Combination therapies comprising eribulin-based antibody-drug conjugates

Abstract

Methods and compositions for use in treating and / or preventing a cancer, e.g., a folate receptor alpha (FRA)-expressing cancer, are disclosed. The methods comprise administration of an anti-FRA antibody-drug conjugate comprising an eribulin drug moiety and a tyrosine kinase inhibitor. The disclosure further relates to methods of reducing interstitial lung disease (ILD) in a subject being treated for a cancer by co-administration of the disclosed antibody-drug conjugates and a tyrosine kinase inhibitor.

Description

Attorney Reference: 15648.0057-00304COMBINATION THERAPIES COMPRISING ERIBULIN-BASED ANTIBODY-DRUG CONJUGATES

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 754,998, filed on February 6, 2025, and U.S. Provisional Application No. 63 / 872,938, filed on August 29, 2025. Each of these applications is incorporated herein by reference in its entirety for all purposes.

[0002] The present application contains a Sequence Listing which has been submitted electronically in ST.26 XML format and is hereby incorporated by reference in its entirety. Said ST.26 copy, created on February 2, 2026, is named 15648-0057-00304.xml and is 38,570 bytes in size.

[0003] Disclosed herein are methods of treating cancer using antibody-drug conjugates in combination with additional therapies, particularly tyrosine kinase inhibitors.

[0004] Cancer is among the leading causes of morbidity and mortality worldwide, with approximately 20 million new cases and 9.7 million cancer-related deaths in 2022. The most common causes of cancer death are cancers of: lung (1.8 million deaths); colorectal cancer (900,000 deaths); liver (760,000 deaths); breast (670,000 deaths); and stomach (660.000 deaths). The number of new cancer cases is expected to rise by about 77% to approximately 35 million new cancer cases per year in 2050. See, e.g., International Agency for Research on Cancer GLOBOCAN 2022.

[0005] Microtubules are dynamic filamentous cytoskeletal proteins that are involved in a variety of cellular functions, including intracellular migration and transport, cell signaling, and die maintenance of cell shape. Microtubules also play a critical role in mitotic cell division by forming the mitotic spindle required to segregate chromosomes into two daughter cells. The biological functions of microtubules in all cells are re ulated in large part by dieir polymerization dynamics, which occurs by the reversible, non-covalent addition of a and [3 tubulin dimers at both ends of microtubules. This dynamic behavior and resulting control over microtubule lengtii is vital to die proper functioning of the mitotic spindle. Even minor alteration of microtubule dynamics can engage the spindle checkpoint, arrest cell cycle progression at mitosis, and subsequently lead to cell death. See, e.g., Mukhtar et al. (2014) Mol. Cancer Ther. 13:275-84. Due to their rapid cell division, cancer cells are generally more sensitive to compounds that bind to tubulin and disrupt its normal function, as compared to normal cells. For this reason, tubulin inhibitors and odier microtubule-targeted agents have become a promising class of drugs for the treatment of cancer. See, e.g., Dumontet and Jordan (2010) Nat. Rev. Drug Discov. 9:790-803.

[0006] Folate receptor alpha (FRA) is a glycophosphatidylinositol (GPI)-linked membrane protein that binds folate. While the role of FRA in the biology of normal and cancerous tissue is not fully understood, it is highly over-expressed in a high percentage of ovarian cancers of epithelial origin, as well as in a percentage of non-small cell lung carcinomas. See, e.g., O'Shannessy et al. (2013) Int. J. Gynecol. Pathol. 32(3):258-68; see also Christoph et al. (2014) Clin. Lung Cancer L5(5):320-30. FRA also has limited expression in normal tissues. These properties make FRA an attractive target forAttorney Reference: 15648.0057-00304cancer immunotherapy. Treatment of FRA-expressing cancer using antibody-drug conjugates (ADCs) with biological activity against FRA-expressing tumor cells, e.g., an anti-FRA ADC, e.g., MORAb-202 has previously been reported. The structure and composition of MORAb-202, including antibody sequences, is disclosed in PCT Application No. PCT / US2017 / 020529 (published as WO 2017 / 151979) and U.S. Pat. No. 10,322,192, which are incorporated herein by reference in their entirety.

[0007] Tyrosine kinases are involved in the modulation of growth factor signaling and thus are a target for cancer therapies. Lenvatinib is an oral receptor tyrosine kinase inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors (VEGFR1 (FLT1), VEGFR2 (KDR) and VEGFR3 (FLT4)) in addition to other proangiogenic and oncogenic pathway-related receptor tyrosine kinases (RTKs) involved in tumor proliferation, including platelet-derived growth factor (PDGF) receptor PDGFRa, fibroblast growth factor receptor (FGFR), KIT, and the RET proto-oncogene (RET). In particular, lenvatinib possesses a binding mode (Type V) to VEGFR2, as confirmed through X-ray crystal structural analysis, and exhibits rapid and potent inhibition of kinase activity, according to kinetic analysis. See, e.g., Okamoto et al. (2014) ACS Med. Chem. Lett. 6(1): 89-94. The lenvatinib structure and methods of synthesis are disclosed in U.S. Pat. No. 7,612,092, which is incorporated herein by reference in its entirety.

[0008] A side effect associated with cancer therapies is interstitial lung disease (ILD), which causes inflammation and progressive scarring of the lungs. Thus, despite the availability of cancer agents such as those mentioned above, there remains a need for improved treatments that are therapeutically effective in treating cancer while reducing ILD risk. In particular, there remains a need for more effective methods and dosing regimens for treating subjects having an FRA-expressing cancer with an anti-FRA ADC, e.g., MORAb-202, e.g., while reducing side effects of treatment, e.g., interstitial lung disease (ILD), in subjects being treated.SUMMARY

[0009] Provided herein are combination therapies for treating and / or preventing cancer comprising administering a therapeutically effective amount of anti-FRA ADC in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In some embodiments, the methods provide therapeutic efficacy and / or reduce ILD risk in treated subjects.

[0010] In various embodiments, the present disclosure provides a method of treating a folate receptor alpha (FRA)-expressing cancer, comprising administering to a subject in need thereof:(a) a composition comprising an antibody-drug conjugate of Formula (I):Ab-(L-D)p(I)whereinAb is an internalizing anti-FRA antibody or internalizing antigen-binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising amino acidAttorney Reference: 15648.0057-00304sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3); and three LCDRs comprising amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3). as defined by the IMGT numbering system;D is eribulin;L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; andp is an integer from 1 to 8; and(b) a composition comprising a tyrosine kinase inhibitor.L0011J In various embodiments, the present disclosure provides a method of reducing risk of interstitial lung disease (ILD) in a subject being treated for a folate receptor alpha (FRA)-expressing cancer, comprising administering to the subject:(a) a composition comprising an antibody-drug conjugate of Formula (I):Ab-(L-D)P(I)whereinAb is an internalizing anti-FRA antibody or internalizing antigen -binding fragment thereof comprising three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising amino acid sequences of SEQ ID NO: 7 (HCDR1). SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3); and three LCDRs comprising amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3), as defined by the IMGT numbering system;D is eribulin;L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; andp is an integer from 1 to 8; and(b) a composition comprising a tyrosine kinase inhibitor.

[0012] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 14.

[0013] In some embodiments, the antibody or antigen-binding fragment comprises a heavy chain comprising an amino acid sequence of SEQ ID NO: 15, and a light chain comprising an amino acid sequence of SEQ ID NO: 16.

[0014] In some embodiments, p is from 3 to 5.Attorney Reference: 15648.0057-00304

[0015] In some embodiments, the antibody-drug conjugate is MORAb-202.

[0016] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 0.5 mg / kg to 1.5 mg / kg of the subject’s body weight. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 0.68 mg / kg of the subject’s body weight. In some embodiments, the antibody-drug conjugate is administered to the subject al a dose of 0.9 mg / kg of the subject’s body weight. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 1.2 mg / kg of the subject’s body weight.

[0017] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg to 50 mg of the antibody-drug conjugate per square meter (m2) of the subject’s body surface area (BSA). In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2to 44 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2to 20 mg / m2of the subject’s BSA.

[0018] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 15 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 13 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 12 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 11 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 7.5 mg / m2of the subject’s BSA.

[0019] In some embodiments, the antibody-drug conjugate is administered to the subject once every three weeks. In some embodiments, the antibody-drug conjugate is administered to the subject once every two weeks. In some embodiments, the antibody-drug conjugate is administered to the subject once per week. In some embodiments, the anti body-drug conjugate is administered to the subject at Day 1 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to the subject at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle.

[0020] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 12 mg / m2of the subject’s BSA at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, tine antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject's BSA at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 11 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle.Attorney Reference: 15648.0057-00304

[0021] In some embodiments, the antibody-drug conjugate is administered intravenously to the subject.

[0022] In some embodiments, the antibody-drug conjugate and the tyrosine kinase inhibitor are in the same composition.

[0023] In some embodiments, the antibody-drug conjugate and (lie tyrosine kinase inhibitor are administered concurrently or sequentially. In some embodiments, the tyrosine kinase inhibitor is administered before the antibody-drug conjugate is administered. In some embodiments, the tyrosine kinase inhibitor is administered after the antibody-drug conjugate is administered.

[0024] In some embodiments, the tyrosine kinase inhibitor is administered to the subject at a dose of 4 mg to 25 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered to the subject at a dose of 20 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered to the subject at a dose of 14 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered to the subject at a dose of 12 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered to the subject at a dose of 8 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered to the subject at a dose of 4 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof.

[0025] In some embodiments, the tyrosine kinase inhibitor is administered to the subject once daily.

[0026] In some embodiments, the tyrosine kinase inhibitor is administered orally to the subject.

[0027] In some embodiments, the tyrosine kinase inhibitor is lenvatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt of lenvatinib is lenvatinib mesylate.

[0028] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle and the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib mesylate. In some embodiments, tire antibody-drug conjugate is administered to the subject at a dose of 11 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle and the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib mesylate. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle and the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib mesylate.

[0029] In some embodiments, the doses of the antibody-drug conjugate and the tyrosine kinase inhibitor are selected to reduce ILD in the subject.Attorney Reference: 15648.0057-00304

[0030] In some embodiments, the subject has a body weight value that is in the upper quartile for weight.

[0031] In some embodiments, the method further comprises administering a corticosteroid to the subject. In some embodiments, the corticosteroid is administered prophylactically to the subject. In some embodiments, die corticosteroid is administered to die subject concurrently or sequentially with the antibody-drug conjugate. In some embodiments, the corticosteroid is administered to the subject before or after the antibody-drug conjugate is administered.

[0032] In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the dexamethasone is administered to the subject at a dose of 2 mg to 12 mg. In some embodiments, dexamethasone is administered to the subject at a dose of 8 mg. In some embodiments, the dexamethasone is administered to the subject at a dose of 4 mg. In some embodiments, the dexamethasone is administered to Ute subject at a dose of 3 mg.

[0033] In some embodiments, the dexamethasone is administered intravenously to the subject.

[0034] In some embodiments, the corticosteroid is administered to the subject at least once a week. In some embodiments, the corticosteroid is administered to the subject at least once a day. In some embodiments, the corticosteroid is administered to the subject two times a day.In some embodiments, the corticosteroid is administered to the subject for at least three days at the start of treatment with the antibody-drug conjugate. In some embodiments, the corticosteroid is administered to the subject one week prior to administration of the antibody-drug conjugate. In some embodiments, the corticosteroid is administered to the subject one week after to administration of the antibody-drug conjugate. In some embodiments, the corticosteroid is administered to the subject for at least three days. In some embodiments, the corticosteroid is administered to the subject on Day 8, Day 9, and Day 10 of a 21-day cycle.

[0035] In some embodiments, the corticosteroid is administered orally to the subject.

[0036] In some embodiments, the corticosteroid is prednisone. In some embodiments, tire corticosteroid is methylprednisolone.

[0037] In some embodiments, the corticosteroid is administered intravenously to the subject.

[0038] In some embodiments, the antibody-drug conjugate is administered to tire subject at a dose of 25 mg / m2of the subject’s BSA at Day 1 of a 21-day cycle and the dexamethasone is administered to the subject two times a day at a dose of 3 mg on Day 8, Day 9, and Day 10 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to tire subject at a dose of 25 mg / m2of tire subject’s BSA at Day 1 of a 21-day cycle and the prednisone is administered to the subject two times a day at a dose of 20 mg on Day 8, Day 9, and Day 10 of a 21-day cycle.

[0039] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 11 mg / m2Attorney Reference: 15648.0057-00304of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle.

[0040] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib or an equivalent amount of lenvatinib mesylate, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle.

[0041] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib or an equivalent amount of lenvatinib mesylate, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle.

[0042] In some embodiments, the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib or an equivalent amount of lenvatinib mesylate, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21 -day cycle.

[0043] In some embodiments, the FRA-expressing cancer is breast cancer, cervical cancer, colorectal cancer, esophageal cancer, fallopian tube cancer, gastric cancer, kidney cancer, lung cancer, non-small cell lung cancer (NSCLC), lung carcinoid, osteosarcoma, ovarian cancer, clear cell ovarian cancer, pancreatic cancer, peritoneal cancer, primary peritoneal cancer, renal cell cancer, uterine cancer, or serous uterine cancer. In some embodiments, the uterine cancer is endometrial cancer (EC). In some embodiments, the primary peritoneal cancer is platinum-resistant primary peritoneal cancer. In some embodiments, the fallopian tube cancer is platinum-resistant fallopian tube cancer.

[0044] In some embodiments, the FRA-expressing cancer is ovarian cancer. In some embodiments, tire ovarian cancer is platinum-resistant ovarian cancer (PROC). In some embodiments, the PROC is a serous ovarian cancer. In some embodiments, the serous ovarian cancer is a high-grade serous ovarian cancer. In some embodiments, the ovarian cancer is not a platinum-refractory ovarian cancer.

[0045] In some embodiments, the FRA-expressing cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In some embodiments, the breast cancer is hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-low breast cancer.

[0046] In some embodiments, the FRA-expressing cancer is non-small cell lung cancer.

[0047] In some embodiments, the FRA-expressing cancer is a metastatic cancer. In some embodiments, the metastatic cancer has no genomic alteration. In some embodiments, the metastatic cancer has at least one known genomic alteration. In some embodiments, the at least one known genomic alteration comprises one or more of the following genes: EGFR, ALK, PI3K, AKT, rnTOR,Attorney Reference: 15648.0057-00304RET, MET, BRAF, NTRK, R0S1, and any gene involved in the RAS-MAPK pathway. In some embodiments, the metastatic cancer is a non-small cell lung cancer.

[0048] In some embodiments, the FRA-expressing cancer is a refractory cancer. In some embodiments, tire refractory cancer is non-responsive to a targeted treatment. In some embodiments, tire targeted treatment is a targeted treatment against any one of the following genes or variants thereof: EGER, ALK, BRAF, RET, MET, NTRK, and ROS1. In some embodiments, the refractory cancer is non-responsive to a platinum-based treatment and / or an immunotherapy-based treatment, wherein if both are used, the treatments are administered concurrently or sequentially. In some embodiments, the platinum-based treatment is a platinum-doublet chemotherapy. In some embodiments, the immunotherapy-based treatment is a checkpoint inhibitor therapy, a CAR T-cell therapy, a cancer vaccine, an immune- targe ting monoclonal antibody, a cytokine, or an immune system modulator.

[0049] In some embodiments, the subject was not administered a prior therapy for the FRA-expressing cancer. In some embodiments, the subject was administered one prior therapy for the FRA-expressing cancer. In some embodiments, the subject was administered two or more prior therapies for the FRA-expressing cancer. In some embodiments, the subject was administered two or three prior therapies for the FRA-expressing cancer. In some embodiments, the subject was administered no more than one additional prior therapy after developing resistance to a prior platinum-based therapy. In some embodiments, the number of prior therapies does not include a primary therapy to which the subject exhibited refractory disease.

[0050] In some embodiments, the FRA-expressing cancer has an FRA expression level of less than 5%. In some embodiments, tire FRA-expressing cancer has an FRA expression level of at least 5%. In some embodiments, the FRA-expressing cancer has an FRA expression level of 5% to 24%. In some embodiments, the FRA-expressing cancer has an FRA expression level of 24% to 74%. In some embodiments, tire FRA-expressing cancer has an FRA expression level of at least 75%. In some embodiments, the FRA expression level is determined by immunohistochemistry.

[0051] In some embodiments, the subject, at the start of treatment, does not have one or more of: interstitial lung disease (ILD) and / or pneumonitis, a history of ILD and / or pneumonitis, a lungspecific clinically significant illness, pleural effusion, pericardial effusion, prior pneumonectomy, a history of chest radiotherapy within the past two years, autoimmune disorder with pulmonary involvement, connective tissue disorder with pulmonary involvement, and inflammatory disorder with pulmonary involvement.

[0052] In some embodiments, the subject does not have a serum albumin level at the start of treatment of less titan 3 g / dL and / or a proteinuria of greater than 1 gm.Attorney Reference: 15648.0057-00304BRIEF DESCRIPTION OF DRAWINGS

[0053] FIG. 1 shows the study design of a BSA-based dosing regimen for MORAb-202 in subjects with ovarian cancer (OC) and / or endometrial cancer (EC). ILD = interstitial lung disease, BID - twice a day, IDMC independent data monitoring committee.

[0054] FIG. 2 shows (lie study design of a BSA-based dosing regimen for MORAb-202 in combination with lenvatinib. QD = once daily, PO = orally, IV = intravenous, RD = recommended dose, RD-1 = the dose level one lower than the RD.

[0055] FIG. 3 shows the steps followed to determine the recommended dose (RD) of MORAb-202 monotherapy. DLT = dose-limiting toxicity, Gr = grade, ILD = interstitial lung disease, QW = once weekly.fDexamethasone administered at 8 mg by IV prior to administration of each MORAb-202 dose.

[0056] FIG. 4 shows the steps followed to determine the recommended dose (RD) of MORAb-202 in combination with lenvatinib. DLT = dose-limiting toxicity, Gr = grade, ILD = interstitial lung disease, QW = once weekly. ^Dexamethasone administered at 8 mg by IV prior to administration of each MORAb-202 dose.

[0057] FIG. 5A shows the study design for MORAb-202 and lenvatinib combination regimens in SK-OV-3 xenograft mice. FIG. 5B shows the tumor volume of non-treated mice and mice administered 2.7 mg / kg MORAb-202, 10 mg / kg lenvatinib, or a combination of both. * p < 0.05, ** p < 0.01 and **** p < 0.0001.

[0058] FIGs. 6A-6D show tumor volume, relative tumor volume, and relative body weight for SK-OV-3 xenograft mice treated with 2.7 mg / kg MORAb-202 and 3 mg / kg lenvatinib (FIG. 6A), 2.7 mg / kg MORAb-202 and 10 mg / kg lenvatinib (FIG. 6B), 4.7 mg / kg MORAb-202 and 3 mg / kg lenvatinib (FIG. 6C), and 4.7 mg / kg MORAb-202 and 10 mg / kg lenvatinib (FIG. 6D).

