in which a known activating mutation occurs in the EGFR tyrosine kinase domain and has not previously received any EGFR TKI therapy in the treatment of metastatic NSCLC.

In another embodiment, the patient is tested or selected to have NSCLC and is shown to develop acquired resistance to EGFR TKI (such as erlotinib or gefitinib). Drug sensitivity can be measured using well-known methods in the art. For example, drug sensitivity can be determined by measuring the response of a tumor cell to a drug. In another embodiment, drug sensitivity/resistance can be confirmed by EGFR mutations or the occurrence of other mutations known to be associated with drug sensitivity/resistance (eg, G719X, exon 19 deletion, L858R, L861Q). , T790M, L747S, D761Y, amplification of MET receptors and activation of IGFR signaling, or K-RAS mutations).

In a particular embodiment, the patient has previously received EGFR TKI therapy and responded to the treatment, but the condition subsequently progresses, thereby developing resistance to the therapy.

In another embodiment, the patient's NSCLC is characterized by a mutation in the EGFR tyrosine kinase domain that makes NSCLC sensitive to TKI therapy.

In another embodiment, the patient's NSCLC is characterized by a mutation in the EGFR tyrosine kinase domain (SEQ ID NO: 15), ie, a deletion of exon 19 of less than 10 contiguous amino acids, including the EGFR tyrosine kinase structure. Deletion of amino acids R748 and E749 in the domain (SEQ ID NO: 15).

In another embodiment, the patient meets one or more of the following clinical criteria: 1) no smoking history; 2) female; 3) NSCLC adenocarcinoma subtype or bronchial variant; 4) Asian race and/or 5 ) includes one of the following EGFR mutant groups: a tyrosine kinase domain mutation and a truncation mutation involving exons 2 to 7.

Sixth, combined therapy

As described herein, administration of an anti-ErbB3 antibody with TKI (such as erlotinib or gefitinib) as an adjunct therapy can effectively improve the condition of NSCLC subjects. In one embodiment, the anti-ErbB3 antibody is antibody A and the TKI is erlotinib. In another embodiment, the NSCLC is characterized by an activating mutation (SEQ ID NO: 15) in the EGFR tyrosine kinase domain. Preferably, the mutation sensitizes NSCLC to TKI therapy. In one such embodiment, EGFR mutations result in amino acid deletions in exon 19 of the EGFR gene. In another such embodiment, the E746-A750 deletion (ie SEQ ID) is mutated to the EGFR tyrosine kinase domain. NO: 743-750 residues of 15). In other such examples, the mutations are: L747-T751 deletion, L747-P753 deletion, L747-E749 deletion, E746-A750 deletion, E746-T751 deletion or exon 19 deletion of less than 10 contiguous amino acids, including Deletion of amino acids R748 and E749 in the EGFR tyrosine kinase domain (SEQ ID NO: 15). In other such examples, NSCLC has a point mutation in exon 18, such as a G719A mutation, a G719C mutation, or a G719S mutation. In another embodiment, the NSCLC has a point mutation in exon 21, such as a L858R mutation, a L858M mutation, or a L861Q mutation. In other embodiments, the EGFR gene does not contain mutations that are resistant to TKI therapy, such as L747S mutation, D761Y mutation, T790M mutation, D770-N771insNPG insertion mutation, D770-N771insSVD insertion mutation, A767-V769dusp ASV insertion mutation, or EGFR Such other mutations in exon 20 of the gene. The full length of the EGFR sequence is shown in SEQ ID NO: 14.

Auxiliary or combined administration as employed herein includes the simultaneous administration of the compound in the same or different dosage forms, or the administration of the compound alone (e.g., continuous administration). For example, the antibody can be administered concurrently with the TKI, at which time the antibody and TKI are co-formulated. Alternatively, the antibody can be administered in combination with TKI, wherein both the antibody and the TKI are formulated separately and administered simultaneously or sequentially. For example, the antibody can be administered first, followed by the TKI, and vice versa.

In one embodiment, the TKI is an oral formulation. In a particular embodiment, the TKI is erlotinib, and the optional dosage is 150 mg/day, 100 mg/day, 80 mg/day, and/or 50 mg/ day. In another embodiment, the TKI is administered at its maximum tolerated dose. The dose of TKI may change over time. For example, the initial dose of TKI may be higher, and then may decrease over time. In another embodiment, the initial dose of TKI may be lower, and then may increase over time.

In another embodiment, the anti-ErbB3 antibody is a formulation for intravenous administration. In a particular embodiment, the anti-ErbB3 antibody is optionally administered at a dose of 40 mg/kg, 20 mg/kg, 12 mg/kg, 10 mg/kg, 6 mg/kg, and/or 3.2 mg/kg. The dose of the antibody may change over time. For example, the initial dose of an antibody may be higher, and then it may decrease over time. In another embodiment, the initial dose of the antibody may be lower and then may increase over time. For example, the initial dose of an antibody may be higher, and then it may decrease over time. In another embodiment, the initial dose of the antibody may be lower and then may increase over time. In one embodiment, the antibody A antibody is administered at a dose of 3.2, 6, 10, 12, 15, 20 or 40 mg/kg.

Seven, treatment plan

For example, suitable treatment regimens include: (A) daily administration of a TKI to a patient (ie, a human subject); and (B) administration of an anti-ErbB3 antibody to the patient weekly, biweekly, or every three weeks.

In one embodiment, erlotinib is used in combination with Antibody A, which is administered once every few days. For example, suitable erlotinib per Daily doses include 100, 125 or 150 mg/day. In another embodiment, the method of administration comprises administering a dose of Antibody A to the patient and administering a dose of Antibody A after at least 7 days. In another embodiment, antibody A is administered 4 times in a cycle of 4 weeks, i.e., one dose per week. In another embodiment, Antibody A is administered in two doses per 4 week period, i.e., one dose is administered every two weeks. In another embodiment, Antibody A is administered one dose every three weeks. In an embodiment, the dosing cycle can be repeated as necessary.

In another embodiment, the dose of each dose of Antibody A is unchanged. In another embodiment, each dose of the antibody is administered differently. For example, the maintenance (or subsequent) dose of the antibody can be greater than or equal to the loading dose administered for the first time. In another embodiment, the maintenance dose of the antibody can be less than or equal to the loading dose. Typical dosages include 3.2, 6, 10, 15, 20, and 40 mg/kg.

