Treatment methods using anti-C-MET antibody-drug conjugates

Abstract

This application relates in particular to an improved method for treating solid tumors, including, but not limited to, non-small cell lung cancer ("NSCLC") tumors, gastroesophageal adenocarcinoma ("GEA") tumors, colorectal cancer ("CRC") tumors, and MET gene-amplified progressive solid tumors, using an anti-C-MET antibody-drug conjugate ("anti-c-Met ADC"). In certain embodiments, the anti-c-Met ADC comprises terisotuzumab, a c-Met-targeting antibody conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload.

Description

[Technical Field]

[0001] 1. Cross-reference of related applications This application claims the benefits of U.S. Provisional Patent Application No. 63 / 503,929, filed on 23 May 2023, and U.S. Provisional Patent Application No. 63 / 555,506, filed on 20 February 2024, both of which are incorporated herein by reference in their entirety.

[0002] 2. Sequence Listing This application includes a sequence listing, submitted electronically in XML format, which is incorporated herein by reference in its entirety. The XML copy, created on 4 May 2023, is named 13371-287-888_SEQLISTING.xml and has a size of 20,912 bytes.

[0003] 3. Technical Fields This application relates in particular to an improved method for treating solid tumors, including non-small cell lung cancer ("NSCLC") tumors, gastroesophageal adenocarcinoma ("GEA") tumors, colorectal cancer ("CRC") tumors, MET gene amplification progressive solid tumors, hepatocellular carcinoma (HCC) tumors, biliary tract cancer (BTC) tumors, pancreatic ductal adenocarcinoma (PDAC) tumors, esophageal squamous cell carcinoma (ESCC) tumors, triple-negative breast cancer (TNBC) tumors, hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer (HR+ / HER2-BC) tumors, head and neck squamous cell carcinoma (HNSCC) tumors, or MET gene mutation tumors, by administering a therapeutically effective dose of anti-c-MET antibody-drug conjugate ("anti-c-Met ADC") to human subjects having such solid tumors. In certain embodiments, the anti-c-Met ADC comprises terisotuzumab, a c-Met-targeting antibody conjugated to a potent topoisomerase 1 inhibitor (Top1i) payload. [Background technology]

[0004] 4. Background c-Met is a signaling tyrosine kinase receptor expressed on the surface of epithelial and endothelial cells. Activation of c-Met by hepatocyte growth factor (HGF), its only known ligand, is known to regulate cell proliferation, angiogenesis, survival, and cell motility.

[0005] Antibody-drug conjugates (ADCs) are a new class of therapeutic agents that contain antibodies conjugated to cytotoxic drugs via a chemical linker. The therapeutic concept of ADCs is to combine the binding ability of an antibody with a cytotoxic drug, and the antibody is used to deliver the cytotoxic drug to tumor cells by binding to a target surface antigen, including a target surface antigen that is overexpressed or amplified within the tumor cells. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] There remains a need in this field to develop therapeutic methods using ADCs to treat solid tumors, particularly to find therapeutically effective doses and administration regimens for ADCs. [Means for solving the problem]

[0007] 5. Overview This application relates to a method for treating a non-squamous non-small cell lung cancer ("NSCLC") tumor expressing c-Met, wherein the treatment involves a human subject having the NSCLC tumor and an anti-c-Met antibody-drug conjugate ("anti-c-Met ADC") having the following structure:

[0008] [ka] (Where n is 2, 4, 6, 8 or 10, and Ab is terisotuzumab. (Such anti-c-Met ADCs are also referred to as ADC1 in the present disclosure.)) Disclose a method comprising intravenous administration of a therapeutically effective amount of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg or 6.0 mg / kg every 3 weeks, thereby treating the NSCLC tumor.

[0009] In some embodiments, the NSCLC tumor expressing c-Met is refractory or recurrent.

[0010] In some embodiments, the NSCLC tumor expressing c-Met expresses wild-type epidermal growth factor receptor (EGFR-wt).

[0011] In some embodiments, the NSCLC tumor expressing c-Met expresses mutant EGFR (EGFR-mu).

[0012] In some embodiments, the NSCLC tumor expressing c-Met is a progressive solid tumor that is progressing during any standard therapy, not suitable for surgical resection, or not suitable for other approved treatment options that have shown clinical utility.

[0013] In some embodiments, the NSCLC tumor expressing c-Met is progressing after treatment with at least platinum-based chemotherapy and immunotherapy checkpoint inhibitors and / or appropriate targeted therapy.

[0014] In some embodiments, the NSCLC tumor expressing c-Met is progressing after treatment with at least platinum-based combination chemotherapy of two drugs and / or tyrosine kinase inhibitors.

[0015] In some embodiments, the human subject has received no more than two prior lines of cytotoxic chemotherapy excluding adjuvant therapy.

[0016] In some embodiments, administration of the anti-c-Met ADC results in an overall response rate greater than 15%, greater than 20%, greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0017] In some embodiments, administration of the anti-c-Met ADC achieves partial response (PR) in a human subject.

[0018] In some embodiments, administration of the anti-c-Met ADC achieves complete response (CR) in a human subject.

[0019] In some embodiments, administration of the anti-c-Met ADC achieves stable disease (SD) in a human subject.

[0020] In some embodiments, n takes the value of 2.

[0021] In some embodiments, n takes the value of 4.

[0022] In some embodiments, n takes the value of 6.

[0023] In some embodiments, n takes the value of 8.

[0024] In some embodiments, n takes the value of 10.

[0025] In some embodiments, the average drug-to-antibody ratio (DAR) of the anti-c-Met ADC is from about 5.4 to about 6.6.

[0026] In some embodiments, NSCLC tumors expressing c-Met are refractory or recurrent NSCLC tumors, and a therapeutically effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects. The mean daily action rate (DAR) of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0027] In some embodiments, NSCLC tumors expressing c-Met are refractory or recurrent NSCLC tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects. The mean daily action rate (DAR) of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0028] In some embodiments, NSCLC tumors expressing c-Met are refractory or recurrent NSCLC tumors, and a therapeutically effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects. The mean daily response rate (DAR) of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC results in an overall response rate of over 25%.

[0029] In some embodiments, NSCLC tumors expressing c-Met are refractory or recurrent NSCLC tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects. The mean daily response rate (DAR) of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC results in an overall response rate of over 25%.

[0030] This application relates to a method for treating gastroesophageal adenocarcinoma ("GEA") tumors expressing c-Met, wherein the anti-c-Met ADC having the following structure is used in human subjects having the GEA tumor:

[0031] [ka] Further disclosures include a method for treating a GEA tumor by intravenously administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) every three weeks.

[0032] In some embodiments, GEA tumors expressing c-Met are refractory or recurrent.

[0033] In some embodiments, the c-Met-expressing GEA tumors are histopathologically or cytologically confirmed advanced GEA that is unsuitable for surgical resection, has progressed after treatment with at least one prior cytotoxic chemotherapy regimen for locally advanced or metastatic disease, and the human subjects have not received more than two lines of prior cytotoxic chemotherapy regimens.

[0034] In some embodiments, GEA tumors expressing c-Met progress during immune checkpoint inhibitor therapy.

[0035] In some embodiments, GEA tumors expressing c-Met progress during HER2-targeted therapy.

[0036] In some embodiments, administration of anti-c-Met ADC results in overall response rates of over 25%, over 30%, over 35%, over 40%, over 45%, over 50%, over 55%, over 60%, over 65%, over 70%, over 75%, or over 80%.

[0037] In some embodiments, administration of anti-c-Met ADCs achieves a partial response (PR) in human subjects.

[0038] In some embodiments, administration of anti-c-Met ADCs achieves complete response (CR) in human subjects.

[0039] In some embodiments, administration of anti-c-Met ADC achieves stable disease (SD) in human subjects.

[0040] In some embodiments, n takes the value of 2.

[0041] In some embodiments, n takes the value 4.

[0042] In some embodiments, n takes the value 6.

[0043] In some embodiments, n takes the value 8.

[0044] In some embodiments, n takes the value 10.

[0045] In some embodiments, the average DAR of anti-c-Met ADCs is approximately 5.4 to 6.6.

[0046] In some embodiments, the GEA tumors expressing c-Met are refractory or recurrent GEA tumors, and a therapeutically effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects. The mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0047] In some embodiments, the GEA tumors expressing c-Met are refractory or recurrent GEA tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects. The mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0048] In some embodiments, GEA tumors expressing c-Met are refractory or recurrent GEA tumors, and a therapeutically effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects. The mean daily response rate (DAR) of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC results in an overall response rate of over 25%.

[0049] In some embodiments, GEA tumors expressing c-Met are refractory or recurrent GEA tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects. The mean daily response rate (DAR) of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC results in an overall response rate of over 25%.

[0050] This application relates to a method for treating a colorectal cancer ("CRC") tumor expressing c-Met, wherein the anti-c-Met ADC having the following structure is used in a human subject having the CRC tumor:

[0051] [ka] Further disclosures include a method comprising administering a therapeutically effective dose of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks at doses of 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg, thereby treating the CRC tumor.

[0052] In some embodiments, CRC tumors expressing c-Met are refractory or recurrent.

[0053] In some embodiments, the c-Met-expressing CRC tumors are histopathologically or cytologically identified advanced CRC that lack the BRAF V600E mutation and are not dMMR+ / MSI-Hi.

[0054] In one embodiment, a CRC tumor expressing c-Met is a progressive CRC histopathologically or cytologically confirmed to have a MET genomic alteration. In another embodiment, a CRC tumor expressing c-Met is a progressive CRC histopathologically or cytologically confirmed to have a KRAS genomic alteration. In yet another embodiment, a CRC tumor expressing c-Met is a progressive CRC histopathologically or cytologically confirmed to have an EGFR genomic alteration. In yet another embodiment, only subjects with tumors having one or more of the MET, KRAS, or EGFR genomic alterations are treated, and subjects with tumors lacking one or more of the aforementioned mutations are excluded from treatment.

[0055] In one embodiment, a CRC tumor expressing c-Met is a histopathologically or cytologically confirmed advanced CRC without MET genomic alterations. In another embodiment, a CRC tumor expressing c-Met is a histopathologically or cytologically confirmed advanced CRC without KRAS genomic alterations. In yet another embodiment, a CRC tumor expressing c-Met is a histopathologically or cytologically confirmed advanced CRC without EGFR genomic alterations. In yet another embodiment, only subjects with tumors lacking one or more of the MET, KRAS, or EGFR genomic alterations are treated, and subjects with tumors lacking one or more of the aforementioned mutations are excluded from treatment.

[0056] In some embodiments, c-Met-expressing CRC tumors progress during treatment with one or a combination of prior therapies including fluoropyrimidine, oxaliplatin, irinotecan, anti-EGFR antibodies, and / or anti-vascular endothelial growth factor monoclonal antibodies.

[0057] In some embodiments, c-Met-expressing CRC tumors progress during applicable targeted therapy.

[0058] In some embodiments, administration of anti-c-Met ADC results in overall response rates of over 10%, over 15%, over 20%, over 25%, over 30%, over 35%, over 40%, over 45%, over 50%, over 55%, over 60%, over 65%, over 70%, over 75%, or over 80%.

[0059] In some embodiments, administration of anti-c-Met ADCs achieves a partial response (PR) in human subjects.

[0060] In some embodiments, administration of anti-c-Met ADCs achieves complete response (CR) in human subjects.

[0061] In some embodiments, administration of anti-c-Met ADC achieves stable disease (SD) in human subjects.

[0062] In some embodiments, n takes the value of 2.

[0063] In some embodiments, n takes the value 4.

[0064] In some embodiments, n takes the value 6.

[0065] In some embodiments, n takes the value 8.

[0066] In some embodiments, n takes the value 10.

[0067] In some embodiments, the average DAR of anti-c-Met ADCs is approximately 5.4 to 6.6.

[0068] In some embodiments, the c-Met-expressing CRC tumors are refractory or recurrent CRC tumors, and a therapeutically effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects. The mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0069] In some embodiments, the c-Met-expressing CRC tumors are refractory or recurrent CRC tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects. The mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0070] In some embodiments, the c-Met-expressing CRC tumors were refractory or recurrent CRC tumors, and a therapeutically effective dose of anti-c-Met ADC of 2.4 mg / kg was administered intravenously every three weeks to multiple human subjects. The mean daily response rate (DAR) of anti-c-Met ADC was approximately 6, and administration of anti-c-Met ADC resulted in an overall response rate of over 25%.

[0071] In some embodiments, the c-Met-expressing CRC tumors were refractory or recurrent CRC tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg was administered intravenously every three weeks to multiple human subjects. The mean DAR of anti-c-Met ADC was approximately 6, and administration of anti-c-Met ADC resulted in an overall response rate of over 25%.

[0072] This application relates to a method for treating a MET gene-amplified progressive solid tumor expressing c-Met, wherein the treatment involves a human subject having the MET gene-amplified progressive tumor, wherein the anti-c-Met ADC having the following structure:

[0073] [ka] Further disclosures include a method for treating MET gene-amplifying progressive solid tumors by intravenously administering therapeutically effective doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) every three weeks.

[0074] In some embodiments, MET gene-amplified progressive solid tumors expressing c-Met are refractory or recurrent.

[0075] In some embodiments, n takes the value of 2.

[0076] In some embodiments, n takes the value 4.

[0077] In some embodiments, n takes the value 6.

[0078] In some embodiments, n takes the value 8.

[0079] In some embodiments, n takes the value 10.

[0080] In some embodiments, the average DAR of anti-c-Met ADCs is approximately 5.4 to 6.6.

[0081] In some embodiments, MET gene amplification progressive solid tumors expressing c-Met are refractory or recurrent MET gene amplification progressive solid tumors, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and anti-c-Met ADC administration achieves a partial response (PR) in human subjects.

[0082] In some embodiments, MET gene amplification progressive solid tumors expressing c-Met are refractory or recurrent MET gene amplification progressive solid tumors, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0083] In some embodiments, MET gene-amplifying progressive solid tumors expressing c-Met are refractory or recurrent MET gene-amplifying progressive solid tumors, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0084] In some embodiments, MET gene-amplified progressive solid tumors expressing c-Met are refractory or recurrent MET gene-amplified progressive solid tumors, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0085] 5.1 Exemplary Embodiments This disclosure includes the following non-limiting exemplary embodiments. 5.1.1 Embodiments of NSCLC 1. A method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors, comprising: an anti-C-MET antibody-drug conjugate ("anti-c-Met ADC") having the following structure, administered to a human subject or population of human subjects having the NSCLC tumor:

[0086] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat the NSCLC tumor. 2. The method according to Embodiment 1, wherein NSCLC is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the NSCLC tumor expresses wild-type epidermal growth factor receptor (EGFR-wt). 4. The method according to any one of Embodiments 1 to 2, wherein the NSCLC tumor expresses mutant EGFR (EGFR-mu). 5. The method according to any one of Embodiments 1 to 2, wherein the NSCLC tumor is an advanced solid tumor that has progressed during any standard treatment, is unsuitable for surgical resection, or is unsuitable for other approved treatment options that have demonstrated clinical benefit. 6. The method according to Embodiment 5, wherein the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate targeted therapy. 7. The method according to Embodiment 5, wherein the NSCLC tumor has progressed after treatment with at least platinum-based dual chemotherapy and / or a tyrosine kinase inhibitor. 8. The method according to any one of Embodiments 5 to 7, wherein the human subject has received two or fewer lines of prior cytotoxic chemotherapy, excluding adjuvant therapy. 9. The method according to any one of Embodiments 1 to 8, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 10. A method according to any one of the administration forms 1 to 9, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 11. The method according to any one of Embodiments 1 to 9, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 12. The method according to any one of Embodiments 1 to 9, wherein administration of an anti-c-Met ADC achieves stable (SD) in human subjects. 13. The method according to any one of Embodiments 1 to 12, wherein n takes the value of 2. 14. The method according to any one of Embodiments 1 to 12, wherein n takes the value of 4. 15. The method according to any one of Embodiments 1 to 12, wherein n takes the value 6. 16. The method according to any one of Embodiments 1 to 12, wherein n takes the value of 8. 17. The method according to any one of Embodiments 1 to 12, wherein n takes the value of 10. 18. The method according to any one of Embodiments 1 to 17, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6. 19. The method according to any one of Embodiments 1 to 17, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. 20. The method according to any one of Embodiments 1 to 17, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a PR in human subjects. 21. The method according to any one of Embodiments 1 to 17 and 19, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%. 22. The method according to any one of Embodiments 1 to 17 and 20, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%. 23. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 24. The method according to any one of Embodiments 1 to 23, wherein the tumor expresses c-Met. 25. The method according to any one of claims 1 to 24, wherein the tumor has a MET gene mutation.

[0087] 5.1.2 Embodiments of GEA 1. A method for treating gastroesophageal adenocarcinoma ("GEA") tumors, comprising administering an anti-c-Met ADC having the following structure to a human subject or population of human subjects having the GEA tumor:

[0088] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks to treat the GEA tumor. 2. The method according to Embodiment 1, wherein the GEA tumor is refractory or recurrent. 3. The method according to Embodiment 2, wherein the GEA tumor is progressing during immune checkpoint inhibitor therapy. 4. The method according to any one of Embodiments 1 to 3, wherein the GEA tumor is progressing during HER2-targeted therapy. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 6. The method according to any one of Embodiments 1 to 5, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 7. The method according to any one of Embodiments 1 to 5, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 8. The method according to any one of Embodiments 1 to 5, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 9. The method according to any one of Embodiments 1 to 8, wherein n takes the value of 2. 10. The method according to any one of Embodiments 1 to 8, wherein n takes the value of 4. 11. The method according to any one of Embodiments 1 to 8, wherein n takes the value 6. 12. The method according to any one of Embodiments 1 to 8, wherein n takes the value of 8. 13. The method according to any one of Embodiments 1 to 8, wherein n takes the value of 10. 14. The method according to any one of Embodiments 1 to 13, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6. 15. The method according to any one of Embodiments 1 to 13, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 13, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 17. The method according to any one of Embodiments 1 to 13 and 15, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of more than 25%. 18. The method according to any one of Embodiments 1 to 13 and 16, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of more than 25%. 19. The method according to Embodiment 1, wherein an anti-c-Met ADC is administered in combination with an anti-PD1 antibody or an anti-PD-L1 antibody. 20. The method according to Embodiment 19, wherein an anti-c-Met ADC is administered in combination with an anti-PD1 antibody, and the anti-PD1 antibody is budigalimab, nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, or tripalimab. 21. The method according to Embodiment 19, wherein an anti-c-Met ADC is administered in combination with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumab, or durvalumab. 22. The method according to Embodiment 19, 20, or 21, wherein an anti-c-Met ADC is administered in combination with fluorouracil (5-FU) and leucovorin (LV) / folic acid. 23. Anti-c-Met ADC is administered once every four weeks at a dose of 2.4 or 3.0 mg / kg, and 5-FU is administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin 400 mg / m² once every two weeks. 2 The method according to Embodiment 22, administered in the specified dose. 24. Anti-c-Met ADC is administered once every three weeks at a dose of 2.4 or 3.0 mg / kg, and 5-FU is administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin 400 mg / m² once every two weeks. 2 The method according to Embodiment 22, administered in the specified dose. 25. Anti-c-Met ADC is administered once every two weeks at a dose of 1.2 or 1.6 mg / kg, and 5-FU is administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin 400 mg / m² once every two weeks. 2 The method according to Embodiment 22, administered in the specified dose. 26. Anti-c-Met ADC is administered in combination with fluorouracil (5-FU), leucovorin (LV) / folic acid, and budigalimab, with anti-c-Met ADC administered once every four weeks at a dose of 2.4 or 3.0 mg / kg, budigalimab administered once every four weeks at a dose of 500 mg, and 5-FU administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin 400 mg / m² once every two weeks.2 The method according to embodiment 1, administered at the dosage of 27. The anti-c-Met ADC is administered in combination with fluorouracil (5-FU), leucovorin (LV) / folic acid, and buparlisib, the anti-c-Met ADC is administered once every two weeks at a dosage of 1.2 or 1.6 mg / kg, buparlisib is administered once every two weeks at a dosage of 250 mg, 5-FU is administered once every two weeks at a dosage of 2400 mg / m 2 and leucovorin is administered once every two weeks at a dosage of 400 mg / m 2 The method according to embodiment 1, administered at the dosage of 28. The method according to any one of embodiments 1 to 27, wherein the tumor expresses c-Met. 29. The method according to any one of embodiments 1 to 28, wherein the tumor has a MET gene mutation.