[0059] FIG. 7A shows the study design of MORAb-202 and lenvatinib combination regimens in SK-OV-3 xenograft mice. FIG. 7B shows the tumor volume of non-treated mice and mice administered 2.7 mg / kg MORAb-202, 10 mg / kg lenvatinib, or a combination of both. FIG. 7C shows the tumor volume of non-treated mice and mice administered 0.5 mg / kg eribulin, 10 mg / kg lenvatinib, or a combination of both.

[0060] FIG. 8A shows the tumor volume of Caov-3 xenograft mice administered no treatment, MORAb-202, lenvatinib, or a combination of both. FIG. 8B shows the relative body weight of Caov-3 xenograft mice administered no treatment, MORAb-202, lenvatinib, or a combination of both.

[0061] FIG. 9A shows the study design of MORAb-202 and lenvatinib combination regimens in SK-OV-3 xenograft mice. FIG. 9B shows the survival probability of SK-OV-3 xenograft mice administered no treatment, MORAb-202 (administered intravenously or by intraperitoneal injection (ip)), lenvatinib, or a combination of both.Attorney Reference: 15648.0057-00304

[0062] FIG. 10A shows the tumor volume of OVISE xenograft mice administered no treatment, MORAb-202, lenvatinib, or a combination of both. FIG. 8B shows the relative body weight administered no treatment, MORAb-202, lenvatinib, or a combination of both.DETAILED DESCRIPTION

[0063] The disclosed methods may be understood more readily by reference to the following detailed description taken in connection with tire accompanying figures, which form a part of this disclosure. It is to be understood that the disclosure is not limited to the specific methods described and / or shown herein, and that the terminology used herein is for the purpose of describing particular embodiments by way of example only and is not intended to be limiting of the claimed methods.

[0064] Throughout this text, the descriptions refer to methods of using compositions, e.g., an anti-FRA ADC, e.g., MORAb-202. Where the disclosure describes or claims a feature or embodiment associated with a method of using said compositions, such a feature or embodiment is equally applicable to the composition.

[0065] It is to be appreciated that certain features of the disclosed methods, which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.

[0066] All references cited herein are incorporated by reference for any purpose. Where a reference and the specification conflict, the specification will control.

[0067] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with tire definitions provided herein.

[0068] As used herein, tire singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise.

[0069] When a range of values is expressed, it includes embodiments using any particular value within the range. Further, reference to values stated in ranges includes each and every value within that range. All ranges are inclusive of their endpoints and combinable. When values are expressed as approximations, by use of tire antecedent “about,” it will be understood that the particular value forms another embodiment. Reference to a particular numerical value includes at least that particular value, unless tire context clearly dictates otherwise. The use of “or” will mean “and / or” unless the specific context of its use dictates otherwise.

[0070] The terms “about” or “approximately” in the context of numerical values and ranges refers to values or ranges that approximate or are close to the recited values or ranges such that the embodiment may perform as intended, such as having a desired amount of nucleic acids orAttorney Reference: 15648.0057-00304polypeptides in a reaction mixture, as is apparent to the skilled person from the teachings contained herein. This is due, at least in part, to the varying properties of nucleic acid compositions, age, race, gender, anatomical, and physiological variations and die inexactitude of biological systems. Thus, these terms encompass values beyond diose resulting from systematic error. It should be understood dial this definition of “about” applies to die entirety of die present disclosure, unless odierwise specified in certain contexts, e.g., in descriptions of average number of drug moieties per individual antibody moiety or within a mixture of ADCs. Unless context indicates otherwise, the term “about” means + / - 10% of a numerical amount. It should be understood that this definition of “about” applies to all descriptions of numerical values disclosed herein, e.g., average number of drug moieties per individual antibody moiety or within a mixture of ADCs.

[0071] As used herein, “administered prophylactically” refers to the administration of a therapeutic agent to a subject prior to die subject having or developing symptoms of a condition meant to be prevented or reduced in severity by the administration of the therapeutic agent. For example, a corticosteroid may be administered prophylactically to a subject to reduce die risk of developing ILD.

[0072] The term “agent” is used herein to refer to a chemical compound, a mixture of chemical compounds, a biological macromolecule, an extract made from biological materials, or a combination thereof. The term “therapeutic agent,” “drug,” or “drug moiety” refers to an agent that is capable of modulating a biological process and / or has biological activity.

[0073] The term “antibody” is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, lipid, or combinations of the foregoing, through at least one antigen recognition site wititin the variable region of the immunoglobulin molecule. The heavy chain of an antibody comprises a heavy chain variable domain (VH) and a heavy chain constant region (CH). The light chain comprises a light chain variable domain (VL) and a light chain constant domain (CL). For the purposes of this application, die mature heavy chain and light chain variable domains each comprises three complementarity determining regions (CDR1, CDR2, and CDR3) within four framework regions (FR1, FR2, FR3, and FR4) arranged from N-terminus to C-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. An “antibody” can be naturally occurring or man-made, such as monoclonal antibodies produced by conventional hybridoma technology. The term “antibody” includes, unless context indicates otherwise, full-lengtli monoclonal antibodies and full-length polyclonal antibodies, as well as antibody fragments such as Fab, Fab’, F(ab’)2, Fv, and single chain antibodies. An antibody can be any one of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses thereof (e.g., isotypes IgGl, IgG2, IgG3, IgG4). The term further encompasses human antibodies, chimeric antibodies, humanized antibodies, and any modified immunoglobulin molecule containing an antigen recognition site, so long as it demonstrates the desired biological activity.

[0074] The term “chimeric antibody,” as used herein, refers to antibodies wherein the amino acid sequence of the immunoglobulin molecule is derived from two or more species. In some instances, theAttorney Reference: 15648.0057-00304variable regions of both heavy and light chains correspond to the variable regions of antibodies derived from one species with the desired specificity, affinity, and activity while the constant regions are homologous to antibodies derived from another species (e.g., human) to minimize an immune response in the latter species.

[0075] The term “human antibody,’’ as used herein, refers an antibody produced by a human or an antibody having an amino acid sequence of an antibody produced by a human.

[0076] As used herein, the term “humanized antibody” refers to forms of antibodies that contain sequences from non-human (e.g., murine) antibodies as well as human antibodies. Such antibodies are chimeric antibodies which contain minimal sequence derived from non-human immunoglobulin. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. The humanized antibody optionally also will comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. The humanized antibody can be further modified by the substitution of residues, either in the Fv framework region and / or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and / or activity.

[0077] The term “monoclonal antibody,” as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of antibodies directed against (or specific for) different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256:495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). Monoclonal antibodies may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352:624-8, and Marks etal. (1991) J. Mol. Biol. 222:581-97, for example.

[0078] The monoclonal antibodies described herein specifically include “chimeric” antibodies, in which a portion of the heavy and / or light chant is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they specifically bind the target antigen and / or exhibit the desired biological activity.Attorney Reference: 15648.0057-00304

[0079] The terms “antibody-drug conjugate,” “antibody conjugate,” “conjugate,” “immunoconjugate ,” and “ADC” are used interchangeably, and refer to a compound (e.g., eribulin) or derivative thereof that is linked to an antibody (e.g., an anti -FRA antibody) and is defined by tire generic formula: Ab-(I.-D),, (Formula I), wherein Ab = an antibody moiety (i.e., an antibody or antigen-binding fragment), L = a linker moiety, D = a drug moiety, and p = tire number of drug moieties per antibody moiety.

[0080] The term “antigen-binding fragment” or “antigen-binding portion” of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., FRA). In some embodiments, antigen-binding fragments retain the ability to internalize into an antigen-expressing cell. In some embodiments, antigen-binding fragments also retain immune effector activity. It has been shown that fragments of a full-length antibody can perform the antigenbinding function of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding fragment” or “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment, which comprises a single variable domain, e.g., a VH domain (see, e.g., Ward et al. (1989) Nature 341:544-6; and Winter et al., WO 90 / 05144); and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv)). See, e.g., Bird et al. (1988) Science 242:423-6; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-83. Such single chain antibodies are also intended to be encompassed within tire term “antigen-binding fragment” or “antigen-binding portion” of an antibody, and are known in tire art as an exemplary type of binding fragment that can internalize into cells upon binding. See, e.g., Zhu et al. (2010) 9:2131-41; He et al. (2010) J. Nucl. Med. 51:427-32; and Fitting et al. (2015) MAbs 7:390-402. In certain embodiments, scFv molecules are incorporated into a fusion protein. Other forms of single chain antibodies such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies in which VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow for pairing between the two domains on tire same chain, thereby forcing tire domains to pair with complementary domains of another chain and creating two antigen binding sites. See, e.g., Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-8; and Poljak et al. (1994) Structure 2:1121-3. Antigen-binding fragments are obtained using conventional techniques known to those of skill in the art, and the binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as are intact antibodies. Antigen -binding fragments may be prepared by cleavage of the intact protein, e.g., by protease or chemical cleavage.Attorney Reference: 15648.0057-00304

[0081] “Body surface area’’ or “BSA” as used herein refers to the total surface area of a subject being treated with the methods disclosed herein. A subject’s body surface area may be calculated to determine tire most appropriate dose for a compound, e.g., an antibody-drug conjugate, e.g., air anti-FRA ADC, to be administered to tire subject. In general, values for a subject’s body surface area may be derived from calculations based on the subject’s body weight. Exemplary methods of calculating a subject’s body surface area are disclosed below.

[0082] The term “cancer” refers to a physiological condition in a mammal in which a population of cells is characterized by unregulated cell growth. Examples of cancers include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, leukemia, breast cancer (e.g., triple negative breast cancer), cervical cancer, colorectal cancer, esophageal cancer, fallopian tube cancer, gastric cancer, kidney cancer, lung cancer (e.g., non-small cell lung cancer), ovarian cancer (e.g., platinum resistant ovarian cancer, endometrial cancer), pancreatic cancer, peritoneal cancer. Triple negative breast cancer refers to breast cancer that is negative for expression of the genes for estrogen receptor (ER), progesterone receptor (PR), and Her2 / neu. More particular examples of such cancers include bladder cancer, triple negative breast cancer, hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-low breast cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, fallopian tube cancer, gastric cancer, gastrointestinal cancer, glioblastoma, hepatoma, hepatocellular cancer, hepatic carcinoma, kidney cancer, liver cancer, serous ovarian cancer, serous high-grade ovarian cancer, clear cell ovarian cancer, platinum resistant ovarian cancer, squamous cell cancer, small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, metastatic non-small cell lung cancer, lung carcinoid, melanoma, osteosarcoma, pancreatic cancer, peritoneal cancer, primary peritoneal cancer, prostate cancer, renal cell cancer, salivary gland carcinoma, thyroid cancer, uterine cancer, serous uterine cancer, vulval cancer, and various types of head and neck cancers.

[0083] The terms “cancer cell” and “tumor cell” refer to individual cells or the total population of cells derived from a tumor, including both non-tumorigenic cells and cancer stem cells. As used herein, the term “tumor cell” will be modified by the term “non-tumorigenic” when referring solely to those tumor cells lacking tire capacity to renew and differentiate to distinguish those tumor cells from cancer stem cells.

[0084] The term “chemotherapeutic agent” or “anti-cancer agent” is used herein to refer to all chemical compounds that are effective in treating cancer regardless of mechanism of action. Inhibition of metastasis or angiogenesis is frequently a property of a chemotherapeutic agent. Non-limiting examples of chemotherapeutic agents include alkylating agents, for example, nitrogen mustards, ethyleneimine compounds, and alkyl sulphonates; antimetabolites, for example, folic acid and purine or pyrimidine antagonists; anti-mitotic agents, for example, anti-tubulin agents such as eribulin or eribulin mesylate (Halaven™) or derivatives thereof, vinca alkaloids, and auristatins; cytotoxic antibiotics; compounds that damage or interfere with DNA expression or replication, for example,Attorney Reference: 15648.0057-00304DNA minor groove binders; and growth factor receptor antagonists. In addition, chemotherapeutic agents include antibodies, biological molecules, and small molecules. A chemotherapeutic agent may be a cytotoxic or cytostatic agent. The term “cytostatic agent” refers to an agent that inhibits or suppresses cell growth and / or multiplication of cells.

[0085] The term “co-administration” or administration “in combination with” one or more therapeutic agents includes concurrent and consecutive administration in any order.

[0086] “Corticosteroid,” as used herein, is any compound belonging to a class of steroid hormones that are typically produced in the adrenal cortex of vertebrates. The term as used herein also encompasses synthetic analogs of such hormones, e.g., pharmaceutical compositions which mimic the actions of naturally occurring corticosteroids. Dexamethasone is an exemplary embodiment of a corticosteroid. Prednisone and methylprednisolone are also exemplary embodiments of a corticosteroid.

[0087] The term “cytotoxic agent” refers to a substance that causes cell death primarily by interfering with a cell’s expression activity and / or functioning. Examples of cytotoxic agents include, but are not limited to, anti-mitotic agents, such as eribulin, auristatins (e.g., monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF)), maytansinoids (e.g., maytansine), dolastatins, duostatins, cryptophycins, vinca alkaloids (e.g.. vincristine, vinblastine), taxanes. taxols, and colchicines; anthracyclines (e.g., daunorubicin, doxorubicin, dihydroxyanthracindione); cytotoxic antibiotics (e.g., mitomycins, actinomycins, duocarmycins (e.g., CC-1065), auromycins, duomycins, calicheamicins, endomycins. phenomycins); alkylating agents (e.g., cisplatin); intercalating agents (e.g., ethidium bromide); topoisomerase inhibitors (e.g., etoposide, tenoposide); radioisotopes, such as At211, 1131, 1125, Y90, Re186, Re188, Sm153, Bi212or213, P32, and radioactive isotopes of lutetium (e.g., Lu177); and toxins of bacterial, fungal, plant or animal origin (e.g., ricin (e.g., ricin A-chain), diphtheria toxin, Pseudomonas exotoxin A (e.g., PE40), endotoxin, mitogellin, combrestatin, restrictocin, gelonin, alpha-sarcin, abrin (e.g., abrin A-chain), modeccin (e.g., modeccin A-chain), curicin, crotin, Sapaonaria officinalis inhibitor, glucocorticoid).

[0088] An “effective amount” of an ADC as disclosed herein is an amount sufficient to perform a specifically stated purpose, for example to produce a dierapeutic effect after administration, such as a reduction in tumor growth rate or tumor volume, a reduction in a symptom of cancer, or some odier indicia of treatment efficacy. An effective amount can be determined in a routine manner in relation to the stated purpose. The term “therapeutically effective amount” refers to an amount of a therapeutic agent, e.g., an ADC or a tyrosine kinase inhibitor, effective when administered alone or in combination to treat a disease or disorder in a subject. In the case of cancer, a therapeutically effective amount of a therapeutic agent, e.g., an ADC or a tyrosine kinase inhibitor, can reduce the number of cancer cells, reduce tumor size, inhibit (e.g., slow or stop) tumor metastasis, inhibit (e.g., slow or stop) tumor growth, and / or relieve one or more symptoms. Treatment and therapeutically effective amounts for treatment encompass but do not require complete treatment. For instance, the term encompassesAttorney Reference: 15648.0057-00304but does not require complete stopping of tumor growth. Treatment encompasses delay in progression, reduction in tumor volume or in one or more symptoms of a disease, and partial or complete remission.

[0089] The term “epitope” refers to the portion of an antigen capable of being recognized and specifically bound by an antibody. When tlie antigen is a polypeptide, epitopes can be formed from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of the polypeptide. The epitope bound by an antibody may be identified using any epitope mapping technique known in the art, including X-ray crystallography for epitope identification by direct visualization of the antigen-antibody complex, as well as monitoring the binding of the antibody to fragments or mutated variations of the antigen, or monitoring solvent accessibility of different parts of the antibody and the antigen. Exemplary strategies used to map antibody epitopes include, but are not limited to, array-based oligo-peptide scanning, limited proteolysis, site -directed mutagenesis, high-throughput mutagenesis mapping, hydrogen-deuterium exchange, and mass spectrometry. See, e.g., Gershoni et al. (2007) 21:145-56; and Hager-Braun and Tomer (2005) Expert Rev. Proteomics 2:745-56.

[0090] The term “eribulin,” as used herein, refers to a synthetic analog of halichondrin B, a macrocyclic compound that was originally isolated from the marine sponge Halichondria okadais. The term “eribulin drug moiety” refers to the component of an ADC that has the structure of eribulin, and is attached to the linker of the ADC via its C-35 amine. Eribulin is a microtubule dynamics inhibitor which is thought to bind tubulin and induce cell cycle arrest at the G2 / M phase by inhibiting mitotic spindle assembly. The term “eribulin mesylate” refers to the mesylate salt of eribulin, which is marketed under the trade name Halaven™. The eribulin structure and methods of synthesis are disclosed in U.S. Pat. No. 6,214,865, which is incorporated herein by reference.

[0091] The term “fibroblast growth factor receptor inhibitor” or “FGFR inhibitor” refers to a small molecule compound that inhibits the kinase activities of at least one human FGF receptor (FGFR) (e.g., FGFR1, FGFR2, FGFR3, FGFR4). The term FGFR encompasses naturally occurring variants of FGFR, including but not limited to splice variants, allelic variants, and isoforms.

[0092] The term “folate receptor alpha” or “FRA” or “FRa,” as used herein, refers to any native form of human FRA. The term encompasses ful I -length FRA (e.g., NCBI Reference Sequence:NP 000793; SEQ ID NO: 37), as well as any form of human FRA that results from cellular processing. The term also encompasses naturally occurring variants of FRA, including but not limited to splice variants, allelic variants, and isoforms. FRA can be isolated from a human, or may be produced recombinantly or by synthetic methods.

[0093] The term “anti-FRA antibody” or “antibody that specifically binds FRA” refers to any form of an antibody or fragment thereof that specifically binds FRA, and encompasses monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, and biologically functional antibody fragments so long as they specifically bind FRA. Preferably the anti-FRA antibody used inAttorney Reference: 15648.0057-00304the ADCs disclosed herein is an internalizing antibody or internalizing antibody fragment. MORAb-003 is an exemplary internalizing anti-human FRA antibody that may be used in the present disclosure, e.g., as part of an anti-FRA ADC. As used herein, the terms “specific,” “specifically binds,” and “binds specifically” refer to the selective binding of the antibody to the target antigen epitope. Antibodies can be tested for specificity of binding by comparing binding to appropriate antigen to binding to irrelevant antigen or antigen mixture under a given set of conditions. If the antibody binds to the appropriate antigen with at least 2, 5, 7, and preferably 10 times more affinity than to irrelevant antigen or antigen mixture, then it is considered to be specific. In one embodiment, a specific anti-FRA antibody is one that only binds the FRA antigen, but does not bind (or exhibits minimal binding) to other antigens.

[0094] The term “FRA-expressing cancer” or “cancer that expresses FRA” refers to any type of cancer characterized in that the cancer cells express FRA. In some embodiments, the cancer expresses FRA on the surface of the cancer cell. Exemplary methods for detecting FRA expression and exemplary FRA-expressing cancers are detailed below.