In a particular embodiment, the subject treatment regimen is the combination of Antibody A and erlotinib, the doses of which are listed below in Table 6.

In other specific embodiments, Antibody A is administered in combination with erlotinib administered at a daily dose of 100, 125 or 150 mg, wherein Antibody A is administered weekly, every two weeks or every three weeks at a dose of 6 Mg/kg. In other embodiments, Antibody A is administered in combination with erlotinib administered at a daily dose of 100, 125 or 150 mg, wherein Antibody A is administered weekly, every two weeks or every three weeks at a dose of 12 mg. /kg. In other embodiments, Antibody A is administered in combination with erlotinib administered at a daily dose of 100, 125 or 150 mg, wherein Antibody A is administered weekly, every two weeks or every three weeks at a dose of 20 Mg/kg.

Eight, typical results

Subjects treated according to the methods disclosed herein may have at least one indication or symptom associated with NSCLC that may be improved.

In one embodiment, the subject's tumor shrinks and/or the growth rate is reduced, ie, tumor growth is inhibited. In another embodiment, the amount of adverse cell proliferation is decreased or inhibited. In another embodiment, one or more of the following may occur: a decrease in the number of cancer cells; a decrease in tumor volume; a suppression, delay, slowing or cessation of proliferation of peripheral cells by cancer cells; slowing or suppression of tumor metastasis; Tumor growth is inhibited; tumor recurrence is blocked or delayed; one or more cancer-related symptoms are somewhat relieved.

In other embodiments, this improvement is measured by a reduction in the number of measurable tumor lesions and/or a reduction in volume. The measurable lesion refers to the accurate measurement of at least one of the dimensions (the longest straight will be recorded) Path): CT scan (5 mm or less on CT scan level) or lesion with a caliper >10 mm in clinical examination or >20 mm diameter in chest X-ray measurement. The size of non-target lesions (such as pathological lymph nodes) can also be used as an indicator of improvement. In one embodiment, the lesion can be measured through chest x-ray or CT or MRI film.

In other embodiments, the therapeutic response can be assessed using cytology or histology. If the measurable tumor meets the criteria for response or stable disease, consider any cytological confirmation of any neoplastic effusion that occurs or worsens during treatment to identify it as a response or a stable condition (the effusion may be a side effect of treatment) ) or disease progression.

Typical treatment responses to therapy may include: partial response (PR): a reduction in the total size of the target lesion by more than 30% compared to the sum of the baseline diameters; stable disease (SD): compared to the sum of the smallest diameters during the study, the sum of the lesion diameters is Reduced but not partially responded, or increased but did not progress to disease; or complete response (CR): all non-target lesions disappeared and tumor marker levels normalized. All lymph nodes must be free of pathological lesions in size (short axis <10 mm).

Incomplete/non-disease progression refers to the presence of one or more non-target lesions and/or tumor markers that continue to be above normal.

Disease progression (PD) refers to a 20% increase in the sum of the target lesions compared to the smallest size sum during the study period (eg, the baseline sum is the smallest of the study period, and the baseline sum must also be included). Except relative In addition to a 20% increase, the sum of absolute values must exceed 5 mm. The presence of one or more new lesions is also considered progression.

In some embodiments, an effective amount of the composition described herein produces at least one of the following effects: lung tumor volume reduction; reduced metastasis; complete remission; partial remission; stable condition; increased overall response rate; or pathological complete response. In some embodiments, the clinical benefit rate achieved by the effective amount (CBR=CR+PR+SD 6 months) was similar to the clinical benefit rate of erlotinib alone. In other embodiments, the increase in clinical benefit rate is improved by about 20%, 20%, 40%, 50%, 60%, 70%, 80% or higher.

Nine, kit and unit dosage form

Also provided are kits comprising: a pharmaceutical composition comprising an anti-ErbB3 antibody (e.g., Antibody A); and a pharmaceutically acceptable carrier in an amount effective to achieve the therapeutically effective amount employed in the foregoing methods. The kit may also include instructions such as a dosing regimen as needed to enable a medical practitioner (such as a doctor, nurse or patient) to administer the composition contained in the kit to a subject afflicted with cancer (e.g., NSCLC). In an embodiment, the kit further includes a TKI. In another embodiment, the kit includes a syringe.

The kit may optionally comprise a plurality of single dose pharmaceutical composition packs containing an effective amount of an antibody (e.g., Antibody A) for use in a single administration as described above. If desired, the kit can include the instruments or devices required to administer the pharmaceutical composition. For example, the kit can provide one or more prefilled syringes containing the amount of antibody A listed above. About 100 times the dose administered in the method (in mg/kg). If desired, the kit may further comprise a TKI, such as erlotinib or gefitinib in a desired unit dosage form (e.g., unit dosage form sold by a TKI manufacturer) for administration.

It will be apparent to those skilled in the <Desc/Clms Page number number> change.

X. Methods for selecting therapy for patients with NSCLC

Also provided herein are methods of selecting a therapy for a patient with NSCLC, comprising: (a) determining whether the cancer of the patient comprises an activating mutation of the EGFR tyrosine kinase domain; and (b) if included, administering to the patient the following An effective amount: (1) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprising SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) Amino acid sequence, and CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and (2) Erlotinib. In one embodiment, the activating mutation of the EGFR tyrosine kinase domain is a deletion of the residue E746-A750 of the EGFR tyrosine kinase domain (SEQ ID NO: 15). In one embodiment, the anti-ErbB3 antibody is Antibody A.

The following examples are for illustrative purposes only, given the skilled artisan It is apparent that various modifications and changes can be made thereto without departing from the scope of the disclosure, and thus the examples should not be construed as limiting the scope of the invention.

Example Example 1: Human Clinical Trial

Antibody Phase A and erlotinib in patients with non-small cell lung cancer (NSCLC) were used in Phase 1-2 trials.

Phase 1 Target and subject choice

The primary goal of Phase 1 was to determine the safety of the combination of antibody A + erlotinib and to determine the recommended phase 2 antibody A + erlotinib in combination.