[0089] 5.1.3 Embodiments of CRC 1. A method of treating a colorectal cancer (「CRC」) tumor, comprising administering to a human subject or population of human subjects having said CRC tumor an anti-c-Met ADC having the following structure:

[0090]

Chemical formula

[0091] 5.1.4 Embodiments of MET Amp 1. A method for treating MET gene amplification progressive solid tumors, comprising: a human subject or population of human subjects having the MET gene amplification progressive tumor, wherein an anti-c-Met ADC having the following structure:

[0092] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, thereby treating the MET gene-amplifying progressive solid tumor. 2. The method according to Embodiment 1, wherein the MET gene amplification progressive solid tumor is refractory or recurrent. 3. The method according to Embodiment 1 or 2, wherein n takes the value of 2. 4. The method according to Embodiment 1 or 2, wherein n takes the value 6. 5. The method according to Embodiment 1 or 2, wherein n takes the value of 8. 6. The method according to Embodiment 1 or 2, wherein n takes the value of 10. 7. The method according to any one of Embodiments 1 to 6, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6. 8. The method according to any one of Embodiments 1 to 6, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately , and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. 9. The method according to any one of Embodiments 1 to 6, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. 10. The method according to any one of Embodiments 1 to 6 and 8, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of more than 25%. 11. The method according to any one of Embodiments 1 to 6 and 9, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of more than 25%. 12. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 13. The method according to any one of Embodiments 1 to 12, wherein the tumor expresses c-Met. 14. The method according to any one of claims 1 to 13, wherein the tumor has a MET gene mutation.

[0093] 5.1.5 Embodiments of HCC 1. A method for treating hepatocellular carcinoma ("HCC") tumors, comprising administering an anti-c-Met ADC having the following structure to a human subject or population of human subjects having the HCC tumor:

[0094] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat the HCC tumor. 2. The method according to Embodiment 1, wherein the HCC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the HCC tumor is locally advanced or metastatic, with disease progression during or after one line of prior systemic therapy. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, more than 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the HCC tumor is a refractory or recurrent HCC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the HCC tumor is a refractory or recurrent HCC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 12 and 14, wherein the HCC tumor is a refractory or recurrent HCC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of more than 25%. 17. The method according to any one of Embodiments 1 to 12 and 15, wherein the HCC tumor is a refractory or recurrent HCC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of more than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0095] 5.1.6 Embodiments of PDAC 1. A method for treating pancreatic ductal adenocarcinoma ("PDAC") tumors, comprising: a human subject or population of human subjects having the PDAC tumor, and an anti-c-Met ADC having the following structure:

[0096] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat the PDAC tumor. 2. The method according to Embodiment 1, wherein the PDAC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor that progresses during or after one systemic therapy. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor that progresses during or after one systemic therapy, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 12 and 14, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%. 17. The method according to any one of Embodiments 1 to 12 and 15, wherein the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC tumor that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0097] 5.1.7 Embodiments of BTC 1. A method for treating biliary tract cancer ("BTC") tumors, comprising administering an anti-c-Met ADC having the following structure to a human subject or population of human subjects having the BTC tumor:

[0098] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat the BTC tumor. 2. The method according to Embodiment 1, wherein the BTC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer, which progresses during or after one systemic therapy. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor that progresses during or after one systemic therapy, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor that progresses during or after one systemic therapy, and an effective therapeutic dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 12 and 14, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%. 17. The method according to any one of Embodiments 1 to 12 and 15, wherein the BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic BTC tumor that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0099] 5.1.8 Embodiments of ESCC 1. A method for treating esophageal squamous cell carcinoma ("ESCC") tumors, comprising administering an anti-c-Met ADC having the following structure to a human subject or population of human subjects having the ESCC tumor:

[0100] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat the ESCC tumor. 2. The method according to Embodiment 1, wherein the ESCC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the ESCC tumor is histologically or cytologically confirmed to be locally advanced or metastatic, and the disease progresses during two lines or less of prior cytotoxic chemotherapy. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the ESCC tumor is histologically or cytologically confirmed to be locally advanced or metastatic, with disease progression during two or fewer lines of prior cytotoxic chemotherapy, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the ESCC tumor is histologically or cytologically confirmed to be locally advanced or metastatic, with disease progression during two or fewer lines of prior cytotoxic chemotherapy, and an effective therapeutic dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 12 and 14, wherein the ESCC tumor is histologically or cytologically confirmed to be locally advanced or metastatic, with disease progression during two or fewer lines of prior cytotoxic chemotherapy, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate greater than 25%. 17. The method according to any one of Embodiments 1 to 12 and 15, wherein the ESCC tumor is histologically or cytologically confirmed to be locally advanced or metastatic, the disease progresses during two or fewer lines of prior cytotoxic chemotherapy, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate greater than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0101] 5.1.9 Embodiments of TNBC 1. A method for treating triple-negative breast cancer tumors ("TNBC"), comprising administering an anti-c-Met ADC having the following structure to a human subject or population of human subjects having the TNBC tumor:

[0102] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks, thereby treating the TNBC tumor. 2. The method according to Embodiment 1, wherein the TNBC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC tumor that progresses after at least one line of prior systemic therapy. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC tumor that has progressed after at least one line of prior systemic therapy, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC tumor that has progressed after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 12 and 14, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC tumor that has progressed after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate greater than 25%. 17. The method according to any one of Embodiments 1 to 12 and 15, wherein the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC tumor that progresses after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate greater than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0103] 5.1.10 Embodiments of HR+ / HER2- BC 1. A method for treating hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer ("HR+ / HER2-BC") tumors, comprising: a human subject or population of human subjects having the HR+ / HER2-BC tumor, wherein an anti-c-Met ADC having the following structure:

[0104] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, thereby treating the HR+ / HER2- BC tumor. 2. The method according to Embodiment 1, wherein the HR+ / HER2- BC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- breast cancer tumor that progresses after at least one line of prior endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in human subjects. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic and unresectable HR+ / HER2- BC tumor that progresses after at least one line of prior endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, and the therapeutic effective dose of anti-c-Met ADC is administered intravenously every three weeks to human subjects at a dose of 2.4 mg / kg, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- BC tumor that progresses after at least one line of prior endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1-12 and 14, wherein the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic and unresectable HR+ / HER2- BC tumor that progresses after at least one line of prior endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate greater than 25%. 17. The method according to any one of Embodiments 1-12 and 15, wherein the HR+ / HER2- BC tumor is histologically or cytologically confirmed locally advanced or metastatic and unresectable HR+ / HER2- BC tumor that progresses after at least one line of prior endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate greater than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0105] 5.1.11 Embodiments of HNSCC 1. A method for treating head and neck squamous cell carcinoma (HNSCC) tumors, comprising administering an anti-c-Met ADC having the following structure to a human subject or population of human subjects having the HNSCC tumor:

[0106] [ka] A method comprising administering a therapeutically effective dose of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, comprising 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg, to treat the HNSCC tumor. 2. The method according to Embodiment 1, wherein the HNSCC tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC tumor that progresses after at least one line of prior systemic therapy. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 10%, more than 15%, 20%, more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC tumor that has progressed after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with an average drug-antibody ratio of approximately 5.4 to approximately 6.6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC tumor that has progressed after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1 to 12 and 14, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC tumor that has progressed after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate greater than 25%. 17. The method according to any one of Embodiments 1-12 and 15, wherein the HNSCC tumor is a histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC tumor that has progressed after at least one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and the administration of anti-c-Met ADC results in an overall response rate greater than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. 20. The method according to any one of claims 1 to 19, wherein the tumor has a MET gene mutation.

[0107] 5.1.12 Embodiments of MET gene mutation-type progressive solid tumors 1. A method for treating a progressive solid tumor with a MET gene mutation, comprising: a human subject or population of human subjects having the MET gene mutation-type progressive solid tumor, wherein an anti-c-Met ADC having the following structure:

[0108] [ka] A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, thereby treating the MET gene-mutated progressive solid tumor. 2. The method according to Embodiment 1, wherein the MET gene mutation-type progressive solid tumor is refractory or recurrent. 3. The method according to any one of Embodiments 1 to 2, wherein the MET gene mutation-associated progressive solid tumor is a histologically or cytologically confirmed progressive solid tumor having a MET mutation, including mutations in the tyrosine kinase domain, near-membrane region and extracellular domain, which is unsuitable for surgical resection, has progressed after at least one prior systemic therapy and / or for which there are no satisfactory alternative treatment options. 4. The method according to any one of Embodiments 1 to 3, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%. 5. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects. 6. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in a human subject. 7. The method according to any one of Embodiments 1 to 4, wherein administration of an anti-c-Met ADC achieves stable disease (SD) in the subject. 8. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 2. 9. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 4. 10. The method according to any one of Embodiments 1 to 7, wherein n takes the value 6. 11. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 8. 12. The method according to any one of Embodiments 1 to 7, wherein n takes the value of 10. 13. The method according to any one of Embodiments 1 to 12, wherein the anti-c-Met ADC is present in a pharmaceutical formulation having an average DAR of approximately 5.4 to approximately 6.6. 14. The method according to any one of Embodiments 1 to 12, wherein the MET gene mutation-associated progressive solid tumor is histologically or cytologically confirmed to have a MET mutation, is unsuitable for surgical resection, has progressed after at least one prior systemic therapy and / or there are no satisfactory alternative treatment options, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, the anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 5.4 to approximately 6.6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 15. The method according to any one of Embodiments 1 to 12, wherein the MET gene mutation-associated progressive solid tumor is histologically or cytologically confirmed to have a MET mutation, is unsuitable for surgical resection, has progressed after at least one prior systemic therapy and / or there are no satisfactory alternative treatment options, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human patients. 16. The method according to any one of Embodiments 1-12 and 14, wherein the MET gene mutation-associated progressive solid tumor is histologically or cytologically confirmed to have a MET mutation, is unsuitable for surgical resection, has progressed after at least one prior systemic therapy and / or there are no satisfactory alternative treatment options, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate greater than 25%. 17. The method according to any one of Embodiments 1-12 and 15, wherein the MET gene mutation-associated progressive solid tumor is histologically or cytologically confirmed to have a MET mutation, is unsuitable for surgical resection, has progressed after at least one prior systemic therapy and / or there are no satisfactory alternative treatment options, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, anti-c-Met ADC is present in a pharmaceutical formulation with a mean drug-antibody ratio (DAR) of approximately 6, and administration of anti-c-Met ADC results in an overall response rate greater than 25%. 18. The method according to Embodiment 1, wherein the tumor has a MET gene mutation. 19. The method according to any one of Embodiments 1 to 18, wherein the tumor expresses c-Met. [Brief explanation of the drawing]

[0109] 6. Brief Description of the Drawings [Figure 1] Reducing reverse-phase liquid chromatography of ADC1 composition. [Figure 2] Deconvolution of the mass spectrum of the ADC1 composition. [Figure 3] A dose escalation scheme. [Figure 4] Clinical trial design for dose expansion of monotherapy. [Figure 5A] PK profiles of ADC1 composition (Figure 5A) and Top1i (Figure 5B). [Figure 5B]PK profiles of ADC1 composition (Figure 5A) and Top1i (Figure 5B). [Figure 6A] Percentage change in target lesion measurements over time from baseline in all patients (Figure 6A; N=57) and CRC patients (Figure 6B; N=27). [Figure 6B] Percentage change in target lesion measurements over time from baseline in all patients (Figure 6A; N=57) and CRC patients (Figure 6B; N=27). [Figure 7A] This shows the typical cytoplasmic staining intensity of c-Met in non-squamous NSCLCs. SP44 OptiView IHC cytoplasmic staining intensity (20×) for IHC scores of 0 (Figure 7A), 1+ (Figure 7B), 2+ (Figure 7C), and 3+ (Figure 7D). [Figure 7B] This shows the typical cytoplasmic staining intensity of c-Met in non-squamous NSCLCs. SP44 OptiView IHC cytoplasmic staining intensity (20×) for IHC scores of 0 (Figure 7A), 1+ (Figure 7B), 2+ (Figure 7C), and 3+ (Figure 7D). [Figure 7C] This shows the typical cytoplasmic staining intensity of c-Met in non-squamous NSCLCs. SP44 OptiView IHC cytoplasmic staining intensity (20×) for IHC scores of 0 (Figure 7A), 1+ (Figure 7B), 2+ (Figure 7C), and 3+ (Figure 7D). [Figure 7D] This shows the typical cytoplasmic staining intensity of c-Met in non-squamous NSCLCs. SP44 OptiView IHC cytoplasmic staining intensity (20×) for IHC scores of 0 (Figure 7A), 1+ (Figure 7B), 2+ (Figure 7C), and 3+ (Figure 7D). [Figure 8A] The following shows the typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for IHC scores of 0 (Figure 8A), 1+ (Figure 8B), 2+ (Figure 8C), and 3+ (Figure 8D). [Figure 8B] The following shows the typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for IHC scores of 0 (Figure 8A), 1+ (Figure 8B), 2+ (Figure 8C), and 3+ (Figure 8D). [Figure 8C]The following shows the typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for IHC scores of 0 (Figure 8A), 1+ (Figure 8B), 2+ (Figure 8C), and 3+ (Figure 8D). [Figure 8D] The following shows the typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for IHC scores of 0 (Figure 8A), 1+ (Figure 8B), 2+ (Figure 8C), and 3+ (Figure 8D). [Figure 9A-1] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9A-2] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9A-3] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9B-1] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9B-2] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9B-3]The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9C-1] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9C-2] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 9C-3] The following shows typical membrane staining intensities of c-Met in non-squamous NSCLC. SP44 OptiView IHC membrane staining intensity of 20× for c-Met-negative (Figures 9A1-9A3), c-Met-positive (Figures 9B1-9B3), and c-Met-high (Figures 9C1-9C3). [Figure 10] This shows the distribution of SP44 UltraView and OptiView IHC with 3+ intensity staining in a commercial cohort of NSCLC. [Figure 11]The ≥25% 3+ cutoff for SP44 OptiView indicates that it selects a patient population similar to that of SP44 Ultraview. The abbreviations and table values ​​shown in Figure 5 are determined as follows: PPA (positive percent agreement): # oV positive uV positive / total uV positive; NPA (Negative percent agreement): # oV negative uV negative / total uV negative; OPA (Overall percent agreement): # oV positive uV positive + # oV negative uV negative / total number of samples tested; PPV (Positive predictive value): # oV positive uV positive / total # oV positive; NPV (Negative predictive value): # oV negative uV negative / total # oV negative. %BOR represents the best overall effect percentage. [Figure 12] The ≥50% 3+ cutoff for SP44 OptiView indicates that it selects a patient population similar to that of SP44 Ultraview. The abbreviations and table values ​​shown in Figure 12 are determined as follows: PPA (Positive Agreement Rate): # oV positive uV positive / Total uV positive; NPA (Negative Agreement Rate): # oV negative uV negative / Total uV negative; OPA (Overall Agreement Rate): # oV positive uV positive + # oV negative uV negative / Total number of samples; PPV (Positive Predictive Value): # oV positive uV positive / Total # oV positive; NPV (Negative Predictive Value): # oV negative uV negative / Total # oV negative. %BOR represents the Best Overall Efficacy Percentage. [Figure 13A] : Percentage change in target lesion measurements over time from baseline in EGFR-wt non-squamous NSCLC patients (Part 2i), EGFR-mu non-squamous NSCLC patients (Part 2ii), and squamous NSCLC patients (Part 2i); Percentage change in target lesion measurements over time from baseline in EGFR-wt non-squamous NSCLC patients (Part 2i). [Figure 13B]: Percentage change in target lesion measurements over time from baseline in EGFR-wt non-squamous NSCLC patients (Part 2i), EGFR-mu non-squamous NSCLC patients (Part 2ii), and squamous NSCLC patients (Part 2i); Percentage change in target lesion measurements over time from baseline in EGFR-wt non-squamous NSCLC patients (Part 2i). [Figure 14A] Percentage change in target lesion measurements over time from baseline in patients with GEA. [Figure 14B] Percentage change in target lesion measurements over time from baseline in patients with GEA. [Figure 15A] Percentage changes in target lesion measurements over time from baseline in CRC patients in Part 1 (Figure 15A) and CRC patients in Part 4 (Figure 15B). [Figure 15B-1] Percentage changes in target lesion measurements over time from baseline in CRC patients in Part 1 (Figure 15A) and CRC patients in Part 4 (Figure 15B). [Figure 15B-2] Percentage changes in target lesion measurements over time from baseline in CRC patients in Part 1 (Figure 15A) and CRC patients in Part 4 (Figure 15B). [Figure 15B-3] Percentage changes in target lesion measurements over time from baseline in CRC patients in Part 1 (Figure 15A) and CRC patients in Part 4 (Figure 15B). [Figure 16] : Percentage change in target lesion measurements over time from baseline in patients with MET-amplified tumors (N=27). [Modes for carrying out the invention]

[0110] 7. Detailed explanation Provided herein is a method for treating solid tumors in human subjects by administering a therapeutically effective dose of anti-c-Met ADC. The therapeutically effective dose of anti-c-Met ADC is sufficient to produce a stable, partial, or complete response and / or an increase in overall survival in the subject according to RECIST v1.1. In a preferred embodiment, the anti-c-Met ADC is ADC1 (see Section 6.2).

[0111] Solid tumors treatable by the methods described herein include, but are not limited to, non-small cell lung cancer ("NSCLC") tumors, gastroesophageal adenocarcinoma ("GEA") tumors, colorectal cancer ("CRC") tumors, MET-amplified progressive solid tumors, hepatocellular carcinoma ("HCC") tumors, biliary tract cancer ("BTC") tumors, pancreatic ductal adenocarcinoma ("PDAC") tumors, esophageal squamous cell carcinoma (ESCC) tumors, triple-negative ("TN") breast cancer ("BC") tumors, hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer ("HR+ / HER2-BC") tumors, head and neck squamous cell carcinoma ("HNSCC") tumors, or MET gene mutation tumors. The treatment method comprises administering a therapeutically effective dose of anti-c-Met ADC to a human subject having one of the solid tumors. The therapeutically effective dose of anti-c-Met ADC is sufficient to produce a stable, partial, or complete response and / or an increase in overall survival in the subject according to RECIST v1.1. In a preferred embodiment, the anti-c-Met ADC is ADC1 (see Section 6.2). In such a preferred embodiment, ADC1 is administered once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg.

[0112] 7.1 Definition Where used in this disclosure, the singular forms “a,” “an,” and “the” refer to multiple objects unless the context specifically indicates otherwise. The terms “a” (or “an”), and the terms “one or more” and “at least one” may be used interchangeably herein unless the context specifically indicates otherwise.

[0113] When used herein in phrases such as "A and / or B," the term "and / or" is to mean "A and B," "A or B," "A," or "B."

[0114] As used in this disclosure and unless otherwise specified, the terms “about” and “approximately” generally refer to a range of numbers that a person skilled in the art would consider equal to (i.e., having the same function or result as) the stated value. Often, the terms “about” and “approximately” may include numbers rounded to the nearest significant figure. In certain embodiments, the terms “about” and “approximately” shall be construed to allow for normal variation as determined by a person skilled in the art, such as variation within 20%, 10%, or 5%. In certain embodiments, the terms “about” and “approximately” encompass the very value stated. Unless the context specifically indicates otherwise, all numerical values ​​provided herein are modified by the term “about.”

[0115] The terms “patient” and “subject” are used interchangeably herein and refer to human beings. In certain embodiments, the subject is a human adult (i.e., at least 18 years of age).

[0116] Unless the context specifically requires otherwise, the terms “comprise,” “comprises,” and “comprising” are used with the understanding that they are to be interpreted inclusively, not exclusively, to indicate that the described features are included without excluding one or more other such features. However, whenever aspects and embodiments are described herein using the term “comprise” (or “comprises” or “comprising”), it is understood that similar aspects that would otherwise be described in terms of “consist of” (or “consists of” or “consisting of”) and / or “consist essentially of” (or “consists essentially of” or “consisting essentially of”) are also provided.

[0117] As used herein, the term “therapeutic dose” of ADC refers to the amount of ADC sufficient to produce stable, partial, or complete response and / or an increase in overall survival according to RECIST v1.1. RECIST v1.1 is published in New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), Eur Journal of Cancer 45 (2009), pp. 228-247, which is incorporated herein by reference in its entirety. “Complete response (CR)” means the disappearance of all target lesions. Any pathological lymph node (target or non-target) must have a short axis reduction to <10 mm. “Partial response (PR)” means a reduction of at least 30% of the total diameter of target lesions relative to the total diameter at baseline. “Progressive disease (PD)” means an increase of at least 20% of the total diameter of target lesions relative to the minimum total in the study (this includes the baseline total if the baseline total is the minimum in the study). In addition to a relative increase of 20%, the total must also show an absolute increase of at least 5 mm (Note: The appearance of one or more new lesions is also considered progression). "Stable (SD)" means that, based on the minimum total diameter during the trial, there is neither a sufficient reduction to meet the requirements for partial reduction (PR) nor a sufficient increase to meet the requirements for progressive disease (PD).

[0118] 7.2 Anti-c-Met ADC and ADC1 As described herein, the anti-c-Met ADC has the following structure:

[0119] [ka] (In the formula, n is 2, 4, 6, 8 or 10, and Ab is, The amino acid sequence shown as Sequence ID No. 7:

[0120] [ka] The heavy chain variable region including, and the amino acid sequence shown as SEQ ID NO: 8:

[0121] [ka] This is an IgG1 anti-C-MET antibody containing a light chain variable region.