[0095] “Internalizing” as used herein in reference to an antibody or antigen-binding fragment refers to an antibody or antigen -binding fragment that is capable of being taken through the cell’s lipid bilayer membrane to an internal compartment (i.e., “internalized”) upon binding to the cell, preferably into a degradative compartment in the cell. For example, an internalizing anti-FRA antibody is one that is capable of being taken into the cell after binding to FRA on the cell membrane.

[0096] The term “interstitial lung disease” or “ILD” refers to any one of a group of lung diseases characterized by inflammation which may lead to pulmonary fibrosis. Interstitial lung disease (ILD) is known to be a potential adverse effect associated with immunotherapy treatment. An “adverse effect” or “AE” is any untoward medical occurrence in a subject administered a compound, and does not necessarily implicate a causal relationship with the administered compound or indicate that the compound cannot be used in treatment, but may present a limitation on the compound’s use. Methods of identifying and diagnosing interstitial lung disease are well known in the art, for example, evaluating oxygen saturation using pulse oximetry, and assessing ILD-related lung damage using chest computed tomography (CT) scans.

[0097] A “linker” or “linker moiety” is any chemical moiety that is capable of covalently joining a compound, usually a drug moiety such as a chemotherapeutic agent, to another moiety such as an antibody moiety. Linkers can be susceptible to or substantially resistant to acid-induced cleavage, peptidase-induced cleavage, light-based cleavage, esterase-induced cleavage, and / or disulfide bond cleavage, at conditions under which the compound or the antibody remains active.

[0098] The term “p” or “antibody:drug ratio” or “drug-to-antibody ratio” or “DAR” refers to the number of drug moieties per antibody moiety, i.e., drug loading, or the number of -L-D moieties per antibody or antigen- binding fragment (Ab) in ADCs of Formula I. In compositions comprisingAttorney Reference: 15648.0057-00304multiple copies of ADCs of Formula I, “p” refers to the average number of -L-D moieties per antibody or antigen-binding fragment, also referred to as average drug loading.

[0099] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government, or listed in die U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in animals, and more particularly in humans.

[0100] A “pharmaceutical composition’’ refers to a preparation which is in such form as to permit administration and subsequently provide the intended biological activity of the active ingredient(s) and / or to achieve a therapeutic effect, and which contains no additional components which are unacceptably toxic to a subject to which tire formulation would be administered. The pharmaceutical composition may be sterile.

[0101] A “pharmaceutical excipient” comprises a material such as an adjuvant, a carrier, pH-adjusting and buffering agents, tonicity adjusting agents, wetting agents, preservative, and the like.

[0102] For amino acid sequences, sequence identity and / or similarity may be determined using standard techniques known in the art, including, but not limited to, the local sequence identity algorithm of Smith and Waterman (1981) Adv. Appl. Math. 2:482, the sequence identity alignment algorithm of Needleman and Wunsch (1970) J. Mol. Biol. 48:443, the search for similarity method of Pearson and Lipman (1988) Proc. Nat. Acad. Sci. USA 85:2444, computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, Wis.), the Best Fit sequence program described by Devereux et al. (1984) Nucl. Acid Res. 12:387-95, preferably using the default settings, or by inspection. Preferably, percent identity is calculated by FastDB based upon the following parameters: mismatch penalty of 1; gap penalty of 1; gap size penalty of 0.33; and joining penalty of 30 (“Current Methods in Sequence Comparison and Analysis,” Macromolecule Sequencing and Synthesis, Selected Methods and Applications, pp. 127-149 (1988), Alan R. Liss, Inc).

[0103] An example of a useful algorithm is PILEUP. PILEUP creates a multiple sequence alignment from a group of related sequences using progressive, pairwise alignments. It can also plot a tree showing the clustering relationships used to create tire alignment. PILEUP uses a simplification of the progressive alignment method of Feng & Doolittle (1987) J. Mol. Evol. 35:351-60; the method is similar to that described by Higgins and Sharp (1989) CABIOS 5:151-3. Useful PILEUP parameters including a default gap weight of 3.00, a default gap length weight of 0.10, and weighted end gaps.

[0104] Another example of a useful algorithm is the BLAST algorithm, described in: Altschul et al. (1990) J. Mol. Biol. 215:403-10; Altschul et al. (1997) Nucleic Acids Res. 25:3389-402; and Karin et al. (1993) Proc. Natl. Acad. Sci. USA 90:5873-87. A particularly useful BLAST program is tire WU-BLAST-2 program which was obtained from Altschul et al. (1996) Methods in Enzymology 266:460-80. WU-BLAST-2 uses several search parameters, most of which are set to the default values. The adjustable parameters are set with tire following values: overlap span = 1, overlap fraction = 0.125, word threshold (T) = II. The HSP S and HSP S2 parameters are dynamic values and are established byAttorney Reference: 15648.0057-00304the program itself depending upon the composition of the particular sequence and composition of the particular database against which the sequence of interest is being searched; however, the values may be adjusted to increase sensitivity.

[0105] An additional useful algorithm is gapped BLAST as reported by Altschul et al. (1993) Nucl. Acids Res. 25:3389-402. Gapped BLAST uses BLOSUM-62 substitution scores; threshold T parameter set to 9; the tw o-hit method to trigger ungapped extensions, charges gap lengths of k, a cost of 10 + k; Xu set to 16, and Xg set to 40 for database search stage and to 67 for the output stage of the algorithms. Gapped alignments are triggered by a score corresponding to about 22 bits.

[0106] Generally, the amino acid homology, similarity, or identity between proteins disclosed herein and variants thereof, including variants of FRA, and variants of antibody variable domains (including individual variant CDRs), are at least 80% to the sequences depicted herein, and more typically with preferably increasing homologies or identities of at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, and almost 100% or 100%.

[0107] In a similar manner, “percent (%) nucleic acid sequence identity” with respect to the nucleic acid sequence of the antibodies and other proteins identified herein is defined as the percentage of nucleotide residues in a candidate sequence that are identical with the nucleotide residues in the coding sequence of the antigen binding protein. A specific method utilizes the BLASTN module of WU-BLAST-2 set to the default parameters, with overlap span and overlap fraction set to 1 and 0.125, respectively.

[0108] As used herein, a “refractory cancer” is a cancer that is non-responsive, i.e., that has not responded, to at least one prior therapy.

[0109] As used herein, “RECIST” refers to the Response Evaluation Criteria in Solid Tumors (RECIST), a set of standardized guidelines used to measure how well a cancer patient responds to a treatment (Therass et al. (2000) J Natl Cancer Inst. 92:205-16). As used herein, “RECIST 1.1” refers to version 1.1 of RECIST, in which tire guidelines are revised and updated relative to an earlier version of RECIST (Eisenhauer et al. (2009) E r J Cancer. 45:228-47).

[0110] The terms “subject,” “patient,” and “participant” are used interchangeably herein to refer to any animal, such as any mammal, including but not limited to, humans, non-human primates, rodents, and tire like. In some embodiments, tire mammal is a human.

[0111] As used herein, a “targeted treatment” is a cancer treatment that targets certain genes and / or proteins that are involved in tire growth and / or survival of cancer cells.

[0112] The terms “tumor” and “neoplasm” refer to any mass of tissue that results from excessive cell growth or proliferation, ei titer benign or malignant, including precancerous lesions.

[0113] As used herein, “to treat” or “therapeutic,” and grammatically related terms, refer to any improvement of any consequence of disease, such as prolonged survival, less morbidity, and / or a lessening of side effects which are the byproducts of an alternative therapeutic modality. As is readily appreciated in the art, full eradication of disease is preferred but not a requirement for a treatment act.Attorney Reference: 15648.0057-00304“Treatment” or “treat,” as used herein, refers to the administration of a therapy, such as a combination therapy, e.g., an anti-FRA ADC and a tyrosine kinase inhibitor disclosed herein, to a subject. The treatment can be to cure, heal, alleviate, relieve, alter, remedy, ameliorate, palliate, improve, or affect tire disorder, the symptoms of the disorder, or the predisposition toward tire disorder, e.g., a cancer. The terms “treatment” and “therapy” are used interchangeably herein.

[0114] In various embodiments, provided herein is a method of reducing risk of ILD in a subject treated with an anti-FRA ADC. “Reducing risk” as used herein, refers to a change in incidence rate of ILD (for example, a change in number of subjects with ILD) relative to a comparative treatment. For example, a treatment with an anti-FRA ADC disclosed herein using a BSA-based dosing regimen in combination with a tyrosine kinase inhibitor may reduce the risk of ILD in certain subjects as compared to similar subjects administered the anti-FRA ADC at an equivalent body weight-based dose and / or administered without a tyrosine kinase inhibitor over a given time period.

[0115] The term “tyrosine kinase inhibitor” or “TKI” refers to a compound that inhibits die kinase activities of at least one tyrosine kinase. In some embodiments, the tyrosine kinase inhibitor is lenvatinib or a salt thereof. The term “lenvatinib mesylate” refers to the mesylate salt of lenvatinib, which is marketed under the trade name Lenvima™. The structure of lenvatinib is shown below in the Tyrosine Kinase Inhibitor section.

[0116] The term “upper quartile for weight” as used herein refers to a body weight value that is within the top 25% of all body weight values for a given group of subjects, e.g., a group of adults in a general population or a group of subjects with an FRA-expressing cancer. As used herein, the term is inclusive of the value representing the border of the top 25%. For example, the upper quartile for weight for a given group of subjects can be determined by first arranging the body weight values of the subjects in ascending order, dien dividing the set of values into quarters (also known as quartiles), and lastly determining the value between the third and fourth quartiles. A subject who is in die upper quartile for weight has a body weight value that is at least equal to, if not greater than, the value between the dtird and fourth quartiles. In some embodiments, the value between die third and fourth quartiles for a given group of subjects is near or about 80 kilograms.

[0117] As used herein, the term “variant” is used to refer to any naturally occurring variant of a gene, including but not limited to splice variants, allelic variants, isoforms, and homologs (e.g., paralogs or ortiiologs). In contrast to a gene comprising a genomic alteration, a variant of a gene is not linked to or associated with a disease or disorder, e.g., a cancer.

[0118] The term “vascular endothelial growth factor receptor inhibitor” or “VEGFR inhibitor” refers to a small molecule compound that inhibits the kinase activities of at least one human VEGF receptor (VEGFR) (e.g., VEGFR2, VEGFR1, VEGFR3). The term VEGFR encompasses naturally occurring variants of VEGFR, including but not limited to splice variants, allelic variants, and isoforms. In some embodiments, the VEGFR inhibitor is lenvatinib.Attorney Reference: 15648.0057-00304Antibody-Drug Conjugates

[0119] The methods of the present disclosure include the use of compounds with anti-cancer activity. In particular, the compounds include an antibody moiety (including an antigen-binding fragment thereof) conjugated (i.e., covalently attached by a linker) to a drug moiety, wherein the drug moiety, e.g., when not conjugated to an antibody moiety, has a cytotoxic or cytostatic effect. In various embodiments, the drug moiety exhibits reduced or no cytotoxicity when bound in a conjugate, but resumes cytotoxicity after cleavage from the linker and antibody moiety.

[0120] In some embodiments, the ADC comprises a peptide cleavable linker attaching eribulin to an anti-FRA antibody. In some embodiments, the linker comprises a Val-Cit moiety. In some embodiments, the linker comprises a PEG spacer. In some embodiments, the linker comprises a Mal-(PEGh-Val-Cit-pAB linker joining eribulin to an anti-FRA antibody (e.g., an anti-FRA antibody such as MORAb-003). In some embodiments, the anti-FRA ADC is MORAb-202 (also referred to as FZEC). “MORAb-202” refers to an anti-FRA ADC, wherein the anti-FRA antibody or antigenbinding fragment comprises a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16, wherein the linker moiety comprises Mal-(PEG)2-Val-Cit-pAB, and wherein the linker is attached to eribulin via a C-35 amine. The structure of MORAb-202 (including the sequences of the anti-FRA antibody moiety in the ADC) are disclosed in PCT Application No. PCT / US2017 / 020529 (published as WO 2017 / 151979) and U.S. Pat. No. 10,322,192.

[0121] In some embodiments, the anti-FRA ADC (e.g., MORAb-202) exhibits particularly favorable properties across various categories, such as: (i) the ability to retain one or more therapeutic properties exhibited by the antibody and drug moieties in isolation; (ii) the ability to maintain the specific binding properties of the antibody moiety: (iii) optimal drug loading and drug-to-antibody ratios; (iv) the ability to allow delivery, e.g., intracellular delivery, of the drug moiety via stable attachment to the antibody moiety; (v) the ability to retain ADC stability as an intact conjugate until transport or delivery to a target site; (vi) minimal aggregation of the ADC prior to or after administration; (vii) the ability to allow for the therapeutic effect, e.g., cytotoxic effect, of tire drug moiety after cleavage in the cellular environment; (viii) in vivo anti-cancer treatment efficacy comparable to or superior to that of the antibody and drug moieties in isolation; (ix) minimal off-target killing by the drug moiety; and / or (x) desirable pharmacokinetic and pharmacodynamics properties, formulatability, and toxicologic / immunologic profiles.

[0122] An ADC compound of the present disclosure may selectively deliver an effective dose of a cytotoxic or cytostatic agent to FRA-expressing cancer cells or to FRA-expressing tumor tissue. It has been discovered that the disclosed ADCs have potent cytotoxic and / or cytostatic activity against cells expressing FRA. Exemplary FRA-expressing cancers include but are not limited to gastric cancer, ovarian cancer (e.g., serous ovarian cancer, clear cell ovarian cancer, or platinum resistant ovarian cancer), lung cancer (e.g., non-small cell lung cancer, e.g., metastatic non-small cell lung cancer, e.g., lung carcinoid), lung carcinoid, breast cancer (e.g., triple negative breast cancer, e.g., hormoneAttorney Reference: 15648.0057-00304receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-low breast cancer), endometrial cancer (e.g., serous endometrial carcinoma), uterine cancer (e.g., serous uterine cancer), peritoneal cancer (e.g., primary peritoneal cancer), fallopian tube cancer, pancreatic cancer, kidney cancer, renal cell cancer, cervical cancer, esophageal cancer, and osteosarcoma.

[0123] An exemplary ADC has Formula (I):Ab-(L-D), (I)wherein Ab = internalizing anti-folate receptor alpha antibody or internalizing antigenbinding fragment thereof, L = cleavable linker moiety, D = drug moiety, and p = the number of drug moieties per antibody moiety.Antibodies[00124J The antibody moiety (Ab) of an ADC of Formula (1) includes within its scope any antibody or antigen-binding fragment that specifically binds to FRA on a cancer cell. The antibody or antigenbinding fragment may bind to FRA with a dissociation constant (KD) of < 1 mM, < 100 nM or < 10 nM, or any amount in between, as measured by, e.g., BIAcore® analysis. In certain embodiments, the KD is 1 pM to 500 pM. In some embodiments, the KD is between 500 pM to 1 pM, 1 pM to 100 nM, or 100 mM to 10 nM.

[0125] In some embodiments, the antibody moiety is a four-chain antibody (also referred to as an immunoglobulin), comprising two heavy chains and two light chains. In some embodiments the antibody moiety is a two-chain half body (one light chain and one heavy chain), or an antigen-binding fragment of an immunoglobulin.

[0126] In some embodiments, the antibody moiety is an internalizing antibody or internalizing antigen-binding fragment thereof. In some embodiments, the internalizing antibody binds to FRA expressed on the surface of a cell and enters the cell upon binding. In some embodiments, the FRA-targeting antibody moiety is MORAb-003 or an antigen-binding fragment thereof. In some embodiments, tire drug moiety of tire ADC is released from the antibody moiety of the ADC after the ADC enters and is present in a cell expressing the target cancer antigen (i.e., after tire ADC has been internalized).

[0127] Amino acid and nucleic acid sequences of exemplary antibodies that may be used in the ADCs disclosed herein are set forth in Tables 1-9.Table 1. AntibodiesAttorney Reference: 15648.0057-00304Table 2. Amino acid sequences of mAb Rabat CDRsTable 3. Nucleic acid sequences encoding mAb Kabat CDRsTable 4. Amino acid sequences of mAb IMGT CDRsTable 5. Nucleic acid sequences encoding mAb IMGT CDRsAttorney Reference: 15648.0057-00304Table 6. Amino acid sequences of mAb variable regionsTable 7. Nucleic acid sequences encoding mAb variable regionsTable 8. Amino acid sequences of full-length mAb Ig chainsAttorney Reference: 15648.0057-00304“Pre-protein” refers to the precursor form of a protein that undergoes processing before becoming a mature protein. Underlined text indicates the leader sequence.Table 9. Nucleic acid sequences encoding full-length mAh Ig chainsAttorney Reference: 15648.0057-00304Attorney Reference: 15648.0057-00304Attorney Reference: 15648.0057-00304+Nucleic acid sequences do not include leader sequences.

[0128] In various embodiments, an ADC disclosed herein may comprise the set of MORAb-003 heavy and light chain variable domains listed in the tables above, or a set of six MORAb-003 CDR sequences (Kabat and / or IMGT) from the heavy and light chains listed in the tables above. In some embodiments, the ADC further comprises human heavy and light chain constant domains or fragments thereof. For instance, the ADC may comprise a human IgG heavy chain constant domain (such as an IgGl) and a human kappa or lambda light chain constant domain. In various embodiments, the antibody moiety of the described ADCs comprises a human immunoglobulin G subtype 1 (IgGl) heavy chain constant domain with a human Ig kappa light chain constant domain. In some embodiments, the anti-FRA antibody moiety in the ADC comprises the full heavy and light chain sequences listed in the tables above.

[0129] In various embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: heavy chain CDR1 (HCDR1) comprising SEQ ID NO: 1, heavy chain CDR2 (HCDR2) comprising SEQ ID NO: 2, heavy chain CDR3 (HCDR3) comprising SEQ ID NO: 3; light chain CDR1 (LCDR1) comprising SEQ ID NO: 4, light chain CDR2 (LCDR2) comprising SEQ ID NO: 5, and light chain CDR3 (LCDR3) comprising SEQ ID NO: 6, as defined by the Kabat numbering system (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987 and 1991))).

[0130] In some embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs as follows: HCDR1 comprising SEQ ID NO: 7, HCDR2 comprising SEQ ID NO: 8, HCDR3 comprising SEQ ID NO: 9; LCDR1 comprising SEQ ID NO: 10, LCDR2 comprising SEQ ID NO: 11, and LCDR3 comprising SEQ ID NO: 12, as defined by the IMGT numbering system (International ImMunoGeneTics Information System (IMGT®)).

[0131] In various embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14. In some embodiments, the anti-FRA antibody or antigen-binding fragment thereof comprises the heavy chain variable region amino acid sequence of SEQ ID NO: 13 and the light chain variable region amino acid sequence of SEQ ID NO: 14, or sequences that are at least 95% identical to the above-mentioned sequences. In some embodiments, the anti-FRA antibody or antigen-binding fragment thereof has a heavy chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or atAttorney Reference: 15648.0057-00304least 99% identical to SEQ ID NO: 13 and a light chain variable region amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 14.