The secondary objectives of the study were: ̇ Describe the dose-limiting toxicity of antibody A/erlotinib; determine the adverse event profile of antibody A/erlotinib; determine the pharmacokinetic parameters and antibody A in The immunogenicity of rotitan when used together; ̇ obtain preliminary estimates of other major efficacy endpoints (disease control rate, OS, and ORR) in this population for planning subsequent Phase 2/3 randomized trials; 探索 Collecting exploratory clinical data on potential predictive biomarker sets (measured in serum and tumor tissue)

Research design

This study was an open-label 1/2 phase antibody A/erlotinib combination test. Antibody A was administered intravenously for one hour per week, every two weeks, or every three weeks, depending on the distribution of each group. Erlotinib is administered orally once a day. In the present study, the dose was only increased when the ongoing single-dose antibody A study indicated that the planned dose of antibody A was safe and had successfully passed the DLT (dose-limiting toxicity) evaluation period.

Phase 1 uses the initial scheme of the single-person crossover group for the first group (version 1.1). According to the standard 3+3 design used in the first phase of the study, the program has been revised to version 2.1. After revision to the current version, an additional dosing group, an alternate dosing regimen, and a revised 3+3 design were included in the regimen for each of the 6 patients enrolled in groups 4a, 4b, and 4c. Groups 4b and 4c can be parallel recruitment groups. In the present study, the combined dose of antibody A + erlotinib can be increased, but only with the maximum tolerated dose (MTD) of either of the two or the antibodies A and Ero, which have been shown to be tolerable by the patient. The plan for fentanil is limited to the maximum dose.

Groups 1 to 4a administered 4 doses of Antibody A per cycle of four weeks. Group 4b administered 2 doses of Antibody A every four weeks (administered once every two weeks); Group 4c administered 1 dose of Antibody A every three weeks (3 weeks during the cycle). Evaluation and enhancer for DLT The safety assessment period for the determination of the amount is 4 weeks after the first dose. If no DLT was observed in 3 subjects in one group, the next subject may enter the next consecutive dose level.

Groups 4b and 4c were designed to explore alternative dosing regimens (every two weeks and every three weeks, respectively), but it is not intended to explore an increase in dose levels, and the first three patients in groups 4b and 4c were administered for the first time in the DLT assessment period. 4 weeks after the dose. The safety assessment of patients 4 to 6 of each group will continue, but the recruitment of three patients in each group is intended to collect additional PK data in order to determine the Phase 2 dosing regimen.

Patients in groups 4b and 4c will be randomly assigned to either group at the time of recruitment to minimize bias between the simultaneous recruitment groups.

Recruitment ratio

In the first phase, after the dose-limiting toxicity (DLT) evaluation period has passed and the safety data has been reviewed, the next set of recruitment can be performed. However, groups 4b and 4c in Group 4 can be recruited in parallel, and patients will be randomly assigned to these groups to ensure that there is no bias in the assessment of the two dosing regimens. Once the last subject in the final group has completed the DLT evaluation period and the second stage dose has been determined, the second stage of recruitment can begin.

Duration of treatment

The subject can receive treatment until the disease progresses. From the date of the first dose (Day 1 of the first cycle), it will be based on the current RECIST standard [56 Eisenhauer EA, Therasse P, Bogaerts, et al., New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guideline (version 1.1). The European Journal of Cancer, 2009. 45 (228-247)], re-evaluated evidence of disease progression in subjects every eight weeks. If the subject does not develop disease progression, he or she may continue to participate in additional cycles of treatment.

After discontinuation of study treatment, all subjects will be tracked by telephone contact every 4 months (+/- 2 weeks) from the 30-day overall survival (OS) follow-up visit. The tracking is completed when the subject dies or the date of recruitment of the last subject has expired for one year, whichever is earlier.

Dose level

The recommended starting doses for Antibody A and erlotinib are shown in Table 8 below.

¹ As described in the 1.1 version of the protocol, dose level 1 is a single cross group, and only when the subject has DLT, the group will increase to 6 people. If the subject of Group 1 is treated with the DLT assessment period of dose level 2 successfully completed, a higher dose of erlotinib (150 mg) may be selected.

² After the safety and PK data assessment, a medium dose of antibody A and erlotinib (between groups 2, 3 and 4) and an alternative dosing regimen can be explored. If a DLT or PK profile occurs at the time of administration of a higher dose indicating that a lower concentration can be achieved to achieve a sufficient concentration level, a reduced dose of Antibody A or erlotinib will be included.

³ Groups 4b and 4c were recruited in parallel and patients will be randomly assigned between the two groups to ensure that there is no bias in the assessment of the two dosing regimens.

^{4 After the} DLT evaluation period is completed, the dose of erlotinib can be increased by 25 mg per day with a weekly maximum of 150 mg.

After successful completion of the DLT assessment period for Group 4, a panel with an antibody A dose > 20 mg/kg or an alternative dosing regimen can be evaluated.

Each subject will complete a four-week DLT assessment period prior to the assessment of the dose increase. If a subject has DLT and the number of the group has increased to 6 people, all 6 subjects will need to complete a 4-week evaluation period. In any group, if DLT is present in 2 or more subjects, the dose will not be further increased. Groups 4b and 4c were amplified groups of 6 subjects per group and were parallel recruitment groups. Subject to Subjects will be randomly assigned to groups 4b and 4c to ensure that there is no bias in the evaluation of the dosing regimen. In addition, groups 4b and 4c were designed to explore alternative dosing regimens (every two weeks and every three weeks, respectively), but it is not intended to explore an increase in dose levels. The DLT assessment period is the first three patients in groups 4b and 4c, respectively. Four weeks after the first dose was administered. However, if any of the subjects in these groups developed DLT, all 6 subjects in the group needed to complete a 4-week DLT evaluation period to determine the dose level as safe.

Procedure for increasing dose

Those skilled in the art will determine whether to increase the dosage of the next group. For the group with antibody A dose >20 mg/kg or alternative dosing regimen, the PK data and safety data from the previous group and the available data from the ongoing Phase 1 solid tumor study will be analyzed.

In the first phase, only the subjects at the current dose have completed the safety data assessment of the dose and did not meet the MTD criteria before being able to increase to the next dose level. In addition, after completion of the 4-week DLT assessment period, if any grade 3 or higher drug-related toxicity occurs, the potential relationship between these toxicities and the escalating dose of antibody A + erlotinib will be assessed and Take into account when determining the dose increase. Only when an ongoing single-dose antibody A study indicates an antibody A dose pair The dose was increased only when the subjects were safe in 3 cases.