[0122] In a preferred embodiment, Ab is terisotuzumab. In such a preferred embodiment, the anti-c-Met ADC is referred to as ADC1. Terisotuzumab is a humanized recombinant IgG1κ antibody (disclosed as 224G11 [TH7 Hz3] in U.S. Patent No. 8,741,290) that targets a unique epitope of c-Met located within the immunoglobulin-plexin-transcription factor homology (IPT) domain 1, resulting in blockade of both HGF-dependent and HGF-independent c-Met signaling.

[0123] Terisotuzumab contains a heavy chain with the amino acid sequence shown as Sequence ID No. 9 (the constant region is in bold; the CDRs defined according to IMGT nomenclature are underlined (disclosed as Sequence IDs 1-3 in order of appearance)):

[0124] [ka]

[0125] In this embodiment, Ab is the heavy chain of SEQ ID NO: 9 with a C-terminal lysine (K) residue added. and a light chain containing the amino acid sequence shown as Sequence ID No. 10 (underlined CDR sequences defined according to IMGT nomenclature (disclosed as Sequence IDs 4-6 in order of appearance)):

[0126] [ka]

[0127] The terisotuzumab heavy chain is encoded by the following nucleotide sequence (the full-length sequence disclosed as SEQ ID NO: 11):

[0128] [ka] JPEG2026518170000024.jpg98150

[0129] The bold capitalized secretory signal peptides contain the final stop codon (TGA); the constant region is in bold; the CDR is underlined (the CDR sequences are disclosed as SEQ ID NOs. 12-14, respectively, in order of appearance).

[0130] The terisotuzumab light chain is encoded by the following nucleotide sequence (the full-length sequence disclosed as SEQ ID NO: 15):

[0131] [ka]

[0132] The bold capitalized secretory signal peptides contain the final stop codon (TGA); the constant region is in bold; the CDR is underlined (the CDR sequences are disclosed as SEQ ID NOs. 16-18, respectively, in order of appearance).

[0133] In certain embodiments, linker-drug conjugation to terisotuzumab occurs via a binding formed by sulfhydryl groups on cysteine ​​residues of the antibody.

[0134] In certain embodiments, the number (n) of drugs conjugated to terissomab in ADC1 is 2, 4, 6, 8, or 10. In one embodiment, ADC1 is a composition comprising a plurality of ADC1 species where n takes on more than one different value. In some embodiments, the composition of ADC1 has an average drug-to-antibody ratio (DAR) of about 5 to about 7, about 5.4 to about 6.6, or about 5.8, about 5.9, about 6.0, about 6.1, or about 6.2. In some embodiments, the composition of ADC1 has an average of 6 molecules of a topoisomerase 1 inhibitor (Top1i) conjugated to terissomab. In some embodiments, the predominant species of ADC1 in the composition has n = 6. In some embodiments, ADC1 has an average DAR of about 6.

[0135] 7.3. Method of Use 7.3.1 Non-Small Cell Lung Cancer (NSCLC) In one aspect, provided herein is a method of treating a non-small cell lung cancer ("NSCLC") tumor, the method comprising administering to a human subject or population of human subjects having the NSCLC tumor a therapeutically effective amount of an anti-C-MET antibody-drug conjugate (ADC) having the following structure:

[0136] [Chemical formula] (where n is 2, 4, 6, 8, or 10 and Ab is terissomab. Such anti-c-Met ADC is also referred to as ADC1 in this disclosure.) thereby treating the NSCLC tumor.

[0137] In preferred embodiments, ADC1 is administered to human patients once every three weeks at a dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In preferred embodiments, ADC1 is administered parenterally. In preferred embodiments, parenteral administration is intravenous administration. In preferred embodiments, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity.

[0138] In certain embodiments, the NSCLC tumor is advanced. In certain embodiments, the NSCLC tumor is a recurrent NSCLC tumor. In certain embodiments, the NSCLC tumor is a refractory or recurrent NSCLC tumor.

[0139] In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or an appropriate applicable targeted therapy.

[0140] In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based combination chemotherapy of two drugs and / or a tyrosine kinase inhibitor.

[0141] In certain embodiments, the human subject has received no more than two prior lines of cytotoxic chemotherapy excluding adjuvant therapy.

[0142] In certain embodiments, the NSCLC tumor is progressive NSCLC that is not suitable for surgical resection or other approved treatment options (including immunotherapy) that have shown clinical utility.

[0143] In certain embodiments, the NSCLC tumor is non-squamous NSCLC. In certain embodiments, the NSCLC tumor is squamous NSCLC.

[0144] In certain embodiments, the NSCLC tumor is a progressive solid tumor that has progressed during any standard treatment therapy, is not suitable for surgical resection, or is not suitable for other approved treatment options that have shown clinical utility.

[0145] In various embodiments, NSCLC tumors express c-Met. In embodiments, only subjects with NSCLC tumors expressing c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, c-Met-expressing NSCLC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable NSCLC that progresses after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0146] In various embodiments, subjects with NSCLC tumors are treated without knowledge of or evaluation of NSCLC tumor c-Met expression.

[0147] In some embodiments, NSCLC tumors are treated regardless of their EGFR status, i.e., whether the NSCLC tumor expresses wild-type epidermal growth factor receptor (EGFR-wt) or mutant EGFR (EGFR-mu).

[0148] In some embodiments, NSCLC tumors express wild-type epidermal growth factor receptor (EGFR-wt). In certain embodiments, NSCLC tumors express both c-Met and EGFR-wt.

[0149] In other embodiments, NSCLC tumors express mutant EGFR (EGFR-mu). In certain embodiments, NSCLC tumors express both c-Met and EGFR-mu.

[0150] In some embodiments, the EGFR status (wild-type or variant) of NSCLC is detected by an FDA-approved test. One such test uses real-time polymerase chain reaction (PCR) to identify at least 42 mutations in exons 18, 19, 20, and 21 of the EGFR gene. This test has been clinically validated in multiple clinical trials as a companion diagnostic (CDx) for both first-line and second-line EGFR TKI therapy in patients with advanced NSCLC (Heeke et al., (2019) Clinical Lung Cancer 21(1): pp. 56-65). Next-generation sequencing (NGS) can also be used to detect EGFR mutations. Many companies have FDA-approved CDx assays for detecting EGFR mutations, including Foundation One CDx, Thermo Fisher Oncomine NSCLC, and Guardant 360CDx. See also Ding et al., (2019) Thoracic Cancer 10: pp. 1879-1884, discussing the use of the Thermo Fisher Oncomine NSCLC assay.

[0151] In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and / or an appropriate applicable targeted therapy. In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based dual chemotherapy and / or a tyrosine kinase inhibitor. In certain embodiments, the human subject has received two or fewer lines of prior cytotoxic chemotherapy, excluding adjuvant therapy. In certain embodiments, the NSCLC tumor is advanced NSCLC that is unsuitable for surgical resection or other approved treatment options (including immunotherapy) that have demonstrated clinical benefit.

[0152] In certain embodiments, the NSCLC tumor is a tumor with EGFR-wt expression (e.g., an advanced non-squamous NSCLC tumor with EGFR-wt expression). In certain embodiments, only subjects with NSCLC tumors with EGFR-wt expression (e.g., an advanced non-squamous NSCLC tumor with EGFR-wt expression) are treated, and subjects with other NSCLC tumors, such as squamous NSCLC or tumors with EGFR-mu expression, are excluded from treatment. In certain embodiments, only subjects with NSCLC tumors with EGFR-mu expression (e.g., an advanced non-squamous NSCLC tumor with EGFR-mu expression) are treated, and subjects with other NSCLC tumors, such as squamous NSCLC or tumors with EGFR-wt expression, are excluded from treatment. In certain embodiments, the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and immune checkpoint inhibitors and / or appropriate applicable targeted therapies. In certain embodiments, human subjects have received two or fewer lines of prior cytotoxic chemotherapy, excluding adjuvant therapy. In certain embodiments, the NSCLC tumor is advanced NSCLC that is unsuitable for surgical resection or for other approved treatment options (including immunotherapy) that have demonstrated clinical benefit.

[0153] In certain embodiments, the NSCLC tumor is a squamous NSCLC tumor. In certain embodiments, the squamous NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and / or appropriate applicable targeted therapy with an immune checkpoint inhibitor. In certain embodiments, the human subject has received two or fewer lines of prior cytotoxic chemotherapy, excluding adjuvant therapy. In certain embodiments, the NSCLC tumor is advanced squamous NSCLC that is unsuitable for surgical resection or other approved treatment options (including immunotherapy) that have demonstrated clinical benefit.

[0154] In a specific embodiment, the NSCLC tumor is a refractory or recurrent NSCLC tumor, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average daily response rate (DAR) of approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the NSCLC tumor is a refractory or recurrent NSCLC tumor, and an effective therapeutic dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6, and administration of anti-c-Met ADC achieves a PR in human subjects. In a specific embodiment, the NSCLC tumor is a refractory or recurrent NSCLC tumor, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6, and administration of anti-c-Met ADC results in an overall response rate of over 25%. In certain embodiments, the NSCLC tumors are refractory or recurrent NSCLC tumors, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects. The mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC results in an overall response rate of over 25%.

[0155] In embodiments, subjects with EGFR-wt non-squamous (NSQ) NSCLC treated according to the methods of this section will have an overall response rate ("ORR") of 30% or more, for example, 40% or 50% or more. In embodiments, treatment of a selected population of subjects with EGFR-wt NSQ NSCLC tumors will be carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in an ORR of 30%, 40%, or 50% or more when subjects with EGFR-wt NSQ NSCLC tumors are treated.

[0156] In embodiments, subjects having EGFR-wt NSQ NSCLC treated according to the methods of this section will have a clinical benefit rate (CBR12) at 12 weeks of 50% or more, such as 60%, 70% or more. In embodiments, the treatment of a selected population of subjects having EGFR-wt NSQ NSCLC tumors is conducted in a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in a CBR12 of 50% or more, such as 60%, 70% or more when subjects having EGFR-wt NSQ NSCLC tumors are treated.

[0157] In embodiments, subjects having EGFR-wt NSQ NSCLC treated according to the methods of this section will have a clinical benefit rate (CBR) of 60% or more, such as 70% or 80% or more. In embodiments, subjects having EGFR-wt NSQ NSCLC treated according to the methods of this section will have a CBR of 60% or more, such as 70% or 80% or more.

[0158] In embodiments, subjects having EGFR-mu NSQ NSCLC treated according to the methods of this section will have an ORR of 30% or more, such as 40%, 50% or more. In embodiments, the treatment of a selected population of subjects having EGFR-mu NSQ NSCLC tumors is conducted in a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in an ORR of 30% or more, such as 40%, 50% or more when subjects having EGFR-mu NSQ NSCLC tumors are treated.

[0159] In embodiments, subjects having squamous NSCLC treated according to the methods of this section will have a CBR of 20% or more, such as 25% or 30% or more. In embodiments, the treatment of a selected population of subjects having squamous NSCLC tumors is conducted in a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in an ORR of 20% or more, such as 25% or 30% or more when subjects having squamous NSCLC tumors are treated.

[0160] In one embodiment, the treatment method includes the step of performing c-Met immunohistochemistry (IHC) on tumor tissue from a subject (i.e., obtained from a biopsy, excision, or cytological specimen; the tumor tissue may be archived tumor tissue or fresh tumor tissue) to determine the level of c-Met expression within the NSCLC tumor. In an embodiment, a subject having a "positive c-Met expression level of NSCLC" is treated, and the positive c-Met expression level of NSCLC is defined by ≥50% (≥50% 2+) of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC having at least a 2+ membrane or membrane + cytoplasmic staining. In an embodiment, a subject having a "positive c-Met expression level of NSCLC" is treated, and the positive c-Met expression level of NSCLC is defined by ≥75% (≥75% 2+) of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC having at least a 2+ membrane or membrane + cytoplasmic staining. In one embodiment, a subject having a "positive c-Met expression level for NSCLC" is treated, and the positive c-Met expression level for NSCLC is defined as ≥10% (≥10% 3+) of neoplasms derived from tumor tissue, as evaluated by c-Met IHC having at least a 3+ membrane or membrane + cytoplasmic staining. In another embodiment, a subject having a "positive c-Met expression level for NSCLC" is treated, and the positive c-Met expression level for NSCLC is defined as ≥25% (≥25% 3+) of neoplasms derived from tumor tissue, as evaluated by c-Met IHC having at least a 3+ membrane or membrane + cytoplasmic staining. In yet another embodiment, a subject having a "positive c-Met expression level for NSCLC" is treated, and the positive c-Met expression level for NSCLC is defined as ≥50% (≥50% 3+) of neoplasms derived from tumor tissue, as evaluated by c-Met IHC having at least a 3+ membrane or membrane + cytoplasmic staining.

[0161] In some embodiments, only subjects with positive c-Met expression levels for NSCLC are treated. In some embodiments, subjects that do not show positive c-Met expression levels for NSCLC are excluded from treatment. In some embodiments, a population of subjects with NSCLC tumors is evaluated for NSCLC tumor c-Met expression, those showing positive c-Met expression levels for NSCLC are selected for treatment, and those not showing positive c-Met expression levels for NSCLC are excluded from treatment. The level of c-Met expression in NSCLC tumors is considered to be the level of the collected tissue determined by c-Met IHC. In some embodiments, c-Met IHC is performed according to a staining protocol.

[0162] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ results in ORRs of 40%, 45%, and 48% or higher. In embodiments, treatment of a selected population of subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 40%, 45%, and 48% or higher when subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ are treated.

[0163] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥10% 3+ results in ORRs of 55%, 60%, and 64% or higher. In embodiments, treatment of a selected population of subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥10% 3+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 55%, 60%, and 64% or higher when subjects having EGFR-wt NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥10% 3+ result in ORRs of 55%, 60%, and 64% or higher.

[0164] In embodiments, treatment of selected subjects having NSQ EGFR-wt NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥25% 3+ results in ORRs of 50%, 55%, and 60% or higher. In embodiments, treatment of a selected population of subjects having EGFR-wt NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥25% 3+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 50%, 55%, and 60% or higher when subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSQ NSCLC-positive c-Met expression levels of ≥25% 3+ are treated.

[0165] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 3+ results in ORRs of 65%, 70%, and 75% or higher. In embodiments, treatment of a selected population of subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 3+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 65%, 70%, and 75% or higher when subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 3+ are treated.

[0166] In embodiments, treatment of selected subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ and <25% 3+ results in ORRs of 35%, 40%, and 41% or higher. In embodiments, treatment of a selected population of subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 35%, 40%, and 41% or higher when subjects having EGFR-wt NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ are treated.

[0167] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥25% 3+ results in ORRs of 35%, 40%, and 45% or higher. In embodiments, treatment of a selected population of subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥25% 3+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 35%, 40%, and 45% or higher when subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥25% 3+ are treated.

[0168] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ results in ORRs of 35%, 40%, and 45% or higher. In embodiments, treatment of a selected population of subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 35%, 40%, and 45% or higher when subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 2+ are treated.

[0169] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥10% 3+ results in ORRs of 35%, 40%, and 45% or higher. In embodiments, treatment of a selected population of subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥10% 3+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 35%, 40%, and 45% or higher when subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥10% 3+ are treated.

[0170] In embodiments, treatment of selected subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 3+ results in ORRs of 35%, 40%, and 45% or higher. In embodiments, treatment of a selected population of subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 3+ is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 35%, 40%, and 45% or higher when subjects having EGFR-mu NSQ NSCLC tumors exhibiting NSCLC-positive c-Met expression levels of ≥50% 3+ are treated.

[0171] In the embodiment, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, refractory or recurrent tumors) are excluded from treatment.

[0172] 7.3.2 Gastroesophageal Adenocarcinoma (“GEA”) In another embodiment, provided herein is a method for treating a gastroesophageal adenocarcinoma ("GEA") tumor, comprising: a human subject or population of human subjects having the GEA tumor, comprising: ADC1 having the following structure:

[0173] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the GEA tumor.

[0174] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0175] In certain embodiments, the GEA tumor is in an advanced stage. In certain embodiments, the GEA tumor is a recurrent GEA tumor. In certain embodiments, the GEA tumor is a refractory or recurrent GEA tumor.

[0176] In certain embodiments, GEA tumors progress during immune checkpoint inhibitor therapy.

[0177] In certain embodiments, GEA tumors progress during appropriate available therapies (including HER2-targeted therapies).

[0178] In certain embodiments, a GEA tumor is a progressive solid tumor that progresses during any standard treatment, is unsuitable for surgical resection, or is unsuitable for other approved treatment options that have demonstrated clinical benefit.

[0179] In various embodiments, GEA tumors express c-Met. In embodiments, only subjects with GEA tumors expressing c-Met are treated, and subjects with other GEA tumors, such as those without c-Met expression, are excluded from treatment. In certain embodiments, the GEA tumor is histopathologically or cytologically confirmed advanced GEA that is unsuitable for surgical resection, has progressed after treatment with at least one prior cytotoxic chemotherapy regimen for locally advanced or metastatic disease, and the human subject has not received more than two lines of prior cytotoxic chemotherapy regimens. In certain embodiments, the GEA tumor progresses during immune checkpoint inhibitor treatment. In certain embodiments, the GEA tumor progresses during appropriate available therapy (including HER2-targeted therapy).

[0180] In various embodiments, subjects with GEA tumors are treated without knowledge of or evaluation of GEA tumor c-Met expression.

[0181] In one embodiment, the treatment method includes the step of performing c-Met immunohistochemistry (IHC) on tumor tissue from a subject (i.e., obtained from a biopsy, excision, or cytological specimen; the tumor tissue may be archived tumor tissue or fresh tumor tissue) to determine the level of c-Met expression within the GEA tumor. In an embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined by ≥90% (≥90% 1+) of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC having at least a 1+ membrane or membrane + cytoplasmic staining. In an embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined by ≥50% (≥50% 2+) of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC having at least a 2+ membrane or membrane + cytoplasmic staining. In one embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined by ≥50% of neoplasms derived from tumor tissue, as assessed by c-Met IHC having at least a 2+ membrane or membrane + cytoplasmic staining. In another embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined by ≥75% of neoplasms derived from tumor tissue, as assessed by c-Met IHC having at least a 2+ membrane or membrane + cytoplasmic staining. In yet another embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined by ≥10% of neoplasms derived from tumor tissue, as assessed by c-Met IHC having at least a 3+ membrane or membrane + cytoplasmic staining. In one embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined as ≥25 neoplasmic cells derived from tumor tissue, as assessed by c-Met IHC having at least 3+ membrane or membrane+ cytoplasmic staining.In one embodiment, a subject having a "GEA-positive c-Met expression level" is treated, and the GEA-positive c-Met expression level is defined as ≥50% neoplasms derived from tumor tissue, as assessed by c-Met IHC having at least 3+ membrane or membrane+ cytoplasmic staining.

[0182] In one embodiment, only subjects with positive c-Met expression levels for GEA are treated. In another embodiment, subjects who do not show positive c-Met expression levels for GEA are excluded from treatment. In yet another embodiment, a population of subjects with GEA tumors is evaluated for GEA tumor c-Met expression, those showing positive c-Met expression levels for GEA are selected for treatment, and those who do not show positive c-Met expression levels for GEA are excluded from treatment.

[0183] The level of C-Met expression in a GEA tumor is considered to be the level of that in the harvested tissue, as determined by c-Met IHC. In some embodiments, c-Met IHC is performed according to a staining protocol.

[0184] In the embodiment, treatment of selected subjects with GEA tumors exhibiting a positive c-Met expression level of ≥90% 1+ in GEA results in an ORR of 30% or 35% or higher.

[0185] In the embodiment, treatment of selected subjects having GEA tumors exhibiting positive c-Met expression levels of ≥50% 2+ in GEA results in ORRs of 30%, 35%, and 37% or higher.

[0186] In the embodiment, treatment of selected subjects with GEA tumors exhibiting positive c-Met expression levels of ≥75% 2+ in GEA results in ORRs of 35%, 40%, and 45% or higher.

[0187] In the embodiment, treatment of selected subjects having GEA tumors exhibiting GEA-positive c-Met expression levels of ≥10% 3+ results in ORRs of 45%, 50%, and 55% or higher.

[0188] In embodiments, treatment of selected subjects with GEA tumors exhibiting positive c-Met expression levels of ≥25% 3+ in GEA results in ORRs of 45%, 50%, 55%, and 58% or higher.

[0189] In embodiments, GEA patient tumors are treated with anti-c-Met ADC in combination with a therapeutically effective administration regimen of an anti-PD1 or anti-PD-L1 antibody. In embodiments, anti-c-Met ADC is administered in combination with an anti-PD1 antibody, and the anti-PD1 antibody is budigalimab, nivolumab, pembrolizumab, semiprimab, dostallimab, retifanlimab, or tripalimab. In embodiments, anti-c-Met ADC is administered in combination with an anti-PD-L1 antibody, and the anti-PD-L1 antibody is atezolizumab, avelumab, or durvalumab.