[0132] In various embodiments, the anti-FRA antibody comprises a human IgGl heavy chain constant domain with a human Ig kappa light chain constant domain.

[0133] In various embodiments, (lie anti-FRA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 15 or a sequence that is at least 95% identical to SEQ ID NO: 15, and a light chain amino acid sequence of SEQ ID NO: 16 or a sequence that is at least 95% identical to SEQ ID NO: 16. In some embodiments, the antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16, or sequences that are at least 95% identical to the above-mentioned sequences. In some embodiments, the anti-FRA antibody has a heavy chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 15 and / or a light chain amino acid sequence that is at least 96%, at least 97%, at least 98%, or at least 99% identical to SEQ ID NO: 16. In some embodiments, tire anti-FRA antibody comprises a heavy chain amino acid sequence of SEQ ID NO: 15 and a light chain amino acid sequence of SEQ ID NO: 16. In some embodiments, the anti-FRA antibody comprises a heavy chain encoded by the nucleotide sequence of SEQ ID NO: 35 (with the nucleotides encoding the leader sequence), or SEQ ID NO: 31 (without the nucleotides encoding the leader sequence): and a light chain encoded by the nucleotide sequence of SEQ ID NO: 36 (with the nucleotides encoding the leader sequence), or SEQ ID NO: 32 (without the nucleotides encoding the leader sequence). In some embodiments, the heavy chain amino acid sequence lacks the C-terminal lysine. In some embodiments, the anti-FRA antibody has the amino acid sequence of the antibody produced by a cell line deposited under terms in accordance with the Budapest Treaty with tire American Type Culture Collection (ATCC, 10801 University Blvd., Manassas, Va. 20110-2209) on Apr. 24, 2006, under the Accession No. PTA-7552, or such sequences lacking the heavy chain C-terminal lysine. In some embodiments, tire anti-FRA antibody is MORAb-003 (USAN name: farletuzumab), or an antigenbinding fragment thereof. See Ebel et al. (2007) Cancer Immunity 7:6.

[0134] In various embodiments, amino acid substitutions are of single residues. Insertions usually will be on tire order of from about 1 to about 20 amino acid residues, although considerably larger insertions may be tolerated as long as anti-FRA biological function is retained. Deletions usually range from about 1 to about 20 amino acid residues, although in some cases deletions may be much larger. Substitutions, deletions, insertions, or any combination thereof may be used to arrive at a final derivative or variant. Generally, these changes are done on a few amino acids to minimize the alteration of the molecule, particularly the immunogenicity and specificity of the antigen-binding protein. However, larger changes may be tolerated in certain circumstances. Conservative substitutions are generally made in accordance with the following chart depicted as Table 10.Attorney Reference: 15648.0057-00304Table 10. Exemplary Conservative Amino Acid Substitutions

[0135] In some embodiments, the FRA-targeting antibody moiety is MORAb-003. In some embodiments, FRA-targeting antibody moictics such as MORAb-003 provide particularly improved drug:antibody ratio (DAR), tumor targeting, bystander killing, treatment efficacy, and reduced off-target killing. Improved treatment efficacy can be measured in vitro or in vivo, and may include reduced tumor growth rate and / or reduced tumor volume.Linkers

[0136] In various embodiments, the linker in an anti-FRA ADC is stable extracellularly in a sufficient manner to be therapeutically effective. In some embodiments, tire linker is stable outside a cell, such that the ADC remains intact when present in extracellular conditions (e.g., prior to transport or delivery into an FRA-expressing cell). The term “intact,” used in the context of an ADC, means that the antibody moiety remains attached to tire drug moiety. As used herein, “stable,” in the context of a linker or ADC comprising a linker, means that no more than about 20%, no more than about 15%, no more than about 10%, no more than about 5%, no more than about 3%, or no more than about 1% of tire linkers (or any percentage in between) in a sample of ADC are cleaved (or in the case of an overall ADC are otherwise not intact) when the ADC is present in extracellular conditions.

[0137] Whether a linker is stable extracellularly can be determined, for example, by including an anti-FRA ADC in plasma for a predetermined time period (e.g., 2, 4, 6, 8, 16, or 24 hours) and thenAttorney Reference: 15648.0057-00304quantifying the amount of free drug moiety present in the plasma. Stability may allow the ADC time to localize to target tumor cells and prevent the premature release of the drug, which could lower the therapeutic index of the ADC by indiscriminately damaging both normal and tumor tissues. In some embodiments, tire linker is stable outside of a target cell and releases the drug moiety from the ADC once inside of the cell, such that the drug moiety can bind to its target (e.g., to microtubules). Thus, an effective linker will: (i) maintain the specific binding properties of the antibody moiety ; (ii) allow delivery, e.g., intracellular delivery, of the drug moiety via stable attachment to the antibody moiety'; (iii) remain stable and intact until the ADC has been transported or delivered to its target site; and (iv) allow for the therapeutic effect, e.g., cytotoxic effect, of the drug moiety after cleavage.

[0138] A linker may be “cleavable” or “non-cleavable.” See, e.g., Ducry and Stump, Bioconjugate Chem. (2010) 21:5-13. Cleavable linkers are designed to release the drug when subjected to certain environment factors, e.g., when internalized into the target cell, whereas non-cleavable linkers generally rely on the degradation of the antibody moiety itself.

[0139] In some embodiments, the linker is a cleavable linker. A cleavable linker refers to any linker that comprises a cleavable moiety. As used herein, the term “cleavable moiety” refers to any chemical bond that can be cleaved. Suitable cleavable chemical bonds are well known in the art and include, but are not limited to, acid labile bonds, protease / peptidase labile bonds, photolabile bonds, disulfide bonds, and esterase labile bonds. Linkers comprising a cleavable moiety can allow for the release of the drug moiety from the ADC via cleavage at a particular site in the linker. In various embodiments, cleavage of the anti-FRA antibody from the linked toxin activates or increases tire activity of the toxin.

[0140] In some embodiments, the linker is cleavable by a cleaving agent, e.g., an enzyme, that is present in the intracellular environment (e.g., within a lysosome, endosome, or caveolea). The linker can be, e.g., a peptide linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease. In some embodiments, tire linker is a cleavable peptide linker. As used herein, a cleavable peptide linker refers to any linker that comprises a cleavable peptide moiety. The term “cleavable peptide moiety” refers to any chemical bond linking amino acids (natural or synthetic amino acid derivatives) that can be cleaved by an agent that is present in the intracellular environment. For instance, a linker may comprise a valine-citrulline (Val-Cit) sequence that is cleavable by a peptidase such as cathepsin, e.g., cathepsin B.

[0141] In some embodiments, the linker is an enzyme-cleavable linker and a cleavable peptide moiety in the linker is cleavable by the enzyme. In some embodiments, the cleavable peptide moiety is cleavable by cathepsin B. An exemplary dipeptide that may be cleaved by cathepsin B is valinecitrulline (Val-Cit). See, e.g., Dubowchik et al. (2002) Bioconjugate Chem. 13:855-69.

[0142] In some embodiments, the linker or the cleavable peptide moiety in the linker comprises an amino acid unit. In some embodiments, the amino acid unit allows for cleavage of the linker by a protease, thereby facilitating release of the drug moiety from the ADC upon exposure to one or moreAttorney Reference: 15648.0057-00304intracellular proteases, such as one or more lysosomal enzymes. See, e.g., Doronina et al. (2003) Nat. Biotechnol. 21:778-84; and Dubowchik and Walker (1999) Pharm. Therapeutics 83:67-123.Exemplary amino acid units include, but are not limited to, dipeptides. Exemplary dipeptides include, but are not limited to, valine -citrulline (Val-Cit). In some embodiments, the amino acid unit in die linker comprises Val-Cit. An amino acid unit may comprise amino acid residues dial occur naturally and / or minor amino acids and / or non-naturally occurring amino acid analogs, such as citrulline.

[0143] In some embodiments, the linker in an anti-FRA ADC disclosed herein comprises at least one spacer unit joining the antibody moiety to the drug moiety. In some embodiments, the spacer unit joins a cleavage site (e.g., a cleavable peptide moiety) in the linker to the antibody moiety. In some embodiments, the linker comprises one or more polyethylene glycol (PEG) moieties, e.g., 1, 2, 3, 4, 5, or 6 PEG moieties. In some embodiments, the linker comprises two PEG moieties.[00144J In some embodiments, the spacer unit in the linker comprises one or more PEG moieties. In some embodiments, the spacer unit comprises -(PEG)m-, and m is 2. In some embodiments, the spacer unit comprises (PEG)?.

[0145] In some embodiments, the spacer unit links the antibody moiety to the drug moiety indirectly. In some embodiments, the spacer unit links the antibody moiety to the drug moiety indirectly through a cleavable peptide moiety and an attachment moiety to join the spacer unit to the antibody moiety, e.g., a maleimide moiety.

[0146] The spacer unit, in some embodiments, attaches to an anti-FRA antibody moiety (i.e., an anti-FRA antibody or antigen-binding fragment thereof) via a maleimide moiety (Mai).

[0147] A spacer unit that attaches to the antibody or antigen-binding fragment via a Mai moiety is referred to herein as a “Mal-spacer unit.” The term “Mai moiety” or “maleimide moiety,” as used herein, means a compound that contains a maleimide group and that is reactive with a sulfhydryl group, e.g., a sulfhydryl group of a cysteine residue on the antibody moiety. In some embodiments, the Mal-spacer unit is reactive with a cysteine residue on the antibody or antigen-binding fragment. In some embodiments, the Mal-spacer unit is joined to the antibody or antigen-binding fragment via the cysteine residue. In some embodiments, the Mal-spacer unit comprises a (PEGE moiety.

[0148] In certain embodiments, the linker comprises the Mal-spacer unit and a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the amino acid unit comprises Val-Cit. In some embodiments, the linker comprises Mal-(PEG)2and Val-Cit.

[0149] In some embodiments, the Mal-spacer unit attaches an anti-FRA antibody moiety (i.e., an anti-FRA antibody or antigen-binding fragment thereof) to the cleavable moiety in the linker. In some embodiments, the Mal-spacer unit attaches the antibody or antigen-binding fragment to a cleavable peptide moiety. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises Mal-spacer unit-amino acid unit. In some embodiments, theAttorney Reference: 15648.0057-00304Mal-spacer unit comprises a PEG moiety. In some embodiments, the amino acid unit comprises Val-Cit.

[0150] In some embodiments, the linker comprises the structure: Mal-spacer unit-Val-Cit. In some embodiments, the linker comprises die structure: Mal-(PEG)2- Val-Cit. In some embodiments, the linker comprises die structure: Mal-(PEG)2-Val-Cit-pAB.

[0151] In some embodiments, an additional spacer unit is used to attach the cleavable moiety in the linker to the drug moiety, e.g., eribulin. In some embodiments, the eribulin is attached to the cleavable moiety in the linker by a self-immolative spacer unit. In some embodiments, die eribulin is attached to the cleavable moiety in the linker by a self-immolative spacer unit, the cleavable moiety comprises Val-Cit, and a further spacer unit comprising (PEGh joins the cleavable moiety to an anti-FRA antibody moiety. In certain embodiments, the eribulin is joined to an anti-FRA antibody via a Mal-spacer unit in the linker joined to a Val-Cit cleavable moiety and a pAB self-immolative spacer unit.

[0152] A spacer unit may be “self-immolative” or “non-self-immolative.” A “non-self-immolative” spacer unit is one in which part or all of the spacer unit remains bound to the drug moiety upon cleavage of the linker. Examples of non-self-immolative spacer units include, but are not limited to, a glycine spacer unit and a glycine-glycine spacer unit. Non-self-immolative spacer units may eventually degrade over time but do not readily release a linked native drug entirely under cellular conditions. A “self-immolative” spacer unit allows for release of the native drug moiety under intracellular conditions. A “native drug” is one where no part of the spacer unit or other chemical modification remains after cleavage / degradation of the spacer unit.

[0153] Self-immolation chemistry is known in the art and can be readily selected for the disclosed ADCs. In various embodiments, the spacer unit attaching the cleavable moiety in the linker to the drug moiety (e.g., eribulin) is self-immolative, and undergoes self-immolation concurrently with or shortly before / after cleavage of the cleavable moiety under intracellular conditions.

[0154] In certain embodiments, the self-immolative spacer unit in the linker comprises a p-aminobenzyl unit. In some embodiments, a p-aminobenzyl alcohol (pABOH) is attached to an amino acid unit or other cleavable moiety in the linker via an amide bond, and a carbamate, methylcarbamate, or carbonate is made between the pABOH and the drug moiety. See, e.g., Hamann et al. (2005) Expert Opin. Ther. Patents 15:1087-103). In some embodiments, the self-immolative spacer unit is or comprises p-aminobenzyloxycarbonyl (pAB). Without being bound by theory, it is thought that the self-immolation of pAB involves a spontaneous 1 ,6-elimination reaction. See, e.g., Jain et al. (2015) Pharm Res 32:3526-40.

[0155] In various embodiments, the structure of the p-aminobenzyloxycarbonyl (pAB) used in the disclosed ADCs is shown below:Attorney Reference: 15648.0057-00304p-a ino-benz ioxycarboriyl

[0156] In various embodiments, the self-immolative spacer unit attaches the cleavable moiety in the linker to the C-35 amine on eribulin. In some embodiments, the self-immolative spacer unit is pAB. In some embodiments, the pAB attaches the cleavable moiety' in the linker to the C-35 amine on eribulin. In some embodiments, the pAB undergoes self-immolation upon cleavage of the cleavable moiety, and eribulin is released from the ADC in its native, active form. In some embodiments, an anti-FRA antibody (e.g., MORAb-003) is joined to the C-35 amine of eribulin by a linker comprising Mal-(PEGty-Val-Cit-pAB.

[0157] In some embodiments, the pAB undergoes self-immolation upon cleavage of a cleavable peptide moiety in the linker. In some embodiments, the cleavable peptide moiety comprises an amino acid unit. In some embodiments, the linker comprises amino acid unit-pAB. In some embodiments, the amino acid unit is Val-Cit. In some embodiments, the linker comprises Val-Cit-pAB (VCP). In some embodiments, the antibody moiety of the ADC is conjugated to the drug moiety via a linker, wherein the linker comprises a Mal-spaccr unit, a clcavablc amino acid unit, and a pAB. In some embodiments, the spacer unit comprises a PEG moiety. In some embodiments, the linker comprises Mal-(PEG)2-Val-Cit-pAB.

[0158] In some embodiments, the antibody moiety is conjugated to the drug moiety via a linker comprising a maleimide moiety (Mai), a polyethylene glycol (PEG) moiety, valine-citrulline (Val-Cit, “vc,” or “VC”), and a pAB. In some embodiments, the maleimide moiety covalently attaches the linker-drug moiety to the antibody moiety, and the pAB acts as a self-immolative spacer unit. Such linker may be referred to as a "m-vc-pAB” linker, a “Mal-VCP” linker, a “Mal-(PEG)2-VCP” linker, or a “Mal-(PEG)2-Val-Cit-pAB” linker. In some embodiments, the drug moiety is eribulin. The structure of Mal-(PEG)2-Val-Cit-pAB-eribulin is provided below. In some embodiments, the pAB of the Mal-(PEG)2-Val-Cit-pAB linker is attached to the C-35 amine on eribulin. In some embodiments, the Mai of the Mal-(PEG)2-Val-Cit-pAB linker is attached to MORAb-003 via a cysteine residue on MORAb-003.Attorney Reference: 15648.0057-00304

[0159] It has been discovered that ADCs comprising Mal-(PEG)2-Val-Cit-pAB-eribulin demonstrate a particular combination of desirable properties, particularly when paired with an anti- FRA antibody such as MORAb-003 or an antigen-binding fragment thereof. These functional properties are also exemplified in the Examples provided in PCT Application No. PCT / US2017 / 020529 (published as WO 2017 / 151979).

[0160] In some embodiments, an ADC comprises Mal-(PEG)2-Val-Cit-pAB-eribulin and an antibody moiety comprising an internalizing anti-FRA antibody or an antigen-binding fragment thereof that retains the ability to target and internalize in a tumor cell. In some embodiments, the ADC comprises Mal-(PEG)2-Val-Cit-pAB-eribulin and an internalizing anti-FRA antibody or internalizing antigenbinding fragment thereof that targets an FRA-expressing tumor cell. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof that targets an FRA-expressing tumor cell comprises three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2), and SEQ ID NO: 3 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3). as defined by the Kabat numbering system; or three heavy chain complementarity determining regions (HCDRs) comprising amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3); and three light chain complementarity determining regions (LCDRs) comprising amino acid sequences of SEQ ID NO: 10 (LCDR1). SEQ ID NO: 11 (LCDR2). and SEQ ID NO: 12 (LCDR3). as defined by the IMGT numbering system. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof that targets an FRA-expressing tumor cell comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof that targets an FRA-expressing tumor cell comprises a human IgGl heavy chain constant domain and a human Ig kappa light chain constant domain.

[0161] In some embodiments, the ADC has Formula (I):Attorney Reference: 15648.0057-00304Ab-(L-D)^ (I)wherein:Ab is an internalizing anti-FRA antibody or internalizing antigen-binding fragment thereof comprising three HCDRs comprising amino acid sequences of SEQ ID NO: 1 (HCDR1), SEQ ID NO: 2 (HCDR2). and SEQ ID NO: 3 (HCDR3); and three LCDRs comprising amino acid sequences of SEQ ID NO: 4 (LCDR1), SEQ ID NO: 5 (LCDR2), and SEQ ID NO: 6 (LCDR3), as defined by the Kabat numbering system; or three HCDRs comprising amino acid sequences of SEQ ID NO: 7 (HCDR1), SEQ ID NO: 8 (HCDR2), and SEQ ID NO: 9 (HCDR3); and three LCDRs comprising amino acid sequences of SEQ ID NO: 10 (LCDR1), SEQ ID NO: 11 (LCDR2), and SEQ ID NO: 12 (LCDR3). as defined by the IMGT numbering system:D is eribulin;L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; andp is an integer from 1 to 20.

[0162] In some embodiments, the internalizing antibody or internalizing antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 14. In some embodiments, the internalizing antibody is MORAb-003. In some embodiments, / ! is from 1 to 8, or 1 to 6. In some embodiments, p is from 2 to 8, or 2 to 5. In some embodiments, p is from 3 to 4. In some embodiments, p is 4.Drug Moieties

[0163] In some embodiments, the drug moiety (D) of the ADCs described herein is an anti-tubulin agent. In some embodiments, D is or comprises eribulin.

[0164] In some embodiments, the drug moiety is eribulin and the linker of the ADC is attached via the C-35 amine on eribulin.