Definition of dose-limiting toxicity (stage 1)

In the Phase 1 study, any 3-4 grade hematologic or non-hematologic drug-related toxicity, including grade 3-4 infusion reactions associated with Antibody A, was considered a dose limit. Grade 3-4 toxic doses are limited to nausea, vomiting, and diarrhea even when standard antiemetic or anti-diarrheal agents have been used. A level 3 rash is considered a dose limit only if it continues for more than 14 days with the best rash control. In addition, dose-limiting toxicity should be considered as at least three planned doses in the first cycle of treatment due to drug-related toxicity.

All DLT-compliant events, regardless of their severity, should be reported.

Retreatment after dose-limiting toxicity in stage 1

In general, subjects with drug-related dose-limiting toxicity are no longer eligible for additional doses of Antibody A and will be withdrawn from the study. If it is consistently determined that continued treatment is in the best interest of the subject, then it proceeds to the next lower dose group to continue participating in the study. Subjects should have recovered from toxicity to baseline or grade 1 (except for hair loss) prior to retreatment. For DLT caused by low hemoglobin, the subject's hemoglobin concentration should return to baseline levels before retreatment. If any DLT occurs after retreatment, it should be reported to the FDA.

Stage 1 Maximum Tolerated Dose Definition and Recommended Stage 2 Dose

The maximum tolerated dose (MTD) refers to antibody A and erlotide when less than two of the 3-6 patients in the dose group developed DLT. The highest dose level of Nigeria. When at least two patients with DLT were observed in a dose group consisting of 3-6 subjects, the MTD would be determined to have been exceeded, and the other subjects (up to a total of six) were eligible for the next lower dose level. treatment. The recommended combination of Antibody A and Erlotinib in Phase 2 was 20 mg/kg Antibody A and 100 mg Erlotinib; the dose of erlotinib in a single dose was 150 mg per day.

If the MTD is based on the observation of a DLT such as grade 3 AST (aspartate aminotransferase), ALT (alanine aminotransferase) or alkaline phosphatase abnormality in a subject with grade 2 abnormalities and known baseline grade liver metastases, Baseline for the above enzyme levels Subjects with 2 x ULN (upper normal) were enrolled in the standard to continue to increase the dose (ie, the MTD of the population that caused elevated levels of liver enzymes due to liver metastasis). In this case, if two different MTDs are defined for the two groups, the second stage will be at baseline AST, SLT or alkaline phosphatase. Subjects with 2 x ULN were treated with higher MTD.

Subject selection and suspension

In Phase 1, approximately 25 to 37 subjects were recruited, depending on the expansion required and the number of additional groups. In Phase 2, approximately 229 evaluable subjects were recruited.

Three separate NSCLC subject groups will be recruited to the parallel group at the same time. These parallel groups will be further defined below.

Group A includes NSCLC subjects who have received at least one chemotherapy regimen that is considered NSCLC standard care and whose mutation status of the EGFR tyrosine kinase domain of the tumor is wild-type. This includes chemotherapy regimens that also contain biological agents such as bevacizumab or cetuximab.

Group B included subjects who had not previously received any EGFR TKI therapy for cancer in the treatment of metastatic NSCLC; however, there must be known activating mutations in the EGFR tyrosine kinase domain of such subjects.

Group C included subjects who had previously received EGFR TKI therapy and responded to treatment, but whose condition subsequently progressed, thereby developing resistance to the therapy. These subjects must meet the first two of the following criteria and Jackman et al. [Jackman D, Pao W, Riely GJ, et al. Clinical Definition of Acquired Resistance to Epidermal Growth Factor Receptor TKIs in Non-Small-Cell Lung Cancer. J Clin Oncol, 2009. (Epub ahead of print) doi: 10.1200/JCO.2009.25.8574] and Mok [70 Mok TS. Living with Imperfection. J Clin Oncol, 2009. (Epub ahead of print) doi: 10.1200/JCO .2009.24.7049] An additional standard (3a or 3b) adapted: 1. Previously treated with a single dose of an EGFR kinase inhibitor (eg gefitinib or erlotinib); 2. with gefitinib Or erlotinib for a minimum of 30 days of continuous treatment, the disease will progress systematically; and, 3. Any of the following: a. Tumor EGFR mutations are known to be associated with drug sensitivity (ie G719X, Exon 19 deletion, L858R, L861Q); or, b. The subject's tumor is characterized by EGFR wild-type or EGFR-unknown status; however, the records show that the subject has continued to use EGFR kinase inhibitor therapy for at least 12 weeks. There is a reaction.

The EGFR classification (wild type or mutation status) is based on information available to the research unit at the time of recruitment. However, samples obtained at baseline were subsequently evaluated to confirm the status of EGFR. Any differences are adjusted during the analysis.

standard constrain

For Phases 1 and 2, the three groups of NSCLC patients eligible to participate in the study must meet the criteria for one of the following groups: Group A : The mutation status of the subject's tumor EGFR tyrosine kinase domain is Wild type. The subject's cancer relapses or progresses after undergoing at least one chemotherapy regimen that is considered NSCLC standard care. This includes chemotherapy regimens that also include biologics such as bevacizumab or cetuximab; or, group B : Subjects must have never received any EGFR TKI therapy for NSCLC, and the tumor's EGFR tyrosine kinase ( The TKI) domain must have a known activating mutation; or, Group C : As described above, the subject's cancer must show acquired resistance to EGFR TKI formation. For these subjects, any number of therapies were previously accepted.

Subjects must be structurally or cytologically diagnosed with locally advanced or metastatic non-small cell lung cancer

Subjects to be considered in the Phase II study must have a biopsy that must be biopsied and must be willing to undergo a biopsy prior to treatment unless the following two conditions are met: ■ Subject prior to enrollment A biopsy was performed within 2 months and sufficient tumor tissue was available for use; and ■ Since the biopsy, the subject has not undergone any intervention.