[0190] In one embodiment, anti-c-Met ADC is administered in combination with an anti-PD1 or anti-PD-L1 antibody, fluorouracil (5-FU), and leucovorin (LV) / folic acid. In one embodiment, anti-c-Met ADC is administered in combination with an anti-PD1 or anti-PD-L1 antibody, fluorouracil (5-FU), and leucovorin (LV) / folic acid, with anti-c-Met ADC administered once every four weeks at a dose of 2.4 or 3.0 mg / kg, and 5-FU administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin is given once every two weeks at 400 mg / m². 2 It is administered in the following doses. In one embodiment, anti-c-Met ADC is administered in combination with an anti-PD1 or anti-PD-L1 antibody, fluorouracil (5-FU), and leucovorin (LV) / fophosphate, with anti-c-Met ADC administered once every three weeks at a dose of 2.4 or 3.0 mg / kg, and 5-FU administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin is given once every two weeks at 400 mg / m². 2It is administered in the following doses. In embodiments, anti-c-Met ADC is administered in combination with an anti-PD1 or anti-PD-L1 antibody, fluorouracil (5-FU), and leucovorin (LV) / fophosphate, with anti-c-Met ADC administered once every two weeks at a dose of 1.2, 1.6, or 2.0 mg / kg, and 5-FU administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin is given once every two weeks at 400 mg / m². 2 It is administered in the following dosage.

[0191] In embodiments, anti-c-Met ADC is administered in combination with fluorouracil (5-FU), leucovorin (LV) / folic acid, and budigalimab. In embodiments, anti-c-Met ADC is administered once every four weeks at a dose of 2.4 or 3.0 mg / kg, budigalimab is administered once every four weeks at a dose of 500 mg, and 5-FU is administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin is given once every two weeks at 400 mg / m². 2 The drugs are administered in the following doses. In one embodiment, c-Met-ADC and budigalimab are administered once every four weeks on the same day. In another embodiment, anti-c-Met ADC is administered once every two weeks at a dose of 1.2 or 2.4 mg / kg, budigalimab is administered once every two weeks at a dose of 250 mg, and 5-FU is administered once every two weeks at a dose of 2400 mg / m². 2 The drug is administered at the following doses: leucovorin is given once every two weeks at 400 mg / m². 2 It is administered in the following doses. In one embodiment, c-Met ADC and budigalimab are administered once every two weeks on the same day. In another embodiment, anti-c-Met ADC is administered once every four weeks, budigalimab is administered once every two weeks, and anti-c-Met ADC is administered on the same day as any other budigalimab administration.

[0192] In embodiments, anti-c-Met ADC is administered in combination with ramucirumab. In embodiments, treatment of patients with the combination of anti-c-Met and ramucirumab is limited to those who have previously received prior systemic therapy for progressive or metastatic disease, including fluoropyrimidines and platinum agents, and who have experienced documented, objective radiographic or clinical disease progression at or after the completion of such systemic therapy. In embodiments, anti-c-Met ADC is administered once every three weeks at a dose of 1.2, 1.6, 2.4, or 3.0 mg / kg, and ramucirumab is administered in a therapeutically effective dosing regimen. In embodiments, anti-c-Met ADC is administered once every three weeks at a dose of 1.6 mg / kg, and ramucirumab is administered in a therapeutically effective dosing regimen. In embodiments, anti-c-Met ADC is administered once every three weeks at a dose of 2.4 mg / kg, and ramucirumab is administered in a therapeutically effective dosing regimen.

[0193] In a specific embodiment, the GEA tumor is a refractory or recurrent GEA tumor, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the GEA tumor is a refractory or recurrent GEA tumor, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects. In a specific embodiment, the GEA tumor is a refractory or recurrent GEA tumor, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to multiple human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC results in an overall response rate of at least 25%. In a specific embodiment, the GEA tumor was a refractory or recurrent GEA tumor, and a therapeutically effective dose of anti-c-Met ADC of 3.0 mg / kg was administered intravenously every three weeks to multiple human subjects. The mean DAR of anti-c-Met ADC was approximately 6, and administration of anti-c-Met ADC resulted in an overall response rate of at least 25%.

[0194] In embodiments, subjects having GEA treated according to the methods of this section will have an overall response rate ("ORR") of 20% or more, e.g., 25% or 30% or more. In embodiments, treatment of a selected population of subjects having GEA tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) when subjects having GEA tumors are treated, results in an ORR of 20% or more, e.g., 25% or 30% or more.

[0195] In embodiments, subjects having GEA treated according to the methods of this section will have a clinical benefit rate ("CBR") of 60% or more, for example, 70% or 80% or more. In embodiments, treatment of a selected population of subjects having GEA tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in a CBR of 60% or more, for example, 70% or 80% or more, when subjects having GEA tumors are treated.

[0196] In one embodiment, the clinical benefit rate (CBR12) confirmed at 12 weeks is 30%, 35%, or 40% or higher. In the embodiment, treatment of a selected population of subjects with GEA tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) when subjects with GEA tumors are treated, yields a CBR12 of 30%, 35%, or 40% or higher.

[0197] In one embodiment, the treatment method includes the step of determining the level of MET gene amplification within a GEA tumor. Detection of MET gene amplification can be carried out, for example, by fluorescence in situ hybridization (FISH). In embodiments, MET amplification is localized MET gene amplification, which is amplification of a portion of a chromosome and is distinct from amplification due to aneuploidy. In embodiments, detection is carried out according to the MET FISH protocol described in Section 7.4 and Example 5 of this specification.

[0198] In one embodiment, subjects who are positive for MET gene amplification are treated. In another embodiment, only those subjects who are positive for MET gene amplification are treated. In yet another embodiment, subjects who do not show MET gene amplification positivity are excluded from treatment. In yet another embodiment, a population of subjects with GEA tumors is evaluated for GEA tumor MET gene amplification, those who are positive for MET gene amplification are selected for treatment, and those who do not show MET gene amplification are excluded from treatment.

[0199] In embodiments, treatment of selected subjects with GEA tumors showing MET gene amplification positivity results in ORRs of 50%, 55%, and 60% or higher. In embodiments, treatment of a selected population of subjects with GEA tumors showing MET gene amplification positivity is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) when subjects with GEA tumors showing MET gene amplification positivity are treated, result in ORRs of 50%, 55%, and 60% or higher.

[0200] In embodiments, treatment of selected subjects with GEA tumors exhibiting localized MET gene amplification positivity results in ORRs of 60%, 65%, 70%, 75%, and 80% or higher. In embodiments, treatment of a selected population of subjects with GEA tumors exhibiting localized MET gene amplification positivity is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) when subjects with GEA tumors exhibiting localized MET gene amplification positivity are treated, result in ORRs of 60%, 65%, 70%, 75%, and 80% or higher.

[0201] In embodiments, MET gene amplification is detected by determining the gene copy number. The gene copy number can be determined, for example, by next-generation sequencing (NGS) or PCR as a means of determining c-Met gene amplification in GEA tumors of candidate patients for anti-c-Met ADC treatment. These methods can be performed on tumor tissue or blood samples from patients.

[0202] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, refractory or recurrent tumors) are excluded from treatment.

[0203] 7.3.3 Colorectal cancer ("CRC") In another embodiment, provided herein is a method for treating a colorectal cancer ("CRC") tumor, comprising: a human subject or population of human subjects having the CRC tumor, wherein ADC1 having the following structure:

[0204] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the CRC tumor.

[0205] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0206] In one embodiment, ADC1 is administered in combination with bevacizumab for the treatment of CRC in human patients. In this embodiment, bevacizumab is administered at a dose of 7.5 mg / kg Q3W. In this embodiment, when ADC1 is administered in the aforementioned combination with bevacizumab, it is administered to human patients at a dose of 1.6 mg / kg, 2.4 mg / kg, or 3.0 mg / kg once every three weeks. With regard to subjects receiving the combination of ADC1 and bevacizumab, in this embodiment, such subjects are those who do not have the BRAF V600E mutation, do not have DNA mismatch repair deficiency (dMMR), and do not have high microsatellite instability (MSI-H), and have a history of histopathologically or cytologically confirmed progressive CRC that progresses during treatment with fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, or irinotecan. In the embodiment, the subjects receiving the combination of ADC1 and bevacizumab had not previously received treatment with TAS-102 or regorafenib.

[0207] In one embodiment, ADC1 is administered in combination with fluorouracil, folinic acid, and bevacizumab for the treatment of CRC in human patients. In this embodiment, the patients receiving the combination of ADC1, fluorouracil, folinic acid, and bevacizumab have unresectable mCRC that is MSS or pMMr, BRAF V600E wild-type, and have progressed after first-line chemotherapy with or without anti-VEGF or anti-EGFR antibodies. In this embodiment, the fluorouracil dose is 2400 g / m². 2 The drug was administered in Q2W at the following dose, with folinic acid at 200 mg / m². 2ADC1 is administered at a dose of Q2W, and bevacizumab is administered at a dose of 5 mg / kg at Q2W. In embodiments, when ADC1 is administered in the aforementioned combination with fluorouracil, folinic acid, and bevacizumab, it is administered to human patients at the following doses and frequencies: 1) 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg once every three weeks; 2) 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg once every two weeks; or 3) 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg once every four weeks.

[0208] In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0209] In certain embodiments, the CRC tumor is in an advanced stage. In certain embodiments, the CRC tumor is a recurrent CRC tumor. In certain embodiments, the CRC tumor is a refractory or recurrent CRC tumor.

[0210] In a particular embodiment, the CRC tumor is progressing during treatment with any one or a combination of prior therapies including fluoropyrimidines (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, anti-EGFR antibodies (e.g., cetuximab or panitumumab), and / or anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (e.g., bevacizumab, ramucirumab, or aflibercept).

[0211] In certain embodiments, the CRC tumor progresses during the application of targeted therapy.

[0212] In a particular embodiment, a human subject is determined by their attending physician to be unsuitable for or unable to tolerate standard therapy.

[0213] In certain embodiments, a CRC tumor is a progressive solid tumor that progresses during any standard treatment, is unsuitable for surgical resection, or is unsuitable for other approved treatment options that have demonstrated clinical benefit.

[0214] In certain embodiments, the CRC tumor is free of the BRAF V600E mutation. In certain embodiments, the CRC tumor is not dMMR+ / MSI-Hi. In certain embodiments, the CRC tumor is free of the BRAF V600E mutation and is not dMMR+ / MSI-Hi. In embodiments, only subjects with CRC tumors that are not dMMR+ / MSI-Hi are treated, and subjects with CRC tumors that are dMMR+ / MSI-Hi are excluded from treatment. In embodiments, only subjects with CRC tumors that are free of the BRAF V600E mutation are treated, and subjects with CRC tumors that are free of the BRAF V600E mutation are excluded from treatment. In certain embodiments, the CRC tumor is histopathologically or cytologically confirmed advanced CRC that is free of the BRAF V600E mutation and is not dMMR+ / MSI-Hi. In certain embodiments, the CRC tumor is progressing during treatment with any one or a combination of prior therapies including fluoropyrimidines (e.g., 5-fluorouracil or capecitabine), oxaliplatin, irinotecan, anti-EGFR antibodies (e.g., cetuximab or panitumumab), and / or anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (e.g., bevacizumab, ramucirumab, or aflibercept). In certain embodiments, the CRC tumor is progressing during applicable targeted therapy.

[0215] In various embodiments, CRC tumors express c-Met. In embodiments, only subjects with c-Met-expressing CRC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing CRC tumors are histologically or cytologically confirmed locally advanced or metastatic tumors that progress after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0216] In various embodiments, subjects with CRC tumors are treated without knowledge of or evaluation of CRC tumor c-Met expression.

[0217] In a specific embodiment, the CRC tumor is a refractory or recurrent CRC tumor, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the CRC tumor is a refractory or recurrent CRC tumor, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and the administration of anti-c-Met ADC achieves a PR in human subjects.

[0218] In certain embodiments, the CRC tumor is a refractory or recurrent CRC tumor, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In certain embodiments, the CRC tumor is a refractory or recurrent CRC tumor, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 15%.

[0219] In certain embodiments, subjects with CRC tumors have not received first-line systemic treatment for CRC (including combination chemotherapy with or without targeted therapy), and prior adjuvant chemotherapy for localized CRC is optionally acceptable, provided that: treatment was completed ≥ 12 months prior to treatment with anti-c-Met ADC; no prior systemic regimen containing a c-Met targeted antibody or ADC has been received; and there is no evidence of active interstitial lung disease or pneumonia by screening chest CT scan. In embodiments, subjects meet one or more of the above criteria. In embodiments, subjects in this paragraph are treated with c-Met ADC in combination with chemotherapy and / or other antibodies. In embodiments, c-Met ADC is administered in combination with leucovorin (LV), fluorouracil (5-FU), or oxaliplatin (FOLFOX). In embodiments, c-Met ADC is administered in combination with 5-FU / LV. In some embodiments, c-Met ADC is administered in combination with 5-FU / LV and panatimumab. In some embodiments, c-Met ADC is administered in combination with 5-FU / LV and bevacizumab. In some embodiments, c-Met ADC is administered in combination with FOLFOX and bevacizumab.

[0220] In certain embodiments, the subjects are: 1) having a CRC tumor with a primary tumor on the left side; 2) the tumor is classified as KRAS / NRAS / BRAFV600E wild-type; 3) the tumor is not dMMR+ / MSI-H; 4) not having received first-line systemic treatment for CRC (including combination chemotherapy with or without targeted therapy) and having optionally received prior adjuvant chemotherapy for localized CRC, provided that treatment was completed ≥ 12 months prior to treatment with anti-c-Met ADC; 5) not having received prior treatment with any anti-EGFR drug; 6) not having received prior systemic regimens containing c-Met targeted antibodies or ADCs; and 7) having no evidence of active interstitial lung disease or pneumonia on a screening chest CT scan. In embodiments, the subjects meet one or more of the above criteria. In embodiments, the subjects in this paragraph are treated with c-Met ADC in combination with chemotherapy.

[0221] In embodiments, subjects having CRC treated according to the methods of this section will have an overall response rate ("ORR") of 15% or more, for example, 20%, 22%, 24%, 25%, 30%, or 35% or more. In embodiments, treatment of a selected population of subjects having CRC tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) when subjects having CRC tumors are treated, results in an ORR of 15% or more, for example, 20%, 22%, 24%, 25%, 30%, or 35% or more.

[0222] In embodiments, subjects having CRC treated according to the methods of this section will have a clinical benefit rate ("CBR") of 60% or more, for example, 70% or 80% or more. In embodiments, treatment of a selected population of subjects having CRC tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in a CBR of 60% or more, for example, 70% or 80% or more, when subjects having CRC tumors are treated.

[0223] In embodiments, subjects having CRC treated according to the methods of this section will have a clinical benefit rate ("CBR12") at 12 weeks of 40% or higher, e.g., 50% or 60% or higher. In embodiments, treatment of a selected population of subjects having CRC tumors will be carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in a CBR12 of 40% or higher, e.g., 50% or 60% or higher, when subjects having CRC tumors are treated.

[0224] In embodiments, subjects having CRC treated according to the methods of this section will have a clinical benefit rate ("CBR24") at 24 weeks of 30% or more, e.g., 40% or 50% or more. In embodiments, treatment of a selected population of subjects having CRC tumors will be carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) results in a CBR24 of 30% or more, e.g., 40% or 50% or more, when subjects having CRC tumors are treated.

[0225] In embodiments, subjects having CRC treated according to the methods of this section will have a progression-free survival ("PFS") of 3 months or more, 4 months or more, 5 months or more, or 6 months or more. In embodiments, treatment of a selected population of subjects having CRC tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) if subjects having CRC tumors are treated, results in a PFS of 3 months or more, 4 months or more, 5 months or more, or 6 months or more.

[0226] In embodiments, subjects having CRC treated according to the methods of this section will have a duration of response ("DoR") of 3 months or more than 3 months, 4 months or more than 4 months, 5 months or more than 5 months, or 6 months or more. In embodiments, treatment of a selected population of subjects having CRC tumors is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) when subjects having CRC tumors are treated, results in a DoR of 3 months or more than 3 months, 4 months or more than 4 months, 5 months or more than 5 months, or 6 months or more.

[0227] In one embodiment, the treatment method includes the step of performing c-Met immunohistochemistry (IHC) on tumor tissue from a subject (i.e., obtained from a biopsy, excision, or cytological specimen; the tumor tissue may be archived tumor tissue or fresh tumor tissue) to determine the level of c-Met expression within the CRC tumor. In an embodiment, a subject having a "positive c-Met expression level of CRC" is treated, and the positive c-Met expression level of CRC is defined by ≥10% of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC with 3+ membrane or membrane+cytoplasmic staining. In an embodiment, the positive c-Met expression level of CRC is defined by ≥50% of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC with 2+ membrane or membrane+cytoplasmic staining. In an embodiment, the positive c-Met expression level of CRC is defined by ≥75% of neoplastic cells derived from tumor tissue, as assessed by c-Met IHC with 2+ membrane or membrane+cytoplasmic staining.

[0228] In one embodiment, only subjects with positive c-Met expression levels in CRC are treated. In another embodiment, subjects that do not show positive c-Met expression levels in CRC are excluded from treatment. In yet another embodiment, a population of subjects with CRC tumors is evaluated for CRC tumor c-Met expression, those showing positive c-Met expression levels in CRC are selected for treatment, and those not showing positive c-Met expression levels in CRC are excluded from treatment. In yet another embodiment, subjects with positive c-Met expression levels in CRC are treated with the administration of c-Met ADCs in combination with chemotherapy and / or other antibodies, e.g., 5-FU / LV; FOLFOX; 5-FU / LV and panatimumab; 5-FU / LV and bevacizumab; or c-Met ADCs in combination with FOLFOX and bevacizumab.

[0229] In the embodiment, treatment of selected subjects having CRC tumors exhibiting positive c-Met expression levels in CRC results in ORRs of 30%, 35%, and 37% or higher. In the embodiment, treatment of a selected population of subjects having CRC tumors exhibiting positive c-Met expression levels in CRC is carried out with regimens that 1) meet the eligibility criteria of Section 8.2.1, and 2) result in ORRs of 30%, 35%, and 37% or higher when subjects having CRC tumors exhibiting positive c-Met expression levels in CRC are treated.

[0230] In embodiments, treatment of selected subjects having CRC tumors exhibiting positive c-Met expression levels in CRC results in a median PFS of 5, 5.2, 5.4, 5.5 months or longer. In embodiments, treatment of a selected population of subjects having CRC tumors exhibiting positive c-Met expression levels in CRC is carried out with a regimen that 1) meets the eligibility criteria of Section 8.2.1, and 2) when subjects having CRC tumors exhibiting positive c-Met expression levels in CRC are treated, results in a median PFS of 5, 5.2, 5.4, 5.5 months or longer.

[0231] The level of C-Met expression in a CRC tumor is considered to be the level of that in the harvested tissue, as determined by c-Met IHC. In some embodiments, c-Met IHC is performed according to a staining protocol.

[0232] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, refractory or recurrent tumors) are excluded from treatment.

[0233] 7.3.4 MET gene amplification progressive solid tumors In another embodiment, provided herein is a method for treating a MET gene-amplifying progressive solid tumor, wherein a human subject or population of human subjects having the MET gene-amplifying progressive solid tumor is given an ADC1 having the following structure:

[0234] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the MET gene-amplifying progressive solid tumor.

[0235] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0236] In one embodiment, only subjects with MET gene amplification progressive solid tumors are treated, while subjects with solid tumors that do not undergo MET gene amplification are excluded from treatment. In one particular embodiment, the MET gene amplification progressive solid tumor is a recurrent MET gene amplification progressive solid tumor. In one particular embodiment, the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor.

[0237] In various embodiments, MET gene-amplified progressive solid tumors express c-Met. In embodiments, only subjects with MET gene-amplified progressive solid tumors expressing c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment.

[0238] In various embodiments, subjects with MET gene amplification progressive solid tumors are treated without knowledge of or evaluation of MET gene amplification progressive solid tumor c-Met expression.

[0239] In a specific embodiment, the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0240] In a specific embodiment, the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

[0241] In certain embodiments, the MET gene amplification progressive solid tumors are refractory or recurrent MET gene amplification progressive solid tumors, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In certain embodiments, the MET gene amplification progressive solid tumors are refractory or recurrent MET gene amplification progressive solid tumors, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0242] In some embodiments, MET gene amplification is determined using next-generation sequencing assays (NGS). In some embodiments, MET gene amplification is determined using fluorescence in situ hybridization assays (FISH). In preferred embodiments, FISH is performed on formalin-fixed paraffin-embedded (FFPE) tissue. Unstained sliced ​​histological specimens undergo standard deparaffinization and rehydration procedures followed by digestion with a protease solution, after which the cellular DNA and probes of the specimens are denatured, and then hybridization of the target DNA sequence and probes takes place, with the FISH results obtained by counting the hybridization signals of the probes in each cell.

[0243] In embodiments, subjects with MET-amplifying tumors treated according to the methods of this section will have an overall response rate ("ORR") of 30% or more, for example, 40%, 50%, 60%, or 70% or more. In embodiments, subjects with MET-amplifying tumors treated according to the methods of this section will have a clinical benefit rate ("CBR") of 60% or more, for example, 70%, or 80% or more.