[0165] In some embodiments, the natural form of eribulin used for joining to the linker and antibody moiety is shown below:

[0166] In certain embodiments, an ADC is prepared by reacting an intermediate, which is the precursor of a linker, with eribulin under appropriate conditions. In certain embodiments, reactiveAttorney Reference: 15648.0057-00304groups are used on eribulin and / or the intermediate or linker. The product of the reaction between eribulin and tire intermediate is subsequently reacted with an anti-FRA antibody or antigen-binding fragment under appropriate conditions. Alternatively, the linker or intermediate may first be reacted widr the antibody or a derivatized antibody, and then reacted with eribulin.

[0167] A number of different reactions are available for covalent attachment of eribulin and / or linker to the antibody moiety. This is often accomplished by reaction of one or more amino acid residues of the antibody molecule, e.g., tire sulfhydryl groups of cysteine. For instance, non-specific covalent attachment may be undertaken using a carbodiimide reaction to link a carboxy (or amino) group on a compound to an amino (or carboxy) group on an antibody moiety. Additionally, bifunctional agents such as dialdehydes or imidoesters may also be used to link the amino group on a compound to an amino group on an antibody moiety. Also available for attachment of drugs to binding agents is tire Schiff base reaction. This method involves the periodate oxidation of a drug that contains glycol or hydroxy groups, thus forming an aldehyde which is then reacted with the binding agent. Attachment occurs via formation of a Schiff base with amino groups of the binding agent. Isothiocyanates may also be used as coupling agents for covalently attaching drugs to binding agents. Other techniques are known to the skilled artisan and within the scope of the present disclosure.Drug Loading

[0168] Drug loading is represented by p, and is also referred to herein as tire drug-to-antibody ratio (DAR). Drug loading may range from 1 to 20 drug moieties per antibody moiety. In some embodiments, p is an integer from 1 to 20. In some embodiments, p is an integer from 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3, or 1 to 2. In some embodiments, p is an integer from 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. In some embodiments, p is an integer from 3 to 5. In some embodiments, p is an integer from 3 to 4. In some embodiments, p is 1 , 2, 3, 4, 5, or 6. In some embodiments, p is 3 or 4.

[0169] Drug loading may be limited by the number of attachment sites on the antibody moiety. In some embodiments, the linker moiety (L) of tire ADC attaches to tire antibody moiety through a chemically active group on one or more amino acid residues on the antibody moiety. For example, the linker may be attached to the antibody moiety via a free amino, imino, hydroxyl, thiol, or carboxyl group (e.g., to the N- or C-terminus, to the epsilon amino group of one or more lysine residues, to tire free carboxylic acid group of one or more glutamic acid or aspartic acid residues, or to the sulfhydryl group of one or more cysteine residues). The site to which the linker is attached can be a natural residue in the amino acid sequence of the antibody moiety, or it can be introduced into the antibody moiety, e.g., by DNA recombinant technology (e.g., by introducing a cysteine residue into the amino acid sequence) or by protein biochemistry (e.g., by reduction, pH adjustment, or hydrolysis).

[0170] In some embodiments, the number of drug moieties that can be conjugated to an anti-FRA antibody moiety is limited by the number of free cysteine residues. For example, where theAttorney Reference: 15648.0057-00304attachment is a cysteine thiol group, an anti-FRA antibody may have only one or a few cysteine thiol groups, or may have only one or a few sufficiently reactive thiol groups through which a linker may be attached. Generally, antibodies do not contain many free and reactive cysteine thiol groups that may be linked to a drug moiety. Indeed, most cysteine thiol residues in antibodies exist as disulfide bridges. Over-attachment of linker-toxin to an antibody may destabilize (lie antibody by reducing the cysteine residues available to form disulfide bridges. Therefore, an optimal drug:antibody ratio should increase potency of the ADC (by increasing the number of attached drug moieties per antibody) without destabilizing the antibody moiety. In some embodiments, an optimal ratio is about 3 to 4.

[0171] In some embodiments, a linker attached to an antibody moiety through a Mai moiety provides a ratio of about 3 to 4. In some embodiments, a linker comprising a short spacer unit (e.g., a short PEG spacer unit such as (PEG)z) provides a ratio of about 3 to 4. In some embodiments, a linker comprising a peptide cleavable moiety provides a ratio of about 3 to 4. In some embodiments, an ADC comprising Mal-(PEG)2-Val-Cit-pAB-eribulin joined to an anti-FRA antibody such as MORAb-003 has a ratio of about 3 to 4.

[0172] In some embodiments, an antibody moiety, e.g., MORAb-003, is exposed to reducing conditions prior to conjugation in order to generate one or more free cysteine residues. In some embodiments, the antibody is reduced with a reducing agent such as dithiothreitol (DTT) or tris(2-carboxyethyljphosphine (TCEP), under partial or total reducing conditions, to generate reactive cysteine thiol groups. In certain embodiments, the antibody is subjected to denaturing conditions to reveal reactive nucleophilic groups on amino acid residues, such as lysine or cysteine.

[0173] Where more than one nucleophilic group reacts with a drug-linker intermediate or a linker moiety reagent followed by drug moiety reagent, in a reaction mixture comprising multiple copies of the antibody moiety and linker moiety, then the resulting product may be a mixture of ADC compounds with a distribution of one or more drug moieties attached to each copy of the antibody moiety in the mixture. In some embodiments, the drug loading in a mixture of ADCs resulting from a conjugation reaction ranges from 1 to 20 drug moieties attached per antibody moiety. The average number of drug moieties per antibody moiety (i.e., the average drug loading, or average p) may be calculated by any conventional method known in the art, e.g., by mass spectrometry (e.g., reversephase LC-MS), and / or high-performance liquid chromatography (e.g., HIC-HPLC). In some embodiments, the average number of drug moieties per antibody moiety is determined by hydrophobic interaction chromatography-high performance liquid chromatography (HIC-HPLC). In some embodiments, the average number of drug moieties per antibody moiety is determined by reverse-phase liquid chromatography-mass spectrometry (LC-MS). In some embodiments, the average number of drug moieties per antibody moiety is from about 3 to about 4; about 3.1 to about 3.9; about 3.2 to about 3.8; about 3.2 to about 3.7; about 3.2 to about 3.6; about 3.3 to about 3.8; or about 3.3 to about 3.7. In some embodiments, the average number of drug moieties per antibody moiety is from about 3.2 to about 3.8. In some embodiments, the average number of drug moieties perAttorney Reference: 15648.0057-00304antibody moiety is about 3.8. In some embodiments, the average number of drug moieties per antibody moiety is from 3 to 4; 3.1 to 3.9; 3.2 to 3.8; 3.2 to 3.7; 3.2 to 3.6; 3.3 to 3.8; or 3.3 to 3.7. In some embodiments, the average number of drug moieties per antibody moiety is from 3.2 to 3.8. In some embodiments, the average number of drug moieties per antibody moiety is 3.8.

[0174] In some embodiments, (lie average number of drug moieties per antibody moiety is from about 3.5 to about 4.5; about 3.6 to about 4.4; about 3.7 to about 4.3; about 3.7 to about 4.2; or about 3.8 to about 4.2. In some embodiments, the average number of drug moieties per antibody moiety is from about 3.6 to about 4.4. In some embodiments, the average number of drug moieties per antibody moiety is about 4.0. In some embodiments, the average number of drug moieties per antibody moiety is from 3.5 to 4.5; 3.6 to 4.4; 3.7 to 4.3; 3.7 to 4.2; or 3.8 to 4.2. In some embodiments, tire average number of drug moieties per antibody moiety is from 3.6 to 4.4. In some embodiments, the average number of drug moieties per antibody moiety is 4.0.

[0175] Individual ADC compounds having particular DAR ratios, or “species,” may be identified in the mixture by mass spectroscopy and separated by ultra performance liquid chromatography (UPLC) or HPLC, e.g., hydrophobic interaction chromatography (HIC-HPLC). In certain embodiments, a homogeneous or nearly homogenous ADC with a single loading value may be isolated from the conjugation mixture, e.g., by electrophoresis or chromatography.

[0176] In some embodiments, drug loading and / or average drug loading in an ADC (e.g., in MORAb-202) is about 4. In some embodiments, a drug loading and / or an average drug loading of about 4 provides beneficial properties. See, e.g., PCT / US2017 / 020529 (published as WO 2017 / 151979); see also U.S. Patent No. 10,322,192.

[0177] In some embodiments, an ADC has Formula (I):Ab-(L-D)^ (I)wherein:Ab is an internalizing anti-folate receptor alpha antibody or antigen-binding fragment thereof comprising a heavy chain variable region comprising an amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising an amino acid sequence of SEQ ID NO: 14;D is eribulin;L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; andp is an integer from 1 to 8.

[0178] In some embodiments, an ADC has Formula (I):Ab-(L-D), (I)wherein:Ab is an internalizing anti-folate receptor alpha antibody or antigen-binding fragment thereof comprising a heavy chain amino acid sequence of SEQ ID NO: 15, and a light chain amino acid sequence of SEQ ID NO: 16;D is eribulin;Attorney Reference: 15648.0057-00304L is a cleavable linker comprising Mal-(PEG)2-Val-Cit-pAB; andp is an integer of about 4.Tyrosine Kinase Inhibitors

[0179] The methods of the present disclosure include the use of tyrosine kinase inhibitors. Examples of tyrosine kinases inhibitors include axitinib, dasatinib, erlotinib, gefitinib, imatinib, erdafitinib. futibatinib, lenvatinib, nilotinib, pazopanib, pemigatinib. sunitinib, and tasurgratinib, as well as salts thereof. In some embodiments, the tyrosine kinase inhibitor is an epidermal growth factor receptor (EGFR) inhibitor. In some embodiments, the tyrosine kinase inhibitor is a fibroblast growth factor receptor (FGFR) inhibitor. In some embodiments, the tyrosine kinase inhibitor is a platelet-derived growth factor receptor (PDGFR) inhibitor. In some embodiments, the tyrosine kinase inhibitor is a VEGFR inhibitor. In some embodiments, the tyrosine kinase inhibitor inhibits more than one target, e.g., VEGFR and FGFR. or VEGFR, FGFR, and PDGFR.

[0180] In some embodiments, the tyrosine kinase inhibitor is axitinib, erdafitinib, futibatinib, lenvatinib, pazopanib, pemigatinib, sunitinib, or tasurgratinib. or pharmaceutically acceptable salts thereof. In some embodiments, the tyrosine kinase inhibitor is lenvatinib or a salt thereof.

[0181] In various embodiments, the structure of lenvatinib (4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide methanesulfonate) is shown below:

[0182] Methods relating to treatment using lenvatinib or pharmaceutically acceptable salts thereof, such as lenvatinib mesylate, and methods of synthesis are described in U.S. Pat. No. 7,612,092.

[0183] In some embodiments, a pharmaceutically acceptable salt of lenvatinib is used. Examples of salts include, but are not limited to, methansulfonic acid salt (e g., lenvatinib mesylate), hydrochloric acid salt, sulfuric acid salt, citric acid salt, hydrobromic acid salt, hydroiodine acid salt, nitric acid salt, bisulfate, phosphoric acid salt, super phosphoric acid salt, isonicotinic acid salt, acetic acid salt, lactic acid salt, salicic acid salt, tartaric acid salt, pantotenic acid salt, ascorbic acid salt, succinic acid salt, maleic acid salt, fumaric acid salt, gluconic acid salt, saccharinic acid salt, formic acid salt, benzoic acid salt, glutaminic acid salt, ethanesulfonic acid salt, benzene sulfonic acid salt, p-Attorney Reference; 15648.0057-00304toluenesulfonic acid salt, and pamoic acid salt (pamoate). In some embodiments, the tyrosine kinase inhibitor is lenvatinib mesylate.

[0184] Pharmaceutical compositions including lenvatinib or a pharmaceutically acceptable salt thereof, such as mesylate salt, can be prepared using standard methods known in the art.Pharmaceutical compositions used in the invention can be prepared, for example, by mixing or dissolving the active ingredient(s), having the desired degree of purity, in a physiologically acceptable diluent, carrier, excipient, or stabilizer. See, e.g., Gennaro et al. (2000) Remington's Pharmaceutical Sciences. Acceptable diluents include water and saline, optionally including buffers such as phosphate, citrate, or other organic acids; antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA). ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN™, PLURONICS™, or PEG.

[0185] In some embodiments, the formulations of the invention contain a pharmaceutically acceptable preservative. In some embodiments the preservative concentration ranges from 0.1 % o 2.0%, typically v / v. Suitable preservatives include those known in the pharmaceutical arts, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben. Further, the formulations comprising lenvatinib, or pharmaceutically acceptable salts thereof, such as mesylate salts, optionally include a pharmaceutically acceptable salt, such as sodium chloride at, for example, about physiological concentrations. In some embodiments, lenvatinib or a pharmaceutically acceptable salt thereof, such as lenvatinib mesylate, is formulated for oral administration, e.g., in liquid, tablet, or capsule form.Therapeutic Uses

[0186] Disclosed herein are methods of treating and / or preventing a cancer (e.g., an FRA-expressing cancer) comprising administering to a subject in need thereof a therapeutically effective amount of an anti-FRA ADC and a therapeutically effective amount of a tyrosine kinase inhibitor. In some embodiments, the method of treating a cancer (e.g., an FRA-expressing cancer) comprises administering to a subject in need thereof a therapeutically effective amount of an anti-FRA ADC and a therapeutically effective amount of a tyrosine kinase inhibitor. In some embodiments, the method of preventing a cancer (e.g., an FRA-expressing cancer) comprises administering to a subject in need thereof a therapeutically effective amount of an anti-FRA ADC and a therapeutically effective amount of a tyrosine kinase inhibitor. In some embodiments, the anti-FRA ADC is MORAb-202. In some embodiments, the tyrosine kinase inhibitor is lenvatinib or a salt thereof, e.g., a mesylate salt. In someAttorney Reference: 15648.0057-00304embodiments, the anti-FRA ADC is MORAb-202 and the tyrosine kinase inhibitor is lenvatinib or a salt thereof, e.g., a mesylate salt.

[0187] In some embodiments, tire methods disclosed herein for treating a cancer comprise treating an FRA-expressing cancer. In some embodiments, tire methods disclosed herein for preventing a cancer comprise preventing an FRA-expressing cancer. Non-limiting examples of FRA-expressing cancers include gastric cancer, ovarian cancer, serous ovarian cancer, serous high-grade ovarian cancer, clear cell ovarian cancer, platinum resistant ovarian cancer, lung cancer, non-small cell lung cancer, metastatic non-small cell lung cancer, lung carcinoid, colorectal cancer, breast cancer, triple negative breast cancer, hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-low breast cancer, endometrial cancer, serous endometrial carcinoma, uterine cancer, serous uterine cancer, peritoneal cancer, primary peritoneal cancer, fallopian tube cancer, pancreatic cancer, kidney cancer, renal cell cancer, cervical cancer, esophageal cancer, and osteosarcoma.

[0188] In some embodiments, the FRA-expressing cancer is uterine cancer. In some embodiments, the uterine cancer is endometrial cancer. In some embodiments, the FRA-expressing cancer is ovarian cancer. In some embodiments, the ovarian cancer is platinum-resistant ovarian cancer (PROC). In some embodiments, the PROC is a serous ovarian cancer. In some embodiments, the serous ovarian cancer is a high-grade serous ovarian cancer. In some embodiments, the ovarian cancer is not a platinum- refractory ovarian cancer. In some embodiments, the FRA-expressing cancer is platinum-resistant primary peritoneal cancer. In some embodiments, the FRA-expressing cancer is platinum-resistant fallopian tube cancer. In some embodiments, the FRA-expressing cancer is breast cancer. In some embodiments, the breast cancer is triple negative breast cancer (TNBC). In some embodiments, the FRA-expressing cancer is non-small cell lung cancer (NSCLC). In some embodiments, the FRA-expressing cancer is endometrial cancer.

[0189] In some embodiments, tire methods disclosed herein for treating and / or preventing cancer in a subject comprise treating a subject with a metastatic cancer. In some embodiments, a subject with a metastatic cancer treated according to die disclosed methods has no genomic alterations. In some embodiments, a subject with a metastatic cancer (e.g., a metastatic non-small cell lung cancer) has at least one genomic alteration (e.g., at least one unknown or known genomic alteration). Examples of known genomic alterations include, but are not limited to, genomic alterations in any one of die following genes: EGFR, ALK, PI3K, AKT, mTOR, RET, MET, BRAF, NTRK, ROS1, and any gene involved in the RAS-MAPK patiiway. In some embodiments, a subject witii a metastatic cancer has at least one known genomic alteration in at least one of any of die aforementioned genes. As used herein, “genomic alteration” refers to any change to die genome, including, but not limited to, a somatic mutation, a copy number variation, and a gene fusion. In some embodiments, the metastatic cancer is a metastatic non-small cell lung cancer.

[0190] In some embodiments, the FRA-expressing cancer is a metastatic cancer. In some embodiments, the metastatic cancer has no genomic alteration. In some embodiments, the metastaticAttorney Reference: 15648.0057-00304cancer has at least one known genomic alteration in at least one of any of the following genes: EGFR, ALK, PI3K, AKT, mTOR, RET, MET, BRAF, NTRK, ROS1, and any gene involved in the RAS-MAPK pathway. In some embodiments, the metastatic cancer is a non-small cell lung cancer.

[0191] In some embodiments, the methods disclosed herein for treating and / or preventing cancer in a subject comprise treating a subject with a refractory cancer. In some embodiments, a subject with a refractory cancer is non-responsive to a prior therapy upon initial treatment. In some embodiments, a subject with a refractory cancer is non-responsive to a targeted treatment, e.g., a treatment specifically targeted against any one of the following genes or variants thereof: epidermal growth factor receptor (EGF ), anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog 1 (BRAF , ret proto-oncogene (RET), MET proto-oncogene, receptor tyrosine kinase (MET), neurotrophic receptor tyrosine kinase (NTRK) and receptor tyrosine kinase (ROSE). In some embodiments, any one of tire aforementioned genes, or variants thereof, against which a targeted treatment is specifically targeted may comprise at least one genomic alteration. For example, a targeted treatment may be specific against a mutation in NTRK1, while another targeted treatment may be specific against a mutation in NTRK2.

[0192] In some embodiments, a subject with a refractory cancer is non-responsive to a platinumbased treatment (e.g., platinum-doublet chemotherapy) and / or an immunotherapy-based treatment (e.g., an immune checkpoint inhibitor). In some embodiments, a subject with a refractory cancer is non-responsive to treatment with platinum-doublet chemotherapy and an immune checkpoint inhibitor. In some embodiments, the platinum-doublet chemotherapy and immune checkpoint inhibitor are administered concurrently or sequentially. In some embodiments, a subject with a refractory cancer is non-responsive to not more than three prior systemic therapies, e.g., not more than two prior systemic therapies. In some embodiments, a subject with a refractory cancer is non-responsive to not more than one prior chemotherapy.