Subject must be 18 years of age or older. The subject or his legal representative must be able to understand and sign the informed consent form. According to RECIST (version 1.1), subjects must have unmeasurable or measurable tumors in the Phase 1 trial and must have measurable disease in the second phase. Subjects must maintain a tumor sample for analysis. Approximately 125 micromolar tumor samples (such as FFPE tissue wax blocks or prepared as slides) are required. During the Phase 1 study, if the subject does not have access to the available tumor tissue, they must be willing to undergo a biopsy prior to the start of treatment. The subject's ECOG fitness score (PS) must be 0, 1, or 2. Subjects must have sufficient bone marrow reserves as evidenced by this: ANC > 1,500 / microliter and platelet count > 100,000 / microliter and hemoglobin > 9 grams / deciliter. Subjects must have appropriate liver function as evidenced by this: serum total bilirubin 1.5 x ULN and AST, ALT and alkaline phosphatase 2 x ULN (if liver metastasis is present, 5 x ULN is acceptable and there is bone metastasis, then 5 x alkaline phosphatase ULN is also acceptable). Subjects must have appropriate renal function as evidenced by this: serum creatinine 1.5 x ULN. Subjects must recover from the clinically significant effects of any previous surgery, radiation therapy, or other anti-tumor therapy. For subjects with known peripheral neuropathy, achieving CTCAE Level 1 is acceptable. During the study period and within 90 days after the last dose of study drug, fertile women and fertile men and their partners must agree to abstinence or effective contraception (effective contraceptive methods are oral contraceptives or dual barriers) Contraception method).

Exclusion criteria

For Phases 1 and 2, subjects may be excluded based on one or more of the following: a history of any second malignancy (recurrence or initial diagnosis) over the past 5 years (previously having carcinoma in situ, basal or squamous Subjects with a history of squamous cell skin cancer are eligible; subjects with other malignancies are eligible, such as those who have not had any disease for at least 5 consecutive years in the past; those who are pregnant or breastfeeding; Infected or unidentified during the first day of the scheduled or scheduled administration Subjects with fever (>38.5 °C) (subjects with tumor fever recruited); CNS malignant (primary or metastatic) unhealed and/or symptomatic subjects; CNS malignancy Subjects who have undergone surgery or radiotherapy are eligible to participate in the trial if they are stable and receive stable or progressive reduction of cortisol for at least 2 weeks prior to the first day of scheduled dosing; known to be allergic to any component of Antibody A Subjects, or subjects who developed a hypersensitivity response to all human monoclonal antibodies; received other recent anti-tumor therapies (including experimental therapies performed within 30 days prior to the scheduled first day of administration of the study or scheduled doses for this study) Subject to any standard chemotherapy or radiation performed within 14 days prior to the first day; the last treatment must have sufficient time from the first day of the scheduled administration of the study to determine the actual or predicted toxicity schedule for the treatment; Subjects with NYHA (New York Heart Association Heart Function Rating) grade III or IV congestive heart failure or LVEF (left ventricular ejection fraction) less than 55%; have a history of severe heart disease (ie, uncontrolled blood pressure, angina Stable, myocardial infarction within 1 year or need Subjects with ventricular dysfunction of the drug may also be excluded; subjects with cerebrovascular accidents in the near term (within 1 year); clinically significant ophthalmologic or gastrointestinal abnormalities (including severe dry eye, dryness angle) Subjects with conjunctivitis, xerosis, severe exposed keratitis; abnormalities that may increase the risk of epithelial-related complications (eg, bullous keratopathy, no iris, severe chemical burns, neutrophilic cornea) Subjects with uncontrolled inflammatory gastrointestinal disease (Crohn's disease, ulcerative colitis, etc.); history of allograft transplantation Subject (subject to a subject with a history of autologous bone marrow or stem cell transplantation); a subject with a history of allergic reactions to a compound resembling a chemical or biological composition of erlotinib; or known to have HIV or Hepatitis B or C (activity, treatment, or both); subjects with any other condition that may interfere with the subject's ability to participate in informed consent, coordination, and participation in the study. Interpretation of the results.

Toxicity control

The therapy can be discontinued for 28 consecutive days in order to recover from toxicity, especially in patients who benefit from the study treatment. If a patient fails to recover from toxicity associated with the study drug within 28 days, it will continue to participate in the study.

Subjects with less than dose-limiting toxicity may continue to receive erlotinib daily.

Dosage adjustment for erlotinib in stages 1 and 2

If a subject has any of the following events above level 2, in addition to stopping antibody A treatment, it should also be based on guidelines established during previous erlotinib clinical trials [57 FDA Medical Review; Tarceva® (Errot OSI Pharmaceuticals Inc. NDA Application No. 021743] Adjustments to erlotinib administration were made as indicated in the following table.

^{1 It is} recommended to control skin toxicity according to the guidelines set by the medical consultants for Genentech, Inc. and OSI Pharmaceuticals, Inc.

Antibody A administration method

Antibody A is supplied in a sterile, disposable bottle containing 10.1 ml of Antibody A at a concentration of 25 mg/ml in 20 mmol of histidine, 150 mmol of sodium chloride, pH 6.5. Antibody A is a colorless liquid solution containing a small amount of visible white amorphous antibody A microparticles. Antibody A should be stored away from light and stored at 2-8 ° C (36 to 46 ° F). It is not necessary to avoid light during the infusion. Antibody A must not condense into ice. Antibody A has been shown to be compatible with Alaris®, Paclitaxel, Lifeshield® and Kawasumi infusion sets using 0.2 micron line filters.

In stage I, antibody A was administered weekly to groups 1 to 4a, group 4b was administered every two weeks, and group 4c was administered every three weeks (+/- 2 days). The dose level is determined by the group in which the subject is recruited. In the Phase II study, the dose of antibody A used in combination with erlotinib is determined by the MTD determined in the Phase I study, or by the pharmacokinetic findings and safety data for the determined target dose of Antibody A.

The pharmacy is provided with the expiration date of the stored antibody A. Stabilization should be continued as required by local regulations and the expiration date should be continuously updated by the sponsor's notice to the pharmacy or printed directly on the MM-12 vial.

Antibody A should be placed at room temperature prior to administration. Do not shake the vial of Antibody A. The appropriate amount of Antibody A was taken from the vial, diluted with 250 ml of normal saline (0.9%), and then administered as a IV infusion with a low protein-conjugated 0.22 micron line filter for an infusion time of 90 minutes (for the first One infusion) or 60 minutes (applicable to no Subsequent infusions in the case of infusion reactions).