[0244] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, locally advanced, refractory, or recurrent tumors) are excluded from treatment.

[0245] 7.3.5 Hepatocellular Carcinoma (“HCC”) In another embodiment, provided herein is a method for treating hepatocellular carcinoma ("HCC") tumors, comprising: a human subject or population of human subjects having the HCC tumor, comprising: ADC1 having the following structure:

[0246] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the HCC tumor.

[0247] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0248] In certain embodiments, the HCC tumor is in an advanced stage. In certain embodiments, the HCC tumor is a recurrent HCC tumor. In certain embodiments, the HCC tumor is a refractory or recurrent HCC tumor. In certain embodiments, the HCC tumor is locally advanced or metastatic HCC in which the disease progresses during or after one line of prior systemic therapy.

[0249] In various embodiments, HCC tumors express c-Met. In embodiments, only subjects with c-Met-expressing HCC tumors are treated, and subjects with solid tumors that do not express c-Met are excluded from treatment. In certain embodiments, c-Met-expressing HCC tumors are advanced. In certain embodiments, c-Met-expressing HCC tumors are recurrent HCC tumors. In certain embodiments, c-Met-expressing tumors are refractory or recurrent HCC tumors. In certain embodiments, c-Met-expressing tumors are locally advanced or metastatic HCC that progresses during or after one line of prior systemic therapy.

[0250] In various embodiments, subjects with HCC tumors are treated without knowledge of or evaluation of HCC tumor c-Met expression.

[0251] In a specific embodiment, the HCC tumor is a locally advanced or metastatic HCC tumor that progresses during or after one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the HCC tumor is a locally advanced or metastatic HCC tumor that progresses during or after one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects.

[0252] In a specific embodiment, the HCC tumor is a locally advanced or metastatic HCC tumor that progresses during or after one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In a specific embodiment, the HCC tumor is a locally advanced or metastatic HCC tumor that progresses during or after one line of prior systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0253] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, locally advanced, metastatic, and disease progression during or after one line of prior systemic therapy) are excluded from treatment.

[0254] 7.3.6 Pancreatic ductal adenocarcinoma (“PDAC”) In another embodiment, provided herein is a method for treating a pancreatic ductal adenocarcinoma ("PDAC") tumor, comprising: a human subject or population of human subjects having the PDAC tumor, comprising: ADC1 having the following structure:

[0255] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the PDAC tumor.

[0256] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0257] In certain embodiments, a PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC that progresses during or after a single systemic therapy (including gemcitabine monotherapy or in combination with other agents, FOLFIRINOX [or another regimen containing both 5-fluorouracil and oxaliplatin], capecitabine monotherapy or in combination with other agents) administered in an adjuvant, locally advanced, or metastatic setting.

[0258] In various embodiments, PDAC tumors express c-Met. In embodiments, only subjects with c-Met-expressing PDAC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing PDAC tumors are histologically or cytologically confirmed advanced or metastatic PDACs that progress during or after a single systemic therapy (including gemcitabine monotherapy or in combination with other agents, FOLFIRINOX [or another regimen containing both 5-fluorouracil and oxaliplatin], capecitabine monotherapy or in combination with other agents) administered in an adjuvant, locally advanced, or metastatic setting.

[0259] In various embodiments, subjects with PDAC tumors are treated without knowledge of or evaluation of PDAC tumor c-Met expression.

[0260] In a specific embodiment, the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects. In a specific embodiment, the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In a specific embodiment, the PDAC tumor is a histologically or cytologically confirmed advanced or metastatic PDAC that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0261] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, histologically or cytologically confirmed progressive or metastatic tumors, and disease progression during or after one systemic therapy) are excluded from treatment.

[0262] 7.3.7 Biliary tract cancer ("BTC") In another embodiment, provided herein is a method for treating a biliary tract cancer ("BTC") tumor, comprising: a human subject or population of human subjects having the BTC tumor, comprising: ADC1 having the following structure:

[0263] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the BTC tumor.

[0264] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0265] In certain embodiments, a BTC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after a single systemic therapy including gemcitabine and / or platinum-based chemotherapy.

[0266] In various embodiments, BTC tumors express c-Met. In embodiments, only subjects with c-Met-expressing BTC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing BTC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after a single systemic therapy including gemcitabine and / or platinum-based chemotherapy.

[0267] In various embodiments, subjects with BTC tumors are treated without knowledge of or evaluation of BTC tumor c-Met expression.

[0268] In a specific embodiment, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects. In specific embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In specific embodiments, the BTC tumor is histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after one systemic therapy, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0269] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, histologically or cytologically confirmed locally advanced or metastatic unresectable intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer that progresses during or after a single systemic therapy) are excluded from treatment.

[0270] 7.3.8 Esophageal Squamous Cell Carcinoma (“ESCC”) In another embodiment, provided herein is a method for treating esophageal squamous cell carcinoma ("ESCC") tumors, comprising: a human subject or population of human subjects having the ESCC tumor, comprising: ADC1 having the following structure:

[0271] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the ESCC tumor.

[0272] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0273] In certain embodiments, the ESCC tumor is histologically or cytologically confirmed to be locally advanced or metastatic, and the disease progresses during two lines or less of prior cytotoxic chemotherapy.

[0274] In various embodiments, ESCC tumors express c-Met. In embodiments, only subjects with c-Met-expressing ESCC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing ESCC tumors are histologically or cytologically confirmed locally advanced or metastatic, with disease progression during two lines or less of prior cytotoxic chemotherapy.

[0275] In various embodiments, subjects with ESCC tumors are treated without knowledge of or evaluation of ESCC tumor c-Met expression.

[0276] In a specific embodiment, the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic, with disease progression during two or fewer lines of prior cytotoxic chemotherapy, and an effective therapeutic dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the ESCC tumor is histologically or cytologically confirmed locally advanced or metastatic, with disease progression during two or fewer lines of prior cytotoxic chemotherapy, and an effective therapeutic dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects. In a specific embodiment, the ESCC tumors were histologically or cytologically confirmed locally advanced or metastatic, progressing during two or fewer lines of prior cytotoxic chemotherapy, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg was administered intravenously every three weeks to multiple human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0277] In some embodiments, subjects with tumors that do not meet the criteria described in this section (for example, including, but not limited to, locally advanced or metastatic tumors that progress during two or fewer lines of prior cytotoxic chemotherapy) are excluded from treatment.

[0278] 7.3.9 Triple-negative breast cancer ("TNBC") In another embodiment, provided herein is a method for treating a triple-negative breast cancer tumor ("TNBC") tumor, wherein a human subject or population of human subjects having the TNBC tumor is given an ADC1 having the following structure:

[0279] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the TNBC tumor.

[0280] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0281] In certain embodiments, a TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC according to the American Society of Clinical Oncology / College of American Pathologists (ASCO / CAP) criteria, which progresses after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0282] In various embodiments, TNBC tumors express c-Met. In embodiments, only subjects with c-Met-expressing TNBC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing TNBC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable TNBCs that progress after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0283] In various embodiments, subjects with TNBC tumors are treated without knowledge of or evaluation of TNBC tumor c-Met expression.

[0284] In a specific embodiment, the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC that has progressed after at least one line of prior systemic therapy administered in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC that has progressed after at least one line of prior systemic therapy administered in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects. In a specific embodiment, the TNBC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable TNBC that has progressed after at least one line of prior systemic therapy administered in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0285] In some embodiments, subjects with tumors that do not meet the criteria described in this section (for example, including, but not limited to, histologically or cytologically confirmed locally advanced or metastatic unresectable tumors that progress after at least one line of prior systemic therapy administered in an advanced / metastatic setting) are excluded from treatment.

[0286] 7.3.10 Hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer ("HR+ / HER2- BC") In another embodiment, provided herein is a method for treating hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer tumors ("HR+ / HER2-BC"), comprising: a human subject or population of human subjects having the HR+ / HER2-BC tumor, comprising: ADC1 having the following structure:

[0287] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to thereby treat the HR+ / HER2- BC tumor.

[0288] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0289] In certain embodiments, an HR+ / HER2- BC tumor is an unresectable HR+ / HER2- breast cancer that is histologically or cytologically confirmed to be locally advanced or metastatic according to ASCO / CAP criteria, progressing after treatment with at least one endocrine therapy and a cyclin-dependent kinase (CDK) 4 / 6 inhibitor in an advanced / metastatic setting.

[0290] In various embodiments, HR+ / HER2- BC tumors express c-Met. In embodiments, only subjects with c-Met-expressing HR+ / HER2- BC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing HR+ / HER2- BC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- BC tumors that progress after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0291] In various embodiments, subjects with HR+ / HER2- BC tumors are treated without knowledge of or evaluation of HR+ / HER2- BC tumor c-Met expression.

[0292] In a specific embodiment, the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- breast cancer that has progressed after at least one endocrine therapy and cyclin-dependent kinase (CDK) 4 / 6 inhibitor treatment in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every 3 weeks to human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, and anti-c-Met ADC administration achieves a partial response (PR) in human subjects. In a specific embodiment, the HR+ / HER2- BC tumor is a histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- breast cancer that has progressed after at least one endocrine therapy and cyclin-dependent kinase (CDK) 4 / 6 inhibitor treatment in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every 3 weeks to human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, and anti-c-Met ADC administration achieves a partial response (PR) in human subjects. In a specific embodiment, HR+ / HER2- BC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- breast cancers that have progressed after at least one endocrine therapy and cyclin-dependent kinase (CDK) 4 / 6 inhibitor treatment in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25% with anti-c-Met ADC administration. In a specific embodiment, HR+ / HER2- BC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- breast cancers that have progressed after at least one endocrine therapy and cyclin-dependent kinase (CDK) 4 / 6 inhibitor treatment in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25% with anti-c-Met ADC administration.

[0293] In some embodiments, subjects with tumors that do not meet the criteria described in this section (e.g., including, but not limited to, histologically or cytologically confirmed locally advanced or metastatic unresectable HR+ / HER2- breast cancer that progresses after at least one endocrine therapy and cyclin-dependent kinase (CDK) 4 / 6 inhibitor treatment in an advanced / metastatic setting) are excluded from treatment.

[0294] 7.3.11 Head and Neck Squamous Cell Carcinoma (“HNSCC”) In another embodiment, provided herein is a method for treating a head and neck squamous cell carcinoma (HNSCC) tumor, wherein a human subject or population of human subjects having the HNSCC tumor is given an ADC1 having the following structure:

[0295] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the HNSCC tumor.

[0296] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0297] In a particular embodiment, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC that progresses after at least one line of prior systemic therapy in an advanced / metastatic setting.

[0298] In various embodiments, HNSCC tumors express c-Met. In embodiments, only subjects with c-Met-expressing HNSCC tumors are treated, and subjects with non-c-Met-expressing tumors are excluded from treatment. In certain embodiments, c-Met-expressing HNSCC tumors are histologically or cytologically confirmed locally advanced or metastatic unresectable HNSCC that progresses after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0299] In various embodiments, subjects with HNSCC tumors are treated without knowledge of or evaluation of HNSCC tumor c-Met expression.

[0300] In a specific embodiment, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC that has progressed after at least one line of prior systemic therapy in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC that has progressed after at least one line of prior systemic therapy in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, with an average DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a PR in human subjects. In a specific embodiment, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC that has progressed after at least one line of prior systemic therapy in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In a specific embodiment, the HNSCC tumor is histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC that has progressed after at least one line of prior systemic therapy in an advanced / metastatic setting, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every 3 weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0301] In some embodiments, subjects with tumors that do not meet the criteria described in this section (e.g., including, but not limited to, histologically or cytologically confirmed locally advanced or recurrent / metastatic unresectable HNSCC that progresses after at least one line of prior systemic therapy in an advanced / metastatic setting) are excluded from treatment.

[0302] 7.3.12 MET gene mutation-type advanced solid tumor "mutMET" In another embodiment, provided herein is a method for treating a MET gene mutation-associated progressive solid tumor, comprising: a human subject or population of human subjects having the MET gene mutation-associated progressive solid tumor, wherein an ADC1 having the following structure:

[0303] [ka] A method comprising administering a therapeutically effective dose of (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) to treat the MET gene-amplifying progressive solid tumor.

[0304] In a preferred embodiment, ADC1 is administered to human patients once every three weeks at doses of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg. In a preferred embodiment, ADC1 is administered parenterally. In a preferred embodiment, parenteral administration is intravenous. In a preferred embodiment, ADC1 is administered once every three weeks until disease progression, withdrawal of consent, or unacceptable toxicity occurs.

[0305] In various embodiments, MET-mutated progressive solid tumors express c-Met. In embodiments, only subjects with MET-mutated progressive solid tumors expressing c-Met are treated, and subjects with tumors that do not express c-Met are excluded from treatment. In certain embodiments, c-Met-expressing MET-mutated progressive solid tumors are histologically or cytologically confirmed locally progressive or metastatic unresectable MET-mutated progressive solid tumors that progress after at least one line of prior systemic therapy administered in an advanced / metastatic setting.

[0306] In various embodiments, subjects with MET gene mutation-induced progressive solid tumors are treated without knowledge of or evaluation of c-Met expression in MET gene mutation-induced progressive solid tumors.

[0307] In certain embodiments, a MET-mutated progressive solid tumor is a histologically or cytologically confirmed progressive solid tumor having a MET mutation (including mutations in the tyrosine kinase domain, near-membrane region, and extracellular domain, which are locally determined by next-generation sequencing (NGS) or validated qPCR on the tissue). In embodiments, subjects are treated if they are unsuitable for surgical resection, have progressed after at least one prior systemic therapy, and / or have no satisfactory alternative treatment options. In embodiments, only subjects with a MET-mutated progressive solid tumor are treated, and subjects without such tumors are excluded from treatment. In embodiments, only subjects with a MET-mutated progressive solid tumor, unsuitable for surgical resection, have progressed after at least one prior systemic therapy, and / or have no satisfactory alternative treatment options are treated, and subjects that do not meet these criteria are excluded from treatment.

[0308] In a specific embodiment, MET gene mutation-associated progressive solid tumors are unsuitable for surgical resection, disease progression after at least one prior systemic therapy, and / or no satisfactory alternative treatment options are available, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, MET gene mutation-associated progressive solid tumors are unsuitable for surgical resection, disease progression after at least one prior systemic therapy, and / or no satisfactory alternative treatment options are available, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, and administration of anti-c-Met ADC achieves a partial response (PR) in human subjects. In a specific embodiment, MET gene-mutated progressive solid tumors are unsuitable for surgical resection, disease has progressed after at least one prior systemic therapy, and / or there are no satisfactory alternative treatment options, and a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%. In a specific embodiment, MET gene-mutated progressive solid tumors are unsuitable for surgical resection, disease has progressed after at least one prior systemic therapy, and / or there are no satisfactory alternative treatment options, and a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, with a mean DAR of approximately 6 for anti-c-Met ADC, resulting in an overall response rate of over 25%.

[0309] In some embodiments, subjects with tumors that do not meet the criteria described in this section (including, but not limited to, subjects whose tumors are unsuitable for surgical resection, whose disease has progressed after at least one prior systemic therapy, and / or for whom there are no satisfactory alternative treatment options) are excluded from treatment.

[0310] In some embodiments, MET gene mutations are determined using next-generation sequencing assays (NGS). In some embodiments, MET gene mutations are detected using fragment length analysis (FLA). In one embodiment, NGS and FLA are used together. In embodiments, MET gene mutations are detected using tumor-derived DNA samples. In embodiments, MET gene mutations are detected using tumor-derived RNA samples. MET gene mutations include MET exon 14 skipping mutations. MET exon 14 skipping mutations and methods for detecting these mutations are known to those skilled in the art. The entire text is incorporated herein by reference, Heydt et al., Cancers (Basel). 2023 Jun;15(11):2932.

[0311] 7.3.13 Treatment endpoints In various aspects and embodiments of the therapeutic methods described herein, administration of anti-c-Met ADC (e.g., ADC1) provides an overall response rate superior to standard therapeutic therapy for tumors. In various aspects and embodiments of the therapeutic methods described herein, administration of anti-c-Met ADC (e.g., ADC1) provides an overall response rate greater than 25%, greater than 30%, greater than 35%, greater than 40%, greater than 45%, greater than 50%, greater than 55%, greater than 60%, greater than 65%, greater than 70%, greater than 75%, or greater than 80%.

[0312] In embodiments, subjects treated by the disclosed method have a clinical benefit rate ("CBR") of more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%.

[0313] In various aspects and embodiments of the therapeutic methods described herein, administration of anti-c-Met ADCs (e.g., ADC1) exhibits an acceptable safety and tolerability profile.

[0314] In various aspects and embodiments of the therapeutic methods described herein, administration of an anti-c-Met ADC (e.g., ADC1) achieves a partial response (PR) in human subjects.

[0315] In various aspects and embodiments of the therapeutic methods described herein, administration of an anti-c-Met ADC (e.g., ADC1) achieves complete response (CR) in human subjects.

[0316] In various aspects and embodiments of the therapeutic methods described herein, administration of an anti-c-Met ADC (e.g., ADC1) achieves stable (SD) in human subjects.

[0317] In the embodiments, subjects treated by the disclosed method have a progression-free survival ("PFS") of 3 months or more, 4 months or more, 5 months or more, or 6 months or more.

[0318] In embodiments, subjects treated by the disclosed method have a duration of response ("DoR") of 3 months or more, 4 months or more, 5 months or more, or 6 months or more.

[0319] In various aspects and embodiments of the therapeutic methods described herein, anti-c-Met ADCs (e.g., ADC1) are administered intravenously to human subjects.

[0320] In various aspects and embodiments, one or more of the eligibility criteria set out in Section 7.2.1 are used to determine whether a human subject is eligible for treatment.

[0321] 7.4 Diagnosis 7.4.1 C-Met expression IHC is used to evaluate candidate patients for treatment selection with anti-c-Met ADCs based on the c-Met expression levels observed in tumor tissue. In some embodiments, c-Met IHC is performed on at least one tumor tissue derived from the subject, and at least one tumor tissue is selected from archived tumor tissue and / or fresh tumor.

[0322] c-Met-specific immunohistochemistry (c-Met IHC) is intended as a means to determine c-Met overexpression in tumor tissue of candidate patients for treatment with anti-c-Met ADCs. For this purpose, IHC scores 0, 1+, 2+, and 3+ represent the visual c-Met staining intensity of individual neoplastic cells derived from tumor tissue: 0 orders, undyed 1+=weak staining 2+ = moderate staining 3+ = Strong staining It is represented by this. Typically, there are approximately 100 human cells in a 20× fixed field of view. As used herein, IHC scoring refers to the intensity of membrane c-Met staining or the intensity of membrane + cytoplasm c-Met staining.

[0323] In some embodiments, patients selected for treatment with anti-c-Met ADCs have c-Met overexpression as determined by IHC, and the IHC is 1) A step of staining the membrane or membrane + cytoplasm of neoplastic cells of a tumor with a diagnostic reagent specific to c-Met, and 2) A step in which the intensity of membrane or membrane + cytoplasmic staining is scored, and the IHC scoring is performed using values ​​scaled so that the score corresponds to score 0, score 1+, score 2+, and / or score 3+. The scores include, where a score of 0 corresponds to the minimum visual membrane or membrane + cytoplasmic staining intensity of the negative control or near-negative control, a score of 3+ corresponds to the maximum visual membrane or membrane + cytoplasmic staining intensity of the positive control or near-positive control, and scores of 1+ and 2+ correspond to 1 / 3 or about 1 / 3 and 2 / 3 or about 2 / 3 of the maximum visual membrane or membrane + cytoplasmic staining intensity of the positive control, respectively.

[0324] In embodiments, subjects treated by the methods of the present invention (including the methods for treating subjects having tumors as described in Section 7.3 above) are subjects having tumors exhibiting c-Met expression at a level equal to or exceeding a predetermined cutoff level of expression. The c-Met expression cutoff is expressed as a combination of a percentage and a minimum staining intensity. For example, a c-Met expression cutoff ≥ 10% 1+ is met when at least 10% of the cells in the field of view exhibit IHC staining of 1 or higher.

[0325] In one embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 10% 1+, the subject with the tumor is selected for treatment. In another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 10% 2+, the subject with the tumor is selected for treatment. In yet another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 10% 3+, the subject with the tumor is selected for treatment.

[0326] In one embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 25% 1+, the subject with the tumor is selected for treatment. In another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 25% 2+, the subject with the tumor is selected for treatment. In yet another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 25% 3+, the subject with the tumor is selected for treatment.

[0327] In one embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 50% 1+, the subject with the tumor is selected for treatment. In another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 50% 2+, the subject with the tumor is selected for treatment. In yet another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 50% 3+, the subject with the tumor is selected for treatment.

[0328] In one embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 75% 1+, the subject with the tumor is selected for treatment. In another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 75% 2+, the subject with the tumor is selected for treatment. In yet another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 75% 3+, the subject with the tumor is selected for treatment.

[0329] In one embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 90% 1+, the subject with the tumor is selected for treatment. In another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 90% 2+, the subject with the tumor is selected for treatment. In yet another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 90% 3+, the subject with the tumor is selected for treatment.

[0330] In one embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 100% 1+, the subject with the tumor is selected for treatment. In another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 100% 2+, the subject with the tumor is selected for treatment. In yet another embodiment, if the tumor satisfies the c-Met IHC cutoff ≥ 100% 3+, the subject with the tumor is selected for treatment.

[0331] In one embodiment, subjects that do not meet the IHC cutoff are excluded from treatment. In another embodiment, tumors from a population of subjects with tumors are evaluated for IHC staining, and tumors that meet the selected IHC cutoff are selected for treatment, while tumors that do not meet the IHC cutoff are excluded from treatment.

[0332] Details of a method for visualizing and determining the level of c-Met overexpression are shown below and in Example 4. For the purposes of this application, including the claims, the specific assay used in Example 4 is referred to as the “c-Met staining protocol.” Briefly, a c-Met IHC staining assay for c-Met overexpression was developed using the Ventana c-Met CONFIRM (SP44) kit (catalog no. 790-4430). The assay is intended for use in selecting patients for treatment with anti-c-Met ADCs. In this assay, tissue samples are stained with Ventana anti-c-Met antibody and then scored by determining the percentage of neoplastic cells in tumor tissue stained at a specific intensity level from weak / low to strong / high (i.e., 0, 1+, 2+, 3+). This assay results in staining of the c-Met protein in both the cytoplasm and the cell membrane, and the membrane staining or membrane + cytoplasmic staining is used for IHC scoring.

[0333] If different IHC methods yield different c-Met IHC scoring results, the c-Met IHC scoring result determined by the method described in Example 4 will be used to determine whether a particular form falls within the scope of the embodiment. For example, the “c-Met staining protocol” would be used to evaluate c-Met protein expression. If the reagents used in this protocol are no longer available, another FDA-approved protocol for evaluating c-Met expression levels by IHC may be used.

[0334] c-Met IHC detection is a diagnostic method that provides visualization of the c-Met antigen after localization by a primary anti-C-MET antibody. In some embodiments, the primary anti-C-MET antibody is selected from mouse IgG, mouse IgM, or rabbit antibodies. In some embodiments, IHC detection includes direct visualization of the primary anti-cMet antibody. In some embodiments, IHC detection includes indirect visualization of the primary anti-cMet antibody. In some embodiments, the indirect visualization includes a species-specific secondary antibody of the primary anti-cMet antibody. In some embodiments, the indirect visualization further includes a tertiary antibody conjugated to the secondary antibody, the tertiary antibody being conjugated to at least one enzyme. In some embodiments, the indirect visualization further includes a dye source having a substrate specific to at least one enzyme of the tertiary antibody. In some embodiments, the dye source yields a detectable precipitate, preferably detectable by visualization and / or colorimetric shift. In certain embodiments, the substrate is hydrogen peroxide. In a particular embodiment, the dye source is 3,3'-diaminobenzidine tetrahydrochloride (DAB).

[0335] In some embodiments, c-Met expression is determined using the OptiView DAB IHC detection kit (Ventana catalog numbers 760-700). The OptiView kit uses an indirect method of precipitation, which visualizes specific mouse and rabbit primary antibodies bound to the antigen.

[0336] In some embodiments, IHC detection of c-Met expression includes the step of staining tumor tissue, which is then frozen, formalin-fixed, and / or paraffin-embedded. In some embodiments, tumor tissue staining is performed by a slide staining apparatus. As intended, such a slide staining apparatus automates the slide staining steps, e.g., washing the slide to remove unbound material after the antibody incubation step, and / or applying a coverslip to the slide. In some embodiments, the slide staining apparatus is a VENTANA® slide staining apparatus. In some embodiments, the slide staining apparatus is a VENTANA® BenchMark series instrument (i.e., BenchMark ULTRA IHC / ISH System).

[0337] Formalin-fixed paraffin-embedded tissues are suitable for use with the OptiView DAB IHC detection kit and VENTANA® BenchMark series instruments. In some embodiments, the preparation of tumor tissue for IHC detection includes the step of contacting the tumor tissue with a fixative. In some embodiments, a formalin-based fixative, such as 10% neutral buffered formalin (NBF), is used.

[0338] To minimize variability in visualization results, the thickness of tumor tissue sections, the type of fixation, and the duration of fixation can be optimized. In some embodiments, tumor tissue sections are approximately 2 μm to 6 μm thick. In some embodiments, tumor tissue sections are approximately 2, 3, 4, 5, or 6 μm thick. Slide heating is intended to dry the tumor tissue sections after slide mounting or to enhance tissue adhesion to the glass microscope slide. In some embodiments, the slide containing the tumor tissue sections is heated, preferably by firing. In some embodiments, the slide is heated at 60°C ± 5°C for 2 to 24 hours. Excessive heating of the tumor tissue should be avoided as it may reduce the availability of the antigen. In some embodiments, the slide is contacted with cold acetone (i.e., 4 to 8°C) for 10 minutes. In some embodiments, the slide is air-dried for at least 30 minutes after contact with cold acetone, preferably overnight.

[0339] Positive tissue controls are intended to be prepared using the c-Met IHC staining procedure. Positive tissue controls may be, for example, tumor tissue or non-tumorous gallbladder tissue. Some or all of the positive tissue controls should be characterized by strong staining. Positive tissue controls may contain both positive and negative staining and can function as both positive and negative control tissues. Unstained cellular components should indicate the absence of specific staining and serve as an indicator of background staining. In some embodiments, the same tissue used for positive tissue controls is used as a negative tissue control. In some embodiments, the positive or negative control tissues are prepared in the same manner as the test tissues.

[0340] Negative controls assist in interpreting the c-Met IHC score. In some embodiments, a negative reagent control is used instead of the primary anti-C-MET antibody to evaluate nonspecific staining. In some embodiments, the negative control reagent is a diluent only. In preferred embodiments, the incubation time for the negative reagent control is equal to the incubation time for the primary antibody.

[0341] The OptiView DAB IHC detection kit (Ventana catalog number 760-700) intended for this invention precipitates a brown reaction product at or around c-Met antigen sites localized by a primary anti-C-MET antibody.

[0342] In some embodiments, detection of c-Met expression by IHC is performed by a qualified pathologist familiar with immunohistochemical procedures. In some embodiments, detection of c-Met expression is performed after the step of evaluating positive and negative controls. Staining of negative reagent controls is recorded, and these results are compared to stained material to verify that the observed visualization is not due to nonspecific interaction. Positive tissue controls are examined to verify that the reagent is functioning correctly. If the positive tissue control does not show positive staining, the results from the test specimen should be considered invalid for the purposes of the therapeutic method disclosed herein. Negative tissue controls should be examined after the positive tissue controls to verify specific labeling of the target antigen by the primary antibody. The absence of specific staining in the negative tissue control supports the absence of anti-c-Met primary antibody binding. If specific staining occurs in the negative tissue control, the results from the test specimen should be considered invalid for the purposes of the therapeutic method disclosed herein. Nonspecific staining may appear diffuse. Sporadic faint staining may also indicate excessive formalin fixation of cells. Necrotic or degenerated cells may be stained nonspecifically.

[0343] In some embodiments of the treatment method, intact cells of tumor tissue are assayed for c-Met expression by IHC. Biopsy, excision, or cytological specimens of patient tissue samples are examined after controls as described herein, and staining intensity is evaluated in the context of any nonspecific background staining of controls (i.e., negative tissue control and negative reagent control). The cellular morphology of the tissue sample should also be examined by a qualified pathologist familiar with immunohistochemical procedures. In some embodiments, the tissue sample is contacted with hematoxylin or eosin staining.

[0344] In some embodiments, patients selected for treatment have their c-Met expression in tumor tissue determined by an IHC assay, which is a c-Met staining protocol. In some embodiments, the c-Met IHC assay is performed using an automated slide staining device. In some embodiments, the c-Met IHC assay includes the steps of: 1) attaching a barcode label to a slide containing tumor tissue (the barcode corresponds to one or more automated IHC protocols performed by the automated slide staining device); 2) filling the automated slide staining device with a primary anti-C-MET antibody, at least one negative reagent control, and / or one or more detection reagents; 3) mounting at least one slide containing tumor tissue into the automated slide staining device; 4) operating the automated slide staining device according to one or more automated IHC protocols to stain the c-Met tumor tissue on the slide; and 5) detecting and scoring the c-Met IHC stain of the slide. In some embodiments, the automated slide staining device is a Ventana BenchMark series instrument, and optionally a Ventana BenchMark Ultra automated staining instrument. In some embodiments, the barcode corresponds to the SP44 IHC protocol. In some embodiments, the SP44 IHC protocol is selected from a deparaffinization protocol, a cell conditioning protocol (i.e., Ventana catalog numbers 950-224), an antibody protocol (i.e., for SP44: Ventana catalog numbers 790-4430, or for rabbit monoclonal negative control Ig: Ventana catalog number 790-4795), a detection protocol (i.e., OptiView DAB IHC detection kit: Ventana catalog number 760-700), or a counterstaining protocol (i.e., for hematoxylin II: Ventana catalog number 790-2208, or for bluing reagents: Ventana catalog number 760-2037). In some embodiments, the primary anti-cMet antibody is an SP44 antibody. In some embodiments, one or more negative reagent controls are negative control immunoglobulins.In some embodiments, one or more detection reagents are from the OptiView detection kit and are optionally selected from Reaction Buffer (Ventana catalog no. 950-300), Ultra Liquid Coverslip (Ventana catalog no. 650-210), or EZ Prep (Ventana catalog no. 950-102).

[0345] 7.4.2 MET amplification 7.4.2.1 Detection of MET gene amplification In one embodiment, the amplification of the MET gene is due to aneuploidy. In another embodiment, the amplification of the MET gene is a focal amplification of the MET gene. Focal amplification is amplification of a portion of the chromosome and is distinct from amplification due to aneuploidy. A normal diploid cell without amplified MET genes contains two copies of the MET gene. In one embodiment, the presence of more than two copies of the MET gene in a cell indicates that the MET gene is amplified. In another embodiment, the presence of three or more, four or more, five or more, six or more, seven or more, eight or more, ten or more, fifteen or more, or twenty or more copies of the MET gene in a cell indicates that the MET gene is amplified.

[0346] Several techniques for evaluating MET gene amplification are known to those skilled in the art and can be used to detect MET copy numbers in tumor cells. Fluorescence in situ hybridization (FISH) uses a fluorescently labeled probe that specifically binds to the MET gene region on the chromosome, allowing the gene copy number (GCN) to be visualized under a microscope. Chromogenic in situ hybridization (CISH) is similar to FISH, but instead of a fluorescent probe, a chromogenic probe that produces a visible signal under a microscope is used. Polymerase chain reaction (PCR) amplifies a specific region of DNA using specific primers. The amplification product can then be quantified to determine the GCN of the MET gene. Next-generation sequencing (NGS) can provide information on the GCN of the MET gene, as well as other genetic alterations such as mutations or rearrangements.

[0347] MET FISH is intended as a means of determining MET gene amplification in tumors of candidate patients for ADC1 therapy. In one embodiment, the MET FISH assay is a two-color spot-count FISH assay that detects the allele copy number of the corresponding locus using an orange probe for the MET gene at locus 7q31.2 and a green probe for CEP7. Formalin-fixed paraffin-embedded (FFPE) slides are processed, hybridized with MET and CEP7 probes in buffer, and washed. Tumor cells are evaluated based on MET / CEP7 cutoff criteria.

[0348] Other methods for determining gene amplification are also being considered. Gene copy number can be determined, for example, by next-generation sequencing (NGS) or PCR as a means of determining MET gene amplification in tumors of candidate patients for ADC1 treatment. In one embodiment, the assay utilizes NGS. A non-limiting example of NGS tissue biopsy testing is Foundation Medicine F1CDxm, which can identify MET amplification from tumor tissue of patients with MET copy number ≥ (4+ploidy), for example, diploidy, where amplified MET is defined as MET copy number ≥ 6.

[0349] In one embodiment, the treatment method includes the step of determining the level of MET amplification within the tumor. In one embodiment, MET amplification is determined by MET FISH. In one embodiment, amplification is determined by performing an amplification assay, such as MET FISH, on tumor tissue from a subject (i.e., obtained from a biopsy, excision, or cytological sample; the tumor tissue may be archived tumor tissue or fresh tumor tissue), and further including the step of determining whether the tumor tissue is negative or positive for MET amplification. In some embodiments, MET FISH is performed according to a MET FISH protocol. In some embodiments, MET FISH is performed on at least one tumor tissue derived from a subject, and at least one tumor tissue is selected from archived tumor tissue and / or fresh tumor tissue. The level of MET amplification of the tumor is considered to be the level of its collected tissue.

[0350] In one embodiment, MET amplification within a tumor is determined by performing MET FISH on neoplastic cells derived from tumor tissue from a subject, and determining whether the neoplastic cells are i) MET gene amplification positive or ii) MET gene amplification negative based on the results of the MET FISH assay. In one embodiment, MET FISH is performed according to the MET FISH protocol described herein.

[0351] Circulating tumor DNA (ctDNA) can also be used to determine MET amplification. In embodiments, a blood sample is taken from the subject and tested for the presence of MET-amplified ctDNA. In embodiments, ctDNA is tested for MET amplification by a PCR-based assay or an NGS-based assay. A non-limiting example of an NGS liquid biopsy (ctDNA) test is Guardant360 CDx. Guardant360 CDx can detect local MET amplification from ctDNA in the blood when the plasma MET copy number (CN) ≥ 2.16. Plasma copy number is a combination of germ cell copy number, tumor tissue copy number, and variant allele frequency (MAF).

[0352] In embodiments, subjects treated by the methods of the present invention (including the methods for treating subjects having tumors as described in Section 7.3 above) are subjects having tumors exhibiting MET amplification. In embodiments, subjects having tumors are selected for treatment if the tumor exhibits MET amplification.

[0353] In one embodiment, subjects with tumors that do not show MET amplification are excluded from treatment. In another embodiment, tumors from a population of subjects with tumors are evaluated for MET amplification, and those showing MET amplification are selected for treatment, while those not showing MET amplification are excluded from treatment.

[0354] In the embodiment, the test that satisfies the specified MET amplification cutoff is performed in a College of American Pathologists (CAP) accredited laboratory and / or a Clinical Laboratory Improvement Amendments (CLIA) accredited laboratory, or an equivalent accredited laboratory.

[0355] 7.4.2.2 Determination of MET gene amplification status MET gene amplification negativity is defined as a MET / CEP7 signal ratio <1.8 from tumor tissue evaluated by a MET FISH assay, e.g., the MET FISH protocol. MET gene amplification positivity is defined as a MET / CEP7 signal ratio ≥1.8 from tumor tissue evaluated by a MET FISH assay, e.g., the MET FISH protocol. Low MET gene amplification is defined as a MET / CEP7 signal ratio between 1.8 and 2.2 from tumor tissue evaluated by a MET FISH assay, e.g., the MET FISH protocol. Intermediate MET amplification is defined as a MET / CEP7 signal ratio >2.2 to <5.0 from tumor tissue evaluated by a MET FISH assay, e.g., the MET FISH protocol. High MET amplification is defined as a MET / CEP7 signal ratio ≥5.0 from tumor tissue evaluated by a MET FISH assay, e.g., the MET FISH protocol. These amplification cutoffs are summarized in the table below.

[0356] [Table 1]

[0357] In some embodiments, the genome copy number (GCN) is determined by NGS. In embodiments, MET amplification negativity is defined as GCN < 5 from tumor tissue evaluated by NGS assay, and MET amplification positivity is defined as GCN ≥ 5. Low MET amplification is defined as GCN ≥ 5 and < 10 from tumor tissue evaluated by NGS assay. High MET amplification is defined as GCN ≥ 10 from tumor tissue evaluated by NGS assay. These amplification cutoffs are summarized in the table below.

[0358] [Table 2]

[0359] Comparing and correlating different types of gene amplification assays to identify patients with the same or substantially the same degree of MET amplification is within the scope of the skills of those skilled in the art. For example, correlating non-FISH assay results (e.g., NGS or CISH) with MET FISH assay results is within the scope of the art, and therefore non-FISH assays can be used to identify subjects whose MET / CEP7 signal ratio is 1.8 or greater, or 1.8 to 2.2, or >2.2 to <5.0, or 5.0 or greater when assayed by a MET FISH assay.

[0360] In certain embodiments, subjects with tumor tissue exhibiting MET amplification negativity are excluded from treatment with anti-cMet-ADC. In certain embodiments, subjects with tumor tissue exhibiting local MET amplification negativity are excluded from treatment with anti-cMet-ADC.

[0361] In some embodiments, patients selected for treatment with anti-cMet-ADC have tumor tissue that is MET amplification positive. In some embodiments, patients selected for treatment with anti-cMet-ADC have tumor tissue that is locally MET amplification positive.

[0362] In certain embodiments, subjects with GEA tumor tissue exhibiting MET amplification negativity are excluded from treatment with anti-cMet-ADC. In certain embodiments, subjects with GEA tumor tissue exhibiting local MET amplification negativity are excluded from treatment with anti-cMet-ADC.

[0363] In some embodiments, patients selected for treatment with anti-cMet-ADC have GEA tumor tissue that is MET amplification positive. In some embodiments, patients selected for treatment with anti-cMet-ADC have GEA tumor tissue that is locally MET amplification positive.

[0364] 7.4.3 EGFR status In some embodiments, patients selected for treatment have EGFR wild-type MET amplification-positive non-squamous NSCLC. In some embodiments, the EGFR status (wild-type or variant) of the NSCLC is detected by an FDA-approved test. One such test uses real-time polymerase chain reaction (PCR) to identify mutations in exons 18, 19, 20, and 21 of the EGFR gene. This test has been clinically validated in multiple clinical trials as a companion diagnostic (CDx) for both first-line and second-line EGFR TKI therapy in patients with advanced NSCLC (Heeke et al., (2019) Clinical Lung Cancer 21(1): pp. 56-65).

[0365] Next-generation sequencing (NGS) can also be used to detect EGFR mutations. Many companies have FDA-approved CDx assays for detecting EGFR mutations, including Foundation One CDx, Thermo Fisher Oncomine NSCLC, and Guardant 360CDx. See also Ding et al., (2019) Thoracic Cancer 10: pp. 1879-1884, discussing the use of the Thermo Fisher Oncomine NSCLC assay.

[0366] Actionable EGFR mutations are EGFR mutations that can be targeted by available anticancer therapies. In one embodiment, the absence of actionable EGFR mutations indicates that NSCLC is EGFR wild-type. In another embodiment, the absence of EGFR exon 19 deletions and EGFR L858R mutations indicates that NSCLC is EGFR wild-type. In yet another embodiment, the absence of EGFR exon 19 deletions and EGFR L858R mutations, as well as the absence of one or more of the following mutations: EGFR exon 20 insertion, EGFR L861Q mutation, EGFR G719X mutation, and EGFR S768I mutation, indicates that NSCLC is EGFR wild-type. In yet another embodiment, the absence of EGFR exon 19 deletions, EGFR L858R mutations, and EGFR exon 20 insertions indicates that NSCLC is EGFR wild-type. In another embodiment, the absence of EGFR exon 19 deletion, EGFR L858R mutation, EGFR exon 20 insertion, EGFR L861Q mutation, EGFR G719X mutation, and EGFR S768I mutation indicates that NSCLC is EGFR wild-type. [Examples]

[0367] 8. Examples The following examples, which highlight certain features and characteristics of exemplary embodiments of the methods described herein, are provided for illustrative purposes only.

[0368] [Example 1] 8.1 ADC-1 DAR The DAR profiles of compositions containing multiple ADC1 species (referred to herein as ADC1 compositions) were determined using reductive reverse-phase liquid chromatography (r-RPLC). Proteins were reduced to their light and heavy chain subunits using dithiothreitol. The reduced protein subunits interacted with immobilized hydrophobic ligands on the chromatography column resin, enabling the separation and quantification of light and heavy chains with different drug loads. Two-wavelength detection at 280 nm and 370 nm allowed for the distinction between conjugated and unconjugated light and heavy chains. Chromatograms are shown in Figure 1.

[0369] Using the following formula, we calculated the weighted average of individual protein subunits conjugated to different drug loads based on corrected peak area (CPA) using two wavelength detections at 280 nm and 370 nm:

[0370]

number

[0371] The r-RPLC method determined that the average DAR of the ADC1 composition was within the range of DAR 5.4 to 6.6.

[0372] The DAR distribution of ADC1 compositions was characterized by intact native mass spectrometry using size exclusion chromatography (SEC) combined with a Waters Synapt G2-SI high-resolution quadrupole time-of-flight mass spectrometer (QTOF-MS). Non-denaturing mobile phases and mild ionization conditions enabled the analysis and determination of drug loads in intact ADC1 antibody-drug conjugates. The obtained mass spectrometry data were deconvoluted using a commercially available advanced maximum entropy (MaxEnt) algorithm to determine the drug-antibody ratio. The deconvoluted mass spectra of the ADC1 compositions are shown in Figure 2. Figure 2 shows that the most dominant ADC1 species has n=6.

[0373] [Example 2] Phase 1 human first-dose study to evaluate the safety, pharmacokinetics (PK), and efficacy of 8.2-ADC1 Disclosed herein is an ongoing Phase 1 human first-dose study aimed at evaluating the safety, pharmacokinetics (PK), and efficacy of the ADC1 composition described in Example 1 in adult subjects with advanced solid tumors. The primary objectives of the study are to evaluate the safety, tolerability, and PK of the ADC1 composition, to determine the recommended Phase 2 dose (RP2D) of the ADC1 composition administered as monotherapy, and to evaluate the efficacy of the ADC1 composition in subjects with the following advanced solid tumors: non-squamous non-small cell lung cancer (NSCLC), squamous NSCLC, gastroesophageal junction adenocarcinoma (GEA), and colorectal cancer (CRC). Approximately 500 subjects will be enrolled in the Phase 1 study.

[0374] Ongoing trials include dose escalation of monotherapy with ADC1 compositions in advanced solid tumors (Part 1), and dose expansion of monotherapy with ADC1 compositions in the following advanced solid tumor indications: Selected biomarkers: c-Met-intermediate / high non-squamous NSCLC expressing wild-type epidermal growth factor receptor (EGFR) (EGFR-wt NSCLC) (Part 2i), c-Met-intermediate / high non-squamous NSCLC expressing mutant EGFR (EGFR-mu NSCLC) (Part 2ii), c-Met overexpression (OE) squamous NSCLC (Part 2iii), and c-Met OE GEA (Part 3). Non-selective: c-Met non-selective CRC (Part 4). Other dose expansion trials of monotherapy with ADC1 compositions include MET-amplified selected advanced solid tumors (Part 5) and MET-mutation selected advanced solid tumors (Part 6). The combination studies include the safety introduction of the ADC1 composition in combination with bevacizumab in progressive CRC (Part 7a), and the dose-optimized expansion of the ADC1 composition in combination with bevacizumab compared to TAS-102 (standard treatment control) in patients with unresectable mCRC that is MSS or pMMR, BRAF V600E wild-type, and has progressed after fluoropyrimidine (e.g., 5-fluorouracil or capecitabine), oxaliplatin, and irinotecan (Part 7b).

[0375] Part 1 will enroll subjects with advanced solid tumors characterized by MET amplification in multiple indications, including cholangiocarcinoma, ovarian cancer, colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and breast cancer. Part 1 will also investigate gastric / gastroesophageal junction adenocarcinoma (GEA), head and neck squamous cell carcinoma (HNSCC), and renal cell carcinoma (RCC).

[0376] In the study, the ADC1 composition will be administered intravenously (IV) once every 21 days (Q3W) in a 21-day cycle for up to 24 months in the context of this study, until disease progression, withdrawal of consent, or unacceptable toxicity occurs. For Part 7a of the combination study, approximately 60 subjects will receive the ADC1 composition in combination with bevacizumab once every 21 days (Q3W) in a 21-day cycle. For Part 7b, approximately 20 subjects will receive TAS-102 in combination with bevacizumab in a 28-day cycle, once every 14 days (Q2W), with TAS-102 administered twice daily on days D1-5 and D8-12 of each 28-day cycle. The maximum treatment duration is 2 years.

[0377] Table 1 shows an overview of the treatment groups and interventions in the trial.

[0378] [Table 3] JPEG2026518170000042.jpg79150

[0379] 8.2.1 Main eligibility criteria: (1) Male or female, 18 years of age or older (2) Histological diagnosis of malignant solid tumors (WHO criteria) (3) Measurable lesions based on the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (4) Regarding Part 1 only - A history of progressive solid tumors that have progressed during any standard treatment, are unsuitable for surgical resection, or are unsuitable for other approved treatment options that have demonstrated clinical benefit. (5) Regarding Part 2 only - A history of progressive c-Met OE non-squamous EGFR-wt or EGFR-mu, or a history of progressive c-Met OE squamous NSCLC that has progressed after treatment with at least the following: Platinum-based chemotherapy and immune checkpoint inhibitors and / or appropriate targeted therapy (where applicable) for non-squamous EGFR-wt and squamous NSCLC (Parts 2i and 2iii) • Platinum-based dual chemotherapy and / or tyrosine kinase inhibitors (TKIs) for non-squamous EGFR-muNSCLC (Part 2ii) Inclusion in the study requires that the patient has received no more than two lines of prior cytotoxic chemotherapy, excluding adjuvant therapy, and has advanced NSCLC that is unsuitable for surgical resection or other approved treatment options, including immunotherapy, that have demonstrated clinical benefit. (6) Regarding Part 3 only - A history of diagnosis of progressive, histopathologically or cytologically confirmed c-Met OE GEA that has progressed after treatment with at least one prior cytotoxic chemotherapy regimen for locally advanced or metastatic disease, has not received more than two lines of prior cytotoxic chemotherapy regimens, and is unsuitable for surgical resection. The subjects are: • If applicable, immune checkpoint inhibitors • Appropriate available therapies, including HER2-targeted therapy, where applicable. It must be progressing during treatment. (7) Regarding Part 4 only, there is no -BRAF V600E mutation, and it is not dMMR+ / MSI-Hi. • Fluoropyrimidines (e.g., 5-fluorouracil or capecitabine) Oxaliplatin Irinotecan • If applicable, anti-EGFR (including, but not limited to, cetuximab or panitumumab) • If applicable, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (including, but not limited to, bevacizumab, ramucirumab, or aflibercept) • Targeted therapy, if applicable. Patients with a history of progressive CRC, confirmed histopathologically or cytologically, that progresses during treatment with [medical name]. This study will include patients who, according to the investigating physician, are unsuitable for or unable to tolerate standard therapy. Prior treatment with lonsurf or regorafenib is also acceptable. (8) With respect to Part 5 only - Subjects having histologically or cytologically confirmed progressive solid tumors characterized by MET amplification, which are unsuitable for surgical resection, and whose disease has progressed after at least one prior systemic therapy, and / or for which there are no satisfactory alternative treatment options. • This program is for patients who cannot tolerate standard treatment. (9) Part 6 only - Subjects having histologically or cytologically confirmed progressive solid tumors with MET mutations (including mutations in the tyrosine kinase domain, near-membrane region and extracellular domain, locally determined by next-generation sequencing (NGS) or validated qPCR on tissue), which are unsuitable for surgical resection, and whose disease has progressed after at least one prior systemic therapy, and / or for which there are no satisfactory alternative treatment options. • This program is for patients who cannot tolerate standard treatment. (10) Regarding Part 7 (with CRC) only: No mutations, not dMMR+ / MSI-H, • Fluoropyrimidines (e.g., 5-fluorouracil or capecitabine) Oxaliplatin Irinotecan • If applicable, anti-EGFR (including, but not limited to, cetuximab or panitumumab) • If applicable, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody (including, but not limited to, bevacizumab, ramucirumab, or aflibercept) • Targeted therapy, if applicable. Patients with a history of progressive CRC, confirmed histopathologically or cytologically, that progresses during treatment with [medical name]. This study will include patients who, according to the investigating physician, are unsuitable for or unable to tolerate standard therapy. Patients previously treated with TAS-102 or regorafenib are not eligible. (11) In the opinion of the physician in charge of the clinical trial, average life expectancy ≥ 3 months (12) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is 0 or 1. (13) The target should be a test value that meets the following criteria: • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels within 7 days prior to administration on day 1 of cycle 1 are ≤3.0 × upper limit of normal (ULN); Regarding patients with liver metastases: AST and ALT ≤ 5.0 × ULN; • Estimated creatinine clearance ≥ 30 ml / min calculated by the modified Cockcroft-Gault formula; • Total bilirubin within 7 days prior to administration on day 1 of cycle 1 ≤ 1.5 × ULN (In subjects with a history of Gilbert's syndrome, total bilirubin ≤ 3 × ULN may be required). • Neutrophil absolute count (ANC) ≥ 1,500 / mm³ 3 (No granulocyte colony-stimulating factor [G-CSF] administration in the past 10 days); • Platelet count ≥ 100,000 / μL (no platelet transfusions in the past 14 days); • Hemoglobin ≥ 8 g / dL (no red blood cell transfusions in the past 14 days) Albumin ≥ 3 g / dL (14) No history of interstitial lung disease (ILD) or pneumonia requiring treatment with systemic steroids, and no evidence of active ILD or pneumonia. (15) No history of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonia, or idiopathic pneumonia. (16) No history of clinically significant lung-specific diseases, including but not limited to: • Underlying lung impairment (i.e., pulmonary embolism, severe asthma, severe COPD, restrictive lung disease, pleural effusion, dependence on oxygen supplementation, etc., within 3 months of trial registration) • Any autoimmune disorder, connective tissue disorder, or inflammatory disorder (i.e., rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc.) with a history of lung injury or suspected lung injury at the time of screening, and a history of lung resection. (17) Regarding Part 7 only: Subjects previously treated with TAS-102 or regorafenib are not eligible.

[0380] 8.2.2 Pharmacokinetic Analysis Whole blood samples are collected in appropriately labeled tubes and processed. Serum concentrations of ADC1 (total antibody and ADC), plasma concentrations of the unconjugated Top1 inhibitor payload, and relative titers of serum ADC1 anti-drug antibody (ADA) are determined using validated methods.

[0381] This Phase 1 trial has commenced and is ongoing. The dose escalation scheme is shown in Figure 3, and the dose expansion design for monotherapy is shown in Figure 4. Initial results are described in Example 3.

[0382] [Example 3] 8.3 Dose escalation results from a human initial dose study of a novel C-Met-targeted antibody-drug conjugate, ADC1, in progressive solid tumors. As of April 2023, 57 patients were enrolled in the dose-escalation study, with a median follow-up period of 6.5 months. The median age was 58 years (range, 34–79), 25 patients (54%) were male, and cancer types included CRC (n=27), NSCLC (n=5), GEA (n=7), and MET gene amplification (n=11). The median number of prior treatment lines was 5 (1–13). The ADC1 composition described in Example 1 showed an acceptable safety profile as shown in Table 2.

[0383] [Table 4]

[0384] Initial PK data show ADC exposure exceeding dose-proportionality (half-life 5-8 days) and volume-proportional payload exposure (half-life 6-12 days). The PK profiles of ADC1 composition compared to Top1i are shown in Figures 5A and 5B. The PK parameters at the maximum tolerated dose (3 mg / kg) are shown in Table 3.

[0385] [Table 5]

[0386] The clinical activity observed with the ADC1 composition is shown in Table 4. Figures 6A and 6B show the percentage change in target lesion measurements over time from baseline in all patients (A; N=57) and CRC patients (B; N=27).

[0387] [Table 6]

[0388] Table 5 summarizes the overall response rates (n / N) by dose and disease.

[0389] [Table 7]

[0390] [Example 4] 8.4 c-Met staining protocol To determine whether candidate patients with NSCLC are suitable candidates for treatment with anti-cMet ADCs, the following assays were developed. IHC staining assays for determining c-Met overexpression were developed using the Ventana c-Met CONFIRM(SP44) kit and the c-Met SP44 OptiView IHC staining assay.

[0391] Aspects of this assay and its protocol are suitable for use in pre-screening of patients with NSCLC for treatment with anti-cMet ADCs.

[0392] 8.4.1 Materials and Methods

[0393] Sample preparation Formalin-fixed, paraffin-embedded tumor tissue, processed according to standard procedures, was sectioned to approximately 4 microns and floated on positively charged glass slides. The tissue was fixed using 10% neutral buffered formalin. To avoid a time-dependent decrease in antigenicity, the slides were stained immediately after sectioning.

[0394] Immunohistochemical procedure Immunohistochemistry (IHC) of c-Met was performed using the Ventana BenchMark Ultra automated staining platform. The primary antibody used was anti-c-Met clone SP44. The OptiView DAB IHC detection kit was used for indirect visualization of the primary antibody for c-Met expression determination.

[0395] The staining procedure using the Ventana Benchmark instrument included the following steps: 1) Attach a slide barcode label corresponding to the SP44 IHC protocol to be implemented (Table 3); 2) Place the SP44 antibody, rabbit monoclonal negative control Ig, and OptiView detection kit dispenser into the reagent tray; optionally check for bulk liquid (Table 4) and empty waste liquid; 3) Place the slide to be examined into the automatic slide staining device; and 4) Start the staining run using the Ventana instrument.

[0396] Upon completion of the Ventana instrument run, the slide was removed and soaked in a mild detergent to remove the oil coverslip. The slide was thoroughly rinsed with distilled water and then dehydrated with a stepwise alcohol series. The slide was punctured with xylene and the coverslip was applied using a permanent mounting medium.

[0397] [Table 8]

[0398] [Table 9]

[0399] 8.4.2 Results and Analysis Evaluation and interpretation of slides Neoplastic cells stained with the c-Met SP44 OptiView IHC assay were visually evaluated for positivity based on the intensity of the diaminobenzidine (DAB) signal. The IHC signal may be uniformly distributed throughout the neoplasm, or it may be heterogeneously distributed if there are few stain-positive cells.

[0400] c-Met(SP44) IHC staining in NSCLC showed that membrane staining is often accompanied by cytoplasmic staining (i.e., both cytoplasmic and membrane). When the staining pattern appears as membrane staining, it can be circumferential (the predominant staining pattern) or partial (i.e., basal-outer staining in adenocarcinoma). Both membrane and cytoplasmic staining showed a wide range of intensity, from no staining (IHC score 0) to strong staining (IHC score 3+). Cytoplasmic staining was generally less intense than membrane staining. In some situations, the intensity of cytoplasmic staining was similar to that of membrane staining (i.e., especially at moderate or strong intensity), requiring careful differentiation of membrane staining from cytoplasmic staining.

[0401] Normal lung tissue, bronchial epithelium, lung cells, and alveolar macrophages generally did not show strong levels of c-Met overexpression. However, bronchial epithelium and lung cells stained with an IHC score of 2+ to 3+ in the basolateral pattern. Staining of normal cellular components may be suitable as an internal control of the method. Typical staining intensity guidelines for cytoplasmic and membrane staining are shown in Tables 8 and 9, respectively.

[0402] [Table 10]

[0403] [Table 11]

[0404] Scoring algorithm IHC slides of c-Met-stained tumor tissue were evaluated for membrane staining in neoplastic cells. Non-squamous NSCLC samples with membrane staining <25% 3+ were considered c-Met negative. Non-squamous NSCLC samples with ≥25% viable tumor cells showing 3+ membrane staining were considered c-Met positive. Non-squamous NSCLC samples with ≥25% to <50% viable tumor cells showing 3+ membrane staining were considered moderately c-Met. Non-squamous NSCLC samples with ≥50% viable tumor cells showing 3+ membrane staining were considered highly c-Met. Table 10 shows different intensities of membrane staining and positive / negative status based on the scoring algorithm.

[0405] [Table 12]

[0406] 8.4.3 All Validation for IHC Platforms Comparison of c-Met IHC assays: SP44 "Ultraview" vs. SP44 "Optiview" We compared the analytical methods of SP44 Ultraview and SP44 OptiView in a large cohort of commercially available NSCLC tissue (Figure 10). These results indicate that the SP44 OptiView IHC assay selected a similar patient population to SP44 Ultraview at an ≥25% 3+ membrane staining cutoff. The overall agreement rate at this cutoff between the two assays was 93%. A Phase I clinical trial treated patients with an H score of 150 using the SP44 UltraView assay with anti-cMet ADCs. After rescoring the slides, the optimal cutoff using the SP44 Ultraview IHC assay was ≥25% 3+, with a best overall response of 56%. Statistical modeling showed that the best overall response of the OptiView IHC assay using Phase I data was 52% (Figure 11).

[0407] Similarly, the SP44 OptiView IHC assay showed a 99% overall agreement rate with the SP44 Ultraview IHC assay at an ≥50% 3+ membrane staining cutoff (Figure 12). A Phase I clinical trial treated patients with an H score of 150 using the SP44 UltraView assay with anti-cMet ADCs. After rescoring the slides, the SP44 Ultraview IHC assay showed a best overall response of 67% at an ≥50% 3+ membrane staining cutoff. Statistical modeling showed the best overall response of the OptiView IHC assay using Phase I data to be 63% (Figure 12).

[0408] [Example 5] 8.5 MET FISH Protocol The SureFISH MET amplification probe and CEP7 FISH assay is a two-color spot count FISH assay that detects the allele copy number of the corresponding locus using an orange probe for the MET gene at locus 7q31.2 and a green probe for CEP7. Formalin-fixed paraffin-embedded (FFPE) slides are processed and hybridized with MET and CEP7 probes at a 1:50 dilution ratio using buffer (tDenHyb-2®), and washed with NeoGenomics according to the standard FISH protocol. Based on a pathological review of serial H&E slides, 50 nucleated cells within a circled tumor area are individually counted by a nationally certified cytogenetic technician meeting CAP / CLIA criteria. Nationally certified technicians are trained in ratio-based FISH analysis procedures with an annual competency assessment and participate in bi-annual laboratory proficiency tests. Scores are evaluated based on the MET / CEP7 cutoff criteria listed below according to the literature and validated by NeoGenomics. For validation reporting, the counted FISH scores are reviewed by the facility's medical director at NeoGenomics to confirm the amplification status. For real-time clinical trial reporting, the raw data scores of the samples are interpreted for amplification status by a certified pathologist approved for the trial.

[0409] [Example 6] 8.6 Dose escalation results from a human initial dose study of a novel C-Met-targeted antibody-drug conjugate, ADC1, in progressive solid tumors as of November 10, 2023. Initially, c-Met expression levels were considered an eligibility criterion in Parts 2 and 3 of this study, but were later abandoned as such.

[0410] 8.6.1 (NSCLC) Part 2 Results At the time of the initial data cut, a total of 19 patients were enrolled in Part 2 of the trial (10 patients enrolled in Part 2i, 5 patients enrolled in Part 2ii, and 4 patients enrolled in Part 2iii).

[0411] Figure 13A shows the percentage change in target lesion measurements over time from baseline in patients (N=16) with EGFR-wt non-squamous (NSQ) NSCLC (Part 2i), EGFR-mu non-squamous NSCLC (Part 2ii), and squamous NSCLC (Part 2iii).

[0412] The best overall risk ratio (ORR), confirmed ORR, and confirmed chronic brain birth rate (CBR) for EGFR-wt non-squamous NSCLC patients were 40%, 30%, and 70%, respectively. For EGFR-mu non-squamous NSCLC patients, the best ORR, confirmed ORR, and confirmed CBR were 80%, 80%, and 80%, respectively. For squamous NSCLC patients, the best ORR, confirmed ORR, and confirmed CBR were 0%, 0%, and 25%, respectively.

[0413] At the time of the second data cut, 48 subjects with 2L+NSQ NSCLC-EGFR-wt were enrolled in Part 2i; 11 subjects had c-Met expression ≥25% 3+, 10 subjects had c-Met expression ranging from ≥50% 2+ to <25% 3+, and 27 subjects were not selected for c-Met.

[0414] The confirmed objective response rate (ORR) at the second data cut of Part 2i, as assessed by the investigators, was 43.8% (21 / 48), and the unconfirmed best overall response rate was 54.2% (26 / 48). The confirmed clinical benefit rate (CBR12) at 12 weeks was 62.5% (30 / 48). The confirmed clinical benefit rate (CBR24) at 24 weeks was 47.9% (23 / 48). As the majority of patients (62.5%) were still receiving treatment at the second data cut, the overall duration of response (DOR) for the 21 responding patients was 5.5 months, and the median progression-free survival (PFS) and median overall survival (OS) were 6.9 months and 12.0 months, respectively. Figure 13B shows the percentage change in target lesion measurements over time from baseline in EGFR-wt non-squamous NSCLC patients (Part 2i) at the second data cut.

[0415] Subjects with NSQ NSCLC tumors exhibiting positive c-Met expression levels (defined as ≥50% (≥50% 2+) neoplasms derived from tumor tissue, assessed by c-Met IHC with at least 2+ membrane or membrane+cytoplasmic staining) showed an ORR of 48.6%. Subjects with tumors that did not meet the ≥50% 2+ threshold had an ORR of 30%. Subjects with NSQ NSCLC tumors exhibiting positive c-Met expression levels (defined as ≥25% (≥25% 3+) neoplasms derived from tumor tissue, assessed by c-Met IHC with 3+ membrane or membrane+cytoplasmic staining) showed an ORR of 53.3%. Subjects with tumors that did not meet the ≥25% 3+ threshold had an ORR of 40.6%. The table below summarizes the ORR observed in EGFR-wt NSQ NSCLC tumors by IHC cutoff.

[0416] [Table 13]

[0417] For subjects enrolled in Part 2ii with EGFR-mu NSQ NSCLC tumors, the ORR was 37.9%. For subjects with EGFR-mu NSQ NSCLC tumors with c-Met expression ≥25%3+, the ORR was 46.2%. The table below summarizes the ORR observed in EGFR-mu NSQ NSCLC tumors by IHC cutoff.

[0418] [Table 14]

[0419] 8.6.2 (GEA) Part 3 Results At the initial data cut, a total of 22 patients were enrolled in Part 3 of the trial. Figure 14A shows the percentage change in target lesion measurements over time from baseline in GEA patients (N=22). The best ORR, confirmed ORR, and confirmed CBR for GEA patients with one prior therapy were 40%, 30%, and 80%, respectively. For GEA patients with two or more prior therapies, the best ORR, confirmed ORR, and confirmed CBR were 36%, 27%, and 63%, respectively.

[0420] At the second data cut, 42 subjects with 2L+GEA were enrolled. Initially, patients were prospectively selected for enrollment based on a c-Met expression >90% 1+ cutoff. However, since more than 80% of pre-screened patients met the pre-specified selection criteria, the prospective selection requirement was removed. Of the 42 enrolled GEA patients, 20 were enrolled using prospective c-Met selection (>90% 1+ cutoff), and 22 were enrolled using a non-selective method.

[0421] In Part 3 GEA patients, the investigator-assessed confirmed objective response rate (ORR) was 28.6% (12 / 42). One complete response was observed. The confirmed clinical benefit rate (CBR) was 71.4%. The confirmed clinical benefit rate at 12 weeks (CBR12) was 40.5% (17 / 42). The duration of treatment (DOR) was 4.2 months for all 12 responding patients. The median progression-free survival (PFS) and median overall survival (OS) were 3.98 months and 5.95 months, respectively.

[0422] Figure 14B shows the percentage change in target lesion measurements over time from baseline in GEA patients (N=41) since the second data cut.

[0423] For GEA patients with one prior therapy, the best ORR, confirmed ORR, and confirmed CBR were 40%, 30%, and 80%, respectively. For GEA patients with two or more prior therapies, the best ORR, confirmed ORR, and confirmed CBR were 36%, 27%, and 63%, respectively.

[0424] Subjects with GEA tumors exhibiting positive c-Met expression levels for GEA (defined as ≥50% (≥50% 2+) neoplasms derived from tumor tissue, as assessed by c-Met IHC with 2+ membrane or membrane+ cytoplasmic staining) showed an ORR of 37.9%. Subjects with tumors that did not meet the ≥50% 2+ threshold had an ORR of 7.7%.

[0425] [Table 15]

[0426] In subjects with GEA tumors positive for MET gene amplification, the ORR was 58%, compared to 17% in subjects with tumors not positive for MET gene amplification. When amplification due to aneuploidy was excluded, the ORR was 78%, compared to 16% in subjects with tumors not positive for local MET gene amplification.

[0427] [Table 16] 8.6.3 (CRC) Results of Part 1 (Monotherapy Dose Escalation) and Part 4 (Colorectal Cancer) At the time of the initial data cut, out of a total of 122 patients, 29 were enrolled in Part 1 of the trial and 93 patients were enrolled in Part 4.

[0428] Figures 15A and 15B show the percentage change in target lesion measurements over time from baseline in CRC patients from Part 1 (Figure 15A; N=26) and CRC patients from Part 4 (Figure 15B; N=86).

[0429] In patients who received ADC1 1.6 mg / kg in Parts 1 and 4 combined, the ORR and CBR were 6% and 75%, respectively. In patients who received ADC1 2.4 mg / kg in Parts 1 and 4 combined, the ORR and CBR were 18% and 78%, respectively. In patients who received ADC1 3.0 mg / kg in Parts 1 and 4 combined, the ORR and CBR were 24% and 68%, respectively. The median progression-free survival was 5.1 months for patients who received 1.6 mg / kg, 5.3 months for patients who received 2.4 mg / kg, and 4.1 months for patients who received 3.0 mg / kg. The median overall survival was 9.63 months for patients who received 2.4 mg / kg and 9.2 months for patients who received 3.0 mg / kg. The median duration of response was 5.32 months for patients receiving 2.4 mg / kg and 4.14 months for patients receiving 3.0 mg / kg.

[0430] Higher ADC exposure correlated with a higher probability of response (e.g., ORR and CBR). Both 2.4 and 3.0 mg / kg doses of the ADC1 composition demonstrated efficacy, with 2.4 mg / kg showing a better safety profile and overall tolerability. 8.6.4 (MET Amplification) Part 5 Results At the time of the initial data cut, 29 patients were enrolled in Part 5 of the trial.

[0431] Figure 16 shows the percentage change in target lesion measurements over time from baseline in patients with MET-amplified tumors (N=27).

[0432] The best ORR, confirmed ORR, and confirmed CBR for patients treated with ADC1 2.4 mg / kg were 36.4%, 36.4%, and 81.8%, respectively. For patients treated with ADC1 3.0 mg / kg, the best ORR, confirmed ORR, and confirmed CBR were 75.1%, 62.5%, and 87.5%, respectively.

[0433] 8.6.5 Summary of adverse events that occurred during treatment in all treatment groups

[0434] [Table 17]

[0435] [Table 18]

[0436] Hematological toxicity was the most dose-limiting toxicity, but it was well managed at doses ≤3 mg / kg.

[0437] All references cited herein are incorporated herein by reference in whole and for all purposes to the same extent that individual publications or patents or patent applications are specifically and individually indicated as being incorporated herein by reference in whole for all purposes.

Claims

1. A method for treating non-squamous non-small cell lung cancer ("NSCLC") tumors expressing c-Met, comprising: an anti-c-Met antibody-drug conjugate ("anti-c-Met ADC") having the following structure, administered to a human subject or population of human subjects having an NSCLC tumor: 【Chemistry 1】 A method comprising administering an effective therapeutic dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat NSCLC tumors.

2. The method according to claim 1, wherein NSCLC is refractory or recurrent.

3. The method according to Embodiment 1 or 2, further comprising the step of determining the c-Met expression level of the tumor.

4. The method according to any one of claims 1 to 3, wherein the NSCLC tumor expresses wild-type epidermal growth factor receptor (EGFR-wt).

5. The method according to any one of claims 1 to 3, wherein the NSCLC tumor expresses mutant EGFR (EGFR-mu).

6. The method according to any one of claims 1 to 3, wherein the NSCLC tumor is a non-squamous NSCLC tumor having EGFR-wt expression.

7. The method according to any one of claims 1 to 3, wherein the NSCLC tumor is a non-squamous NSCLC tumor having EGFR-mu expression.

8. The method according to any one of claims 1 to 3, wherein the tumor has a MET gene mutation.

9. The method according to any one of claims 1 to 3, wherein the NSCLC tumor is an advanced solid tumor that is progressing during any standard treatment, unsuitable for surgical resection, or unsuitable for other approved treatment options that have demonstrated clinical benefit.

10. The method according to claim 6 or 8, wherein the NSCLC tumor has progressed after treatment with at least platinum-based chemotherapy and an immune checkpoint inhibitor and / or appropriate targeted therapy.

11. The method according to claim 7, wherein the NSCLC tumor has progressed after treatment with at least platinum-based dual chemotherapy and / or a tyrosine kinase inhibitor.

12. The method according to any one of claims 6 to 8 and 10 to 11, wherein the human subject has received two or fewer prior lines of cytotoxic chemotherapy, excluding adjuvant therapy.

13. The method according to any one of claims 1 to 12, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%.

14. The method according to any one of claims 1 to 13, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects.

15. The method according to any one of claims 1 to 13, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in human subjects.

16. The method according to any one of claims 1 to 13, wherein administration of an anti-c-Met ADC achieves stable (SD) in a human subject.

17. The method according to any one of claims 1 to 16, wherein n takes the value of 2.

18. The method according to any one of claims 1 to 16, wherein n takes the value of 4.

19. The method according to any one of claims 1 to 16, wherein n takes the value of 6.

20. The method according to any one of claims 1 to 16, wherein n takes the value of 8.

21. The method according to any one of claims 1 to 16, wherein n takes the value of 10.

22. The method according to any one of claims 1 to 21, wherein the mean drug antibody ratio (DAR) of anti-c-Met ADC is approximately 5.4 to approximately 6.

6.

23. The method according to any one of claims 1 to 21, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

24. The method according to any one of claims 1 to 21, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

25. The method according to any one of claims 1 to 21 and 23, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

26. The method according to any one of claims 1 to 21 and 24, wherein the NSCLC tumor is a refractory or recurrent NSCLC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

27. A method for treating gastroesophageal adenocarcinoma ("GEA") tumors expressing c-Met, comprising: a human subject or population of human subjects having a GEA tumor, and an anti-c-Met ADC having the following structure: 【Chemistry 2】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks, thereby treating a GEA tumor.

28. The method according to claim 27, wherein the GEA tumor is refractory or recurrent.

29. The method according to claim 27 or 28, further comprising the step of determining the c-Met expression level of a tumor.

30. The method according to claim 27 or 28, wherein the GEA tumor has a MET gene mutation.

31. The method according to any one of claims 27 to 30, wherein the GEA tumor is a histopathologically or cytologically confirmed advanced c-Met-expressing GEA that is unsuitable for surgical resection, has progressed after treatment with at least one prior cytotoxic chemotherapy regimen for locally advanced or metastatic disease, and the human subject has not received more than two lines of prior cytotoxic chemotherapy regimens.

32. The method according to claim 30 or 31, wherein the GEA tumor is progressing during immune checkpoint inhibitor therapy.

33. The method according to any one of claims 30 to 32, wherein the GEA tumor is progressing during HER2-targeted therapy.

34. The method according to any one of claims 27 to 33, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%.

35. The method according to any one of claims 27 to 34, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects.

36. The method according to any one of claims 27 to 34, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in human subjects.

37. The method according to any one of claims 27 to 34, wherein administration of an anti-c-Met ADC achieves stable (SD) in the subject.

38. The method according to any one of claims 27 to 37, wherein n takes the value of 2.

39. The method according to any one of claims 27 to 37, wherein n takes the value of 4.

40. The method according to any one of claims 27 to 37, wherein n takes the value of 6.

41. The method according to any one of claims 27 to 37, wherein n takes the value of 8.

42. The method according to any one of claims 27 to 37, wherein n takes the value of 10.

43. The method according to any one of claims 27 to 42, wherein the average DAR of anti-c-Met ADC is about 5.4 to about 6.

6.

44. The method according to any one of claims 27 to 42, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients.

45. The method according to any one of claims 27 to 42, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human patients.

46. The method according to any one of claims 27 to 42 and 44, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

47. The method according to any one of claims 27 to 42 and 45, wherein the GEA tumor is a refractory or recurrent GEA tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

48. A method for treating colorectal cancer ("CRC") tumors expressing cMeth, comprising: a human subject or population of human subjects having a CRC tumor, in which an anti-c-Meth ADC having the following structure: 【Transformation 3】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab intravenously every three weeks to treat CRC tumors.

49. The method according to claim 48, wherein the CRC tumor is refractory or recurrent.

50. The method according to claim 48 or 49, further comprising the step of determining the c-Met expression level of a tumor.

51. The method according to any one of claims 48 to 50, wherein the CRC tumor is histopathologically or cytologically confirmed progressive CRC, lacking the BRAF V600E mutation and not being dMMR+ / MSI-Hi.

52. The method according to claim 51, wherein the CRC tumor is progressing during treatment with any one or a combination thereof of prior therapies comprising fluoropyrimidine, oxaliplatin, irinotecan, anti-EGFR antibody, and / or anti-vascular endothelial growth factor monoclonal antibody.

53. The method according to claim 51 or 52, wherein the CRC tumor is progressing during applicable targeted therapy.

54. The method according to any one of claims 48 to 53, wherein administration of an anti-c-Met ADC results in an overall response rate of more than 25%, more than 30%, more than 35%, more than 40%, more than 45%, more than 50%, more than 55%, more than 60%, more than 65%, more than 70%, more than 75%, or more than 80%.

55. The method according to any one of claims 48 to 53, wherein administration of an anti-c-Met ADC achieves a partial response (PR) in human subjects.

56. The method according to any one of claims 48 to 53, wherein administration of an anti-c-Met ADC achieves a complete response (CR) in human subjects.

57. The method according to any one of claims 48 to 53, wherein administration of an anti-c-Met ADC achieves stable (SD) in a human subject.

58. The method according to any one of claims 48 to 57, wherein n takes the value of 2.

59. The method according to any one of claims 48 to 57, wherein n takes the value of 4.

60. The method according to any one of claims 48 to 57, wherein n takes the value of 6.

61. The method according to any one of claims 48 to 57, wherein n takes the value of 8.

62. The method according to any one of claims 48 to 57, wherein n takes the value of 10.

63. The method according to any one of claims 48 to 62, wherein the average DAR of anti-c-Met ADC is about 5.4 to about 6.

6.

64. The method according to any one of claims 48 to 62, wherein the CRC tumor is a refractory or recurrent CRC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

65. The method according to any one of claims 48 to 62, wherein the CRC tumor is a refractory or recurrent CRC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

66. The method according to any one of claims 48 to 62 and 64, wherein the CRC tumor is a refractory or recurrent CRC tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

67. The method according to any one of claims 48 to 62 and 65, wherein the CRC tumor is a refractory or recurrent CRC tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

68. The method according to claim 48, wherein the tumor has a MET gene mutation.

69. A method for treating MET gene-amplified progressive solid tumors expressing cMet, comprising: a human subject or population of human subjects having a MET gene-amplified progressive tumor; and an anti-c-Met ADC having the following structure: 【Chemistry 4】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.4 mg / kg, 3.0 mg / kg, 3.5 mg / kg, 4.0 mg / kg, or 6.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, thereby treating MET gene-amplifying progressive solid tumors.

70. The method according to claim 69, wherein the MET gene amplification progressive solid tumor is refractory or recurrent.

71. The method according to claim 69 or 70, wherein n takes the value of 2.

72. The method according to claim 69 or 70, wherein n takes the value of 4.

73. The method according to claim 69 or 70, wherein n takes the value of 6.

74. The method according to claim 69 or 70, wherein n takes the value of 8.

75. The method according to claim 69 or 70, wherein n takes the value of 10.

76. The method according to any one of claims 69 to 75, wherein the average DAR of anti-c-Met ADC is about 5.4 to about 6.

6.

77. The method according to any one of claims 69 to 75, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

78. The method according to any one of claims 69 to 75, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously to human subjects every three weeks, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC achieves a partial response (PR) in human subjects.

79. The method according to any one of claims 69 to 75 and 77, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 2.4 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

80. The method according to any one of claims 69 to 75 and 78, wherein the MET gene amplification progressive solid tumor is a refractory or recurrent MET gene amplification progressive solid tumor, a therapeutic effective dose of anti-c-Met ADC of 3.0 mg / kg is administered intravenously every three weeks to multiple human subjects, the mean DAR of anti-c-Met ADC is approximately 6, and the administration of anti-c-Met ADC results in an overall response rate of more than 25%.

81. The method according to claim 69, wherein the tumor has a MET gene mutation.

82. A method for treating colorectal cancer ("CRC") tumors expressing c-Met, comprising: a human subject or population of human subjects having a CRC tumor, in which an anti-c-Met ADC having the following structure: 【Transformation 5】 The treatment comprises administering an effective therapeutic dose of 1.6 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab intravenously every four weeks, where n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab. a) Folic acid 200 mg / ２ Administer intravenously every two weeks. b) 5-FU 2400mg / m ２ Administer intravenously every two weeks, and c) Intravenously administer bevacizumab 5 mg / kg every two weeks to the subjects to treat the CRC tumors. A method that further includes this.

83. The method according to claim 82, wherein the CRC tumor is recurrent or refractory.

84. The method according to claim 82, wherein the CRC tumor is unresectable.

85. The method according to claim 82, further comprising the step of determining the c-Met expression level of the tumor.

86. The method according to claim 82, wherein the tumor has a MET gene mutation.

87. A method for treating colorectal cancer ("CRC") tumors expressing c-Met, comprising: a human subject having a CRC tumor, and an anti-c-Met ADC having the following structure: 【Transformation 6】 The treatment comprises administering an effective therapeutic dose of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every two weeks at doses of 0.8 mg / kg, 1.0 mg / kg, 1.2 mg / kg, 1.6 mg / kg, 2.0 mg / kg, or 2.4 mg / kg, every two weeks. a) Folic acid 200 mg / ２ Administer intravenously every two weeks. b) 5-FU 2400mg / m ２ Administer intravenously every two weeks, and c) Intravenously administer bevacizumab 5 mg / kg every two weeks to the subjects to treat the CRC tumors. A method that further includes this.

88. The method according to claim 87, wherein the CRC tumor is recurrent or refractory.

89. The method according to claim 87, wherein the CRC tumor is unresectable.

90. The method according to claim 87, further comprising the step of determining the c-Met expression level of a tumor.

91. The method according to claim 87, wherein the tumor has a MET gene mutation.

92. A method for treating hepatocellular carcinoma ("HCC") tumors expressing c-Met, comprising: a human subject or population of human subjects having an HCC tumor, in which an anti-c-Met ADC having the following structure: 【Transformation 7】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab intravenously every three weeks to treat HCC tumors.

93. The method according to claim 93, wherein the HCC tumor is recurrent or refractory.

94. The method according to claim 93, wherein the HCC tumor is unresectable.

95. The method according to claim 93, further comprising the step of determining the c-Met expression level of a tumor.

96. A method for treating c-Met-expressing biliary tract cancer ("BTC") tumors, comprising: a human subject or population of human subjects having a BTC tumor, and an anti-c-Met ADC having the following structure: 【Transformation 8】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, thereby treating BTC tumors.

97. The method according to claim 97, wherein the BTC tumor is recurrent or refractory.

98. The method according to claim 97, wherein the BTC tumor is unresectable.

99. The method according to claim 97, further comprising determining the c-Met expression level of a tumor.

100. The method according to claim 93, wherein the tumor has a MET gene mutation.

101. A method for treating pancreatic ductal adenocarcinoma ("PDAC") tumors expressing c-Met, comprising: a human subject or population of human subjects having a PDAC tumor, wherein the anti-c-Met ADC having the following structure: 【Chemistry 9】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab intravenously every three weeks to treat a PDAC tumor.

102. The method according to claim 102, wherein the PDAC tumor is recurrent or refractory.

103. The method according to claim 102, wherein the PDAC tumor is unresectable.

104. The method according to claim 102, further comprising the step of determining the c-Met expression level of a tumor.

105. The method according to claim 102, wherein the tumor has a MET gene mutation.

106. A method for treating esophageal squamous cell carcinoma ("ESCC") tumors expressing c-Met, comprising: an anti-c-Met ADC having the following structure in a human subject having an ESCC tumor: 【Chemistry 10】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab intravenously every three weeks to treat ESCC tumors.

107. The method according to claim 107, wherein the ESCC tumor is recurrent or refractory.

108. The method according to claim 107, wherein the ESCC tumor is unresectable.

109. The method according to claim 107, further comprising the step of determining the c-Met expression level of a tumor.

110. The method according to claim 107, wherein the tumor has a MET gene mutation.

111. A method for treating triple-negative breast cancer tumors ("TNBC") expressing c-Meth, comprising: a human subject or population of human subjects having a TNBC tumor, in which an anti-c-Meth ADC having the following structure: 【Chemistry 11】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab intravenously every three weeks to treat a TNBC tumor.

112. The method according to claim 112, wherein the TNBC tumor is recurrent or refractory.

113. The method according to claim 112, wherein the TNBC tumor is unresectable.

114. The method according to claim 112, further comprising the step of determining the c-Met expression level of a tumor.

115. The method according to claim 112, wherein the tumor has a MET gene mutation.

116. A method for treating hormone receptor-positive / human epidermal growth factor receptor 2-negative breast cancer tumors ("HR+ / HER2-BC") that express c-Met, wherein an anti-c-Met ADC having the following structure is administered to a human subject or population of human subjects having HR+ / HER2-BC tumors: 【Chemistry 12】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab (wherein n is 2, 4, 6, 8, or 10, and Ab is terisotuzumab) intravenously every three weeks, thereby treating HR+ / HER2-BC tumors.

117. The method according to claim 117, wherein the HR+ / HER2-BC tumor is recurrent or refractory.

118. The method according to claim 117, further comprising the step of determining the c-Met expression level of a tumor.

119. The method according to claim 117, wherein the HR+ / HER2-BC tumor is unresectable.

120. The method according to claim 117, wherein the tumor has a MET gene mutation.

121. A method for treating head and neck squamous cell carcinoma ("HNSCC") tumors expressing c-Met, comprising: a human subject having an HNSCC tumor or a population of human subjects, in which an anti-c-Met ADC having the following structure: 【Chemistry 13】 A method comprising administering a therapeutically effective dose of 1.6 mg / kg, 2.0 mg / kg, 2.4 mg / kg, or 3.0 mg / kg of terisotuzumab intravenously every three weeks to treat HNSCC tumors.

122. The method according to claim 122, wherein the HNSCC tumor is recurrent or refractory.

123. The method according to claim 122, further comprising the step of determining the c-Met expression level of a tumor.

124. The method according to claim 122, wherein the HNSCC tumor is unresectable.

125. The method according to claim 122, wherein the tumor has a MET gene mutation.

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