[0193] In some embodiments, tire FRA-expressing cancer is a refractory cancer. In some embodiments, tire refractory cancer is non-responsive to a targeted treatment. In some embodiments, tire targeted treatment is a targeted treatment against any one of the following genes or variants thereof: EGFR, ALK, BRAF, RET, MET, NTRK, and ROS1. In some embodiments, the refractory cancer is non-responsive to a platinum-based treatment and / or an immunotherapy-based treatment. In some embodiments when a refractory cancer is non-responsive to a platinum-based treatment and an immunotherapy-based treatment, the platinum-based treatment and the immunotherapy-based treatment were administered concurrently or sequentially. In some embodiments, the platinum-based treatment is a platinum-doublet chemotherapy. In some embodiments, tire immunotherapy -based treatment is a checkpoint inhibitor therapy, a CAR T-cell therapy, a cancer vaccine, an immune-targeting monoclonal antibody, a cytokine, or an immune system modulator. In some embodiments, the checkpoint inhibitor is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 receptor inhibitor.Attorney Reference: 15648.0057-00304

[0194] In some embodiments, the methods disclosed herein for treating and / or preventing cancer in a subject comprise treating a subject who was not administered a prior therapy for the cancer. In some embodiments, tire methods disclosed herein for treating and / or preventing cancer in a subject comprise treating a subject who was administered at least one prior therapy for the cancer. In some embodiments, tlie subject was administered one prior therapy for tlie cancer. In some embodiments, the subject was administered two or more prior therapies for the cancer. In some embodiments, the subject was administered two or three prior therapies for the cancer. In some embodiments, the subject was administered no more than one additional prior therapy after developing resistance to a prior platinum-based therapy. In some embodiments, the number of prior therapies does not include a primary therapy to which tlie subject exhibited refractory disease. In some embodiments, tlie cancer is an FRA-expressing cancer.[00195J In some embodiments, the FRA-expressing cancer has an FRA expression level of less than 5%. In some embodiments, the FRA-expressing cancer has an FRA expression level of at least 5%. In some embodiments, the FRA-expressing cancer has an FRA expression level of 5% to 24% (e.g., low-FRA expression). In some embodiments, a subject’s FRA expression level is defined as low-FRA expression if the subject has an FRA expression level of 5% to 24%. In some embodiments, the FRA-expressing cancer has an FRA expression level of 24% to 74% (e.g., medium-FRA expression). In some embodiments, a subject’s FRA expression level is defined as medium-FRA expression if the subject has an FRA expression level of 24% to 74%. In some embodiments, tlie FRA-expressing cancer has an FRA expression level of at least 75% (e.g., high-FRA expression). In some embodiments, a subject’s FRA expression level is defined as high-FRA expression if the subject has an FRA expression level of at least 75%. In some embodiments, the FRA expression level is determined by immunohistochemistry.

[0196] The dosage of the anti-FRA ADC and tlie tyrosine kinase inhibitor may be dependent upon a number of factors including pharmacodynamic characteristics of each therapeutic agent; route of administration; the health of the subject being treated; the extent of treatment desired; the nature and kind of concurrent therapy, if any; the frequency of treatment; the nature of tlie effect desired; the age, sex, and weight of the subject; the severity of the symptoms; and other factors, as can be assessed by those of skill in the art. The therapeutic agents are administered using amounts and regimens that obtain the desired effect (e.g., tumor regression). The amounts and regimens may have additive or synergistic effects on one or more features of cancer treatment (e.g., tumor regression), as is known in the art.Anti-FRA ADC Dosing

[0197] In some embodiments, the dose of the anti-FRA ADC is administered to the subject based on the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 0.2 mg / kg to about 10 mg / kg of the subject’s body weight. In some embodiments, theAttorney Reference: 15648.0057-00304anti-FRA ADC is administered to the subject at a dose of about 0.5 mg / kg to about 1.5 mg / kg of the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 0.5 mg / kg of the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 0.6 mg / kg of die subject’s body weight. In some embodiments, llie anti-FRA ADC is administered to the subject at a dose of about 0.68 mg / kg of the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 0.7 mg / kg of the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 0.9 mg / kg of the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 1.2 mg / kg of the subject’s body weight. In some embodiments, the anti-FRA ADC is administered to the subject at a dose of about 1.5 mg / kg of the subject’s body weight.

[0198] In some embodiments, the dose of the anti-FRA ADC is based on the subject’s body surface area (BSA). In some embodiments, methods of treatment employing a BSA-based dosing may reduce risk of interstitial lung disease (ILD) in a subject in need of treatment with an anti-FRA ADC. See, e.g., PCT / US2023 / 018214 (published as WO 2023 / 200814), which is incorporated herein by reference in its entirety, including for its disclosure of BSA dosages and methods of selecting BSA doses for an anti-FRA ADC, e.g., MORAb-202.

[0199] In some embodiments, the anti-FRA ADC is administered at a dose of 8 mg to 50 mg per square meter (m2) of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 8 mg / m2to 44 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 8 mg / m2to 20 mg / m2of the subject’s BSA. In some embodiments, the dose is 5 mg / m2to 75 mg / m2, 10 mg / m2to 60 mg / m2, 15 mg / m2to 45 mg / m2, 20 mg / m2to 40 mg / m2, or 25 mg / m2to 35 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 33 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 25 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 17 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 15 mg / m2of the subject’s BSA In some embodiments, the anti-FRA ADC is administered at a dose of 14 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 13 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 12 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 11 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 10 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 9 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 8 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is administered at a dose of 7.5 mg / m2of the subject’s BSA. Any of these doses may be administered once per week, once every two weeks, once every three weeks, on Day 1 of a 21-day cycle, on Day 1 and Day 8 of aAttorney Reference: 15648.0057-0030421-day cycle, on Day 1, Day 8, and Day 15 of a 21-day cycle, or on Day 1, Day 8, and Day 15 of a 28-day cycle.

[0200] In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 8 mg to 50 mg per square meter (m2) of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 8 mg / m2to 44 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 8 mg / m2to 20 mg / m2of the subject’s BSA. In some embodiments, the dose is 5 mg / m2to 75 mg / m2, 10 mg / m2to 60 mg / m2, 15 mg / m2to 45 mg / m2, 20 mg / m2to 40 mg / m2, or 25 mg / m2to 35 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 33 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 25 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 17 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 15 mg / m2of die subject’s BSA In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 14 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 13 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 12 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 11 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 10 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 9 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 8 mg / m2of the subject’s BSA. In some embodiments, the anti-FRA ADC is formulated for administration at a dose of 7.5 mg / m2of the subject’s BSA. Any of these doses may be formulated for administration administered once per week, once every two weeks, once every three weeks, on Day 1 of a 21-day cycle, on Day 1 and Day 8 of a 21-day cycle, on Day 1, Day 8, and Day 15 of a 21-day cycle, or on Day 1, Day 8, and Day 15 of a 28-day cycle.

[0201] BSA may be calculated using any accepted method known in the art. Formulas for calculating a subject’s BSA include, for example, the Dubois and Dubois formula, or any variation thereof (Dubois D, Dubois EF. (1916) Arch Intern Med. 1916; 17:863-871); the Mosteller formula, or any variation thereof (Mosteller RD. (1987) N Engl J Med. 22;317(17) : 1098): or the Haycock formula (Haycock GB et al. (1978) J Pediatr. Jul;93(l):62-6). Exemplary formulas for calculating BSA are provided below:(II) BSA (m2) = 0.20247 x Height (m)°725x Weight (kg)"425(DuBois and DuBois);(III) BSA (m2) = 0.007184 x Height (cm)0725x Weight (kg)°425(variation of Dubois and Dubois); (IV) BSA (m2) = ([Height (cm) x Weight ( kg) ] / 3600 )M(Mosteller);or(V) BSA (m2) = 0.024265 x Height (cm)03964x BW (kg)05378(Haycock).Attorney Reference: 15648.0057-00304

[0202] In some embodiments, the actual dose of the anti-FRA ADC to be administered to a subject is calculated as shown below:(VI) Scheduled dose (mg / m2) x body surface area (BSA) (m2) = Actual dose (mg)

[0203] As used herein, “scheduled dose” refers to a dose selected from the range of doses provided above, e.g., 8 mg / m2to 44 mg / m2, to be administered to a subject. For example, the anti-FRA ADC may be administered at a scheduled dose of 14 mg / m2to a subject with an exemplary BSA of 1.8 square meters (m2), as calculated by Formula (III) above using hypothetical values of a height of 160 cm and a BW of 80 kg. In this particular example, according to Formula (VI) provided above, the amount of ADC administered to the subject, or actual dose, is 25.2 mg.

[0204] In some embodiments, the treatment dose is recalculated on the first day of each treatment cycle, using the subject’s height measured at intake and the subject’s weight measured on or prior to the first day of each treatment cycle, e.g., two days prior to the first day of each treatment cycle.

[0205] In some embodiments, the anti-FRA ADC is administered weekly, every two weeks, every three weeks, every four weeks, monthly, or any administration frequency in between. In some embodiments, the anti-FRA ADC is administered every four weeks. In some embodiments, the anti-FRA ADC is administered on a 28-day cycle. A treatment cycle of once every four weeks or a 28-day cycle may also be referred to as “Q4W.” In some embodiments, the ADC is administered once every three weeks. In some embodiments, die anti-FRA ADC is administered on a 21-day cycle. A treatment cycle of once every three weeks or a 21-day cycle may also be referred to as “Q3W.” In some embodiments, the ADC is administered once every two weeks. In some embodiments, the anti-FRA ADC is administered on a 14-day cycle. A treatment cycle of once every two weeks or a 14-day cycle may also be referred to as “Q2W.” In some embodiments, the anti-FRA ADC is administered once per week. In some embodiments, die ADC is administered on a 7-day cycle. A treatment cycle of once per week or a 7-day cycle may also be referred to as “QW.”

[0206] In some embodiments, die anti-FRA ADC is administered once or twice a week, on a cycle selected from the group consisting of: (i) one week of therapy followed by two, three or four weeks off; (ii) two weeks of therapy follow ed by one, two, three, or four w eeks off; (iii) three w eeks of dierapy followed by one, two, three, four, or five w eeks off; (iv) four weeks of therapy followed by one, two, three, four, or five weeks off; and (v) five weeks of therapy follow ed by one, two, three, four, or five weeks off. The cycle may be repeated 4, 6, 8, 10, 12, 16, or 20 times, or more. In some embodiments, the anti-FRA ADC is administered once per week on a cycle of two weeks of therapy followed by one week off. In some embodiments, the anti-FRA ADC is administered at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered once per week on a cycle of three weeks of therapy followed by one week off. In some embodiments, the anti-FRA antibody-drug conjugate is administered at Day 1, Day 8, and Day 15 of a 28-day cycle.Attorney Reference: 15648.0057-00304

[0207] In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 8 mg / m2to 44 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 8 mg / m2to 44 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 8 mg / m2to 44 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 15 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 15 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 15 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 14 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 14 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 14 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 13 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 13 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 13 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 12 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 12 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 12 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 11 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 11 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 11 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 10 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 10 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 10 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 9 mg / m2. In some embodiments, tire anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 9 mg / m2. In some embodiments, tire anti-FRA ADC is administered once per week at a BSA-dependent dose of 9 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 8 mg / m2. In some embodiments, tire anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 8 mg / m2. In some embodiments, tire anti-FRA ADC is administered once per week at a BSA-dependent dose of 8 mg / m2. In some embodiments, the anti-FRA ADC is administered once every three weeks at a BSA-dependent dose of 7.5 mg / m2. In some embodiments, the anti-FRA ADC is administered once every two weeks at a BSA-dependent dose of 7.5 mg / m2. In some embodiments, the anti-FRA ADC is administered once per week at a BSA-dependent dose of 7.5 mg / m2.Attorney Reference: 15648.0057-00304

[0208] In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2to 44 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2to 44 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, tire anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2to 44 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, tire anti-FRA ADC is administered at a BSA-dependent dose of 15 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 15 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 15 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 14 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 14 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 14 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 13 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 13 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 13 mg / m2at Day 1 , Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 12 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 12 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 12 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 11 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 11 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 11 mg / m2at Day l, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 10 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 10 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, tire anti-FRA ADC is administered at a BSA-dependent dose of 10 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 9 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 9 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 9 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2at Day 1 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle. InAttorney Reference: 15648.0057-00304some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 7.5 mg / m2at Day 1 of a 21 -day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 7.5 mg / m2at Day 1 and Day 8 of a 21-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 7.5 mg / m2at Day 1, Day 8, and Day 15 of a 21-day cycle.

[0209] In some embodiments, (lie anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2to 44 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 15 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 14 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 13 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 12 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 11 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 10 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 9 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 8 mg / m2at Day 1 , Day 8, and Day 15 of a 28-day cycle. In some embodiments, the anti-FRA ADC is administered at a BSA-dependent dose of 7.5 mg / m2at Day 1, Day 8, and Day 15 of a 28-day cycle.

[0210] Without being bound by theory, BSA-based dosing as disclosed herein may lower exposure levels, e.g., in subjects with higher body weights (BW) when administered the disclosed ADCs, which may help to reduce ILD risk. Without being bound by theory, BW-based dosing may result in higher exposure for subjects in the upper quartile of weight, compared to subjects with a lower body weight. Other exemplary dosing regimens that may reduce tire total dose and exposure burden in a treated subject include dosing using BW with a maximum total dose cap or adjusted ideal body weight (AIBW). In some embodiments, BSA-based dosing is preferred due to its ease-of-use, greater familiarity with practitioners, and reduced likelihood of producing dosing errors.

[0211] In some embodiments, a subject treated with an anti-FRA ADC as disclosed herein has a body weight value that is in the upper quartile of weight. In some embodiments, a subject treated with an anti-FRA ADC as disclosed herein has a body weight of at least 80 kg.

[0212] The ADCs disclosed herein may be administered to a subject by any suitable administration route to have a therapeutic effect. In some embodiments, the anti-FRA ADC is administered to the subject intravenously.Tyrosine Kinase Inhibitor Dosing

[0213] In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 0.1 mg to 100 mg. It will be understood that references herein to doses of a tyrosine kinase inhibitor refer to a freeAttorney Reference: 15648.0057-00304base of the tyrosine kinase inhibitor (unless context indicates otherwise), and that a corresponding amount of a salt thereof may also be used for any dose disclosed herein. For example, a 10 mg dose of lenvatinib corresponds to 12.25 mg of lenvatinib mesylate. Similarly, a 4 mg dose of lenvatinib corresponds to 4.90 mg of lenvatinib mesylate.

[0214] In some embodiments, (lie tyrosine kinase inhibitor is administered at a dose of 4 mg to 25 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 8 mg to 12 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 25 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 20 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 14 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 12 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 10 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 8 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered at a dose of 4 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the dose administered to the subject is based on the subject’s body weight. Any of these doses may be administered once per day, once every other day, once per week, once every two weeks, or once every three weeks. In some embodiments, the dose is administered once per day. In some embodiments, tire tyrosine kinase inhibitor is lenvatinib. In some embodiments, tire salt of the tyrosine kinase inhibitor is lenvatinib mesylate.

[0215] In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 4 mg to 25 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 8 mg to 12 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 25 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 20 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 14 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 12 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In someAttorney Reference: 15648.0057-00304embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 10 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is formulated for administration at a dose of 8 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, (lie tyrosine kinase inhibitor is formulated for administration at a dose of 4 mg of a free base of (lie tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the dose is formulated for administration to the subject based on tire subject’s body weight. Any of these doses may be formulated for administration once per day, once every other day, once per week, once every two weeks, or once every three weeks. In some embodiments, the dose is formulated for administration once per day. In some embodiments, the tyrosine kinase inhibitor is lenvatinib. In some embodiments, the salt of the tyrosine kinase inhibitor is lenvatinib mesylate.

[0216] In some embodiments, the tyrosine kinase inhibitor is administered once a day. A treatment cycle of once per day may also be referred to as “QD.” In some embodiments, tire tyrosine kinase inhibitor is administered once daily on Day 1 and Day 8 of a 21 -day cycle. In some embodiments, the tyrosine kinase inhibitor is administered once daily on Days 1, 8, and 15 of a 28-day cycle, or on Days 1, 8, 5, and 22 of a 35-day cycle. In some embodiments, the tyrosine kinase inhibitor is lenvatinib.

[0217] In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 0.1 mg to 100 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 4 mg to 24 mg of a free base of tire tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 24 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 20 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, tire tyrosine kinase inhibitor is administered once a day at a dose of 14 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 12 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, tire tyrosine kinase inhibitor is administered once a day at a dose of 10 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 8 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is administered once a day at a dose of 4 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof. In some embodiments, the tyrosine kinase inhibitor is lenvatinib. In some embodiments, the salt of the tyrosine kinase inhibitor is lenvatinib mesylate.

[0218] In some embodiments, the tyrosine kinase inhibitor is administered orally.Attorney Reference: 15648.0057-00304Combination Therapies

[0219] In some embodiments, the methods disclosed herein for treating an FRA-expressing cancer comprise administering to a subject in need thereof a therapeutically effective amount of an anti-FRA ADC of Formula (I) as disclosed herein, e.g. , MORAb-202, in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In some embodiments, the methods disclosed herein for reducing risk of ILD in a subject being treated for an FRA-expressing cancer comprise administering to the subject a therapeutically effective amount of an anti-FRA ADC of Formula (I) as disclosed herein, e.g., MORAb-202, in combination with a therapeutically effective amount of a tyrosine kinase inhibitor. In some embodiments, the anti-FRA ADC is administered to the subject at a dose based on the subject’s BSA.

[0220] In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered sequentially or concurrently. In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered intermittently. In some embodiments, the anti-FRA ADC is administered in conjunction with the tyrosine kinase inhibitor. In some embodiments, the tyrosine kinase inhibitor is administered before the antibody-drug conjugate is administered. In some embodiments, the tyrosine kinase inhibitor is administered after the antibody-drug conjugate is administered. The length of time between administrations of the anti-FRA ADC and the tyrosine kinase inhibitor may be adjusted to achieve the desired therapeutic effect.

[0221] In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered simultaneously. In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered only a few minutes apart. In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered several hours (e.g., about 2, 4, 6, 10, 12, 24, or 36 hours) apart. In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered several days (e.g., about 1, 2, 3, 4, 5, 6, 7, 10, 14, 17, or 21 days) apart. In some embodiments, the anti-FRA ADC and tire tyrosine kinase inhibitor are administered several weeks (e.g., about 1, 2, or 3 weeks) apart. It may be advantageous to administer more than one dose of one of tire anti-FRA ADC and tire tyrosine kinase inhibitor between administrations of the other therapeutic agent. For example, one therapeutic agent may be administered at 1 hour and then again at 11 hours following administration of the other therapeutic agent. In some embodiments, the therapeutic effects of each tire anti-FRA ADC and the tyrosine kinase inhibitor overlap for at least a portion of the duration. The overall therapeutic effect of the combination therapy may be attributable in part to the combined or synergistic effects of the combination therapy.