Erlotinib administration

Erlotinib administration begins on the day following the first dose of antibody A (ie, day 2 of the first cycle). The dose level should be determined by the group that recruited the subject. In the Phase II study, the dose of erlotinib used in combination with Antibody A is determined by the MTD determined in Phase I study, or by the optimal target dose of erlotinib as determined by pharmacokinetic findings and safety data. . Patients randomized to receive erlotinib alone will receive 150 mg of erlotinib daily.

Erlotinib should be taken orally (oral) at least one hour before meals or at least two hours after meals. Please take it at the same time every day. On the day of receiving the antibody A infusion, the subject should take erlotinib just prior to the administration of Antibody A (eg, within a few minutes of the start of the infusion).

Pharmacokinetic assessment

Serum levels of antibody A and erlotinib should be measured in an ELISA array at a central analytical laboratory. In order to better understand the PK and safety properties of antibody A combined with erlotinib, it is also possible to measure additional analytes.

Tumor sample

Tumor samples were soaked in formalin and then embedded in paraffin blocks. These samples were used to determine the subject's EGFR mutation status, assess potential predictive biomarkers, and complete other association studies. Other mutations can also be assessed as needed. Saved paraffin blocks (if available) can be used. In this regard, approximately 125 microliters of tumor sample is required.

In the Phase II study, tumor samples were collected from all patients by biopsy performed prior to the first dose and, if possible, at disease progression (post-treatment biopsy is available). Tumor samples collected through the above biopsy will be compared with historical samples and analyzed to find biomarkers predicting the response to antibody A binding to erlotinib.

result

From February 2010 to July 2011, a total of 33 patients underwent Phase I studies (median age 63 years; 49% men; 18% ECOG 0, 82% ECOG 1). 64% of patients had adenocarcinoma, 27% had previously received 3 or more therapies (range 0-7), and 91% had used platinum. 45% of patients had a wild-type EGFR status and never received treatment or never responded to EGFR-TKI (EGFR wild type). 28% developed acquired resistance to erlotinib (EGFR resistant). The most common toxicities observed were diarrhea (82%), rash (64%) and fatigue (64%). DLT observed in different groups had diarrhea, mucositis, rash, and poor vital function. The observed clinical activities included 1 partial response (EGFR TKI early EGFR mutation) and 14 stable conditions. The average duration of disease stability was 21.6 weeks (range 7.1-89.3 weeks). In the overall population, the median progression-free survival was 7.9 weeks, and the 16-week progression-free survival rate was 41%. For EGFR wild-type and EGFR-resistant patients, the median progression-free survival was 7.6 weeks and 15 weeks, respectively, and the 16-week progression-free survival rate was 32% and 44%. 7/20 EGFR wild-type patients and 5/9 EGFR-resistant patients are stable. The overall survival (OS) of all 33 patients in the Phase 1 study was 9.8 months (6.5-indeterminate). In EGFR wild-type patients, the median overall survival was 9.8 months (6.5-indeterminate), whereas in EGFR-resistant patients, the overall survival was 11.0 months (4.0-indeterminate). In contrast, in the published study in a similar patient population, the median overall survival of erlotinib was 5.3 months (TITAN study) and 6.3 months (BR.21 study).

Figure 2 provides data from Phase 1 clinical trials with Antibody A and Erlotinib.

Figure 3 shows a 3+3 design for assessing patient toxicity in Phase 1, in which antibody A and erlotinib doses are gradually increased until the maximum tolerated dose or maximum target dose is identified. Panel B provides medical history data for 33 patients enrolled in the study.

Figure 4A shows the reported adverse events and Figure 4B provides a summary of the number of adverse events in the dosing group. Such events are similar to the known erlotinib toxicity, and when used in combination with antibody A, there is a tendency to occur more frequently, but not more severely.

A summary of the main results is presented in Table 10:

Figure 5 shows progression free survival (PFS) for all patients in Phase 1 study and patients in Groups A and C. The median progression-free survival was 7.9 weeks (95% CI: 7.6-20.1). The median progression-free survival of group A (EGFR wild type) was 7.6 weeks (7.3-23). The median progression-free survival of group C (EGFR-resistant) was 15 weeks (7.6-indeterminate).

Figure 6 provides a waterfall diagram of the overall survival data for Phase I. The overall survival period (all) was 9.8 months (6.5-indefinite). The overall survival of group A (EGFR wild type) was 9.8 months (6.5-indeterminate). The overall survival of group C (EGFR resistant) was 11.0 months (4.0-indeterminate).

Phase 2

In Phase 2, the trial will assess the combined effect of antibody A and erlotinib in three different populations of approximately 229 NSCLC patients. See Figure 1.

The primary goal of Phase 2 was to estimate the progression-free survival of the combination of antibody A plus erlotinib in the three different patient groups described above, as defined below:

Group A (n=120): The mutation status of the tumor EGFR tyrosine kinase domain of the subject was wild type. Subjects have received at least one chemotherapy regimen that is considered NSCLC standard care when handling metastatic NSCLC. Group A subjects were randomized to receive either antibody A plus erlotinib or erlotinib alone at a 2:1 ratio.

Group B (n=66): There must be a known activating mutation in the subject's tumor EGFR tyrosine kinase domain. Subjects have never received any EGFR TKI therapy before treatment of metastatic NSCLC. Group B subjects were randomized to receive either antibody A plus erlotinib or erlotinib alone at a 2:1 ratio.

Group C (n=43): As described above, the subject's cancer has been shown to acquire acquired resistance to EGFR TKI. For these subjects, any number of therapies were previously accepted. All subjects in this group will receive antibody A plus erlotinib.

Recommended Stage 2 dose

The recommended Phase 2 dose of erlotinib is 100 mg/day, and Antibody A was 20 mg/kg once every two weeks.

Administration adjustment of phase 2 antibody A

In the second phase, if there is a grade 1 or 2 toxicity that may be associated with antibody A treatment, then it will be decided whether to continue treatment. If the subject develops grade 3 or higher toxicity associated with antibody A treatment, further treatment with antibody A should be controlled until the toxicity drops to level 1 or baseline. Subjects should discontinue the study if antibody A treatment ceases for 28 consecutive days and toxicity is not relieved (to baseline or grade 1).

The dose of antibody A in the future can be reduced according to toxicity.

Stage 2 erlotinib administration adjustment

Any dosing adjustments made to erlotinib will follow the Stage 1 method described above.