[0222] In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are coadministered to the subject by separate administration of each active agent. In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor are administered as separate compositions. In some embodiments, both the anti-FRA ADC and the tyrosine kinase inhibitor are administered intravenously. In some embodiments, the anti-FRA ADC and the tyrosine kinase inhibitor areAttorney Reference: 15648.0057-00304administered in separate forms, e.g., as separate tablets or solutions. In some embodiments, the tyrosine kinase inhibitor is administered orally and the anti-FRA ADC is administered intravenously. In some embodiments, tire tyrosine kinase inhibitor is orally administered in a once-daily tablet.

[0223] In some embodiments, tire anti-FRA ADC and the tyrosine kinase inhibitor are coadministered to die subject in a single dosage form. In some embodiments, die anti-FRA ADC and the tyrosine kinase inhibitor are formulated in the same solution. The formulation of die anti-FRA ADC and the tyrosine kinase inhibitor may be selected appropriately. In some embodiments, die anti-FRA ADC, the tyrosine kinase inhibitor, or bodi, are formulated into a solution for parenteral administration. In some embodiments, the antibody-drug conjugate and the tyrosine kinase inhibitor are in the same composition.

[0224] In some embodiments, the combination therapies disclosed herein comprise a lower dose of one or more of the individual therapeutic agents (z.e„ the anti-FRA ADC and / or the tyrosine kinase inhibitor) than would be administered if the individual therapy were administered alone. This decreased dose may reduce one or more side effects associated with the monotherapy and / or maintain the therapeutic effect otherwise seen at higher doses of monotherapy. In some embodiments, the combination therapy achieves the same or greater therapeutic benefit using a smaller amount (e.g., a lower dose and / or a less frequent dosing schedule) of the anti-FRA ADC, the tyrosine kinase inhibitor, or both, compared to the treatment outcome achieved with monotherapy of either or both agent(s) individually. In some embodiments, the use of a smaller amount of the anti-FRA ADC, the tyrosine kinase inhibitor, or both results in a reduction in the number, severity, frequency, and / or duration of one or more side effects associated with the therapeutic agents when administered individually (e.g., ILD). As non-limiting examples, the combination therapy may comprise, compared to the doses generally used for monotherapies: (i) lower dose of the anti-FRA ADC and lower dose of the tyrosine kinase inhibitor; (ii) lower dose of the anti-FRA ADC and the same dose of the tyrosine kinase inhibitor; (iii) lower dose of the tyrosine kinase inhibitor and tire same dose of tire anti-FRA ADC.

[0225] In some embodiments, tire combination therapies disclosed herein reduce a risk of ILD in a subject by at least 5%, at least 10%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, or at least 20% following administration of the combination therapy, as compared to a treatment in which the anti-FRA ADC is administered alone.

[0226] In some embodiments, the methods as disclosed herein further comprise administration of at least one additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a corticosteroid. Without being bound by theory, it is hypothesized that a potential mechanism for ILD may involve an FRA-independent interaction between the anti-FRA ADCs as disclosed herein and pulmonary macrophages in the pre-inflammatory lung microenvironment. An “FRA-independent interaction” refers to an interaction, e.g., binding or phagocytosis, between an anti-FRA ADC and a cell that is not caused by recognition and binding to an FRA antigen on the cell. This interaction may result in the induction of cytokines within a subject’s lung tissue. Further, withoutAttorney Reference: 15648.0057-00304being bound by theory, free eribulin may be released into a subject’s lung tissue following the internalization of anti-FRA ADCs into macrophages. Without being bound by theory, the release of free eribulin into the lung tissue may cause tissue damage due to the bystander effects of the ADCs disclosed herein. An immune-mediated mechanism may thus drive the development of ILD. Without being bound by theory, (lie administration of a corticosteroid may alleviate symptoms or altogether prevent the development of ILD due to its immune modulatory and anti-inflammatory effects.

[0227] In some embodiments, the corticosteroid is administered prophylactically. In some embodiments, the corticosteroid is administered concurrently or sequentially with one or more components of tire combination therapy. In some embodiments, tire corticosteroid is administered before or after one or more components of tire combination therapy are administered. In some embodiments, the corticosteroid is administered one week before one or more therapeutic agents of the combination therapy are administered. In some embodiments, tire corticosteroid is administered before administration of the anti-FRA ADC. In some embodiments, the corticosteroid is administered one week before administration of the anti-FRA ADC. In some embodiments, a single dose of the corticosteroid is administered one week before administration of the anti-FRA ADC. In some embodiments, more than one dose of the corticosteroid is administered one week before administration of the anti-FRA ADC.

[0228] In some embodiments, the corticosteroid is administered one week after one or more therapeutic agents of the combination therapy are administered. In some embodiments, the corticosteroid is administered after administration of the anti-FRA ADC. In some embodiments, the corticosteroid is administered one week after administration of the anti-FRA ADC. In some embodiments, a single dose of the corticosteroid is administered one week after administration of the anti-FRA ADC. In some embodiments, more than one dose of the corticosteroid is administered one week after administration of the anti-FRA ADC.

[0229] In some embodiments, tire corticosteroid is administered at least once a week. In some embodiments, tire corticosteroid is administered at least once a day. In some embodiments, tire corticosteroid is administered two times a day. In some embodiments, the corticosteroid is administered for at least three days at the start of treatment with the anti-FRA ADC. In some embodiments, tire corticosteroid is administered one week prior to administration of tire anti-FRA ADC. In some embodiments, the corticosteroid is administered on Days 8, 9, and 10 of a 21-day cycle.

[0230] In some embodiments, the corticosteroid is dexamethasone. In some embodiments, the corticosteroid is prednisone. In some embodiments, the corticosteroid is methylprednisolone.

[0231] In some embodiments, the corticosteroid is administered orally. In some embodiments, tire corticosteroid is administered intravenously.

[0232] In some embodiments, when the corticosteroid (e.g., dexamethasone or prednisone) is administered orally, it is administered at a dose of 1 mg to 40 mg, e.g., 10 mg to 40 mg, 2 mg to 12Attorney Reference: 15648.0057-00304mg, 2 mg to 5 mg, or 0.5 mg to 2 mg. In some embodiments, when the corticosteroid is administered orally, it is administered at a dose of 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 8 mg, 10 mg, or 20 mg.

[0233] In some embodiments, tire corticosteroid is dexamethasone. In some embodiments, the dexamethasone is administered to the subject at a dose determined to be therapeutically effective, e.g., at 3 mg, 4 mg, or 8 mg. In some embodiments, the dexamethasone is administered to the subject at a dose of 1 mg to 10 mg. In some embodiments, tire dexamethasone is administered to tire subject at a dose of 8 mg. In some embodiments, the dexamethasone is administered to the subject at a dose of 4 mg. In some embodiments, the dexamethasone is administered to the subject at a dose of 3 mg.

[0234] In some embodiments, the dexamethasone is administered prophylactically. In some embodiments, the dexamethasone is administered to the subject at least once a day, e.g., two times a day. In some embodiments, the dexamethasone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) before or at the start of treatment with the combination therapy. In some embodiments, the dexamethasone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) before or at the start of treatment with the anti-FRA ADC. In some embodiments, the dexamethasone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) after the start of treatment with the combination therapy. In some embodiments, the dexamethasone is administered to the subject for several days (e.g., 1 , 2, 3, 4, 5, or more days) after the start of treatment with the anti-FRA ADC. In some embodiments, the dexamethasone is administered to the subject for at least three days at the start of treatment with the combination therapy. In some embodiments, the dexamethasone is administered to the subject for at least three days at the start of treatment with tire anti-FRA ADC. In some embodiments, the dexamethasone is administered one week before administration of the anti-FRA ADC. In some embodiments, a single dose of the dexamethasone is administered one week before administration of the anti-FRA ADC. In some embodiments, more than one dose of the dexamethasone is administered one week before administration of the anti-FRA ADC. In some embodiments, the dexamethasone is administered one week after administration of the anti-FRA ADC. In some embodiments, a single dose of the dexamethasone is administered one week after administration of the anti-FRA ADC. In some embodiments, more than one dose of the dexamethasone is administered one week after administration of the anti-FRA ADC. In some embodiments, the dexamethasone is administered on Day 8, Day 9, and Day 10 of a 21-day cycle. In some embodiments, the dexamethasone is administered orally to the subject. In some embodiments, tire dexamethasone is administered intravenously to the subject.

[0235] In some embodiments, the corticosteroid is prednisone. In some embodiments, the prednisone is administered to the subject at a dose determined to be therapeutically effective, e.g., at 20 mg. In some embodiments, the prednisone is administered to the subject at a dose of 10 mg to 40 mg. In some embodiments, the prednisone is administered to the subject at a dose of 10 mg, 15 mg, 20 mg,Attorney Reference: 15648.0057-0030425 mg, 30 mg, 35 mg, or 40 mg. In some embodiments, the prednisone is administered to the subject at a dose of 20 mg.

[0236] In some embodiments, the prednisone is administered prophylactically. In some embodiments, tire prednisone is administered at least once a day. In some embodiments, the prednisone is administered twice a day. In some embodiments, the prednisone is administered to die subject for several days (e.g., 10, 11, 12, 13, 14, or more days) before or at the start of treatment with the combination therapy. In some embodiments, the prednisone is administered to the subject for several days e.g., 10, 11, 12, 13, 14, or more days) before or at the start of treatment with the anti-FRA ADC. In some embodiments, the prednisone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) after the start of treatment with the combination therapy. In some embodiments, the prednisone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) after the start of treatment with the anti-FRA ADC. In some embodiments, the prednisone is administered to the subject for at least 14 days before the start of treatment with the combination therapy. In some embodiments, the prednisone is administered to the subject for at least 14 days before the start of treatment with the anti-FRA ADC. In some embodiments, the prednisone is administered one week after administration of the anti-FRA ADC. In some embodiments, a single dose of the prednisone is administered one week after administration of the anti-FRA ADC. In some embodiments, more than one dose of the prednisone is administered one week after administration of the anti-FRA ADC. In some embodiments, the prednisone is administered on Day 8, Day 9, and Day 10 of a 21-day cycle. In some embodiments, the prednisone is administered orally to the subject.

[0237] In some embodiments, the prednisone is administered to the subject twice a day at a dose of 20 mg per dose.

[0238] In some embodiments, when the corticosteroid is administered intravenously, it is administered to the subject at a dose of 300 mg to 1200 mg, e.g., 400 mg to 1100 mg or 500 mg to 1000 mg. In some embodiments, when the corticosteroid is administered intravenously, it is administered to the subject at a dose of 500 mg, 750 mg, or 1000 mg.

[0239] In some embodiments, the corticosteroid is methylprednisolone. In some embodiments, the methylprednisolone is administered to the subject at a dose of 30 mg to 130 mg, e.g., 40 mg to 125 mg. In some embodiments, the methylprednisolone is administered to the subject at a dose of 1 mg / kg of the subject’s body weight. In some embodiments, the methylprednisolone is administered to the subject at a dose of 2 mg / kg of the subject’s body weight. In some embodiments, the methylprednisolone is administered to the subject intravenously.

[0240] In some embodiments, the methylprednisolone is administered orally to the subject. In some embodiments, when the methylprednisolone is administered orally, it is administered to the subject at a dose of 5 mg to 100 mg, e.g., 5 mg to 90 mg, 5 mg to 80 mg, 10 mg to 80 mg, 10 mg to 70 mg, or 10 mg to 60 mg. In some embodiments, the methylprednisolone is administered orally to the subject at 0.5 mg / kg to 1.5 mg / kg of the subject’s body weight. In some embodiments, theAttorney Reference: 15648.0057-00304methylprednisolone is administered orally to the subject at 0.5 mg / kg of the subject’s body weight. In some embodiments, the methylprednisolone is administered orally to die subject at 1 mg / kg of die subject’s body weight. In some embodiments, die mediylprednisolone is administered orally to the subject at 1.5 mg / kg of the subject’s body weight.

[0241] In some embodiments, die mediylprednisolone is administered prophylactically. In some embodiments, the methylprednisolone is administered to the subject at least once a day. In some embodiments, the methylprednisolone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) before or at the start of treatment with die combination therapy. In some embodiments, the methylprednisolone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) before or at the start of treatment with die anti-FRA ADC. In some embodiments, the methylprednisolone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) after the start of treatment with the combination therapy. In some embodiments, the methylprednisolone is administered to the subject for several days (e.g., 1, 2, 3, 4, 5, or more days) after the start of treatment with the anti-FRA ADC. In some embodiments, the methylprednisolone is administered to the subject for at least three days before the start of treatment with the combination therapy. In some embodiments, the methylprednisolone is administered to the subject for at least three days before the start of treatment with the anti-FRA ADC. In some embodiments, the methylprednisolone is administered one week after administration of the anti-FRA ADC. In some embodiments, a single dose of the methylprednisolone is administered one week after administration of the anti-FRA ADC. In some embodiments, more than one dose of the methylprednisolone is administered one week after administration of the anti-FRA ADC. In some embodiments, the corticosteroid is methylprednisolone on Days 8, 9, and 10 of a 21 -day cycle.

[0242] In some embodiments, at least one corticosteroid is administered to a subject developing symptoms of ILD after receiving the combination therapies disclosed herein. In some embodiments, die at least one corticosteroid is administered immediately after a subject develops symptoms of ILD.

[0243] In some embodiments, methylprednisolone is administered immediately after a subject develops symptoms of ILD. In some embodiments, the methylprednisolone is intravenously administered at dose of 500 mg to 1000 mg. In some embodiments, the methylprednisolone is administered once a day for three days. In some embodiments, prednisone is administered following the three days of administration of methylprednisolone. In some embodiments, the prednisone is intravenously administered at a dose of 1 mg / kg to 2 mg / kg of the subject’s body weight. In some embodiments, the prednisone is intravenously administered at a dose of 1 mg / kg of the subject’s body weight. In some embodiments, the prednisone is administered once a day for at least 14 days. In some embodiments, the dose of prednisone is reduced after at least 14 days. In some embodiments, the prednisone is administered for about four to about six weeks.

[0244] In various embodiments, combination therapy treatment efficacy is evaluated for toxicity as well as indicators of efficacy, and adjusted accordingly. Efficacy measures include, but are not limitedAttorney Reference: 15648.0057-00304to, objective response rate (ORR). ORR may be measured at a given time period after treatment, e.g., at or after 24 weeks after the start of treatment. ORR may be determined based on tumor assessments according to RECIST, e.g., RECIST 1.1.

[0245] Prior to tire start of treatment, subjects may be assessed by certain clinical criteria to identify those potentially at higher risk for severe respiratory complications. If a subject is determined to be potentially at higher risk for severe respiratory complications, the subject may be excluded from treatment with the methods disclosed herein. In some embodiments, a subject who is treated according to the foregoing methods is assessed by a pulmonary function test (PFT) prior to treatment. In some embodiments, a subject who is assessed by a PFT and subsequently treated does not have one or more of the following results: a FEV 1 / FVC ratio of less than 0.7, a FEV 1 (forced expiratory volume in the first second) of less than 80%, a FVC (forced vital capacity) of less than 80%, or a DLCO (diffusing capacity of the lungs for carbon monoxide) of less than 80%. In some embodiments, a subject who is treated according to the foregoing methods does not have one or more of the following at the start of treatment: interstitial lung disease (ILD) and / or pneumonitis, a history of ILD and / or pneumonitis, a lung-specific clinically significant illness, pleural effusion, pericardial effusion, prior pneumonectomy, a history of chest radiotherapy within the past two years, autoimmune disorder with pulmonary involvement, connective tissue disorder with pulmonary involvement, or inflammatory disorder with pulmonary involvement. Exemplary lung-specific clinically significant illnesses include, but are not limited to, any underlying pulmonary disorder (e.g., pulmonary embolism), asthma, chronic obstructive pulmonary disease (COPD), restrictive lung disease, or any other lung-specific inflammatory disease or condition.

[0246] In some embodiments, a subject who is treated according to the foregoing methods does not have one or more of the following: a serum albumin level at the start of treatment of less than 3 g / dL, or a proteinuria of greater than 1 gm.Combiiiation Therapy Dosing

[0247] In various embodiments, the present disclosure provides combination therapies for treating and / or preventing cancer comprising administering a therapeutically effective amount of an anti-FRA ADC in conjunction with a therapeutically effective amount of a tyrosine kinase inhibitor.

[0248] In various embodiments, the present disclosure provides combination therapies for reducing risk of ILD in a subject being treated for cancer comprising administering a therapeutically effective amount of an anti-FRA ADC in conjunction with a therapeutically effective amount of a tyrosine kinase inhibitor.

[0249] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 15 mg / m2of the subject’s BSA: and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to die subject once a week at a dose of 14 mg / m2of the subject’s BSA;Attorney Reference: 15648.0057-00304and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor.[00250J In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 1 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of the subject’s BSA; and a ty rosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor.

[0251] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to theAttorney Reference: 15648.0057-00304subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; and a ty rosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of the subject's BSA; and a ty rosine kinase inhibitor.

[0252] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21 -day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor.

[0253] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject's BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADCAttorney Reference: 15648.0057-00304intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor.

[0254] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA: and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 , Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor.

[0255] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a ty rosine kinase inhibitor. In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, tire combination therapy comprises air anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor.Attorney Reference: 15648.0057-00304

[0256] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 15 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0257] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once a week at a dose of 14 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0258] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0259] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0260] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0261] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0262] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0263] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0264] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0265] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg.

[0266] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg.

[0267] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.Attorney Reference: 15648.0057-00304

[0268] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0269] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once every two weeks at a dose of 7.5 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0270] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0271] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0272] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0273] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0274] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0275] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0276] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0277] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg.

[0278] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg.

[0279] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg.Attorney Reference: 15648.0057-00304

[0280] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0281] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject al Day 1 of a 21-day cycle at a dose of 11 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0282] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0283] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 14 mg.

[0284] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0285] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0286] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0287] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0288] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0289] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0290] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of theAttorney Reference: 15648.0057-00304subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0291] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0292] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0293] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0294] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0295] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0296] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0297] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0298] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0299] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2ofAttorney Reference: 15648.0057-00304the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0300] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0301] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0302] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0303] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0304] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg.

[0305] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0306] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0307] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0308] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0309] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tine subject once a day at a dose of 20 mg.Attorney Reference: 15648.0057-00304

[0310] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / nr of the subject's BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0311] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once a week at a dose of 7.5 mg / nr of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0312] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject's BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0313] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0314] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0315] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0316] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0317] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0318] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 7.5 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0319] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 20 mg.

[0320] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 20 mg.

[0321] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.Attorney Reference: 15648.0057-00304

[0322] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0323] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once every three weeks at a dose of 11 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0324] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0325] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0326] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0327] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0328] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0329] In some embodiments, die combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0330] In some embodiments, die combination dierapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0331] In some embodiments, die combination dierapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0332] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 20 mg.

[0333] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.Attorney Reference: 15648.0057-00304

[0334] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0335] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0336] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0337] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0338] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 8 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0339] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0340] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0341] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0342] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0343] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2ofAttorney Reference: 15648.0057-00304the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0344] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0345] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0346] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0347] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0348] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0349] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0350] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0351] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0352] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of theAttorney Reference: 15648.0057-00304subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0353] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg.

[0354] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0355] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0356] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0357] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0358] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; and a ty rosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0359] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject's BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0360] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject's BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0361] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0362] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0363] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject's BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.Attorney Reference: 15648.0057-00304

[0364] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0365] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0366] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0367] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0368] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0369] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0370] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0371] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0372] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0373] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 11 mg.

[0374] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 11 mg.

[0375] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 11 mg.Attorney Reference: 15648.0057-00304

[0376] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0377] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject al Day 1 of a 21-day cycle at a dose of 13 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0378] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0379] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 11 mg.

[0380] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0381] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0382] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0383] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0384] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of die subject’s BSA; and a ty rosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0385] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0386] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of theAttorney Reference: 15648.0057-00304subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0387] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0388] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0389] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0390] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0391] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0392] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0393] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0394] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to die subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0395] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.Attorney Reference: 15648.0057-00304

[0396] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0397] In some embodiments, (lie combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0398] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0399] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0400] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0401] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0402] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 11 mg.

[0403] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once a week at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.

[0404] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.

[0405] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.Attorney Reference: 15648.0057-00304

[0406] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0407] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once a week at a dose of 11 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 8 mg.

[0408] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 8 mg.

[0409] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 8 mg.

[0410] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0411] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0412] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0413] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0414] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0415] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.

[0416] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.

[0417] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.Attorney Reference: 15648.0057-00304

[0418] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0419] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once every three weeks at a dose of 13 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 8 mg.

[0420] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 8 mg.

[0421] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0422] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0423] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0424] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0425] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0426] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0427] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.

[0428] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.

[0429] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 8 mg.Attorney Reference: 15648.0057-00304

[0430] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0431] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject al Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0432] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0433] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0434] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0435] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0436] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 8 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0437] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0438] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0439] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2ofAttorney Reference: 15648.0057-00304the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0440] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0441] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0442] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0443] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0444] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0445] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of tine subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0446] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of tlae subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0447] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0448] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2ofAttorney Reference: 15648.0057-00304the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0449] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0450] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0451] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 8 mg.

[0452] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 15 mg / m2of the subject’s BSA; and a ty rosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0453] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0454] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0455] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0456] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0457] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0458] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.Attorney Reference: 15648.0057-00304

[0459] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0460] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once every two weeks at a dose of 14 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 4 mg.

[0461] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 4 mg.

[0462] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0463] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0464] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0465] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0466] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0467] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0468] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 4 mg.

[0469] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 4 mg.

[0470] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.Attorney Reference: 15648.0057-00304

[0471] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0472] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to die subject once every three weeks at a dose of 7.5 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 4 mg.

[0473] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 4 mg.

[0474] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 4 mg.

[0475] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to die subject once a day at a dose of 4 mg.

[0476] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0477] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0478] In some embodiments, die combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0479] In some embodiments, die combination dierapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0480] In some embodiments, die combination dierapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of die subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0481] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0482] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of theAttorney Reference: 15648.0057-00304subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0483] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0484] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0485] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0486] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0487] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0488] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0489] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0490] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to die subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0491] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.Attorney Reference: 15648.0057-00304

[0492] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21 -day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0493] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0494] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0495] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0496] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0497] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0498] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of tire subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0499] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.

[0500] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; and a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 4 mg.Attorney Reference: 15648.0057-00304

[0501] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once a week at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid.

[0502] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every two weeks at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; a ty rosine kinase inhibitor; and a corticosteroid.

[0503] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every three weeks at aAttorney Reference: 15648.0057-00304dose of 14 mg / m2of the subject’s BSA; a ty rosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to (lie subject once every three weeks at a dose of 12 mg / m2of the subject's BSA; a ty rosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid.

[0504] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 1 -day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject at Day 1 of a 21 -day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject at Day 1 of a 21 -day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of the subject's BSA; a ty rosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid.

[0505] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADCAttorney Reference: 15648.0057-00304intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 13 mg / nf of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti -FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid.

[0506] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a ty rosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject's BSA; a tyrosine kinase inhibitor; and a corticosteroid.

[0507] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAAttorney Reference: 15648.0057-00304ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, tire combination therapy comprises an anti-FRAADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, lire combination therapy comprises an anti-FRAADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid. In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor; and a corticosteroid.

[0508] In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject once a week at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0509] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0510] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0511] In some embodiments, tire combination therapy comprises an anti-FRAADC intravenously administered to the subject once a week at a dose of 12 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0512] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once a week at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0513] In some embodiments, the combination therapy comprises an anti-FRAADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0514] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject's BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0515] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to die subject twice per day at a dose of 3 mg.

[0516] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0517] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0518] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0519] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0520] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 8 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0521] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to tire subject twice per day at a dose of 3 mg.

[0522] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0523] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0524] In some embodiments, (lie combmation therapy comprises an anti-FRA ADC intravenously administered to tire subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to tire subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0525] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0526] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0527] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0528] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0529] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0530] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to tire subject twice per day at a dose of 3 mg.

[0531] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0532] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0533] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to die subject twice per day at a dose of 3 mg.

[0534] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0535] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0536] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0537] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0538] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0539] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0540] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0541] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21 -day cycle at a dose of 8 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0542] In some embodiments, (lie combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0543] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0544] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0545] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0546] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0547] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 11 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0548] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0549] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0550] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 15 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0551] In some embodiments, (lie combmation therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0552] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0553] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0554] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0555] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0556] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 28-day cycle at a dose of 7.5 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 14 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0557] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once a week at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0558] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0559] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 13 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0560] In some embodiments, (lie combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once a week at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0561] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0562] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0563] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once a week at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0564] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0565] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0566] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every two weeks at a dose of 13 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to tire subject twice per day at a dose of 3 mg.

[0567] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0568] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0569] In some embodiments, (lie combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every two weeks at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to die subject twice per day at a dose of 3 mg.

[0570] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every two weeks at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0571] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0572] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0573] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0574] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 12 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0575] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject once every three weeks at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to tire subject twice per day at a dose of 3 mg.

[0576] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 8 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0577] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject once every three weeks at a dose of 7.5 mg / nr of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0578] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to die subject twice per day at a dose of 3 mg.

[0579] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0580] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0581] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0582] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0583] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 of a 21-day cycle at a dose of 8 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0584] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 of a 21-day cycle at a dose of 7.5 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to tire subject twice per day at a dose of 3 mg.

[0585] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 15 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.Attorney Reference: 15648.0057-00304

[0586] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0587] In some embodiments, (lie combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1 and Day 8 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0588] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 12 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0589] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 11 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0590] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 8 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0591] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1 and Day 8 of a 21-day cycle at a dose of 7.5 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject tw ice per day at a dose of 3 mg.

[0592] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 15 mg / m2of tire subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0593] In some embodiments, tire combination therapy comprises an anti-FRA ADC intravenously administered to tire subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 14 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally administered to the subject twice per day at a dose of 3 mg.

[0594] In some embodiments, the combination therapy comprises an anti-FRA ADC intravenously administered to the subject at Day 1, Day 8, and Day 15 of a 21-day cycle at a dose of 13 mg / m2of the subject’s BSA; a tyrosine kinase inhibitor orally administered to the subject once a day at a dose of 20 mg; and a corticosteroid orally...

Claims

Attorney Reference: 15648.0057-00304CLAIMS1. A method of treating a folate receptor alpha (FRA)-expressing cancer, comprising administering to a subject in need thereof:(a) a composition comprising an antibody-drug conjugate, wherein the antibody-drug conjugate is MORAb-202; and(b) a composition comprising a tyrosine kinase inhibitor.

2. A method of reducing risk of interstitial lung disease (ILD) in a subject being treated for a folate receptor alpha (FRA)-expressing cancer, comprising administering to the subject:(a) a composition comprising an antibody-drug conjugate, wherein the antibody-drug conjugate is MORAb-202; and(b) a composition comprising a tyrosine kinase inhibitor.

3. The method of claim 1 or claim 2, wherein the antibody-drug conjugate is administered to the subject at a dose of 0.5 mg / kg to 1.5 mg / kg of the subject’s body weight, optionally wherein the antibody-drug conjugate is administered to the subject at a dose of 0.68 mg / kg, 0.9 mg / kg, or 1.2 mg / kg of the subject’s body weight.

4. The method of claim 1 or claim 2, wherein the antibody-drug conjugate is administered to the subject at a dose of 8 mg to 50 mg of the antibody-drug conjugate per square meter (m2) of the subject’s body surface area (BSA), optionally wherein the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2to 44 mg / m2of the subject’s BSA, further optionally wherein the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2to 20 mg / m2of the subject’s BSA.

5. The method of any one of claims 1, 2, and 4, wherein the antibody-drug conjugate is administered to the subject at a dose of 15 mg / m2, 14 mg / m2, 13 mg / m2, 12 mg / m2, 11 mg / m2, 8 mg / m2, or 7.5 mg / m2of the subject’s BSA.

6. The method of any one of claims 1 to 5, wherein the antibody-drug conjugate is administered to the subject:(a) once every three weeks:(b) once every two weeks;(c) once per week;(d) at Day 1 of a 21-day cycle;(e) at Day 1 and Day 8 of a 21-day cycle;(f) at Day 1, Day 8, and Day 15 of a 21-day cycle;Attorney Reference: 15648.0057-00304(g) at Day 1, 5, and 9 of a 21 -day cycle; or(h) at Day 1, Day 8, and Day 15 of a 28-day cycle.

7. The method of any one of claims 4 to 6, wherein the antibody-drug conjugate is administered to the subject al a dose of:(a) 12 mg / m2of the subject’s BSA at Day 1 and Day 8 of a 21-day cycle;(b) 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle;(c) 14 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle; or (d) 11 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle.

8. The method of any one of claims 1 to 7, wherein the antibody-drug conjugate is administered intravenously to the subject.

9. The method of any one of claims 1 to 8, wherein:(a) the antibody-drug conjugate and the tyrosine kinase inhibitor are in the same composition; or(b) the antibody-drug conjugate and the tyrosine kinase inhibitor are administered concurrently or sequentially, optionally wherein the tyrosine kinase inhibitor is administered before or after the antibody-drug conjugate is administered.

10. The method of any one of claims 1 to 9, wherein the tyrosine kinase inhibitor is lenvatinib or a pharmaceutically acceptable salt thereof, optionally wherein the pharmaceutically acceptable salt of lenvatinib is lenvatinib mesylate.

11. The method of any one of claims 1 to 10, wherein the tyrosine kinase inhibitor is administered to the subject at a dose of 4 mg to 25 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof, optionally wherein tire tyrosine kinase inhibitor is administered to tire subject at a dose of 20 mg, 14 mg, 12 mg, 8 mg, or 4 mg of a free base of the tyrosine kinase inhibitor or an equivalent amount of a salt thereof.

12. The method of any one of claims 1 to 11, wherein the tyrosine kinase inhibitor is administered to the subject once daily, optionally wherein the tyrosine kinase inhibitor is administered orally to tire subject.

13. The method of claim any one of claims 10 to 12, wherein:Attorney Reference: 15648.0057-00304(a) the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSAat Day 1, Day 8, and Day 15 of a 21-day cycle and tire lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib mesylate;(b) the antibody-drug conjugate is administered to the subject at a dose of 11 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle and (lie lenvatinib is administered to (lie subject once daily at a dose of 14 mg of lenvatinib mesylate; or(c) the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle and the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib mesylate.

14. The method of any one of claims 1 to 13, wherein the doses of the antibody-drug conjugate and the tyrosine kinase inhibitor are selected to reduce 1LD in the subject.

15. The method of any one of claims 1 to 14, wherein the subject has a body weight value that is in the upper quartile for weight.

16. The method of any one of claims 1 to 15, further comprising administering a corticosteroid to the subject.

17. The method of claim 16, wherein the corticosteroid is administered prophylactically to the subject, optionally wherein the corticosteroid is administered to the subject concurrently or sequentially with the antibody-drug conjugate, further optionally wherein the corticosteroid is administered to the subject before or after the antibody-drug conjugate is administered.

18. The method of claim 16 or claim 17, wherein the corticosteroid is dexamethasone, prednisone, or methylprednisolone, optionally wherein tire corticosteroid is administered to the subject at least once a week.

19. The method of claim 18, wherein the dexamethasone is administered to tire subject at a dose of 2 mg to 12 mg, optionally wherein the dexamethasone is administered to the subject at a dose of 8 mg, 4 mg, or 3 mg, further optionally wherein the dexamethasone is administered orally to the subject.

20. The method of any one of claims 16 to 19, wherein the corticosteroid is administered to the subject at least once a day, optionally wherein the corticosteroid is administered to the subject two times a day, further optionally wherein the corticosteroid is administered to the subject for at least three days at the start of treatment with the antibody-drug conjugate.Attorney Reference: 15648.0057-0030421. The method of any one of claims 16 to 20, wherein the corticosteroid is administered to the subject one week prior to administration of the antibody-drug conjugate or one week after administration of the antibody-drug conjugate, optionally wherein the corticosteroid is administered to tire subject for al least three days, further optionally wherein the corticosteroid is administered to tire subject on Day 8, Day 9, and Day 10 of a 21-day cycle.

22. The method of any one of claims 16 to 21, wherein the corticosteroid is administered intravenously to the subject.

23. The method of claim 18, wherein:(a) the antibody-drug conjugate is administered to the subject at a dose of 25 mg / m2of the subject’s BSA at Day 1 of a 21-day cycle and the dexamethasone is administered to the subject two times a day at a dose of 3 mg on Day 8, Day 9, and Day 10 of a 21-day cycle;(b) the antibody-drug conjugate is administered to the subject at a dose of 25 mg / m2of the subject’s BSA at Day 1 of a 21-day cycle and the prednisone is administered to the subject two times a day at a dose of 20 mg on Day 8, Day 9, and Day 10 of a 21-day cycle;(c) the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle; or(d) the antibody-drug conjugate is administered to the subject at a dose of 8 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle, and the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle.

24. The method of claim 18, wherein:(a) the antibody-drug conjugate is administered to the subject at a dose of 14 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle,(b) the lenvatinib is administered to tire subject once daily at a dose of 14 mg of lenvatinib or an equivalent amount of lenvatinib mesylate, and(c) tire dexamethasone is administered to tire subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle.

25. The method of claim 18, wherein:(a) the antibody-drug conjugate is administered to the subject at a dose of 11 mg / m2of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle,(b) the lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib or an equivalent amount of lenvatinib mesylate, andAttorney Reference: 15648.0057-00304(c) the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21 -day cycle.

26. The method of claim 18, wherein:(a) the antibody-drug conjugate is administered to tire subject at a dose of 8 mg / nr of the subject’s BSA at Day 1, Day 8, and Day 15 of a 21-day cycle,(b) tire lenvatinib is administered to the subject once daily at a dose of 14 mg of lenvatinib or an equivalent amount of lenvatinib mesylate, and(c) the dexamethasone is administered to the subject at a dose of 8 mg on Day 1, Day 8, and Day 15 of a 21-day cycle.

27. The method of any one of claims 1 to 26, wherein the FRA-expressing cancer is breast cancer, cervical cancer, colorectal cancer, esophageal cancer, fallopian tube cancer, gastric cancer, kidney cancer, lung cancer, non-small cell lung cancer (NSCLC), lung carcinoid, osteosarcoma, ovarian cancer, clear cell ovarian cancer, pancreatic cancer, peritoneal cancer, primary peritoneal cancer, renal cell cancer, uterine cancer, or serous uterine cancer.

28. The method of claim 27, wherein the FRA-expressing cancer is:(a) uterine cancer, optionally endometrial cancer (EC);(b) primary peritoneal cancer, optionally platinum-resistant primary peritoneal cancer;(c) fallopian tube cancer, optionally platinum-resistant fallopian tube cancer;(d) ovarian cancer, optionally platinum-resistant ovarian cancer (PROC), further optionally wherein die PROC is a serous ovarian cancer, further optionally wherein the serous ovarian cancer is a high-grade serious ovarian cancer;(e) not platinum-refractory ovarian cancer;(e) breast cancer, optionally triple negative breast cancer (TNBC) or hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (IIER2)-low breast cancer; or(f) lung cancer, optionally non-small cell lung cancer (NSCLC).

29. The method of any one of claims 1 to 28, wherein the FRA-expressing cancer is a metastatic cancer, optionally wherein the metastatic cancer has no genomic alteration or the metastatic cancer has at least one known genomic alteration in at least one of any of the following genes: EGFR, ALK, PI3K, AKT, mTOR, RET, MET, BRAE NTRK, ROS1, and any gene involved in the RAS-MAPK pathway, further optionally wherein the metastatic cancer is non-small cell lung cancer.

30. The method of any one of claims 1 to 29, wherein the FRA-expressing cancer is a refractory cancer, optionally wherein the refractory cancer is non-responsive to a targeted treatment, furtherAttorney Reference: 15648.0057-00304optionally wherein the targeted treatment is a targeted treatment against any one of the following genes or variants thereof: EGFR, ALK, BRAF, RET, MET, NTRK, and ROSE31. The method of claim 30, wherein the refractory cancer is non-responsive to a platinum-based treatment and / or an immunotherapy-based treatment, wherein if both are used, the treatments are administered concurrently or sequentially, optionally wherein the platinum-based treatment is a platinum-doublet chemotherapy and the immunotherapy -based treatment is a checkpoint inhibitor therapy, a CAR T-cell therapy, a cancer vaccine, an immune-targeting monoclonal antibody, a cytokine, or an immune system modulator.

32. The method of any one of claims 1 to 31, wherein:(a) the subject was not administered a prior therapy for the FRA-expressing cancer;(b) the subject was administered one prior therapy for the FRA-expressing cancer; or (c) the subject was administered two or more prior therapies for the FRA-expressing cancer, optionally wherein the subject was administered two or three prior therapies for the FRA-expressing cancer, further optionally wherein the subject was administered no more than one additional prior therapy after developing resistance to a prior platinum-based therapy.

33. The method of claim 32, wherein the number of prior therapies does not include a primary therapy to which tire subject exhibited refractory disease.

34. The method of any one of claims 1 to 33, wherein the FRA-expressing cancer has an FRA expression level of less than 5%, at least 5%, 5% to 24%, 24% to 74%, or at least 75%, optionally wherein die FRA expression level is determined by immunohistochemistry.

35. The method of any one of claims 1 to 34, wherein:(a) the subject, at the start of treatment, does not have one or more of: interstitial lung disease (ILD) and / or pneumonitis, a history of ILD and / or pneumonitis, a lung-specific clinically significant illness, pleural effusion, pericardial effusion, prior pneumonectomy, a history of chest radiotherapy within die past two years, autoimmune disorder with pulmonary involvement, connective tissue disorder witii pulmonary involvement, and inflammatory disorder with pulmonary involvement; and / or(b) the subject does not have a serum albumin level at the start of treatment of less than 3 g / dL and / or a proteinuria of greater than 1 gm.

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