Statistical Analysis

The categorical variables will be aggregated by frequency distribution (number of subjects and proportions), while continuous variables will be aggregated by descriptive statistics (mean, standard deviation, median, minimum, and maximum).

A safety analysis will be performed using an intention to treat (ITT) population (all subjects who have received at least one study drug infusion). Efficacy analysis will be performed using the intention-to-treat population and the evaluable subject population (subjects receiving 6 or more doses of Antibody A). The results of the EGFR test completed on the baseline subject sample will be compared to the initial recruitment group (Group A, Group B, Group C). If any discrepancies are found, another efficacy analysis will be performed to include the correct grouping. In addition to basis The researchers will report the above results in addition to the primary efficacy analysis of the subject group. In addition, sub-analysis will be performed to further identify major prognostic symptom factors and to explore the presence or absence of major biomarkers.

The efficacy endpoints associated with the following tumor assessments will be assessed: overall progression-free survival (PFS) and progression-free survival; objective response rates (diagnosed as complete response and partial response); confirmed complete response rate; first tumor assessment (8th) Week) disease control rate (DCR = ratio of subjects with stable disease, partial response or complete response); duration of objective response; change in tumor load from baseline (longest diameter of target lesion from baseline) The best change in total); and overall survival. In addition, changes in PS (physical scores) that occur over time from baseline are also summarized.

Example 6 : Combination of antibody A and erlotinib in cancer cells with activating mutations in the EGFR tyrosine kinase domain

HCC827 non-small cell lung adenocarcinoma cell line ^{(ATCC CRL-2868 TM) E746} -A750 deletion (: 15 SEQ ID NO) tyrosine kinase domain coding region of the gene encoding the EGFR occurs. This mutation causes HCC827 cells to respond to erlotinib treatment.

HCC827 cells were cultured in RPMI-1640 medium (Lonza) supplemented with 10% fetal bovine serum (Hyclone), 100 units/ml penicillin, and 100 mg/ml streptomycin (Gibco). Cells in 96-well black tissue culture dishes (1000 per well) The cells were cultured, and after overnight growth, they were replaced with low serum medium (0.5% fetal bovine serum) and cultured for 24 hours. To measure the growth response, cells were treated with several concentrations of antibody A, erlotinib or an equimolar combination of antibody A and erlotinib (erl + MM). The concentration of antibody A was 0.0073, 3, 40, 120, 200 and 1000 nanomolar. The cells were grown for 3 days. The ATP level was then measured using the CellTitre-Glo® Cell Viability Assay (Promega) as described below: After using the CellTitre Glo® reagent for 5 minutes in the shaker, the cells were dissolved at room temperature. The equilibration was then repeated for another 10 minutes; the fluorescence signal was measured using an Envision plate tester (Perkin Elmer) and the original fluorescent signal of each treatment was normalized to media control and mapping using Prism software (GraphPad Software, Inc.).

As shown in Figure 7, antibody A binding to erlotinib produced a synergistic effect on cell viability.

Example 7: Synergistic effect of ErbB3 ligand activation with anti-ErbB3 ligand blocking antibody and EGFR signaling with EGFR tyrosine kinase inhibitor

ACHN renal cancer cells were cultured in 96-well culture dishes of 1000 cells per well; HCC827 NSCLC cells were cultured in 96-well culture dishes of 2000 cells per well. After the cells were grown overnight, they were replaced with low serum medium (0.5% fetal bovine serum) and cultured for 24 hours, followed by blocking doses of various doses of antibody A (ie anti-ErbB3 ligand). , erlotinib (ie EGFR tyrosine kinase inhibitor) or antibody A + erlotinib for 3 days. ATP levels were measured using a CellTitre-Glo® (Promega Corp.) detection system, which was subsequently formatted as a vehicle control. The Bliss synergy/additive analysis is then performed. According to the Bliss analysis, if the two drugs are accurately added, a partial reaction is calculated by obtaining standardized data of the control products of the various drugs used alone. Subsequently, the difference between the observed and calculated partial reactions is divided by the calculated partial response to yield a bliss index value that is negative (synergistic), near zero (additive) or positive (antagonistic).

The results provided in Figure 8 show that antibody A binding to erlotinib synergistically inhibits cell growth, as is the case with Bliss additive additive analysis (Fitzgerald, JB, et al. , Nat Chem Biol. 2006(9): 458-66). .

Those skilled in the art will recognize that numerous equivalents of the specific embodiments described herein can be determined and carried out using only routine experiment. Such equivalents are included in the scope of the following patent application. Any combination of embodiments disclosed in the scope of the patent application is within the scope of the disclosure.

Figure 1 shows a schematic of a Phase 2 clinical trial.

Figure 2 provides data from Phase 1 clinical trials with Antibody A and Erlotinib. Group 1 included patients receiving 6 mg/kg of Antibody A and 100 mg/day of erlotinib. Group 2 included patients receiving 6 mg/kg of Antibody A and 150 mg/day of erlotinib. Group 3 included patients receiving 12 mg/kg of Antibody A and 150 mg/day of erlotinib. Group 3A included patients receiving 12 mg/kg of Antibody A and 100 mg/day of erlotinib. Group 4A included patients receiving 20 mg/kg (QW) Antibody A and 100 mg/day erlotinib. Group 4B included patients receiving 20 mg/kg (QOW) Antibody A and 100 mg/day erlotinib. Group 4C included patients receiving 20 mg/kg (Q3W) Antibody A and 100 mg/day erlotinib. The title of the field on the right is "The reason for the study suspension."

Panel A of Figure 3 shows a 3+3 design for assessing patient toxicity in Phase 1, in which antibody A and erlotinib doses are gradually increased until the maximum tolerated dose or maximum target dose is identified. Panel B shows medical history data from 33 patients enrolled in the study.

Figure 4A provides a summary of graded adverse events with patient incidence > 10% (n = 33). Figure 4B provides a summary of the number of adverse events (n = 33) for different dosing groups with a patient incidence > 10%. Group 1 = 6 Mg/kg antibody A and 100 mg erlotinib. Group 2 = 6 mg/kg antibody A and 150 mg erlotinib. Group 3 = 12 mg/kg antibody A and 150 mg erlotinib. Group 3A = 12 mg/kg antibody A and 100 mg erlotinib. Group 4a = 20 mg/kg Antibody A (once a week) and 100 mg erlotinib. Group 4b = 20 mg/kg Antibody A (every two weeks) and 100 mg erlotinib. Group 4c = 20 mg/kg Antibody A (every three weeks) and 100 mg erlotinib.

Figure 5 shows progression free survival (PFS) for all patients in Phase 1 study and patients in Groups A and C.

Figure 6 provides a waterfall diagram of the overall survival data for Phase I.

Figure 7 provides a graph of cell viability and demonstrates the synergistic effect of antibody A in combination with erlotinib on the survival of cancer cells in which the EGFR tyrosine kinase domain undergoes activating mutations.

Figure 8 shows the synergistic effect of antibody A in combination with erlotinib on ACHN and HCC827 cells.

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Claims (26)

A method of treating non-small cell lung cancer (NSCLC) in a human patient comprising administering to the patient an effective amount of: (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and wherein the sequences are listed in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3) amino acid sequences, and CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise SEQ ID NO: 8 (CDRL1) SEQ ID NO Amino acid sequences of 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and (b) erlotinib, wherein the method comprises at least one cycle, wherein the cycle is 28 days, and wherein the antibody is erlotinib Apply according to the following dosing regimen 1, 2, 3, 3a, 4a, 4b or 4c: The method of claim 1, wherein the anti-ErbB3 antibody is antibody A. The method of claim 1 or 2, wherein the administration schedule is Dosage 1, wherein the antibody is administered intravenously once a week at a dose of 6 mg/kg, while oral erlotinib is administered at a dose of 100 mg per day. The method of claim 1 or 2, wherein the dosage regimen is Dosage 2, wherein the antibody is administered intravenously once a week at a dose of 6 mg/kg, while oral erlotinib is administered at a dose of 150 mg per day. The method of claim 1 or 2, wherein the dosage regimen is Dosage 3, wherein the antibody is administered intravenously once a week at a dose of 12 mg/kg, while oral erlotinib is administered at a dose of 150 mg per day. The method of claim 1 or 2, wherein the dosage regimen is administration schedule 3a, wherein the antibody is administered intravenously once a week at a dose of 12 mg/kg, while oral erlotinib is administered at a dose of 100 mg per day. The method of claim 1 or 2, wherein the dosage regimen is administration schedule 4a, wherein the antibody is administered intravenously once a week at a dose of 20 mg/kg, while oral erlotinib is administered at a dose of 100 or 150 mg per day. The method of claim 1 or 2, wherein the dosage regimen is administration schedule 4b, wherein the antibody is administered intravenously once every two weeks at a dose of 20 mg/kg, while oral erlotinib is administered. For 100 or 150 mg per day. The method of claim 1 or 2, wherein the dosage regimen is administration schedule 4c, wherein the antibody is administered intravenously every three weeks at a dose of 20 mg/kg, while oral erlotinib is administered. For 100 or 150 mg per day. The method of any one of claims 1-9, wherein the effective amount produces at least one of the following effects: tumor volume reduction; metastasis reduction; complete remission; partial remission; stable condition; overall response rate; or pathology Complete reaction. The method of any one of claims 1-9, wherein the NSCLC is a locally advanced or metastatic cancer. The method of any one of claims 1-9, wherein the subject has an NSCLC tumor, wherein EGFR tyrosine The kinase domain is wild type and the subject has previously experienced at least one regimen containing chemotherapy. The method of any one of claims 1-9, wherein the subject has an NSCLC tumor, wherein the EGFR tyrosine kinase domain comprises an activating mutation, and the subject has never received any EGFR TKI therapy before. The method of any one of claims 1-9, wherein the subject has an NSCLC tumor that has been shown to acquire acquired resistance to EGFR TKI. The method of any one of claims 1-9, wherein the subject's NSCLC is characterized by a mutation in the EGFR tyrosine kinase domain (SEQ ID NO: 15), which sensitizes NSCLC to TKI therapy. The method of any one of claims 1-9, wherein the NSCLC characteristic of the subject is a mutation in the EGFR tyrosine kinase domain, the mutation being a deletion of exon 19 of less than 10 contiguous amino acids, A deletion of the EGFR tyrosine kinase domain amino acids R748 and E749 is included (SEQ ID NO: 15). A method of selecting a therapy for a patient with NSCLC, the method comprising: (a) determining whether the cancer of the patient comprises an activating mutation of the EGFR tyrosine kinase domain (SEQ ID NO: 15); and (b) if included, An effective amount of the following items is then administered to the patient: (1) an anti-ErbB3 antibody, comprising CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, Whereas these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and (2) erlotinib. The method of claim 17, wherein the activating mutation of the EGFR tyrosine kinase domain is a deletion of residue E746-A750 of SEQ ID NO: 15. A composition for treating human patient non-small cell lung cancer (NSCLC), the composition comprising a clinically proven safe and effective amount of: (a) an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and these sequences Included are the amino acid sequences set forth in SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 (CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences are included in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and the amino acid sequence of SEQ ID NO: 10 (CDRL3), and (b) erlotinib. The composition of claim 19, wherein the anti-ErbB3 antibody is antibody A. A composition according to claim 19 or 20, wherein the antibody is administered intravenously at a dose of 6 mg/dose. kg. The composition of claim 19, wherein the antibody is administered intravenously at a dose of 12 mg/kg per dose. The composition of claim 19 or 20, wherein the antibody is administered by intravenous injection at a dose of 20 mg/kg per dose. The composition of any one of claims 19 or 20, wherein erlotinib is administered orally daily, 100 mg per day. The composition of any one of claims 19 or 20, wherein erlotinib is administered orally daily at 150 mg per day. A kit comprising a dose of an anti-ErbB3 antibody comprising CDRH1, CDRH2 and CDRH3 sequences, and these sequences comprising SEQ ID NO: 5 (CDRH1) SEQ ID NO: 6 (CDRH2) and SEQ ID NO: 7 ( The amino acid sequence of CDRH3), and the CDRL1, CDRL2 and CDRL3 sequences, and these sequences comprise the amino acid sequences set forth in SEQ ID NO: 8 (CDRL1) SEQ ID NO: 9 (CDRL2) and SEQ ID NO: 10 (CDRL3), and A dose of erlotinib wherein the antibody and erlotinib dose is the amount shown in the following dosing regimen 1, 2, 3, 3a, 4a, 4b or 4c: