Methods of treating ceacam5-expressing cancers

Abstract

Provided are compositions and methods to treat cancers that express carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).

Description

METHODS OF TREATING CEACAM5-EXPRESSING CANCERS FIELD

[0001] The present disclosure relates to cancer treatments in which the cancers expresscarcinoembryonic antigen-related cell adhesion molecules 5 (CEACAM5). Other aspects of thedisclosure relate to using CEACAM5 as a biomarker for treating cancer.BACKGROUND

[0002] Despite recent advances in the cancer treatment, cancer continues to be a healthchallenge. Current therapeutic approaches such as systemic cytotoxic agents offer limitedtreatment options and entail serious hematological and other toxicities.SUMMARY

[0003] The disclosure provides, at least in part, compositions and methods of usingcarcinoembryonic antigen 5 (CEACAM5) to identify subjects with cancers that express CEACAM5 and determine that such CEACAM5 expressing cancers may be responsive or have a propensity to respond to selected treatments such as microtubule-targeting agents. The disclosure is based, at least in part, on the observation that there is a positive correlation between high CEACAM5 expression and anti-tumor response to a microtubule-targeting agent.

[0004] In one aspect, the disclosure provides a method of treating cancer in a subject, the methodcomprising, selecting the subject for treatment if the subject is bearing a tumor that expresses highly positively CEACAM5; and administering to the subject an effective amount of a microtubule-targeting agent, thereby treating cancer in the subject.

[0005] In certain exemplary embodiments, the microtubule targeting agent is not tusamitamabravtansine.

[0006] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0007] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0008] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0009] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0010] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0011] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0012] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0013] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0014] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0015] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0016] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0017] In certain exemplary embodiments, the tumor expresses highly positively CEACAM5 if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0018] In certain exemplary embodiments, the tumor expresses highly positively CEACAM5 if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0019] In certain exemplary embodiments, the tumor expresses highly positively CEACAM5 if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0020] In certain exemplary embodiments, the method of treating cancer comprises selecting thesubject if the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to50% of the tumor cells, the CEACAM5 expression being measured by immunohistochemistry.

[0021] In certain exemplary embodiments, the method of treating cancer comprises selecting thesubject if the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to60% of the tumor cells, the CEACAM5 expression being measured by immunohistochemistry.

[0022] In certain exemplary embodiments, the method of treating cancer comprises selecting thesubject if the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to70% of the tumor cells, the CEACAM5 expression being measured by immunohistochemistry.

[0023] In certain exemplary embodiments, the method of treating cancer comprises selecting thesubject if the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to80% of the tumor cells, the CEACAM5 expression being measured by immunohistochemistry.

[0024] In certain exemplary embodiments, the method of treating cancer comprises selecting thesubject if the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to90% of the tumor cells, the CEACAM5 expression being measured by immunohistochemistry.

[0025] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0026] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, nab-paclitaxel, and paclitaxel.

[0027] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0028] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0029] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0030] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0031] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0032] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0033] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0034] In certain exemplary embodiments, the subject is at least about 18 years old.

[0035] In certain exemplary embodiments, the subject is selected for treatment if the subject isbearing a tumor that expresses CEACAM5 in at least about 50%, 60%, 70% or 80% of its tumor cells.

[0036] In certain exemplary embodiments, the subject is selected for treatment if the subject isbearing a tumor that expresses CEACAM5 in at least about 90% of its tumor cells.

[0037] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0038] In certain embodiments, the microtubule targeting agent is an antibody-drug conjugate(ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0039] In certain exemplary embodiments, the payload is a maytansinoid.

[0040] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0041] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0042] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0043] In certain exemplary embodiments, the microtubule targeting agent is tusamitamabravtansine.

[0044] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits improved Quality of Life, the Quality of Life beingoptionally assessed according to the quality of life (HRQOL) questionnaire.

[0045] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits improved survival.

[0046] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits reduced adverse events (AEs), the AEs being optionally Grade ≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

[0047] In certain exemplary embodiments, the subject exhibits improved Quality of Life withrespect to a patient who has been administered docetaxel, the Quality of Life being optionallyassessed according to the quality of life (HRQOL) questionnaire.

[0048] In certain exemplary embodiments, the subject exhibits improved survival with respect toa patient who has been administered docetaxel.

[0049] In certain exemplary embodiments, the subject exhibits reduced adverse events (AEs)with respect to a patient who has been administered docetaxel, the AEs being optionally Grade≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

[0050] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0051] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0052] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0053] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0054] In another aspect, the disclosure provides a microtubule-targeting agent for use fortreating cancer in a subject in need thereof, wherein the subject is selected for treatment if saidsubject is bearing a tumor that expresses highly positively CEACAM5.

[0055] In another aspect, the disclosure provides the use of an effective amount of a microtubule-targeting agent for the manufacture of a medicament for treating cancer in a subject in needthereof, wherein said medicament is to be administered to the subject if said subject is bearing atumor that expresses highly positively CEACAM5.

[0056] In another aspect, the disclosure provides a method of treating cancer in a subject, themethod comprising, selecting the subject for treatment if the subject is bearing a tumor thatexpresses CEACAM5 in at least about 50% of its tumor cells; and administering to the subject aneffective amount of a microtubule-targeting agent, thereby treating cancer in the subject.

[0057] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0058] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, nab-paclitaxel, and paclitaxel.

[0059] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0060] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0061] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0062] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0063] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0064] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0065] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0066] In certain exemplary embodiments, the subject is at least about 18 years old.

[0067] In certain exemplary embodiments, the subject is selected for treatment if the subject isbearing a tumor that expresses CEACAM5 in at least about 50%, 60%, 70% or 80% of its tumor cells.

[0068] In certain exemplary embodiments, the subject is selected for treatment if the subject isbearing a tumor that expresses CEACAM5 in at least about 90% of its tumor cells.

[0069] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0070] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0071] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0072] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0073] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0074] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0075] In certain exemplary embodiments, the payload is a maytansinoid.

[0076] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0077] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0078] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0079] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0080] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits improved Quality of Life, the Quality of Life beingoptionally assessed according to the quality of life (HRQOL) questionnaire.

[0081] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits improved survival.

[0082] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits reduced adverse events (AEs), the AEs being optionally Grade ≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

[0083] In certain exemplary embodiments, the subject exhibits improved Quality of Life withrespect to a patient who has been administered docetaxel, the Quality of Life being optionallyassessed according to the quality of life (HRQOL) questionnaire.

[0084] In certain exemplary embodiments, the subject exhibits improved survival with respect toa patient who has been administered docetaxel.

[0085] In certain exemplary embodiments, the subject exhibits reduced adverse events (AEs)with respect to a patient who has been administered docetaxel, the AEs being optionally Grade≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

[0086] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0087] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0088] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0089] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0090] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0091] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0092] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0093] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0094] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0095] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0096] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0097] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0098] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0099] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0100] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0101] In another aspect, the disclosure provides a microtubule-targeting agent for use fortreating cancer in a subject in need thereof, wherein the subject is selected for treatment if saidsubject is bearing a tumor that expresses CEACAM5 at an intensity of at least 2+ in greater thanor equal to 50% of its tumor cells.

[0102] In another aspect, the disclosure provides the use of an effective amount of a microtubule-targeting agent for the manufacture of a medicament for treating cancer in a subject in needthereof, wherein said medicament is to be administered to the subject if said subject is bearing atumor that expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 50% ofits tumor cells.

[0103] In another aspect, the disclosure provides a method of treating cancer in a subject, themethod comprising, selecting the subject for treatment if the subject is bearing a tumor thatexpresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 80% of the tumorcells, the CEACAM5 expression being measured by immunohistochemistry; and administering to the subject an effective amount of a microtubule-targeting agent, thereby treating cancer in the subject.

[0104] In certain exemplary embodiments, the method comprises selecting the subject if thetumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 90% of the tumor cells.

[0105] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0106] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, nab-paclitaxel, and paclitaxel.

[0107] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0108] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0109] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0110] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0111] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0112] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0113] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0114] In certain exemplary embodiments, the subject is at least about 18 years old.

[0115] In certain exemplary embodiments, the subject is selected for treatment if the subject isbearing a tumor that expresses CEACAM5 in at least about 90% of its tumor cells.

[0116] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the intensity measured by immunohistochemistry.

[0117] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0118] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0119] In certain exemplary embodiments, the payload is a maytansinoid.

[0120] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0121] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0122] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0123] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0124] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits improved Quality of Life, the Quality of Life beingoptionally assessed according to the quality of life (HRQOL) questionnaire.

[0125] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits improved survival.

[0126] In certain exemplary embodiments, after administration of an effective amount of amicrotubule-targeting agent, the subject exhibits reduced adverse events (AEs), the AEs being optionally Grade ≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

[0127] In certain exemplary embodiments, the subject exhibits improved Quality of Life withrespect to a patient who has been administered docetaxel, the Quality of Life being optionallyassessed according to the quality of life (HRQOL) questionnaire.

[0128] In certain exemplary embodiments, the subject exhibits improved survival with respect toa patient who has been administered docetaxel.

[0129] In certain exemplary embodiments, the subject exhibits reduced adverse events (AEs)with respect to a patient who has been administered docetaxel, the AEs being optionally Grade≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

[0130] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0131] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0132] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0133] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0134] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0135] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0136] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0137] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0138] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0139] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0140] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0141] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0142] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0143] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0144] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0145] In another aspect, the disclosure provides a microtubule-targeting agent for use fortreating cancer in a subject in need thereof, wherein the subject is selected for treatment if saidsubject is bearing a tumor that expresses CEACAM5 at an intensity of at least 2+ in greater thanor equal to 80% of its tumor cells.

[0146] In another aspect, the disclosure provides the use of an effective amount of a microtubule-targeting agent for the manufacture of a medicament for treating cancer in a subject in needthereof, wherein said medicament is to be administered to the subject if said subject is bearing atumor that expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 80% ofits tumor cells.

[0147] In another aspect, the disclosure provides the use of CEACAM5 as a biomarker forpredicting a response of a subject having a cancer to a treatment with an effective amount of a microtubule-targeting agent, wherein said use comprises measuring an expression of CEACAM5in a biological sample from said subject and wherein a highly positive expression of CEACAM5 insaid biological sample is predictive of a cancer responsive to said treatment.

[0148] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0149] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0150] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0151] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0152] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0153] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0154] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0155] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptortyrosine kinase (ROS1) inhibitor, or a combination thereof.

[0156] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0157] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0158] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0159] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0160] In certain exemplary embodiments, the subject is at least about 18 years old.

[0161] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0162] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0163] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0164] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0165] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0166] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0167] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0168] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0169] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0170] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0171] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0172] In certain exemplary embodiments, the payload is a maytansinoid.In certain exemplary embodiments, the maytansinoid is selected from the group consisting ofAnsamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0173] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0174] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0175] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0176] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0177] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0178] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0179] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0180] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0181] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0182] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0183] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0184] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0185] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0186] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0187] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0188] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0189] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0190] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0191] In another aspect, the disclosure provides the use of CEACAM5 for predicting a responseof a subject having a cancer to a treatment with an effective amount of a microtubule-targeting agent, wherein said use comprises measuring an expression of CEACAM5 in isolated tumor cells from said subject and wherein an expression measured in at least about 50% of said isolated tumor cells is predictive of a cancer responsive to said treatment.

[0192] In yet another aspect is provided use of CEACAM5 as a biomarker for selecting a subjectfor a cancer treatment, said treatment being an effective amount of a microtubule-targeting agent,wherein said use comprises measuring an expression of CEACAM5 in a biological sample fromsaid subject and selecting said subject for said treatment if the expression of CEACAM5 is highlypositive in said biological sample.

[0193] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0194] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0195] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0196] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0197] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0198] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0199] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0200] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0201] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0202] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0203] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0204] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certainexemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0205] In certain exemplary embodiments, the subject is at least about 18 years old.

[0206] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0207] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0208] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0209] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0210] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0211] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0212] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0213] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0214] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0215] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0216] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0217] In certain exemplary embodiments, the payload is a maytansinoid.

[0218] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0219] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0220] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0221] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0222] In other embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0223] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0224] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0225] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0226] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0227] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0228] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0229] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0230] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0231] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0232] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0233] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0234] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0235] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0236] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0237] In yet another aspect is provided use of CEACAM5 for selecting a subject for a cancertreatment, said treatment being an effective amount of a microtubule-targeting agent, wherein said use comprises measuring an expression of CEACAM5 in isolated tumor cells from said subject and selecting said subject for said treatment if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[0238] In still another aspect, the disclosure provides use of a kit for in vitro prognosing and / or invitro predicting a response of a subject having a cancer to a treatment of cancer comprising amicrotubule-targeting agent, wherein the kit comprises:

[0239] (a) means for measuring, in isolated tumor cells obtained from said subject, an expressionof CEACAM5,

[0240] (b) means for comparing the expression measured in (a) with a reference value,

[0241] wherein said reference value is an expression of CEACAM5 in at least about 50% of tumorcells, and

[0242] wherein an expression measured in(a) above the reference value is indicative that saidsubject will respond to said treatment.

[0243] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0244] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0245] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0246] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0247] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor, or any combination thereof.

[0248] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0249] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0250] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0251] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0252] In certain exemplary embodiments, the subject is at least about 18 years old.

[0253] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0254] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0255] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0256] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0257] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0258] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0259] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0260] In certain exemplary embodiments, the payload is a maytansinoid.

[0261] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0262] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0263] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0264] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0265] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0266] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0267] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0268] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0269] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0270] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0271] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0272] In certain exemplary embodiments,microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0273] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0274] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0275] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0276] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0277] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0278] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0279] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0280] In still another aspect, the disclosure provides a microtubule-targeting agent for use intreating a cancer in a subject in need thereof, said use comprising measuring an expression ofCEACAM5 in a biological sample from said subject and administering said microtubule-targetingagent to said subject if the expression of CEACAM5 is highly positive in said biological sample.

[0281] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0282] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0283] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0284] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0285] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0286] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0287] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0288] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0289] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0290] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or a combination thereof.

[0291] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0292] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplaryembodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certainexemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0293] In certain exemplary embodiments, the subject is at least about 18 years old.

[0294] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0295] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0296] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0297] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0298] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0299] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0300] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0301] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0302] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0303] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0304] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0305] In certain exemplary embodiments, the payload is a maytansinoid.

[0306] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0307] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0308] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0309] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0310] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0311] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0312] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0313] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0314] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0315] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0316] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0317] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0318] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0319] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0320] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0321] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2to about 200 mg / m2.

[0322] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0323] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0324] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0325] In still another aspect, the disclosure provides a microtubule-targeting agent for use intreating a cancer in a subject in need thereof, said use comprising measuring an expression of CEACAM5 in isolated tumor cells from said subject and administering said microtubule-targeting agent to said subject if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[0326] In yet another aspect, there is provided a method for screening a candidate agent fortreating cancer, the method comprising at least the steps of: a) measuring a cell viability of cells before contacting said cells with said candidate agent,said cells expressing highly positively CEACAM5b) measuring a cell viability of the cells after contacting said cells with said candidateagent, said cells expressing highly positively CEACAM5, c) comparing the cell viabilities measured at step a) and b), wherein a decrease of cellviability measured at step b) compared to the cell viability measured step a) is indicative of a candidate agent active for treating cancer with a microtubule-targeting agent.

[0327] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0328] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0329] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0330] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0331] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0332] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0333] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0334] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptortyrosine kinase (ROS1) inhibitor, or any combination thereof.

[0335] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0336] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor, or a combination thereof.

[0337] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0338] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or non-squamous-cell carcinoma.

[0339] In certain exemplary embodiments, the subject is at least about 18 years old.

[0340] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0341] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0342] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0343] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0344] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0345] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0346] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0347] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0348] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0349] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0350] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0351] In certain exemplary embodiments, the payload is a maytansinoid.

[0352] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0353] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0354] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0355] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0356] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0357] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0358] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0359] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0360] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0361] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0362] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0363] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0364] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0365] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0366] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0367] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0368] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0369] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0370] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0371] In yet another aspect, there is provided a method for screening a candidate agent fortreating cancer, the method comprising at least the steps of: a) measuring a cell viability of cells before contacting said cells with said candidate agent,said cells express CEACAM5 in at least about 50% of isolated tumor cells,b) measuring a cell viability of the cells after contacting said cells with said candidateagent, said cells expressing CEACAM5 in at least about 50% of isolated tumor cells c) wherein a decrease of cell viability measured at step b) compared to the cell viabilitymeasured step a) is indicative of a candidate agent active for treating cancer with a microtubule- targeting agent.

[0372] In yet another aspect there is provided a method for predicting a response of a subjecthaving a cancer to a treatment with an effective amount of a microtubule-targeting agent, said method comprising at least a step of measuring an expression of CEACAM5 in biological samplefrom said subject, wherein a highly positive expression of CEACAM5 in said biological sample ispredictive of a cancer responsive to said treatment.

[0373] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0374] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0375] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0376] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0377] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0378] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0379] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0380] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptortyrosine kinase (ROS1) inhibitor, or any combination thereof.

[0381] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0382] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor, or a combination thereof.

[0383] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0384] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or non-squamous-cell carcinoma.

[0385] In certain exemplary embodiments, the subject is at least about 18 years old.

[0386] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0387] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0388] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0389] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0390] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0391] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0392] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0393] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0394] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0395] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0396] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0397] In certain exemplary embodiments, the payload is a maytansinoid.

[0398] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0399] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0400] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0401] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0402] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0403] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0404] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0405] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0406] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0407] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0408] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0409] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0410] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0411] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0412] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0413] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0414] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0415] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0416] In certain exemplary embodiments, the microtubule targeting agent is not tusamitamabravtansine.

[0417] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0418] In yet another aspect there is provided a method for predicting a response of a subjecthaving a cancer to a treatment with an effective amount of a microtubule-targeting agent, said method comprising at least a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject, wherein an expression measured in at least about 50% of said isolated tumor cells is predictive of a cancer responsive to said treatment.

[0419] In still another aspect, there is provided a method for diagnosing and treating a subjecthaving a cancer with an effective amount of a microtubule-targeting agent, the method comprisingat least a step of measuring an expression of CEACAM5 in a biological sample from said subject,and a step of administering said microtubule-targeting agent if the expression of CEACAM5 ishighly positive in said biological sample.

[0420] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0421] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0422] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0423] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, a gatorbulin.

[0424] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0425] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0426] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0427] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0428] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0429] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0430] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0431] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0432] In certain exemplary embodiments, the subject is at least about 18 years old.

[0433] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0434] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0435] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0436] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0437] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0438] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0439] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0440] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the intensity measured by immunohistochemistry.

[0441] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0442] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0443] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0444] In certain exemplary embodiments, the payload is a maytansinoid.

[0445] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0446] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0447] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0448] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0449] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0450] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0451] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0452] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0453] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0454] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0455] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0456] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0457] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0458] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0459] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0460] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0461] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0462] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0463] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0464] In still another aspect, there is provided a method for diagnosing and treating a subjecthaving a cancer with an effective amount of a microtubule-targeting agent, the method comprising at least a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject,and a step of administering said microtubule-targeting agent if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[0465] In another aspect is provide a method for selecting a treatment of cancer for a subjecthaving a cancer, said method comprising at least a step of measuring an expression of CEACAM5 in a biological sample from said subject, and a step of selecting a treatment of cancer comprising a microtubule-targeting agent if theexpression of CEACAM5 is highly positive in said biological sample.

[0466] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0467] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0468] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0469] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0470] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0471] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0472] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0473] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor, or any combination thereof.

[0474] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0475] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor, or a combination thereof.

[0476] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer,endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0477] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0478] In certain exemplary embodiments, the subject is at least about 18 years old.

[0479] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0480] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0481] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0482] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0483] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0484] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0485] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0486] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0487] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0488] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0489] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0490] In certain exemplary embodiments, the payload is a maytansinoid.

[0491] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0492] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0493] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0494] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0495] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0496] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0497] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0498] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0499] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0500] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0501] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0502] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0503] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0504] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0505] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0506] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0507] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0508] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0509] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0510] In another aspect is provide a method for selecting a treatment of cancer for a subjecthaving a cancer, said method comprising at least a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject, and a step of selecting a treatment of cancer comprising a microtubule-targeting agent if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[0511] In another aspect, there is provided a method for classifying a subject diagnosed withcancer into a patient cohort, said method comprising at least: astep of measuring an expression of CEACAM5 in a biological sample from said subject,and a step of classifying said subject into a patient cohort characterized as responding tomicrotubule-targeting agent if the expression of CEACAM5 is highly positive in said biologicalsample.

[0512] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0513] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0514] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0515] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0516] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0517] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0518] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0519] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0520] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0521] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0522] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0523] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0524] In certain exemplary embodiments, the subject is at least about 18 years old.

[0525] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0526] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0527] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0528] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0529] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ in greater than or equal to 50% of the tumor cells,the expression being measured by immunohistochemistry.

[0530] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0531] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0532] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0533] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0534] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0535] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0536] In certain exemplary embodiments, the payload is a maytansinoid.

[0537] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0538] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0539] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0540] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0541] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0542] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0543] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0544] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0545] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0546] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0547] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0548] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0549] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0550] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0551] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0552] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0553] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0554] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0555] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0556] In another aspect, there is provided a method for classifying a subject diagnosed withcancer into a patient cohort, said method comprising at least: a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject, anda step of classifying said subject into a patient cohort characterized as responding to microtubule-targeting agent if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[0557] In another aspect is provided a microtubule-targeting agent for use in a treatment of acancer in a subject having a cancer, said use comprising, prior to said treatment, identifying said subject as a responder to said a treatment of cancer comprising a microtubule-targeting agent bymeasuring an expression of CEACAM5 in a biological sample from said subject, wherein a highlypositive expression of CEACAM5 is indicative that said subject is a responder to said treatment.

[0558] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0559] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0560] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0561] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0562] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0563] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0564] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0565] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor or combination thereof.

[0566] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0567] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor or combination thereof.

[0568] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer,endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0569] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0570] In certain exemplary embodiments, the subject is at least about 18 years old.

[0571] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0572] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0573] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0574] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0575] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0576] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0577] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0578] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumor cells, the intensity measured by immunohistochemistry.

[0579] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0580] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0581] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0582] In certain exemplary embodiments, the payload is a maytansinoid.

[0583] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0584] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0585] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0586] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0587] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0588] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0589] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0590] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0591] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0592] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0593] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0594] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0595] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0596] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0597] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0598] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0599] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0600] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0601] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0602] In another aspect is provided a microtubule-targeting agent for use in a treatment of acancer in a subject having a cancer, said use comprising, prior to said treatment, identifying said subject as a responder to said a treatment of cancer comprising a microtubule-targeting agent by measuring an expression of CEACAM5 in isolated tumor cells from said subject, wherein an expression of CEACAM5 measured in at least about 50% of said isolated tumor cells is indicative that said subject is a responder to said treatment.

[0603] In another aspect, there is provided a method of determining clinical prognosis of a subjecthaving a cancer to a treatment of cancer comprising a microtubule-targeting therapy, said method comprising at least:a step of measuring an expression of CEACAM5 in a biological sample from said subject, and astep of classifying the subject as having a favorable clinical prognosis to said treatment if the expression of CEACAM5 is highly positive. and optionally wherein the favorable clinical prognosis is indicative of a progression free survival and / or of an overall survival rates improvement.

[0604] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 50% of the biological sample,the expression being measured by immunohistochemistry.

[0605] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if saidexpression consists of at least 2+ intensity in greater than or equal to 80% of the biological sample,the expression being measured by immunohistochemistry.

[0606] In certain exemplary embodiments, the biological sample consists of isolated tumor cells.

[0607] In certain exemplary embodiments, the microtubule-targeting agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[0608] In certain exemplary embodiments, the microtubule-targeting agent is a taxane selectedfrom the group consisting of docetaxel, cabazitaxel, or paclitaxel.

[0609] In certain exemplary embodiments, the microtubule-targeting agent is a vinca-alkaloidselected from vinblastine, vinorelbine, or vincristine.

[0610] In certain exemplary embodiments, the microtubule-targeting agent is an auristatinselected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0611] In certain exemplary embodiments, the subject was previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptortyrosine kinase (ROS1) inhibitor, or any combination thereof.

[0612] In certain exemplary embodiments, the platinum-based chemotherapies comprisecisplatin, oxaliplatin or carboplatin.

[0613] In certain exemplary embodiments, the check-point inhibitors comprise a PD-1 inhibitor, aPD-L1 inhibitor, or a combination thereof.

[0614] In certain exemplary embodiments, the cancer is selected from the group consisting ofcolorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[0615] In certain exemplary embodiments, the cancer is lung cancer. In certain exemplaryembodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0616] In certain exemplary embodiments, the subject is at least about 18 years old.

[0617] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0618] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0619] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC) or CEACAM5 gene expression levels.

[0620] In certain exemplary embodiments, the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonicantigen (CEA) levels.

[0621] In certain exemplary embodiments, the CEACAM5 expression is highly positive if theCEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the expression being measured by immunohistochemistry.

[0622] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if theIog2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value for theCEACAM5 gene expression level measured (or determined) in the tumor is above a referencevalue of at least about 7, or at least about 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0623] In certain exemplary embodiments, the expression of CEACAM5 is highly positive if thelevel of circulating carcinoembryonic antigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greater than or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0624] In certain exemplary embodiments, the cancer expresses CEACAM5 with moderate orhigh intensity as determined by immunohistochemistry. In certain exemplary embodiments, the CEACAM5 expression consists of at least 2+ intensity in greater than or equal to 50% of the tumorcells, the intensity measured by immunohistochemistry.

[0625] In certain exemplary embodiments, the CEACAM5 gene expression is determined bymeasuring levels of CEACAM5 mRNA.

[0626] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

[0627] In certain exemplary embodiments, the microtubule targeting agent is an antibody-drugconjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[0628] In certain exemplary embodiments, the payload is a maytansinoid.

[0629] In certain exemplary embodiments, the maytansinoid is selected from the group consistingof Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

[0630] In certain exemplary embodiments, the ADC comprising the anti-CEACAM5 antibody iscovalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[0631] In certain exemplary embodiments, the anti-CEACAM5 antibody is covalently attached viaa cleavable or non-cleavable linker to the microtubule targeting agent.

[0632] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0633] In certain embodiments, the microtubule targeting agent is not tusamitamab ravtansine.

[0634] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0635] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0636] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0637] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0638] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody.

[0639] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising Ravtansine (DM4).

[0640] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0641] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0642] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0643] In certain exemplary embodiments, the microtubule targeting agentnot animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0644] In certain exemplary embodiments, the microtubule targeting agent is administered at adose from about 20 mg / m2 to about 200 mg / m2.

[0645] In certain exemplary embodiments, the microtubule targeting agent is docetaxel.

[0646] In certain exemplary embodiments, the microtubule targeting agent is administeredintravenously.

[0647] In certain exemplary embodiments, the treatment results in a favorable clinical prognosisand is indicative of a progression free survival and / or an improvement in overall survival rates.

[0648] In another aspect, there is provided a method of determining clinical prognosis of a subjecthaving a cancer to a treatment of cancer comprising a microtubule-targeting therapy, said method comprising at least:a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject, and astep of classifying the subject as having a favorable clinical prognosis to said treatment if the expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells, and optionally wherein the favorable clinical prognosis is indicative of a progression free survival and / or of an overall survival rates improvement.

[0649] In another aspect, the disclosure provides a method of treating cancer in a subject, themethod comprising: (a) selecting the subject for treatment if the subject is bearing a tumor that expressesCEACAM5 in at least about 50% of its tumor cells; (b) administering to the subject an effective amount of tusamitamab ravtansine,such that the subject exhibits improved Quality of Life with respect to a patient who has been administered docetaxel.

[0650] In certain exemplary embodiments, the Quality of Life is assessed according to the qualityof life (HRQOL) questionnaire.

[0651] In certain exemplary embodiments, the cancer is lung cancer.

[0652] In certain exemplary embodiments, the lung cancer is non-small cell lung cancer(NSCLC).

[0653] In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0654] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0655] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0656] In another aspect, the disclosure provides a method of treating cancer in a subject, themethod comprising: (a) selecting the subject for treatment if the subject is bearing a tumor thatexpresses CEACAM5 in at least about 50% of its tumor cells; (b) administering to the subject an effective amount of tusamitamab ravtansine,such that the subject exhibits reduced adverse events (AEs) with respect to a patient who has been administered docetaxel.

[0657] In certain exemplary embodiments, the AEs are Grade ≥3, all grade treatment-related AESor Grade ≥3 treatment-related AEs.

[0658] In certain exemplary embodiments, the cancer is lung cancer.

[0659] In certain exemplary embodiments, the lung cancer is non-small cell lung cancer(NSCLC).

[0660] In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma. In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.

[0661] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0662] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0663] In another aspect, the disclosure provides a method of treating cancer in a subject, themethod comprising: (a) selecting the subject for treatment if the subject is bearing a tumor that expressesCEACAM5 at ≥2+ intensity in at least about 80% of its tumor cells; (b) administering to the subject an effective amount of tusamitamab ravtansine,such that the subject exhibits improved survival with respect to a patient who has been administered docetaxel.

[0664] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about50%, 60%, 70% or 80% of its tumor cells.

[0665] In certain exemplary embodiments, the subject expresses CEACAM5 in at least about90% of its tumor cells.

[0666] In certain exemplary embodiments, the subject is intravenously administered tusamitamabravtansine at 100 mg / m2once every 2 weeks.

[0667] In certain exemplary embodiments, the subject exhibits improved survival with respect toa patient who has been intravenously administered docetaxel at 75 mg / m2 once every 2 weeks.

[0668] In certain exemplary embodiments, the subject exhibits improved progression free survival(PFS) or improved overall survival (OS).

[0669] In certain exemplary embodiments, the cancer is lung cancer.

[0670] In certain exemplary embodiments, the lung cancer is non-small cell lung cancer(NSCLC).

[0671] In certain exemplary embodiments, the NSCLC comprises adenocarcinoma or squamous-cell carcinoma.

[0672] In certain exemplary embodiments, the NSCLC is non-squamous-cell carcinoma.BRIEF DESCRIPTION OF THE FIGURES

[0673] The foregoing and other features and advantages of the disclosure will bemore fully understood from the following detailed description of illustrative embodiments taken in conjunction with the accompanying figures.

[0674] FIG. 1 schematically depicts the design of the CARMEN LC03 study andfurther elaborated in Example 1. The study is a randomized, open-label, phase 3study of SAR408701 versus docetaxel in previously treated, metastatic, nonsquamous non-small-cell lung cancer patients with CEACAM5-positive tumors.

[0675] FIG 2A-2B depicts a table of the schedule of activities for the main phaseof the CARMEN LC03 study.

[0676] FIG 3 depicts a table of the schedule of activities for the crossover phaseof the CARMEN LC03.

[0677] FIG 4 is a graphical representation of a Kaplan-Meier plot showingprogression free survival (PFS) assessed by an Independent Review Committee(IRC)- (ITT population).

[0678] FIG 5 is a graphical representation of a Kaplan-Meier plot showing PFSassessed by the investigator (ITT population).

[0679] FIG 6 is an exploratory analysis of PFS by CECAM5 terciles.

[0680] FIG 7 is a graphical representation of a Kaplan-Meier plot showing PFS ofCEACAM5 expression at greater than 90%.

[0681] FIG 8 is an exploratory analysis of Overall Survival (OS) by CEACAM5terciles.

[0682] FIG 9 is a graphical representation of a Kaplan-Meier plot showing OS ofCEACAM5 expression at 90%.

[0683] FIG 10 compares the performance of the docetaxel arm in the CARMENLC03 with other clinical trials using docetaxel.

[0684] FIG 11 is a summary analysis of the primary and secondary endpoints fromthe CARMEN LC03 trial.

[0685] FIG 12 shows the exploratory results in different subgroups (progression-free survival compared to overall survival).DETAILED DESCRIPTION

[0686] Before the disclosure is described, it is to be understood that disclosure is not limited tomethods and experimental conditions described, as such methods and conditions may vary. It is also to be understood that the terminology used herein is for the purpose of describing embodiments only, and is not intended to be limiting, because the scope of the disclosure will be limited only by the appended claims.

[0687] Unless defined otherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0688] The disclosure provides, at least in part, compositions and methods of usingcarcinoembryonic antigen 5 (CEACAM5) to identify subjects with cancers that express CEACAM5and determine that such CEACAM5 expressing cancers may be responsive to selectedtreatments such as microtubule-targeting agents. Definitions

[0689] As used herein, the term “about” in quantitative terms refers to plus or minus 10% of thevalue it modifies (rounded up to the nearest whole number if the value is not sub-dividable, such as a number of molecules or nucleotides). For example, the phrase “about 100 mg” would encompass 90 mg to 110 mg, inclusive; the phrase “about 2500 mg” would encompass 2250 mg to 2750 mg. When applied to a percentage, the term “about” refers to plus or minus 10% relativeto that percentage. For example, the phrase “about 20%” would encompass 18-22% and “about80%” would encompass 72-88%, inclusive. Moreover, where “about” is used herein in conjunction with a quantitative term it is understood that in addition to the value plus or minus 10%, the exact value of the quantitative term is also contemplated and described. For example, the term “about 23%” expressly contemplates, describes, and includes exactly 23%.

[0690] It is to be noted that the term "a" or "an" entity refers to one or more of that entity; forexample, "a symptom," is understood to represent one or more symptoms. As such, the terms "a" (or "an"), "one or more," and "at least one" can be used interchangeably herein.

[0691] Furthermore, "and / or" where used herein is to be taken as specific disclosure of each ofthe two specified features or components with or without the other. Thus, the term "and / or" as used in a phrase such as "A and / or B" herein is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Likewise, the term "and / or" as used in a phrase such as "A, B, and / or C" is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0692] It is understood that wherever aspects are described herein with the language"comprising," otherwise analogous aspects described in terms of "consisting of” and / or "consisting essentially of” are also provided.

[0693] As used herein “CEACAM5” designates the “carcinoembryonic antigen-related celladhesion molecule 5”, also known as “CD66e” (Cluster of Differentiation 66e) or CEA. CEACAM5is a glycoprotein involved in cell adhesion. CEACAM5 is highly expressed on the surface ofcolorectal, gastric, lung and uterine tumor cells.

[0694] A reference sequence of full length human CEACAM5, including signal peptide (positions1-34) and pro-peptide (positions 686-702), is available from the GenBank database under accession number AAA51967.1 Five non-synonymous SNPs have been identified with a frequency higher than 2% in caucasian population, four of them being localised in the N domain (at positions 80, 83, 112, 113), the last one in the A2 domain (at position 398) of human CEACAM5. GenBank AAA51967.1 contains the major haplotype (I80, V83, I112, I113 and E398).

[0695] A sequence of the extracellular domain of Macaca fascicularis CEACAM5, cloned by theinventors, is disclosed in SEQ ID NO: 10. See also WO2014079886, which is incorporated by reference in its entirety. SEQ ID NO: 10 QLTIESRPFNVAEGKEVLLLAHNVSQNLFGYIWYKGERVDASRRIGSCVIRTQQITPGPAHSGR ETIDFNASLLIQNVTQSDTGSYTIQVIKEDLVNEEATGQFRVYPELPKPYITSNNSNPIEDKDAVA LTCEPETQDTTYLWWVNNQSLPVSPRLELSSDNRTLTVFNIPRNDTTSYKCETQNPVSVRRSD PVTLNVLYGPDAPTISPLNTPYRAGEYLNLTCHAASNPTAQYFWFVNGTFQQSTQELFIPNITVN NSGSYMCQAHNSATGLNRTTVTAITVYAELPKPYITSNNSNPIEDKDAVTLTCEPETQDTTYLW WVNNQRLSVSSRLELSNDNRTLTVFNIPRNDTTFYECETQNPVSVRRSDPVTLNVLYGPDAPTI SPLNTPYRAGENLNLSCHAASNPAAQYFWFVNGTFQQSTQELFIPNITVNNSGSYMCQAHNSA TGLNRTTVTAITVYVELPKPYISSNNSNPIEDKDAVTLTCEPVAENTTYLWWVNNQSLSVSPRL QLSNGNRILTLLSVTRNDTGPYECGIQNSESAKRSDPVTLNVTYGPDTPIISPPDLSYRSGANLN LSCHSDSNPSPQYSWLINGTLRQHTQVLFISKITSNNNGAYACFVSNLATGRNNSIVKNISVSSG DSAPGSSGLSA

[0696] A “domain” may be any region of a protein, generally defined on the basis of sequencehomologies and often related to a specific structural or functional entity. CEACAM family members are known to be composed of Ig-like domains. The term domain is used in this document to designate either individual Ig-like domains, such as “N-domain” or for groups of consecutive domains, such as “A3-B3 domain”.

[0697] A Domain organisation of human CEACAM5 is as follows (based on GenBankAAA51967.1; SEQ ID NO: 11): SEQ ID NO: 11 MESPSAPPHRWCIPWQRLLLTASLLTFWNPPTTAKLTIESTPFNVAEGKEVLLLVHNLPQHLFG YSWYKGERVDGNRQIIGYVIGTQQATPGPAYSGREIIYPNASLLIQNIIQNDTGFYTLHVIKSDLV NEEATGQFRVYPELPKPSISSNNSKPVEDKDAVAFTCEPETQDATYLWWVNNQSLPVSPRLQL SNGNRTLTLFNVTRNDTASYKCETQNPVSARRSDSVILNVLYGPDAPTISPLNTSYRSGENLNL SCHAASNPPAQYSWFVNGTFQQSTQELFIPNITVNNSGSYTCQAHNSDTGLNRTTVTTITVYAE PPKPFITSNNSNPVEDEDAVALTCEPEIQNTTYLWWVNNQSLPVSPRLQLSNDNRTLTLLSVTR NDVGPYECGIQNELSVDHSDPVILNVLYGPDDPTISPSYTYYRPGVNLSLSCHAASNPPAQYS WLIDGNIQQHTQELFISNITEKNSGLYTCQANNSASGHSRTTVKTITVSAELPKPSISSNNSKPVE DKDAVAFTCEPEAQNTTYLWWVNGQSLPVSPRLQLSNGNRTLTLFNVTRNDARAYVCGIQNS VSANRSDPVTLDVLYGPDTPIISPPDSSYLSGANLNLSCHSASNPSPQYSWRINGIPQQHTQVL FIAKITPNNNGTYACFVSNLATGRNNSIVKSITVSASGTSPGLSAGATVGIMIGVLVGVALI Table 1A. Human CEACAM5 domains Human CEACAM5 domains Positions on SEQ ID NO :11Domain N 35 – 142Domain A1 143 – 237Domain B1 238 – 320Domain A2 321 – 415Domain B2 416 – 498Domain A3 499 – 593Domain B3 594 – 685Accordingly, the A3-B3 domain of human CEACAM5 consists of amino acids at positions 499- 685 of SEQ ID NO:11. Domain organization of Macaca fascicularis CEACAM5 is as follows (based on clonedextracellular domain sequence; SEQ ID NO:10):

[0698] Table 1B: Macaca fascicularis CEACAM5 domainsMacaca fascicularis CEACAM5 domains Positions on SEQ ID NO :10Domain N-A1-B1 –1 - 286Domain A2-B2 –287 - 464Domain A3-B3 465 - 654

[0699] Accordingly, the A3-B3 domain of Macaca fascicularis CEACAM5 consists of amino acidsat positions 465-654 of SEQ ID NO:10.

[0700] A "coding sequence" or a sequence "encoding" an expression product, such as a RNA,polypeptide, protein, or enzyme, is a nucleotide sequence that, when expressed, results in the production of that RNA, polypeptide, protein, or enzyme, i.e., the nucleotide sequence encodes an amino acid sequence for that polypeptide, protein or enzyme. A coding sequence for a protein may include a start codon (usually ATG) and a stop codon.

[0701] As used herein, references to specific proteins (e.g., antibodies) can include a polypeptidehaving a native amino acid sequence, as well as variants and modified forms regardless of their origin or mode of preparation. A protein which has a native amino acid sequence is a protein having the same amino acid sequence as obtained from nature. Such native sequence proteins can be isolated from nature or can be prepared using standard recombinant and / or synthetic methods. Native sequence proteins specifically encompass naturally occurring truncated or soluble forms, naturally occurring variant forms (e.g., alternatively spliced forms), naturally occurring allelic variants and forms including post-translational modifications. Native sequence proteins include proteins carrying post-translational modifications such as glycosylation, or phosphorylation, or other modifications of some amino acid residues.

[0702] The term "gene" means a DNA sequence that codes for, or corresponds to, a particularsequence of amino acids which comprises all or part of one or more proteins or enzymes, and may or may not include regulatory DNA sequences, such as promoter sequences, which determine for example the conditions under which the gene is expressed. Some genes, which are not structural genes, may be transcribed from DNA to RNA, but are not translated into an amino acid sequence. Other genes may function as regulators of structural genes or as regulators of DNA transcription. In particular, the term gene may be intended for the genomic sequence encoding a protein, i.e. a sequence comprising regulator, promoter, intron and exon sequences.

[0703] A percentage of “sequence identity” may be determined by comparing the two sequences,optimally aligned over a comparison window, wherein the portion of the polynucleotide orpolypeptide sequence in the comparison window may comprise additions or deletions (i.e., gaps) as compared to the reference sequence (which does not comprise additions or deletions) for optimal alignment of the two sequences. The percentage is calculated by determining the number of positions at which the identical nucleic acid base or amino acid residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison and multiplying the result by 100 to yield the percentage of sequence identity. Optimal alignment of sequences for comparison is conducted by global pairwise alignment, e.g., using the algorithm of Needleman and Wunsch J. Mol. Biol. 48:443 (1970). The percentage of sequence identity can be readily determined for instance using the program Needle, with the BLOSUM62 matrix, and the following parameters gap-open=10, gap-extend=0.5.

[0704] A "conservative amino acid substitution" is one in which an amino acid residue issubstituted by another amino acid residue having a side chain R group with similar chemical properties (e.g., charge, size or hydrophobicity). In general, a conservative amino acid substitution will not substantially change the functional properties of a protein. Examples of groups of amino acids that have side chains with similar chemical properties include 1) aliphatic side chains: glycine, alanine, valine, leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine and threonine; 3) amide-containing side chains: asparagine and glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and tryptophan; 5) basic side chains: lysine, arginine, and histidine; 6) acidic side chains: aspartic acid and glutamic acid; and 7) sulfur-containing side chains: cysteine and methionine. Conservative amino acids substitution groups can also be defined on the basis of amino acid size.

[0705] As used herein, the term "hCEACAM5" means a human cytokine receptor that specificallybinds human CEACAM5.

[0706] Human CEACAM1 full-length protein is available in GenBank database under accessionnumber NP_001703.2. The extracellular domain of human CEACAM1 consists of amino acids at positions 35-428 of this protein. Human CEACAM6 full-length protein is available in GenBank database under accession number NP_002474.3. The extracellular domain of human CEACAM6 consists of amino acids at positions 35-327 of this protein.

[0707] Human CEACAM7 full-length protein is available in GenBank database under accessionnumber NP_008821.1. The extracellular domain of human CEACAM7 consists of amino acids at positions 36-248 of the protein.

[0708] Human CEACAM8 full-length protein is available in GenBank database under accessionnumber NP_001807.2. The extracellular domain of human CEACAM8 consists of amino acids at positions 35-332 of the protein.

[0709] M. fascicularis CEACAM1 extracellular domain consists of amino acids at positions 35-428 of full-length protein, i.e., amino acids 1-394 of the protein.

[0710] M. fascicularis CEACAM6 extracellular domain consists of amino acids at positions 35-327 of full-length protein, i.e., amino acids 1-293 the protein.

[0711] M. fascicularis CEACAM8 extracellular domain consists of amino acids at positions 35-332 of full-length protein, i.e., amino acids 1-298 of the protein.

[0712] The term "antibody", as used herein, refers to immunoglobulin molecules comprising fourpolypeptide chains, two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, as well as multimers thereof (e.g., IgM). Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2 and CH3. Each light chaincomprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chainconstant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In some embodiments, the FRs of the antibody (or antigen-binding portion thereof) may be identical to the human germline sequences or may be naturally or artificially modified. An amino acid consensus sequence may be defined based on a side-by-side analysis of two or more CDRs.

[0713] The term "antibody," as used herein, also includes antigen-binding fragments of fullantibody molecules. The terms "antigen-binding portion" of an antibody, "antigen-binding fragment" of an antibody, and the like, as used herein, include any naturally occurring, enzymatically obtainable, synthetic, or genetically engineered polypeptide or glycoprotein that specifically binds an antigen to form a complex. Antigen-binding fragments of an antibody may be derived, e.g., from full antibody molecules using any suitable standard techniques such as proteolytic digestion or recombinant genetic engineering techniques involving the manipulation and expression of DNA encoding antibody variable and optionally constant domains. Such DNA is known and / or is readily available from, e.g., commercial sources, DNA libraries (including, e.g., phage-antibody libraries), or can be synthesized. The DNA may be sequenced and manipulatedchemically or by using molecular biology techniques, for example, to arrange one or more variable and / or constant domains into a suitable configuration, or to introduce codons, create cysteine residues, modify, add or delete amino acids, etc.

[0714] Non-limiting examples of antigen-binding fragments include: (i) Fab fragments; (ii) F(ab')2fragments; (iii) Fd fragments; (iv) Fv fragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and (vii) minimal recognition units consisting of the amino acid residues that mimic the hypervariable region of an antibody (e.g., an isolated complementarity determining region (CDR) such as a CDR3 peptide, or a constrained FR3-CDR3-FR4 peptide. Other engineered molecules,such as domain-specific antibodies, single domain antibodies, domain-deleted antibodies,chimeric antibodies, CDR-grafted antibodies, diabodies, triabodies, tetrabodies, minibodies, nanobodies (e.g., monovalent nanobodies, and bivalent nanobodies), small modular immunopharmaceuticals (SMIPs), and shark variable IgNAR domains, are also encompassed within the expression "antigen-binding fragment," as used herein.

[0715] An antigen-binding fragment of an antibody will typically comprise at least one variabledomain. The variable domain may be of any size or amino acid composition and will generallycomprise at least one CDR which is adjacent to or in frame with one or more frameworksequences. In antigen-binding fragments having a VH domain associated with a VL domain, the VH and VL domains may be situated relative to one another in any suitable arrangement. Forexample, the variable region may be dimeric and contain VH-VH, VH-VL or VL-VL dimers.Alternatively, the antigen-binding fragment of an antibody may contain a monomeric VH or VL domain.

[0716] In certain embodiments, an antigen-binding fragment of an antibody may contain at leastone variable domain covalently linked to at least one constant domain. Non-limiting, exemplaryconfigurations of variable and constant domains that may be found within an antigen-bindingfragment of an antibody include: (i) VH-CH1; (ii) VH-CH2; (iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH- CH1-CH2-CH3; (vi) VH-CH2-CH3; (vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2; (xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In any configuration ofvariable and constant domains, including any of the exemplary configurations listed above, the variable and constant domains may be either directly linked to one another or may be linked by a full or partial hinge or linker region. A hinge region may in various embodiments consist of at least 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which result in a flexible or semi-flexible linkage between adjacent variable and / or constant domains in a single polypeptide molecule. Moreover, an antigen-binding fragment of an antibody may in various embodiments comprise a homo-dimer or hetero-dimer (or other multimer) of any of the variable and constant domain configurationslisted above in non-covalent association with one another and / or with one or more monomeric VH or VL domain (e.g., by disulfide bond(s)).

[0717] In specific embodiments, the antibody or antibody fragment for use in the method of thedisclosure may be a multispecific antibody, which may be specific for different epitopes of one target polypeptide or may contain antigen-binding domains specific for epitopes of more than one target polypeptide. An exemplary bi-specific antibody format that can be used in the context of the present disclosure involves the use of a first immunoglobulin (Ig) CH3 domain and a second Ig CH3 domain, wherein the first and second Ig CH3 domains differ from one another by at least one amino acid, and wherein at least one amino acid difference reduces binding of the bispecific antibody to Protein A as compared to a bi-specific antibody lacking the amino acid difference. In one embodiment, the first Ig CH3 domain binds Protein A and the second Ig CH3 domain contains a mutation that reduces or abolishes Protein A binding such as an H95R modification (by IMGT exon numbering; H435R by EU numbering). The second CH3 may further comprise an Y96F modification (by IMGT; Y436F by EU). Further modifications that may be found within the second CH3 include: D16E, L18M, N44S, K52N, V57M, and V82I (by IMGT; D356E, L358M, N384S, K392N, V397M, and V422I by EU) in the case of IgG1 antibodies; N44S, K52N, and V82I (IMGT; N384S, K392N, and V422I by EU) in the case of IgG2 antibodies; and Q15R, N44S, K52N, V57M, R69K, E79Q, and V82I (by IMGT; Q355R, N384S, K392N, V397M, R409K, E419Q, and V422I by EU) in the case of IgG4 antibodies. Variations on the bi-specific antibody format described above are contemplated within the scope of the present disclosure. Any multispecific antibody format, including the exemplary bispecific antibody formats disclosed herein, may in various embodiments be adapted for use in the context of an antigen-binding fragment of an anti- CEACAM5 antibody using routine techniques available in the art.

[0718] The CEACAM5 antibodies disclosed herein may comprise one or more amino acidsubstitutions, insertions and / or deletions in the framework and / or CDR regions of the heavy and light chain variable domains as compared to the corresponding germline sequences. Such mutations can be readily ascertained by comparing the amino acid sequences disclosed herein to germline sequences available from, for example, public antibody sequence databases. The present disclosure includes antibodies, and antigen-binding fragments thereof, which are derived from any of the amino acid sequences disclosed herein, wherein one or more amino acids within one or more framework and / or CDR regions are back-mutated to the corresponding germline residue(s) or to a conservative amino acid substitution (natural or non-natural) of the corresponding germline residue(s) (such sequence changes are referred to herein as "germline back-mutations"). A person of ordinary skill in the art, starting with the heavy and light chainvariable region sequences disclosed herein, can easily produce numerous antibodies and antigen-binding fragments which comprise one or more individual germline back-mutations or combinations thereof. In certain embodiments, all of the framework residues and / or CDR residues within the VH and / or VL domains are mutated back to the germline sequence. In other embodiments, only certain residues are mutated back to the germline sequence, e.g., only the mutated residues found within the first 8 amino acids of FR1 or within the last 8 amino acids of FR4, or only the mutated residues found within CDR1, CDR2 or CDR3. Furthermore, the antibodies of the present disclosure may contain any combination of two or more germline back- mutations within the framework and / or CDR regions, i.e., wherein certain individual residues are mutated back to the germline sequence while certain other residues that differ from the germline sequence are maintained. Once obtained, antibodies and antigen-binding fragments that containone or more germline back-mutations can be easily tested for one or more desired property suchas, improved binding specificity, increased binding affinity, improved or enhanced antagonistic or agonistic biological properties (as the case may be), reduced immunogenicity, etc. Antibodies and antigen-binding fragments obtained in this general manner are encompassed within the present disclosure.

[0719] The constant region of an antibody is important in the ability of an antibody to fixcomplement and mediate cell-dependent cytotoxicity. Thus, the isotype of an antibody may be selected based on whether it is desirable for the antibody to mediate cytotoxicity.

[0720] The term "human antibody", as used herein, is intended to include antibodies havingvariable and constant regions derived from human germline immunoglobulin sequences. The human antibodies featured in the disclosure may in various embodiments nonetheless include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs and in some embodiments CDR3. However, the term "human antibody", as used herein, is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0721] The term "recombinant human antibody", as used herein, is intended to include all humanantibodies that are prepared, expressed, created or isolated by recombinant means, such asantibodies expressed using a recombinant expression vector transfected into a host cell(described further below), antibodies isolated from a recombinant, combinatorial human antibody library (described further below), antibodies isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (see e.g., Taylor et al., (1992) Nucl. Acids Res.20:6287-6295, incorporated herein by reference in its entirety,) or antibodies prepared, expressed, created or isolated by any other means that involves splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. In certain embodiments, however, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.

[0722] Human antibodies can exist in two forms that are associated with hinge heterogeneity. Inan embodiment, an immunoglobulin molecule comprises a stable four chain construct of approximately 150-160 kDa in which the dimers are held together by an interchain heavy chain disulfide bond. In another embodiment, the dimers are not linked via inter-chain disulfide bonds and a molecule of about 75-80 kDa is formed composed of a covalently coupled light and heavy chain (half-antibody). These embodiments / forms have been extremely difficult to separate, even after affinity purification.

[0723] The term "humanised antibody" or “humanized antibody” refers to an antibody which iswholly or partially of non-human origin and which has been modified to replace certain amino acids, for instance in the framework regions of the VH and VL domains, in order to avoid or minimize an immune response in humans. The constant domains of a humanized antibody are most of the time human CH and CL domains.

[0724] Numerous methods for humanisation / humanization of an antibody sequence are knownin the art; see e.g., the review by Almagro & Fransson (2008) Front Biosci.13: 1619-1633. One commonly used method is CDR grafting, or antibody reshaping, which involves grafting of the CDR sequences of a donor antibody, generally a mouse antibody, into the framework scaffold of a human antibody of different specificity. Since CDR grafting may reduce the binding specificity and affinity, and thus the biological activity, of a CDR grafted non-human antibody, back mutations may be introduced at selected positions of the CDR grafted antibody in order to retain the binding specificity and affinity of the parent antibody. Identification of positions for possible back mutations can be performed using information available in the literature and in antibody databases. Amino acid residues that are candidates for back mutations are typically those that are located at the surface of an antibody molecule, while residues that are buried or that have a low degree of surface exposure will not normally be altered. An alternative humanization technique to CDR grafting and back mutation is resurfacing, in which non-surface exposed residues of non-humanorigin are retained, while surface residues are altered to human residues. Another alternative technique is known as “guided selection” (Jespers et al. (1994) Biotechnology 12, 899) and can be used to derive from a murine antibody a fully human antibody conserving the epitope and binding characteristics of the parental antibody.

[0725] The frequency of appearance of the second form in various intact IgG isotypes is due to,but not limited to, structural differences associated with the hinge region isotype of the antibody. A single amino acid substitution in the hinge region of the human IgG4 hinge can significantly reduce the appearance of the second form (Angal et al., (1993) Molecular Immunology 30:105, incorporated by reference in its entirety) to levels typically observed using a human IgG1 hinge.The instant disclosure encompasses in various embodiments antibodies having one or moremutations in the hinge, CH2 or CH3 region which may be desirable, for example, in production, to improve the yield of the desired antibody form.

[0726] An "isolated antibody," as used herein, means an antibody that has been identified andseparated and / or recovered from at least one component of its natural environment. For example, an antibody that has been separated or removed from at least one component of an organism, or from a tissue or cell in which the antibody naturally exists or is naturally produced, is an "isolated antibody." In various embodiments, the isolated antibody also includes an antibody in situ within a recombinant cell. In other embodiments, isolated antibodies are antibodies that have been subjected to at least one purification or isolation step. In various embodiments, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0727] The term "specifically binds," or the like, means that an antibody or antigen-bindingfragment thereof forms a complex with an antigen that is relatively stable under physiologicconditions. Methods for determining whether an antibody specifically binds to an antigen are wellknown in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like.

[0728] The term "surface plasmon resonance", as used herein, refers to an optical phenomenonthat allows for the analysis of real-time interactions by detection of alterations in protein concentrations within a biosensor matrix, for example using the BIACORE system (Biacore Life Sciences division of GE Healthcare, Piscataway, NJ).

[0729] The term "KD", as used herein, is intended to refer to the equilibrium dissociation constantof an antibody-antigen interaction.

[0730] “Affinity” is defined, in theory, by the equilibrium association between the whole antibodyand the antigen. It can be experimentally assessed by a variety of known methods, such as measuring association and dissociation rates with surface plasmon resonance or measuring theEC50 (or apparent KD) in an immunochemical assay (ELISA, FACS). In these assays, the EC50 is the concentration of the antibody which induces a response halfway between the baseline and maximum after some specified exposure time on a defined concentration of antigen by ELISA (enzyme-linked immuno-sorbent assay) or cell expressing the antigen by FACS (Fluorescence Activated Cell Sorting).

[0731] A monoclonal antibody binding to antigen 1(Ag1) is “cross-reactive” to antigen 2 (Ag2)when the EC50s are in a similar range for both antigens. In the present application, a monoclonal antibody binding to Ag1 is cross-reactive to Ag2 when the ratio of affinity of Ag2 to affinity of Ag1 is equal or less than 10 (for instance 5, 2, 1 or 0.5), affinities being measured with the same method for both antigens.

[0732] Affinity for human CEACAM5 or for Macaca fascicularis CEACAM5 may be determinedas the EC50 value in an ELISA using soluble recombinant CEACAM5 as capture antigen.

[0733] The antibody of the disclosure may also have an apparent dissociation constant (apparentKD), as may be determined by FACS analysis on tumor cell line MKN45 (DSMZ, ACC 409) or on xenograft tumor cells deriving from patient (CR-IGR-034P available from Oncodesign Biotechnology, tumor collection CReMEC), which is ≤25nM, for instance ≤20nM, ≤10nM, ≤5nM, ≤3nM or ≤1nM. The apparent KD may be within the range 0.01-20 nM, or may be within the range 0.1-20nM, 0.1-10nM, or 0.1-5nM.

[0734] Additionally, antibodies according to the disclosure have been shown to be able to detectCEACAM5 expression by immunohistochemistry in frozen and formalin-fixed and paraffin embedded (FFPE) tissue sections.

[0735] The term "epitope" refers to an antigenic determinant that interacts with a specific antigenbinding site in the variable region of an antibody molecule known as a paratope. A single antigen may have more than one epitope. Thus, different antibodies may bind to different areas on an antigen and may have different biological effects. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. In certain circumstance, an epitope may include moieties of saccharides, phosphoryl groups, or sulfonyl groups on the antigen.

[0736] The term “biomarker” intends to refer a biological molecule, for example a protein or ametabolite, that is differentially present, increased or decreased, in a biological sample obtained from a subject or a group of subjects having a first phenotype, e.g., having a disease such as a cancer, as compared to a biological sample from a subject or a group of subjects having a second phenotype, e.g., not having the disease. In use, the biomarker is isolated from the subject.

[0737] The term “sample” or “biological sample” refers to a biological material isolated from asubject. The biological sample may contain any biological material suitable for detecting the biomarker, i.e., CEACAM5 antigen, and may comprise cellular and / or non-cellular material fromthe subject. The sample may be isolated from any suitable biological tissue (e.g., tumor) or fluidsuch as blood, blood plasma (plasma), blood serum (serum), urine, or cerebral spinal fluid (CSF). In some embodiments, a biological sample is a blood plasma (plasma) or a blood serum (serum) sample.

[0738] The term “microtubule-targeting agent” as used herein refers to a substance or compoundthat affects microtubule function thereby inhibiting or preventing the function of cells and / orcauses destruction of cells.CEA and CEACAM and Related Cancers

[0739] Carcino-embryonic antigen (CEA) is a glycoprotein involved in cell adhesion. CEA wasfirst identified in 1965 (Gold and Freedman, J Exp Med, 121, 439, 1965) as a protein normally expressed by fetal gut during the first six months of gestation, and found in cancers of the pan- creas, liver and colon. The CEA family belongs to the immunoglobulin superfamily. The CEA family, which consists of 18 genes, is sub-divided in two sub-groups of proteins: the carcinoem- bryonic antigen-related cell adhesion molecule (CEACAM) sub-group and the pregnancy-specific glycoprotein subgroup (Kammerer & Zimmermann, BMC Biology 2010, 8:12).

[0740] In humans, the CEACAM sub-group consists of 7 members: CEACAM1, CEACAM3,CEACAM4, CEACAM5, CEACAM6, CEACAM7, CEACAM8. The extracellular domains of CEACAM family members are composed of repeated immunoglobulin-like (Ig-like) domains which have been categorized in 3 types, A, B and N, according to sequence homologies. CEACAM5 contains seven such domains, namely N, A1, B1, A2, B2, A3 and B3.

[0741] CEACAM5 A1, A2 and A3 domains, on the one hand, and B1, B2 and B3 domains, on theother hand, show high sequence homologies, the A domains of human CEACAM5 presenting from 84 to 87% pairwise sequence similarity, and the B domains from 69 to 80%. Furthermore, other human CEACAM members presenting A and / or B domains in their structure, namely CEACAM1, CEACAM6, CEACAM7 and CEACAM8, show homology with human CEACAM5. In particular, the A and B domains of human CEACAM6 protein display sequence homologies with A1 and A3 domains, and any of B1 to B3 domains of human CEACAM5, respectively, which are even higher than observed among the A domains and the B domains of human CEA-CAM5.

[0742] Numerous anti-CEA antibodies were generated in view of CEA-targeted diagnostic ortherapeutic purposes.

[0743] Numerous studies have shown that CEACAM5, identical to the originally identified CEA,is highly expressed on the surface of colorectal, gastric, lung, breast, prostate, ovary, cervix, and bladder tumor cells and weakly ex-pressed in few normal epithelial tissues such as columnar epithelial and goblet cells in colon, mucous neck cells in the stomach and squamous epithelialcells in oesophagus and cervix (Hammarström et al, 2002, in "Tumor markers, Physiology,Pathobiology, Technology and Clinical Applications" Eds. Diamandis E. P. et al., AACC Press, Washington pp 375)..

[0744] In some embodiments the CEACAM5 cancers refers to tissues expressing CEACAM5. Incertain embodiments, CEACAM5 expressers are in at least 50% (e.g., 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more) of the expressing tumor cell population. In some embodiments, the CEACAM5 expressers have greater than 2+ intensity (e.g., intensity of 2, 3, 4, 5, 6 or more) in at least 50% of expressing tumor cell population. CEACAM5 expressers, represent ~20% of lung cancer.

[0745] In some embodiments, the cancers expressing CEACAM5 include several tumor typesincluding colorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer. Treatment Populations

[0746] In some embodiments, the method of treating cancer includes selecting a subject or asubject in need thereof who expresses carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in at least about 50% (e.g., 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more) of tumor cells.

[0747] In some embodiments, the method is for treating cancer in a subject, the methodcomprising: (a) selecting the subject for treatment if the subject is bearing a tumor that expressesCEACAM5 in at least about 50% (e.g., 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more) of its tumor cells; (b) administering to the subject an effective amount of a microtubule-targeting agent,thereby treating cancer in the subject.

[0748] In some embodiments, the subject is selected if the subject is bearing a tumor thatexpresses CEACAM5 in about 50%-100% of its tumor cells or 50-90% or 50-80%, or 50-70% or 50-60% of tumor cells.

[0749] In some embodiments, the subject is selected based on the expression of CEACAM5 thatis identified or determined to have a CEACAM5 immunohistochemical [IHC] intensity of ≥ 2+ in ≥50% of cancer cells (tumor cells). In yet other embodiments, the subject is selected based on theexpression of CEACAM5 that is identified or determined to have a CEACAM5 immunohistochemical [IHC] intensity of ≥ 2+ intensity in ≥ 1% and < 50% of the cancer cells (tumor cells).

[0750] In some embodiments, the subject is selected based on the expression of CEACAM5 thatis identified or determined to have a CEACAM5 immunohistochemical [IHC] intensity of ≥ 2+ in 50%-100% of its tumor cells or 50-90% or 50-80%, or 50-70% or 50-60% of tumor cells.

[0751] In some embodiments, the subject is selected if its Iog2-transformed, quantile-normalized,Transcripts Per Kilobase Million (TPM) value for the CEACAM5 gene expression level in the tumoris above a reference value of at least about 7, or at least about 8, or at least about 9, or at leastabout 10, or at least about 11, or at least about 12, or at least about 13.

[0752] In some embodiments, the subject is selected if its level of circulating carcinoembryonicantigen (CEA) is greater than or equal to 20ng / mL, or greater than or equal to 30ng / mL, or greaterthan or equal to 40ng / mL, or greater than or equal to 50ng / mL.

[0753] In some embodiments, the subject in need thereof is at least 18 years old, has at leastone measurable lesion according to the RECIST v1.1 criteria that has not been irradiated, haslesions that are at least about 10 mm in the longest diameter, has an ECOG performance statusof about 0 to about 1, has cancer in which the CEACAM5 expression is defined as a CEACAM5 immunohistochemistry (IHC) intensity of at least about greater than 2+ in at least about 50% of tumor cell. In some embodiments, the subject expressing CEACAM5 in at least about 50% of tumor cells is also a subject previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor, or any combination thereof.Methods of Identifying or Determining CEACAM5 Expression

[0754] The methods and uses of the disclosure are carried on an isolated biological sample. Insome embodiments, an isolated sample may be a sample isolated from a tumor. A sample isisolated prior to the implementation of the methods and uses as disclosed herein.

[0755] In some embodiments, the amounts of CEACAM5 expression are determined byimmunohistochemistry (IHC) or measuring circulating carcinoembryonic antigen (CEA) or geneexpression levels.

[0756] In some embodiments, the amount of CEACAM5 expression is determined byimmunohistochemical techniques for detecting antigens on cells or in tissue sections. Such immunohistochemical means are those known in the field. Those techniques are highly sensitive and specific and can detect a wide variety of antigens. In some embodiments, immunohistochemistry methods comprise the following steps: binding of an antibody to a specific antigen; formation of an antibody-antigen complex by incubation with a secondary, enzyme- conjugated antibody, and generation of colored deposits at the sites of antibody-antigen binding in presence of substrate and chromogen catalyzed by the enzyme.

[0757] In some embodiments, the CEACAM5 tumor expression may be determined by usingimmunohistochemistry (IHC) assay. The assay may be done using anti-CEACAM5 antibody such as Sanofi’s antibody clone 769. In some embodiments, an anti-CEACAM5 clone 769 is a murine monoclonal antibody with the same specificity as tusamitamab ravtansine to the CEACAM5 target. The assay may be run on Techmate platformer or on a Dako / Agilent Autostainer Link 48 IHC or any other immunohistochemistry platforms. Interpretation of CEACAM5 reactivity is to be performed using semi-quantitative Percent Scores (calculated by summing the percentages of intensities ≥2+) or H-score for CEACAM5 plasma membrane staining (whole or polarized) in tumor cells.

[0758] In some embodiments, the CEACAM5 can be determined by measuring the circulatingCEA. In some embodiments, the circulating CEA is disclosed in PCT / EP2022 / 84107 (WO2023099683) and incorporated herein by reference in its entirety.

[0759] The circulating CEA can be measured using any suitable method, e.g., enzyme-linkedimmunoassay (ELISA), in a sample selected from serum, plasma, and whole blood. In certain embodiments, circulating CEA is measured using ELISA in a serum sample. In certain embodiments, circulating CEA is measured using ELISA in a plasma sample.

[0760] The circulating CEA can be measured at any time before, during, or after treatment. Incertain embodiments, the circulating CEA is measured after performing immunohistochemistryanalysis of CEACAM5 expression on tumor cells of the subject. In certain embodiments, thecirculating CEA is first measured after performing immunohistochemistry analysis of CEACAM5expression on tumor cells of the subject.

[0761] In some embodiments, the expression of CEACAM5 is determined by measuring the geneexpression. In other embodiments, the expression of CEACAM5 is by measuring the mRNA levels.

[0762] In some embodiments, the amount of CEACAM5 gene expression may be expressed asan amount relative to the total gene expression in the tumor sample and relative to the total length of expressed DNA or any other known method. In some embodiments, the amount of CEACAM5 gene expression may be expressed as a log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) value. See U.S. provisional application no.63 / 491,815 filed 23 March 2023incorporated herein by reference in its entirety.

[0763] The amounts of gene transcripts may be measured by any methods known in the art, suchas microarrays, large-scale real-time reverse transcription PCR, RNA-Sequencing (RNA-Seq), Next Generation Sequencing (NGS).

[0764] The gene expression (RNA-seq) of tumor sample may be obtained by any methods knownin the art. RNA-Seq is a sequencing method used to determine gene expression levels. The number of reads determined to have originated from each transcript (usually by alignment) are proportional to their expression level. RNA-Seq may be used to generate a gene expression profile for tumor samples across many cancer types and to determine which gene expression levels are responsible for tumor development. The RNA-Seq data may be harmonized by aligning raw RNA reads to the GRCh38 reference genome build and calculating gene expression levels with standardized protocols. RNA-Seq data may be available as aligned reads (BAM) andexpression levels as: raw counts and normalized with TPM, FPKM, or FPKM-UQ.

[0765] In some embodiments, the gene expression (RNA-seq) may be obtained as follows.

[0766] Genes transcripts (RNA) from an isolated tumor sample may be sequenced by usingKAPA mRNA HYPERPREPKITILLUMINA® Platform. RNA-seq data may be processed as follows: sequencing reads may be mapped to the reference genome GRCh 38 using, for example, Spliced Transcripts Alignment to a Reference (STAR) aligner

[0025] . Gene expression may be first measured in FPKM (Fragments Per Kilobase Million) by CUFFLINK

[0026] and the gene-level FPKM may be converted into TPM (Transcripts Per Kilobase Million)

[0027] . TPM values may be log2- transformed and quantile-normalized for the downstream analysis, including differential geneexpression (DGE) analysis. In some embodiments, samples with several genes detected below10,000 may be excluded from the downstream analysis. RNA-seq may include microenvironment cell populations [MCP] counter analysis, according to published methods.

[0767] In some embodiments, the CEACAM5 gene expression level (mRNA) in a tumor sampleis expressed as a log2-transformed, quantile-normalized, Transcripts Per Kilobase Million (TPM) value.

[0768] In some embodiments, the log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) value for the CEACAM5 gene expression level measured (or determined) in a tumor is compared to a reference value. If the determined value is above the reference value, then the tumor may be qualified as being responsive to a CEACAM5 targeting treatment. A subject in need thereof for whom the determined value is above the reference value may be selected for a CEACAM5 targeting treatment.

[0769] In some embodiments, the reference value may be at least from about 7 to about 13.

[0770] In some embodiments, the reference value may be at least about 7, or may be at leastabout 8, or at least about 9, or at least about 10, or at least about 11, or at least about 12, or at least about 13.

[0771] In some embodiments, the log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) reference value for CEACAM5 mRNA may be at least about 7.

[0772] In some embodiments, the log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) reference value for CEACAM5 mRNA may be about 7-13.

[0773] In some embodiments, the log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) reference value for CEACAM5 mRNA may be about ≥13.

[0774] In some embodiments, the log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) reference value for CEACAM5 mRNA may be about ≥13-15.

[0775] In some embodiments, the log2-transformed, quantile-normalized, Transcripts PerKilobase Million (TPM) reference value for CEACAM5 mRNA may be about > 15.Methods of Treating

[0776] The present disclosure discloses administering to a subject an effective amount of amicrotubule-targeting agent, thereby treating cancer in the subject. As used herein, an “effective amount” or "therapeutically effective amount" is a dose of the therapeutic that results in treatment of a subject expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in at least about 50% of tumor cells.

[0777] As used herein, “treating” refers to causing a detectable improvement in one or moresymptoms associated with cancers or causing a biological effect (e.g., a decrease in the level of a particular biomarker) that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s). For example, a dose of a microtubule-targeting agent whichcauses an improvement in any of the following symptoms or conditions associated with cancerthat express CEACAM5 in at least about 50% of tumor cells is deemed a "therapeutically effectiveamount”.

[0778] In another example, a treatment has not been effective when a dose of a microtubule-targeting agent does not result in a detectable improvement in one or more parameters or symptoms associated with cancer that express CEACAM5 in at least about 50% of tumor cells (e.g., lung cancer) or which does not cause a biological effect that is correlated with the underlying pathologic mechanism(s) giving rise to the condition or symptom(s) of cancer.

[0779] In accordance with the methods of the present disclosure, a therapeutically effectiveamount of a microtubule-targeting agent that is administered to the subject will vary depending upon the age and the size (e.g., body weight or body surface area) of the subject as well as the route of administration and other factors well known to those of ordinary skill in the art.

[0780] In certain embodiments, the dose of a microtubule-targeting agent varies depending onthe body surface area of the subject. In certain embodiments, the dose of a microtubule-targetingagent administered to the subject is from about 20 mg / m2 to about 200 mg / m2. In certainembodiments, the dose of a microtubule-targeting agent administered to the subject is from about30 mg / m2 to about 100 mg / m2, 40 mg / m2 to about 80 mg / m2, or 50 mg / m2 to about 75 mg / m2. Insome embodiments, the microtubule-targeting agent is administered every week or every other week or every three weeks. In certain embodiments, the dose of a microtubule-targeting agentadministered to the subject is from about 20 mg / m2 to about 200 mg / m2 every three weeks or 50mg / m2to 75 mg / m2every three weeks. In some embodiments the

[0781] The therapeutic compositions of the disclosure will be administered with suitable carriers,excipients, and other agents that are incorporated into formulations to provide improved transfer, delivery, tolerance, and the like. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, incorporated herein by reference in its entirety. These formulations include, for example, powders, pastes, ointments, jellies, waxes, oils, lipids, lipid (cationic or anionic) containing vesicles (such as LIPOFECTIN), DNA conjugates, anhydrous absorption pastes, oil-in-water and water-in-oil emulsions, emulsions carbowax (polyethylene glycols of various molecular weights), semi-solid gels, and semi-solid mixtures containing carbowax. See also Powell et al. "Compendium of excipients for parenteral formulations" PDA (1998) J Pharm Sci Technol 52:238-311, incorporated herein by reference in its entirety.

[0782] Various delivery systems are known and can be used to administer the pharmaceuticalcomposition of the disclosure, e.g., encapsulation in liposomes, microparticles, microcapsules,receptor mediated endocytosis (see, e.g., Wu et al. (1987) J. Biol. Chem. 262:4429-4432, incorporated herein by reference in its entirety). Methods of introduction include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, and oral routes. The composition may be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and may be administered together with other biologically active agents. Administration can be systemic or local.

[0783] The pharmaceutical composition can also be delivered in a vesicle, such as a liposome(see Langer (1990) Science 249:1527-1533, incorporated herein by reference in its entirety). In certain situations, the pharmaceutical composition can be delivered in a controlled release system, for example, with the use of a pump or polymeric materials. In another embodiment, a controlled release system can be placed in proximity of the composition’s target, thus requiring only a fraction of the systemic dose.

[0784] The injectable preparations may include dosage forms for intravenous, subcutaneous,intracutaneous, and intramuscular injections, local injection, drip infusions, etc. These injectablepreparations may be prepared by methods publicly known. For example, the injectable preparations may be prepared, e.g., by dissolving, suspending or emulsifying the antibody or its salt described above in a sterile aqueous medium or an oily medium conventionally used for injections. As the aqueous medium for injections, there are, for example, physiological saline, an isotonic solution containing glucose and other auxiliary agents, etc., which may be used in combination with an appropriate solubilizing agent such as an alcohol (e.g., ethanol), apolyalcohol (e.g., propylene glycol, polyethylene glycol), a nonionic surfactant [e.g., polysorbate80, HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)], etc.). As the oily medium, there are employed, e.g., sesame oil, soybean oil, etc., which may be used in combination with a solubilizing agent such as benzyl benzoate, benzyl alcohol, etc. The injection thus prepared can be filled in an appropriate ampoule.

[0785] Advantageously, the pharmaceutical compositions for oral or parenteral use describedabove are prepared into dosage forms in a unit dose suited to fit a dose of the active ingredients.Such dosage forms in a unit dose include, for example, tablets, pills, capsules, injections(ampoules), suppositories, etc.

[0786] In accordance with the methods disclosed herein, the microtubule targeting agent (orpharmaceutical formulation comprising the microtubule targeting agent) can be administered to the patient using any acceptable device or mechanism. For example, the administration can be accomplished using a syringe and needle or with a reusable pen and / or autoinjector deliverydevice. The methods of the present disclosure include the use of numerous reusable pens and / orautoinjector delivery devices to administer the microtubule targeting agent (or pharmaceuticalformulation comprising the microtubule targeting agent). Examples of such devices include, butare not limited to AUTOPEN (Owen Mumford, Inc., Woodstock, UK), DISETRONIC pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 pen, HUMALOG pen, HUMALIN 70 / 30 pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR (Novo Nordisk, Copenhagen, Denmark), BD pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN, OPTIPEN PRO, OPTIPEN STARLET, and OPTICLIK (Sanofi-Aventis, Frankfurt, Germany). Examples of disposable pen and / or autoinjector delivery devices having applications in subcutaneous delivery of a pharmaceutical composition of the present disclosure include, but are not limited to the SOLOSTAR pen (Sanofi- Aventis), the FLEXPEN (Novo Nordisk), and the KWIKPEN (Eli Lilly), the SURECLICK Autoinjector (Amgen, Thousand Oaks, CA), the PENLET (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), and the HUMIRA Pen (AbbVie Inc., North Chicago, IL), to name only a few.

[0787] In one embodiment, the microtubule targeting agent is administered with a prefilledsyringe. In another embodiment, the microtubule targeting agent is administered with a prefilledsyringe containing a safety system. For example, the safety system prevents an accidentalneedle-stick injury. In various embodiments, the microtubule targeting agent is administered witha prefilled syringe containing an ÈRIS safety system (West Pharmaceutical Services Inc.). See also U.S. patent numbers 5,215,534 and 9,248,242, incorporated herein by reference in their entireties.

[0788] In another embodiment, the microtubule targeting agent is administered with an auto-injector. In various embodiments, the microtubule targeting agent is administered with an auto-injector featuring the PUSHCLICK technology (SHL Group). In various embodiments, the autoinjector is a device comprising a syringe that allows for administration of a dose of thecomposition and / or microtubule targeting agent to a subject. See also U.S. patent numbers9,427,531 and 9,566,395, incorporated herein by reference in their entireties.

[0789] The use of a microinfusor to deliver the microtubule targeting agent (or pharmaceuticalformulation comprising the microtubule targeting agent) to a patient is also contemplated herein.As used herein, the term "microinfusor" means a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 mL or more) of a therapeutic formulation over aprolonged period of time (e.g., about 10, 15, 20, 25, 30 or more minutes). See, e.g., U.S.6,629,949; US 6,659,982; and Meehan et al., J. Controlled Release 46:107-116 (1996), incorporated herein by reference in their entireties. Microinfusors are particularly useful for thedelivery of large doses of therapeutic proteins contained within high concentration and / or viscous solutions.

[0790] In some embodiments, the microtubulin targeting agent includes agent is a taxane, amaytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin. In someembodiments, the microtubule-targeting agent is a taxoid, vincas, a maytansinoid or maytansinoidanalog such as DM1 or DM4, an auristatin or dolastatin analog, inhibitors, a DNA alkylating agent, a CC-1065 or CC-1065 analog.

[0791] In some embodiments, the microtubule-targeting agent is a taxane selected from thegroup consisting of docetaxel, cabazitaxel, or paclitaxel. In some embodiments, the microtubule-targeting agent is a vinca-alkaloid selected from vinblastine, vinorelbine, or vincristine. In someembodiments, the microtubule-targeting agent is an auristatin selected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[0792] As used herein “maytansinoids” denotes maytansinoids and maytansinoid analogs.Maytansinoids are drugs that inhibit microtubule formation and that are highly toxic to mammalian cells.

[0793] Examples of suitable maytansinoids include maytansinol and maytansinol analogs.

[0794] Examples of suitable maytansinol analogues include those having a modified aromaticring and those having modifications at other positions. Such suitable maytansinoids are disclosed in U.S. Patent Nos. 4,424,219; 4,256,746; 4,294,757; 4,307,016; 4,313,946; 4,315,929; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 4,450,254; 4,322,348; 4,371,533; 6,333,410; 5,475,092; 5,585,499; and 5,846,545.

[0795] Specific examples of suitable analogues of maytansinol having a modified aromatic ringinclude:

[0796] (1) C-19-dechloro (U.S. Pat. No. 4,256,746) (prepared by LAH reduction of ansamytocinP2);

[0797] (2) C-20-hydroxy (or C-20-demethyl) + / -C-19-dechloro (U.S. Pat. Nos. 4,361,650 and4,307,016) (prepared by demethylation using Streptomyces or Actinomyces or dechlorination using LAH); and

[0798] (3) C-20-demethoxy, C-20-acyloxy (-OCOR), + / -dechloro (U.S. Pat. No 4,294,757)(prepared by acylation using acyl chlorides).

[0799] Specific examples of suitable analogues of maytansinol having modifications of otherpositions include:

[0800] (1) C-9-SH (U.S. Pat. No. 4,424,219) (prepared by the reaction of maytansinol with H2Sor P2S5);

[0801] (2) C-14-alkoxymethyl (demethoxy / CH2OR) (U.S. Pat. No. 4,331,598);

[0802] (3) C-14-hydroxymethyl or acyloxymethyl (CH2OH or CH2OAc) (U.S. Pat. No. 4,450,254)(prepared from Nocardia);

[0803] (4) C-15-hydroxy / acyloxy (U.S. Pat. No. 4,364,866) (prepared by the conversion ofmaytansinol by Streptomyces);

[0804] (5) C-15-methoxy (U.S. Pat. Nos. 4,313,946 and 4,315,929) (isolated from Trewianudiflora);

[0805] (6) C-18-N-demethyl (U.S. Pat. Nos. 4,362,663 and 4,322,348) (prepared by thedemethylation of maytansinol by Streptomyces); and

[0806] (7) 4,5-deoxy (U.S. Pat. No 4,371,533) (prepared by the titanium trichloride / LAH reductionof maytansinol).

[0807] In an embodiment of the disclosure, the cytotoxic conjugates of the present disclosureutilize the thiol-containing maytansinoid (DM1), formally termed N2’-deacetyl-N2’-(3-mercapto-1- oxopropyl)-maytansine, as the cytotoxic agent. DM1 is represented by the following structural formula (I):

[0808] In another embodiment, the cytotoxic conjugates of the present disclosure utilize the thiol-containing maytansinoid DM4, formally termed N2’-deacetyl-N-2’(4-methyl-4-mercapto-1- oxopentyl)-maytansine, as the cytotoxic agent. DM4 is represented by the following structural formula (II):

[0809] In further embodiments of the disclosure, other maytansines, including thiol and disulfide-containing maytansinoids bearing a mono or di-alkyl substitution on the carbon atom bearing the sulfur atom, may be used. These include a maytansinoid having, at C-3, C-14 hydroxymethyl, C-15 hydroxy, or C–20 desmethyl, an acylated amino acid side chain with an acyl group bearing a hindered sulfhydryl group, wherein the carbon atom of the acyl group bearing the thiol functionality has one or two substituents, said substituents being CH3, C2H5, linear or branched alkyl or alkenyl having from 1 to 10 reagents and any aggregate which may be present in the solution.

[0810] In some embodiments, the antibodies targeting CEACAM5 can be covalently attached,directly or via a cleavable or non-cleavable linker, to at least one microtubule-targeting agent.

[0811] “Linker”, as used herein, means a chemical moiety comprising a covalent bond or a chainof atoms that covalently attaches a polypeptide to a drug moiety.

[0812] The conjugates may be prepared by in vitro methods. To link a drug or prodrug to theantibody, a linking group is used. Suitable linking groups are well known in the art and include disulfide groups, thioether groups, acid labile groups, photolabile groups, peptidase labile groupsand esterase labile groups. Conjugation of an antibody of the disclosure with cytotoxic agents orgrowth inhibitory agents may be made using a variety of bifunctional protein coupling agents including but not limited to N-succinimidyl pyridyldithiobutyrate (SPDB), butanoic acid 4-[(5-nitro- 2-pyridinyl)dithio]-2,5-dioxo-1-pyrrolidinyl ester (nitro-SPDB), 4-(Pyridin-2-yldisulfanyl)-2-sulfo- butyric acid (sulfo-SPDB), N-succinimidyl (2-pyridyldithio) propionate (SPDP), succinimidyl (N- maleimidomethyl) cyclohexane-1-carboxylate (SMCC), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCL), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis (p- azidobenzoyl)-hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorinecompounds (such as 1,5-difluoro-2,4- dinitrobenzene). For example, a ricin immunotoxin can beprepared as described in Vitetta et al (1987). Carbon labeled 1-isothiocyanatobenzylmethyldiethylene triaminepentaacetic acid (MX-DTPA) is an exemplary chelating agent forconjugation of radionucleotide to the antibody (WO 94 / 11026).

[0813] The linker may be a "cleavable linker" facilitating release of the cytotoxic agent or growthinhibitory agent in the cell. For example, an acid-labile linker, a peptidase-sensitive linker, anesterase labile linker, a photolabile linker or a disulfide-containing linker (See e.g., U.S. PatentNo.5,208,020) may be used. The linker may be also a "non-cleavable linker" (for example SMCC linker) that might lead to better tolerance in some cases.

[0814] Alternatively, a fusion protein comprising the antibody and microtubule-targeting agentmay be made, by recombinant techniques or peptide synthesis. The length of DNA may comprise respective regions encoding the two portions of the conjugate either adjacent one another orseparated by a region encoding a linker peptide which does not destroy the desired properties ofthe conjugate.

[0815] According to an embodiment, the microtubule-targeting agent is a maytansinoid, such asDM1 or DM4.

[0816] In said conjugate, the antibody is conjugated to said at least one growth inhibitory agentby a linking group. In an embodiment said linking group is a cleavable or a non-cleavable linker,such as SPDB, sulfo-SPDB, or SMCC.

[0817] The conjugate may be selected from the group consisting of:

[0818] an antibody-SPDB-DM4 conjugate of formula (III)Ab-SPDB-DM4

[0819] an antibody-sulfo-SPDB-DM4 conjugate of formula (IV)Ab-SulfoSPDB-DM4 and

[0820] an antibody-SMCC-DM1 conjugate of formula (V)Ab-SMCC-DM1

[0821] In an embodiment the conjugate is a conjugate of formula (III), (IV) or (V) as defined above.

[0822] In general, the conjugate can be obtained by a process comprising the steps of:(i) bringing into contact an optionally-buffered aqueous solution of a cell-binding agent(e.g. an antibody) with solutions of a linker and a cytotoxic compound;(ii) then optionally separating the conjugate which was formed in (i) from the unreacted cell-binding agent.

[0823] The aqueous solution of cell-binding agent can be buffered with buffers such as, e.g.,potassium phosphate, acetate, citrate or N-2-Hydroxyethylpiperazine-N’-2-ethanesulfonic acid(Hepes buffer). The buffer depends upon the nature of the cell-binding agent. The cytotoxiccompound is in solution in an organic polar solvent, e.g., dimethyl sulfoxide (DMSO) ordimethylacetamide (DMA).

[0824] The reaction temperature is usually comprised between 20 and 40°C. The reaction timecan vary from 1 to 24 hours. The reaction between the cell-binding agent and the cytotoxic agent can be monitored by size exclusion chromatography (SEC) with a refractometric and / or UV detector. If the conjugate yield is too low, the reaction time can be extended.

[0825] A number of different chromatography methods can be used by the person skilled in theart in order to perform the separation of step (ii): the conjugate can be purified e.g., by SEC,adsorption chromatography (such as ion exchange chromatography, IEC), hydrophobic interaction chromatograhy (HIC), affinity chromatography, mixed-support chromatography such as hydroxyapatite chromatography, or high performance liquid chromatography (HPLC). Purification by dialysis or diafiltration can also be used.

[0826] As used herein, the term “aggregates” means the associations which can be formedbetween two or more cell-binding agents, said agents being modified or not by conjugation. The aggregates can be formed under the influence of a great number of parameters, such as a high concentration of cell-binding agent in the solution, the pH of the solution, high shearing forces, the number of bonded dimers and their hydrophobic character, the temperature (see Wang & Gosh, 2008, J. Membrane Sci., 318: 311-316, and references cited therein); note that the relative influence of some of these parameters is not clearly established. In the case of proteins and antibodies, the person skilled in the art will refer to Cromwell et al. (2006, AAPS Jounal, 8(3): E572-E579). The content in aggregates can be determined with techniques well known to the skilled person, such as SEC (see Walter et al., 1993, Anal. Biochem., 212(2): 469-480).

[0827] After step (i) or (ii), the conjugate-containing solution can be submitted to an additionalstep (iii) of chromatography, ultrafiltration and / or diafiltration.

[0828] The conjugate is recovered at the end of these steps in an aqueous solution.

[0829] According to an embodiment, the conjugate according to the disclosure is characterisedby a “drug-to-antibody ratio” (or “DAR”) ranging from 1 to 10, for instance from 2 to 5, in particular from 3 to 4. This is generally the case of conjugates including maytansinoid molecules.

[0830] This DAR number can vary with the nature of the antibody and of the drug (viz., themicrotubule-targeting agent) used along with the experimental conditions used for the conjugation(like the ratio growth-inhibitory agent / antibody, the reaction time, the nature of the solvent and ofthe cosolvent if any). Thus, the contact between the antibody and the growth-inhibitory agentleads to a mixture comprising several conjugates differing from one another by different drug-to-antibody ratios; optionally the naked antibody; optionally aggregates. The DAR that is determined is thus a mean value.

[0831] A method which can be used to determine the DAR consists in measuringspectrophotometrically the ratio of the absorbance at of a solution of substantially purified conjugate at λD and 280 nm. 280 nm is a wavelength generally used for measuring protein concentration, such as antibody concentration. The wavelength λD is selected so as to allowdiscriminating the drug from the antibody, viz., as readily known to the skilled person, λD is awavelength at which the drug has a high absorbance and λD is sufficiently remote from 280 nm to avoid substantial overlap in the absorbance peaks of the drug and antibody. λD may be selected as being 252 nm in the case of maytansinoid molecules. A method of DAR calculation may be derived from Antony S. Dimitrov (ed), LLC, 2009, Therapeutic Antibodies and Protocols, vol 525, 445, Springer Science:

[0832] The absorbances for the conjugate at λD (AλD) and at 280 nm (A280) are measured eitheron the monomeric peak of the size exclusion chromatography (SEC) analysis (allowing tocalculate the “DAR(SEC)” parameter) or using a classic spectrophotometer apparatus (allowingto calculate the “DAR(UV)” parameter). The absorbances can be expressed as follows: AλD= (cDx ^DλD) + (cAx ^AλD) A280 = (cD x ^D280) + (cA x ^A280) wherein : cD and cA are respectively the concentrations in the solution of the drug and of the antibody ^DλD and ^D280 are respectively the molar extinction coefficients of the drug at λD and 280nm ^AλD and ^A280 are respectively the molar extinction coefficients of the antibody at λD and280 nm.

[0833] Resolution of these two equations with two unknowns leads to the following equations:cD = [(^A280 x AλD) - (^AλD x A280)] / [(^DλD x ^A280) - (^AλD x ^D280)]cA = [A280 – (cD x ^D280)] / ^A280The average DAR is then calculated from the ratio of the drug concentration to that of the antibody: DAR = cD / cA. Combination Therapies

[0834] In addition to administering a subject a microtubule-targeting agent, the subject may alsobe administered other therapies or treatments. In some embodiments, the microtubule-targeting agent can be combined with other chemotherapeutic agents. In some embodiments, otherchemotherapeutic agents used in combination with cisplatin, or with each other, may include carboplatin, paclitaxel (TAXOL®), albumin-bound paclitaxel (nab-paclitaxel, ABRAXANE®), docetaxel (TAXOTERE®), Gemcitabine (GEMZAR®), vinorelbine (NAVELBINE®), irinotecan (CAMPTOSAR®), etoposide (VP-16), vinblastine, and pemetrexed (ALIMTA®). Additionally, radiotherapy may be used in patients with N2 lymph nodes. In advanced stage IIIB / IV or inoperable NSCLC pts, treatment may include multiple cycles of cisplatin-based chemotherapy plus a 3rd generation cytotoxic agent or a cytostatic drug (anti-EGFR, anti-VEGFR). (See Zarogoulidis et al., J Thorac Dis.2013 Sep; 5(Suppl 4): S389–S396.)

[0835] In some embodiments, the microtubule-targeting agent may be combined withangiogenesis inhibitors, Epidermal growth factor receptor (EGFR) inhibitors, and immune checkpoint inhibitors.

[0836] In some embodiments, angiogenesis inhibitors may include, but are not limited to, Axitinib(INLYTA®), Bevacizumab (AVASTIN®), Cabozantinib (COMETRIQ®), Everolimus (AFINITOR®, ZORTRESS®), Lenalidomide (REVLIMID®), Pazopanib (VOTRIENT®), Ramucirumab (CYRAMZA®), Regorafenib (STIVARGA®), Sorafenib (NEXAVAR®), Sunitinib (SUTENT®), Thalidomide (SYNOVIR®, THALOMID®), Vandetanib (CAPRELSA®), and Ziv- aflibercept (ZALTRAP®).

[0837] Epidermal growth factor receptor (EGFR) inhibitors may include, but are not limited to,gefitinib (IRESSA®), erlotinib (TARCEVA®), lapatinib (TYKERB®), cetuximab (ERBITUX®), neratinib (NERLYNX®), osimertinib (TAGRISSO®), panitumumab (VECTIBIX®), vandetanib (CAPRELSA®), necitumumab (PROTRAZZA®), and dacomitinib (VIZIMPRO®).

[0838] Immune checkpoint inhibitors may include, but are not limited to, Programmed Death 1receptor (PD-1) binding agents (e.g., pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), Programmed Death-ligand 1 (PD-L1) binding agents (e.g., atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®)), CTLA-4 binding agents (e.g. ipilimumab (YERVOY®)), OX40 or OX40L binding agents, Adenosine A2A receptor binding agents, B7-H3 binding agents, B7-H4 binding agents, BTLA binding agents, Indoleamine 2,3-dioxygenase binding agents, Killer-cell Immunoglobulin-like Receptor (KIR) binding agents, Lymphocyte Activation Gene-3 (LAG-3) binding agents, nicotinamide adenine dinucleotide phosphate NADPH oxidase isoform (NOX2) binding agents, T-cell Immunoglobulin domain and Mucin domain 3 (TIM-3) binding agents, V-domain Ig suppressor of T cell activation (VISTA) binding agents, Glucocorticoid-Induced TNFR family Related gene (GITR) binding agents, and Sialic acid-binding immunoglobulin-type lectin 7 (SIGLEC7) binding agents.Tusamitamab ravtansine

[0839] Tusamitamab ravtansine (CAS Registry No. 2254086-60-5) is an immunoconjugate ADCcombining a humanized anti-CEACAM5 antibody (tusamitamab) and the maytansinoid derivative4 (DM4) [N2-deacetyl-N2-(4-methyl-4-mercapto-1-oxopentyl)-maytansine], a potent antimitotic agent that inhibits microtubule assembly. DM4 is covalently bound to the antibody through an optimized linker SPDB [N-succinimidyl 4-(2-pyridyldithio)-butyrate] that is stable in plasma andcleavable inside cells. After binding and internalization in targeted cancer cells, the ADC isdegraded, releasing cytotoxic DM4 metabolites.

[0840] The ADC tusamitamab ravtansine specifically binds to the A3B3 domain of humanCEACAM5 and does not recognize other CEACAMs presenting A or / and B domains in their structure (CEACAM1, CEACAM6, CEACAM7 and CEACAM8). The naked antibody and the ADC bind to recombinant human CEACAM5 with an affinity of ~0.02 nM (ELISA) and display highaffinity for CEACAM5 expressing tumor cells (KDAPP 0.24 – 0.68 nM). Preliminary experimentsindicate that tusamitamab ravtansine is devoid of effector activity.

[0841] After binding to the CEACAM5 antigen, tusamitamab ravtansine is internalized by thecancer cells via antigen-mediated endocytosis, delivered to lysosomes and degraded into the lysine-linked derivative lysine-SPDB-DM4. The lysine-SPDB-DM4 gets further degraded in DM4 that is subsequently S-methylated to form methyl-DM4 [Me-DM4]; all three metabolites have potent cytotoxic activity through binding to tubulin and inhibition of microtubule polymerization.

[0842] In certain embodiments, the microtubule targeting agent is tusamitamab ravtansine.

[0843] In some embodiments, the microtubule-targeting agent is not tusamitamab ravtansine.

[0844] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising tusamitamab.

[0845] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain of SEQ ID NO: 8 and a light chain of SEQ ID NO: 9.

[0846] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises a heavy chain variable domain of SEQ ID NO: 1 and a light chain variable domain of SEQ ID NO: 2.

[0847] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an antibody which comprises CDRs of amino acid sequences ofSEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, NTR and SEQ ID NO: 7.

[0848] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody.

[0849] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising Ravtansine (DM4).

[0850] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a maytansinoid.

[0851] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule destabilizing payload.

[0852] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising a microtubule targeting agent.

[0853] In certain exemplary embodiments, the microtubule targeting agent is not animmunoconjugate comprising an anti-CEACAM5 antibody and a microtubule targeting agent.

[0854] In an embodiment, the sequences of the humanized anti-CEACAM5 antibody or a variantthereof are shown below in SEQ ID NOs: 1-9 and in WO 2020 / 161214.

[0855] The heavy chain variable domain amino acid sequence of SEQ ID NO: 1 isEVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGI TYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVS S.

[0856] The light chain variable domain amino acid sequence of SEQ ID NO: 2 isDIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVP SRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIK.

[0857] The CDR sequences of SEQ ID NOs: 1 and 2 are listed below and encompass SEQ IDNOs: 3-7.

[0858] The amino acid sequence of SEQ ID NO: 3 is GFVFSSYD (HCDR1).

[0859] The amino acid sequence of SEQ ID NO: 4 is ISSGGGIT (HCDR2).

[0860] The amino acid sequence of SEQ ID NO: 5 is AAHYFGSSGPFAY (HCDR3).

[0861] The amino acid sequence of SEQ ID NO: 6 is ENIFSY (LCDR1).

[0862] The amino acid sequence of light chain CDR2 is NTR (LCDR2).

[0863] The amino acid sequence of SEQ ID NO: 7 is QHHYGTPFT (LCDR3).

[0864] The heavy chain amino acid sequence of SEQ ID NO: 8 isEVQLQESGPGLVKPGGSLSLSCAASGFVFSSYDMSWVRQTPERGLEWVAYISSGGGI TYAPSTVKGRFTVSRDNAKNTLYLQMNSLTSEDTAVYYCAAHYFGSSGPFAYWGQGTLVTVS SASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGL YSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLF PPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVL TVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEAL HNHYTQKSLSLSPG.

[0865] The light chain amino acid sequence of SEQ ID NO: 9 isDIQMTQSPASLSASVGDRVTITCRASENIFSYLAWYQQKPGKSPKLLVYNTRTLAEGVP SRFSGSGSGTDFSLTISSLQPEDFATYYCQHHYGTPFTFGSGTKLEIKRTVAAPSVFIFPPSDEQ LKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYE KHKVYACEVTHQGLSSPVTKSFNRGEC.

[0866] In some embodiments, the microtubule-targeting agent is not an ADC containing thehumanized anti-CEACAM5 antibody.

[0867] All publications mentioned herein are incorporated herein by reference in their entirety forall purposes. EXAMPLESExample 1. Phase 3, randomized, open-label, multicenter, efficacy and safety study oftusamitamab ravtansine versus docetaxel.

[0868] This was a Phase 3, randomized, open-label, multicenter, efficacy and safety study oftusamitamab ravtansine versus docetaxel in patients with metastatic non-squamous NSCLCwhose tumors expressed CEACAM5 (measured using the CEACAM5 immunohistochemistryassay). CEACAM5 positivity in this study was defined as membranous CEACAM5 expression in the most recent formalin-fixed paraffin-embedded (FFPE) archival tumor tissue (or if not available in fresh tumor tissue) sample as ≥2+ in intensity in at least 50% of the tumor cell population, demonstrated prospectively by central IHC evaluation.

[0869] Once participants signed a prescreening informed consent form (ICF), the prescreeningphase corresponded to the timing of sending archival tumor material and IHC analyses to allowdetermination of CEACAM5 status by central laboratory. Prescreening for CEACAM5 status was performed in advance during prior anticancer therapy. During the study screening phase, only non-squamous NSCLC CEACAM5 positive participants determined by central assay went through protocol study procedures.

[0870] The study had 3 main periods: screening, study treatment and follow up. After beingscreened the eligible patients were randomized (1:1) to one of the following treatment arms:^ Treatment A: tusamitamab ravtansine every 2 weeks (Q2W cycle) at thedose of 100 mg / m2. ^Treatment B: docetaxel every 3 weeks (Q3W cycle) at the dose of 75 mg / m2.

[0871] Treatment allocation was performed by an Interactive Response Technology (IRT). Alleligible patients were randomly assigned to either of the experimental arm or the control arm in a1:1 proportion. Allocation to the 2 treatment arms was done using stratified randomization basedon Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), previous immune checkpoint inhibitors (ICI) treatment (sequential versus combination with chemotherapy)and geographical region (Asia versus Western Europe and Australia and North America versusRest of the World [RoW]).

[0872] Participants continued to receive their assigned treatment until objective diseaseprogression, unacceptable toxicity, or upon participant’s request to stop treatment, or Investigatordecision, whichever occurred first.

[0873] After discontinuing randomized study intervention, the participant entered the follow upperiod. During the follow-up period, participants that discontinued the study treatment weretreated with standard of care per investigator discretion, and the details were collected as post-study treatment. In case the crossover phase was implemented after the time of the 58% interimanalysis of OS, participants enrolled to the docetaxel treatment arm were also allowed to receivecrossover treatment with tusamitamab ravtansine after documented disease progression.

[0874] The study was designed with 2 primary endpoints that were analyzed on randomizedparticipants at the time of the cut-off date for each given analysis (PFS and OS). Regardless ofthe outcome of PFS analysis, enrollment continued to have the final analysis of OS, unless theresult of either interim analysis of OS was overwhelming for efficacy or futility.Objectives and EndpointsStudy Design

[0875] This Phase 3, randomized, open-label, multicenter study compared tusamitamabravtansine 100 mg / m2(Arm A) and docetaxel 75 mg / m2(Arm B) in patients with metastatic non-squamous - NSCLC expressing CEACAM5 and previously treated with platinum-basedchemotherapy and an immune checkpoint inhibitor.

[0876] To identify non-squamous NSCLC patients with CEACAM5 positive tumors, there was aprescreening phase to perform prospective analyses of CEACAM5 expression on the most recentarchival tumor tissue. An in vitro diagnostic medical device manufactured for Sanofi was providedby a third party. This in vitro diagnostic medical device is a qualitative immunohistochemical assay under performance evaluation, called CEACAM5 IHC 769 assay. For this analysis, at least 5 × 4µm slides from FFPE archival tissue was sent to the central laboratory designated by the Sponsor.If less material was available, a participant could be eligible only after discussion with the Sponsor,confirmed that there may be sufficient material for key CEACAM5 expression analyses. In caseof unavailable archival tissue, a fresh biopsy was considered in participants who had reachablelesion that is suitable for biopsy. This prescreening activity was performed in advance, whenparticipant may be on prior anticancer therapy due to the progression of their underlying diseasecondition.

[0877] Screening visit was performed in patient whose tumor tissue analyses at central laboratorymeets the CEACAM5 expression of ≥2+ in intensity involving ≥50% of the tumor cell population.

[0878] The study had 3 main periods: screening, treatment and follow up. After being screenedthe eligible patients were randomized (1:1) to one of the following treatment arms:^ Treatment A: tusamitamab ravtansine (SAR408701) every 2 weeks (Q2W cycle) atthe dose of 100 mg / m2. ^Treatment B: Docetaxel every 3 weeks (Q3W cycle) at the dose of 75 mg / m2.

[0879] Treatment allocation was performed by an Interactive Response Technology (IRT). Alleligible patients were randomly assigned to either of the experimental arm or the control arm in a1:1 proportion. Allocation to the 2 treatment arms was done using stratified randomization basedon Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), previous ICI treatment (sequential versus combination with chemotherapy) and geographical region (Asia versus Western Europe + Australia + North America versus Rest of the World [RoW]). Duration of the study period

[0880] The duration of the study for a participant prescreened and CEACAM5 positive includeda period for screening of up to 28 days. The cycle duration was 14 days for tusamitamabravtansine and 21 days for docetaxel therapy.

[0881] The expected treatment period for participants who benefit from study intervention mayvary, based on progression date.

[0882] After discontinuation of study intervention, participants returned to the study siteapproximately 30 days (±5 days) (for end-of-treatment [EOT] assessments) after the last IMP administration or before the start of another anticancer therapy, whichever is earlier.

[0883] After the EOT visit, during the FU visits, the participants were monitored for all ongoingrelated AEs and regardless of relationship all the SAEs and adverse event of special interest (AESIs) until resolution or stabilization (i.e., an event ongoing without any change for at least 3 months).

[0884] All new related AEs, SAEs, or Events of Special Interest, including deaths were followeduntil resolution or stabilization.

[0885] For participants who have progressive disease, follow up visits were performed every 12weeks until OS study cut-off date or death (whichever comes first), unless the participant is allocated to crossover tusamimatab ravtansine treatment. In addition, if the participant discontinues study intervention for reasons other than progression, the participant should undergo a tumor assessment and a follow-up visit every 8 weeks until radiological disease progression, death, final study cutoff (OS cut-off date), or withdrawal of participant’s consent, whichever comes first.

[0886] The total estimated duration of enrollment were approximately 50 months. The expectedduration of treatment for participants who benefit from study intervention may vary, based on progression date; but median expected duration of study per participant is estimated as median9 months in docetaxel arm (1 month for screening, 4 months for treatment, and 4 months for theEOT and follow-up visits) and 12.5 months in the tusamitamab ravtansine arm (1 month forscreening, 6.5 months for treatment, and 5 months for EOT follow-up), excluding any potentialimpact of the crossover phase. 4.1.2 Crossover treatment phase (if implemented)

[0887] Crossover to tusamitamab ravtansine treatment was planned by the Sponsor forparticipants randomized to docetaxel upon progression, in the case that: ^the final PFS outcome is statistically significant, and^ statistical power for final analysis of the primary endpoint of OS is expected to notbe significantly altered.

[0888] The decision to implement the crossover phase were communicated to sites by theSponsor in writing after the final analysis of PFS / IA of OS at 58%. If The decision for eachparticipant to receive crossover treatment with tusamitamab ravtansine were based on theInvestigator’s discretion after documented PD per RECIST 1.1 as assessed by the Investigator and confirmed by the Sponsor after review of the eCRF data.

[0889] Intolerance to chemotherapy, withdrawal of consent, or clinical progression withoutdocumented radiological progression per RECIST 1.1 was not sufficient for eligibility for crossoverto tusamitamab ravtansine. Participants allocated to crossover tusamitamab ravtansine treatmentcame to the clinic every 2 weeks for treatment and follow-up procedures as detailed in Section1.3.2.

[0890] Treatment with tusamitamab ravtansine during the crossover phase continued untildisease progression, unacceptable AEs, participant’s decision to discontinue the study, orInvestigator discretion, whichever occurs first. An EOT visit will be performed 30 (±5) days after the last crossover dose for safety follow-up. Inclusion Criteria

[0891] Age

[0892] Participant were ≥18 years of age (or country’s legal age of majority if >18 years) at thetime of signing the informed consent.

[0893] Type of participant and disease characteristics

[0894] Histologically or cytologically proven diagnosis of non-squamous NSCLC metastaticdisease at study entry; - meeting all 3 of the following criteria:

[0895] Having progressive disease during or after platinum-based chemotherapy (at least 2cycles).

[0896] Maintenance therapy following platinum-based chemotherapy was not considered as aseparate regimen. Adjuvant / neoadjuvant treatment for a patient who had a relapse with metastatic disease during or within 6 months of completion of treatment will be considered as first line treatment.

[0897] and

[0898] Having progressive disease during or after one immune checkpoint inhibitor (anti-PD-1 / PD-L1); this could be given as monotherapy or in combination with platinum-based chemotherapy (whatever the order).

[0899] and

[0900] Participant with EGFR sensitizing mutation or BRAF mutation or ALK / ROS alterationsmust be able to demonstrate progression of the disease on approved treatments for these conditions, in addition to platinum-based chemotherapy and immune checkpoint inhibitor.

[0901] I 03. Participants with CEACAM5 expression of ≥2+ in intensity in archival tumor sample(or if not available fresh biopsy sample) involving at least 50% of the tumor cell population as demonstrated prospectively by a centrally assessed ICH assay. At least 5 × 4 µm slides fromFFPE tumor tissue were required. If less material is available, patient could still be eligible afterdiscussion with the Sponsor who assessed and confirmed that there is sufficient relevant materialfor key evaluations.

[0902] I 04. At least one measurable lesion by RECIST v1.1 as determined by local siteinvestigator / radiology assessment. Irradiated lesion can be considered measurable only if progression has been demonstrated on irradiated lesion.

[0903] I 05. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. Sex

[0904] Male or female

[0905] Contraceptive use by men or women should be consistent with local regulations regardingthe methods of highly effective contraception for those participating in clinical studies.

[0906] Male participants

[0907] Male participants: A male participant must agree to use contraception methods during theintervention period and for at least 6 months after the last dose of study intervention. Men being treated with docetaxel should be advised to seek advice on conservation of sperm prior to treatment.

[0908] Female participants

[0909] Female participants: A female participant was eligible to participate if she is not pregnant,not breastfeeding, and at least one of the following conditions applies:

[0910] Not a woman of childbearing potential (WOCBP).

[0911] or

[0912] A WOCBP who agrees to follow the contraceptive guidance during the intervention periodand for at least 7 months after the last dose of study intervention.

[0913] Informed Consent

[0914] Capable of giving signed informed.Inclusion Criteria for Crossover Treatment

[0915] Documented radiological progression per RECIST v1.1 as assessed by the Investigatorduring or after study treatment with docetaxel.

[0916] Written ICF for the crossover treatment phase was signed by the participant in compliancewith the requirements and restrictions listed in the ICF and in this protocol.

[0917] At least one measurable lesion by RECIST v1.1 as determined by local siteinvestigator / radiology assessment. An irradiated lesion was considered measurable only ifprogression was demonstrated on the irradiated lesion.

[0918] Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

[0919] Contraceptive use by men or women was consistent with local regulations regarding themethods of highly effective contraception for those participating in clinical studies. a) Male participants

[0920] Male participants: A male participant must agree to use contraception methods during theintervention period and for at least 6 months after the last dose of study intervention. Men being treated with docetaxel should be advised to seek advice on conservation of sperm prior to treatment.b) Female participants

[0921] Female participants: A female participant was eligible to participate if she was notpregnant not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP); OR A WOCBP who agrees to follow the contraceptive guidance during the intervention period and for at least 7 months after the last dose of study intervention. Exclusion Criteria

[0922] Participants were excluded from the study if any of the following criteria applied:Medical conditions E 01. Untreated brain metastases or history of leptomeningeal disease. Patients with previously treated brain metastases may participate provided they are stable (i.e., without evidence of progression) by imaging performed at least 4 weeks after CNS- directed treatment and at least 2 weeks prior to the first administration of study intervention, and any neurologic symptoms have returned to baseline; and there was no evidence of new or enlarging brain metastases; and the patient did not require anysystemic corticosteroids for management of brain metastases within 2 weeks prior to the first dose of study intervention. E2. Significant concomitant illnesses, including all severe medical conditions which, in theopinion of the investigator or Sponsor, would impair the patient’s participation in the study or interpretation of the results. E3. History within the last 3 years of an invasive malignancy other than the one treated inthis study, with the exception of resected / ablated basal or squamous-cell carcinoma of the skin or carcinoma in situ of the cervix, or other local tumors considered cured by local treatment. E4. History of known acquired immunodeficiency syndrome (AIDS) related illnesses orknown HIV disease requiring antiretroviral treatment, or active hepatitis A, B (defined as either positive HBs antigen or positive hepatitis B viral DNA test above the lower limit of detection of the assay), or C (defined as a known positive hepatitis C antibody result and known quantitative HCV RNA results greater than the lower limits of detection of the assay) infection. HIV serology at screening will be tested only for participants enrolled in German sites and any countries where mandatory as per local requirements.E 5. Nonresolution of any prior treatment related toxicity to < Grade 2 according to NCICTCAE v5.0, except for alopecia, vitiligo and active thyroiditis controlled with hormonal replacement therapy.E 6. Unresolved corneal disorders or any previous corneal disorder that considered byophthalmologist that patient may have higher risk of drug induced keratopathy. The use of contact lenses is not permitted. Patients using contact lenses who are not willing to stop wearing them for the duration of the study intervention.E 7. Medical conditions requiring concomitant administration of medications with narrowtherapeutic window, metabolized by CYPs and for which a dose reduction cannot be considered.E 8. Medical conditions requiring concomitant administration of strong CYP3A inhibitor),unless it can be discontinued at least 2 weeks before first administration of study intervention. Prior / concomitant therapyE 2. Concurrent treatment with any other anticancer therapy.E 3. Prior treatment with docetaxelE 4. Prior therapy targeting CEACAM5E 5. Prior maytansinoid treatment (DM1 or DM4 antibody drug conjugate)E 6. Washout period before the first administration of study intervention of less than 3 weeksor less than 5 times the half-life, whichever is shorter, for prior antitumor therapy (chemotherapy, targeted agents, immunotherapy and radiotherapy, or any investigational treatment.E 7. Any major surgery within the preceding 3 weeks of the first studyintervention administration.E 8. Contraindication to use of corticosteroid premedicationPrior / concurrent clinical study experienceE 9. Previous enrollment in this study and current participation in any other clinicalstudy involving an investigational study treatment or any other type of medical research. Diagnostic assessmentsE 10. Poor organ function as defined by any one of the following:^ Serum creatinine >ULN and eGFR <50 mL / min / 1.73 m2 as estimated using the aMDRDformula. Participants with elevated creatinine are eligible if eGFR ≥50 mL / min / 1.73 m2. ^Total bilirubin >1.0 × ULN.^ AST, ALT >2.5 × ULN or AST, ALT >1.5 × ULN concomitant with ALP >2.5 × ULN. ALP>5 × ULN with normal ALT / AST for patients with bone metastases. E11. Neutrophils <1.5 × 109 / L or platelet count <100 × 109 / L or hemoglobin <9 g / dLExclusion criteria added with amendment 5 for eligibility for the crossover treatment phase (if implemented)

[0923] A participant was considered ineligible for the crossover treatment phase if any of thefollowing criteria apply: Medical conditions

[0924] Untreated brain metastases or history of leptomeningeal disease. Participants with newlydiagnosed active brain metastases were treated with local therapy (such as stereotacticradiosurgery), and treatment-related acute toxicities were resolved before allocation to crossovertusamitamab ravtansine treatment.

[0925] Significant concomitant illnesses, including all severe medical conditions which, in theopinion of the investigator or Sponsor, would impair the patient’s participation in the study or interpretation of the results.

[0926] Nonresolution of any prior treatment related toxicity to Grade <2 according to NCI CTCAEv5.0, except for alopecia, vitiligo, and active thyroiditis controlled with hormone replacement therapy.

[0927] Unresolved corneal disorders or any previous corneal disorder considered by anophthalmologist to place the patient at higher risk of drug-induced keratopathy. The use of contact lenses is not permitted.

[0928] Medical conditions requiring concomitant administration of medications with a narrowtherapeutic window that are metabolized by CYPs (See Appendix 9, Section 10.9) and for which a dose reduction cannot be considered.

[0929] Medical conditions requiring concomitant administration of strong CYP3A inhibitor unlessit can be discontinued at least 2 weeks before first administration of study intervention. Prior / concomitant therapy

[0930] Participant received further line of anticancer treatment after docetaxel.

[0931] Concurrent treatment with any other anticancer therapy

[0932] Washout period before the first administration of tusamitamab ravtansine of less than 3weeks from the last dose of docetaxel.

[0933] Any major surgery within the 3 weeks preceding the first crossover tusamitamabravtansine treatment. Prior / concurrent clinical study experience

[0934] Current participation in any other clinical study involving an investigational study treatmentor any other type of medical research. Diagnostic assessment

[0935] The retreatment criteria are not met.

[0936] Poor renal function as eGFR <50 mL / min / 1.73 m2 per aMDRD formula.Study Interventions and Concomitant Therapy

[0937] Study intervention was defined as any investigational intervention(s), marketed product(s),placebo, or medical device(s) intended to be administered to a study participant according to thestudy protocol. Crossover tusamitamab ravtansine treatment was handled in the same manneras treatment in the main study phase Crossover tusamitamab ravtansine treatment was handledin the same manner as treatment in the main study phase.

[0938] Infusion via a central line was preferred, if available. In case of participants with localintolerance after peripheral IV infusion, the decision to use a central line was left to the Investigator’s decision.

[0939] Using an infusion-controlled pump, tusamitamab ravtansine was administered by IVinfusion over 1hour 30 minutes and docetaxel was administered by IV infusion over 1 hour.Prior to dosing, each participant's dose was individually prepared by the study pharmacist andlabeled with protocol number, participant number, and treatment description.On Day 1 of each treatment cycle, the patient’s BSA was determined using the current weightand baseline height; dose was not adjusted if body weight change is ≤5%. For patients with aBSA >2.2 m2, the dose was calculated based on 2.2 m2 BSA. After first study intervention oftusamitamab ravtansine, patients were observed for acute reactions at site up to 4 hoursdepending on any sign of drug induced allergic reaction. Non-investigational medicinal product Premedication^ Premedication for tusamitamab ravtansine:

[0940] Both SAR408701 and docetaxel had potential risk of infusion related allergic reaction andpremedication was used. All the drugs used as premedication was entered to the concomitantpremedication page.’

[0941] Premedication with histamine H1 antagonist (diphenylhydramine 50 mg PO or equivalent[e.g., dexchlorpheniramine] given approximately 1 hour before tusamitamab ravtansineadministration) was required for all participants. If a participant had previously experienced aninfusion related reaction in a previous tusamitamab ravtansine administration, premedication wasalso include dexamethasone 10 mg IV for future infusions. In case participant did not experienceany hypersensitivity reactions after 4 cycles, the pre-medications was discontinued at thediscretion of the investigator.^ Premedication for docetaxel:

[0942] Premedication consisting of oral corticosteroid, such as dexamethasone 16 mg per day(e.g., 8 mg BID dexamethasone or equivalent corticosteroids) for 3 days starting 1 day prior todocetaxel administration, unless contraindicated, reduced the incidence and severity of fluidretention as well as the severity of hypersensitivity reactions. For docetaxel premedication,product leaflet or site guidance on administration of docetaxel was followed.Preparation, Handling, Storage, and Accountability

[0943] The Investigator or designee confirmed appropriate temperature conditions had beenmaintained during transit for all study intervention received and any discrepancies were reportedand resolved before use of the study intervention.

[0944] Only participants enrolled in the study received study intervention and only authorized sitestaff supplied or administered study intervention. All study intervention was stored in a secure,environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the Investigator and authorized site staff.

[0945] The Investigator, institution, or the head of the medical institution (where applicable) wasresponsible for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, reconciliation, and final disposition records). Concomitant Therapy

[0946] Any medication or vaccine (including over-the-counter or prescription medicines, vitamins,and / or herbal supplements) that the participant was receiving at the time of enrollment or receivedduring the study was recorded along with:^ Reason for use^ Route of use^ Dates of administration including start and end dates

[0947] Concomitant medications were kept to a minimum during the study. However, if thesewere considered necessary for the patient's welfare and were unlikely to interfere with the IMP,they were given at the discretion of the investigator and recorded in the e-CRF. Concomitantmedication was recorded in the eCRF from 28 days prior to the first study interventionadministration, before every cycle during the study treatment period, and for up to 30 days afterthe final dose of study intervention. Once the participant was withdrawn from study treatment,concomitant medication was recorded if used to treat new or unresolved study treatment-relatedadverse events.

[0948] Concomitant medication was considered on a case-by-case basis by the Investigator, inaccordance with the following guidelines: ^Docetaxel is a CYP3A4 substrate. In vivo studies showed that the exposure ofdocetaxel increased 2.2-fold when it was co-administered with ketoconazole, a potent inhibitor of CYP3A4. Protease inhibitors, particularly ritonavir, may increase the exposure of docetaxel. Concomitant use of docetaxel and drugs that inhibit CYP3A4 may increase exposure to docetaxel and should be avoided. ^Palliative radiotherapy was given for control of pain for palliative intents. Sponsorwas notified to obtain prior approval prior to treatment if palliative radiotherapy wasbeing considered, and prior to resuming therapy on the study. The irradiated area should was as small as possible and wase never involved in more than 20% of thebone-marrow in any given 3-week period. In all such cases, the possibility of tumorprogression was ruled out by physical and radiological assessments of the tumor. Ifthe only evaluable lesions were to be irradiated, the participant stopped the studyintervention. The irradiated area was not used as a parameter for responseassessment. ^Any background therapy taken by the participant for concomitant illnesses other thancancer (e.g., hormone-replacement therapy, statin, antihypertensive medication) was allowed. ^Bone-targeting approved drugs (e.g., bisphosphonate or denosumab) were allowed ifthere was no dose increase within 12 weeks prior to the randomization in the current study, and the patient remained at the same dosage throughout the study treatment.

[0949] Supportive treatment as medically indicated for the patient's well-being was prescribed atthe Investigator's discretion. Every medication or treatment taken by the patient during the trial andthe reason for its administration was recorded on the eCRF.Dose Modification

[0950] For the retreatment of patients on Day 1 of each subsequent cycle, the following conditionswere met:^ Neutrophils count ≥1.5 x 109 / L.^ Platelets ≥100 x 109 / L.^ Total bilirubin ≤1.5 x ULN.^ AST, ALT ≤2.5 x ULN or ≤5 x ULN in case of documented liver metastasis.^ No IMP-related toxicity Grade >1 (except for alopecia) or baseline severity.

[0951] Dose adjustment and / or cycle delay were permitted in case of adverse reaction. In caseof toxicity, cycle delays and dose modifications were implemented. Every effort was made toadminister the full dose regimen and maximize dose intensity.

[0952] Dose adjustments were made according to the worst grade of adverse reaction observedwithin a cycle. If a participant experienced several adverse reactions and there were conflictingrecommendations, the most conservative dose adjustment was recommended. Administration ofthe study treatment was discontinued in the event of a TEAE that persisted despite appropriatedose modifications or any other AE that, in the opinion of the Investigator, warranted discontinuation.

[0953] Dose modifications different from those stated in the protocol was only made inconsultation with the Sponsor unless required for immediate participant safety. All changes tostudy treatment administration was recorded in the eCRF.

[0954] In the event of neutropenia, therapeutic G-CSF was administered according to the currentAmerican Society of Clinical Oncology (ASCO) guidelines. In case of neutropenia or febrileneutropenia, prophylactic G-CSF was started and in case of second episode beside prophylacticG-CSF, then dose was reduced.

[0955] The acceptable treatment windows for tusamitamab ravtansine and docetaxeladministrations were 3 days and 4 days respectively.

[0956] One dose reduction was allowed for a participant in either arm in the main study or for atusamitamab ravtansine crossover participant for a safety reason. Dose delay was allowed for safety management. Retreatment of patients that require more than 1 month dose delay needed to be justified with case-by-case risk-benefit assessment for guidance in dose modification ordiscontinuation. Approved product label was followed for patient receiving docetaxel treatment forsupportive care and dose modification requirement due to not listed adverse events. During theconduct of the study, if a second dose reduction was needed, it was decided upon case-by-casediscussion with the Sponsor.

[0957] In case a dose reduction is necessary, the study intervention was administered as follows:Study Assessments and Procedures ^Study procedures and their timing were summarized in the SoA (FIG. 2). Protocolwaivers or exemptions were not allowed. For a regional or national emergencydeclared by a governmental agency, contingency measures. ^Adherence to the study design requirements, including those specified in theSoA, was essential and required for study conduct. ^All screening evaluations was completed and reviewed to confirm that potentialparticipants meet all eligibility criteria. The Investigator maintained a screening log torecord details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable. ^Procedures conducted as part of the participant’s routine clinical management (e.g.,blood count) and obtained before signing of the ICF was utilized for screening orbaseline purposes provided the procedures met the protocol-specified criteria and were performed within the time frame defined in the SoA.^ In patients who prescreened failed limited information as collected as detailed tocharacterize patients that are most likely to express CEACAM5.

[0958] During screening period, demography, medical / surgical and disease history wasevaluated. Demography includes age, gender, race, and ethnicity. Medical / surgical historyincludes relevant history of previous pathologies and surgeries. Disease history included thehistologic types, stage at diagnosis and disease extend at study entry, specific mutations including PD-L1 expression status and previous antitumor therapy (type, start and end dates, reason for discontinuation and response to the therapy) and smoking history.

[0959] Demographic data (age, gender, race, ethnicity, smoking status); age, histology and stageat diagnosis and biomarkers when available [tumor mutation status including PD-L1 expressionstatus and circulating CEA) that were collected during prescreening visit was used for baselinedemographic (except for age at prescreening) and disease characteristics analysis. Age, disease extend at study entry and previous antitumor therapy (type, start and end dates, reason fordiscontinuation and response to the therapy) and change in smoking history was collected atscreening visit. Age at screening was considered as baseline demographic.Efficacy Assessments

[0960] The assessment of PFS and OS with tusamitamab ravtansine compared to docetaxelwere primary objectives.

[0961] All participants treated had at least 1 measurable lesion as per RECIST 1.1for inclusionbased on tumor assessment defined in SoA (FIG.2).

[0962] Tumor assessments were made every 8 weeks interval (±5 days window), and scheduledassessment time points were not modified in case of a cycle delay. Thoracic-abdominal-pelvicCT-scan or MRI and any other examinations as clinically indicated were performed to assessdisease status at baseline, then every 8 weeks during the study treatment period until radiologicaldisease progression or OS study cut-off, whichever came first, and at the end of study treatment,except if already done at last cycle. Participants who had EOT visits due to other reasons thanPD continued tumor assessment until documented PD or OS study cut-off. Tumor assessmentwas performed at EOT for patients and without imaging performed within past 4 weeks. Brain CT-scan or MRI were performed at baseline and followed only for patients with brain lesions atbaseline. Imaging assessments were scheduled using the randomization date as the referencedate for all time-points and were not scheduled based on the date of the previous imaging time-point. Imaging assessment delay to conform to treatment delay was not permitted. The sametumor assessment technique was used throughout the study for a given lesion / participant.

[0963] The tumor assessment images, excluding those performed during crossover treatmentphase, was transferred to the Independent Radiological review Committee for tumor responseevaluation.

[0964] Secondary efficacy variables included the overall response rate (ORR) and the durationof response (DoR).

[0965] The RECIST 1.1 (Response Evaluation Criteria in Solid Tumors) criteria was followed forassessment of tumor response.

[0966] For participants who crossed over to tusamitamab ravtansine after progression ondocetaxel treatment, tumor assessment was performed per site local practice starting from firstdose of crossover tusamitamab ravtansine treatment. There was no central reading of tumorimaging, and efficacy assessments were performed by the Investigator per RECIST 1.1. TheInvestigator reported the BOR and date of progression in the eCRF.Safety Assessments

[0967] Planned time points for all safety assessments were provided in the SoA (FIG. 2). Safetyassessments for participants receiving crossover tusamitamab ravtansine treatment wasperformed per SoA, and crossover safety analyses were conducted separately from those for themain study phase. 8.2.1 Physical examinations ^A complete physical examination included, at a minimum, assessments of theCardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height (at screening only) and weight was also measured and recorded.^ ECOG performance status was assessed before each IMP administration and at thefollow-up visit. ^Investigators payed special attention to clinical signs related to previous seriousillnesses. ^Any new finding or worsening of previous finding were reported as a new adverseevent. 8.2.2 Specific ocular test

[0968] Specific complete ocular tests at baseline and before the start of crossover tusamitamabravtansine treatment included the following: assessment of ocular / visual symptoms and ocularexams including visual acuity, slit lamp under dilatation, and Schirmer’s test.

[0969] Standard specific ocular tests include:^ Assessment of ocular / visual symptoms, (ie, blurred vision, photophobia, dry eye) ateach visit before each study intervention.^ Visual acuity at screening and whenever clinically indicated.^ Slit lamp under dilatation at screening and whenever clinically indicated.^ Schirmer’s test at screening and whenever clinically indicated.^ In participants with any ocular / visual symptom(s) (e.g., blurred vision, photophobia)the complete ocular tests will be repeated at the time of the occurrence of the ocular toxicity, if any regardless of the grade. Then, visual acuity, slit lamp examination under dilatation, and Schirmer’s test was repeated once weekly (if not recommended to haveless frequent assessment by ophthalmologist based on lesion characteristics) until resolution to Grade 1. In case of recurrent ocular toxicity observed in subsequent cycles, visual acuity and slit lamp examination under dilatation, and Schirmer’s test was performed at the time of the event onset, then weekly until resolution to Grade 1.Schirmer’s test is mandatory for baseline assessment; it can be omitted from further ocular assessments if not considered a required examination per reported events category (i.e., no symptom / findings of dry eye). .3 Vital signs^ Temperature and blood pressure was assessed.^ For blood pressure assessment, manual techniques as used only if anautomated device was not available.^ Blood pressure measurements were preceded by at least 5 minutes of rest for theparticipant in a quiet setting without distractions (e.g., television, cell phones). .4 Electrocardiograms^ Single 12-lead ECG was required at baseline, at each cycle during first 4 cycles oftusamitamab ravtansine arm and 3 cycles for docetaxel arm and then every other cycle during treatment period (even cycles for tusamitamab ravtansine and odd cycles for docetaxel) and at end of treatment for both arms as outlined in the SoA (FIG.2). ECG was repeated as clinically indicated. This test was performed before the studyintervention administration on the same day or the day before.^ In addition to before the infusion assessment, single 12-lead ECG was also requiredwithin 30 minutes after the EOI (End of Infusion) at Cycle 1 only for the tusamitamab ravtansine arm.^ Single 12-lead ECG as obtained using an ECG machine that automatically calculatesthe heart rate and measures PR, QRS, and QT intervals. .5 Clinical safety laboratory assessments

[0970] These tests were done at each cycle. During first 2 treatment cycles of the main studyphase as well as the crossover treatment phase, hematology, and liver function tests (i.e., ALT,AST, ALP, and total and direct bilirubin) were assessed weekly. If Grade 4 neutropenia occurred,ANC was assessed every 2-3 days until ANC ≥0.5 x 109 / L. In case of Grade ≥3 liver functionabnormal tests, additional tests were done every 2 to 3 days until recovery to baseline value.Additional tests were performed when clinically appropriate. Tests were performed on the sameday or within the 2 days before initiating study intervention.

[0971] Troponin was tested at baseline (at screening within 7 days of C1D1), at end of Cycle 4for tusamitamab ravtansine and Cycle 3 for docetaxel, and at EOT visit. If the crossover treatmentphase was implemented, troponin was tested before the first dose of tusamitamab ravtansine atthe Cycle 1-crossover visit; after the end of Cycle 4-crossover (before administration of tusamitamab ravtansine at the Cycle 5-crossover visit), and at the EOT-crossover visit.

[0972] The Investigator reviewed the laboratory report,.

[0973] All protocol-required laboratory assessments, as defined, were conducted in accordancewith the laboratory manual and the SoA. Hypersensitivity reactions

[0974] In case of hypersensitivity reactions, dose was modified or discontinued.Ocular toxicity

[0975] It was recommended that topical artificial tears (and / or hyaluronic ophthalmic gel) wereused regularly in all patients treated with tusamitamab ravtansine during the study treatment period.

[0976] The patient was asked about ocular / visual symptoms at each visit, and ocular evaluationincluding visual acuity, slit lamp examination under dilatation, and Schirmer’s test was carried onaccording to Study Procedures. Ocular evaluation was performed at baseline (during thescreening period and as a baseline safety assessment before the start of the crossover treatment), as required during the treatment and at the EOT visit (i.e., occurrence of ocularsymptoms such as blurred vision, photophobia, pain), and when relevant, at FU visit(s). Theoutcome of the examination was available before infusion of the next cycle. If ocular symptomswere present, then a formal ocular examination was performed. In patients with any ocular / visualsymptom(s) (e.g., blurred vision, photophobia) the ocular evaluation was repeated once weekly ifnot less frequent assessment recommended by ophthalmologist, until resolution to Grade 1. Thenthe patient was followed with ocular exam (Slit Lamp and visual acuity) at each cycle until totalresolution of the event.

[0977] Photographs of the cornea were recommended to be taken at the site, if possible, whenocular findings were first documented and to follow progression when relevant. Tonometry andadditional ocular assessment were performed at discretion of ophthalmologist when applicable.

[0978] After resuming study treatment, the patient who had Grade ≥2 keratopathy / keratitis wasfollowed with standard ocular exams (i.e., Slit Lamp examination under dilatation and Visual acuity) by every two cycles, even with no reported symptoms. If no recurrent event during the next four cycles, then regular follow-up (i.e., symptom assessment at each visit with standard ocular exam in case of any ocular sign / symptom) was applied.

[0979] Keratopathy / keratitis management

[0980] Reversible non-inflammatory, microcystic keratopathy was identified as the DLT duringthe dose escalation process in TED13751 study with tusamitamab ravtansine. At slit-lamp examination, it presents as lesions consisting of 100s to 1000s microcysts and / or deposits that are initially observed at the periphery of the cornea, the limbus being preserved. The lesions have a centripetal distribution and evolve towards the center of the corneal upon resolution, following the natural keratinocyte regeneration process.

[0981] For standardization of AE verbatim, keratopathy was preferred term unless otherwisespecified by ophthalmologist due to inflammatory findings on eye exams leading to diagnosis of keratitis.

[0982] The potential ocular / visual toxicity symptoms could include, but are not limited to, blurredvision, dry eye, and photophobia. Curative treatment was used as recommended by anophthalmologist.

[0983] No primary prophylaxis was recommended but prevention of dry eye with artificial tears and avoidance of using contact lenses as ensured during treatment period. Corticosteroidcontaining ocular drugs were recommended in case ocular symptom occurs for the managementof keratopathy / keratitis either and treatment was performed based on discretion ofophthalmologist.

[0984] Management of anemia

[0985] Patients were not started Cycle 1 treatment if hemoglobin was <9.0 g / dL. Red blood celltransfusion was allowed during the screening window, but a 2 weeks washout period was applied.During the treatment, erythrocyte transfusion was given, upon Investigator decision.Erythropoietin was given based on the discretion of the Investigator, except during screening andfirst cycle. Current clinical guidelines were followed for management of anemia.Management of neutropenia

[0986] In patients who experienced either febrile neutropenia, neutrophil count <500 cells / mm3for more than 1 week during study intervention, the prophylactic G-CSF was implemented toensure dose intensity and the dose was reduced in case of recurrent event even after prophylacticG-CSF use. If the patient continued to experience these reactions at lower dose, the treatmentwas discontinued.Liver function tests

[0987] Hepatic enzyme increase has been reported with tusamitamab ravtansine and docetaxeladministration as monotherapy. Patients were carefully followed and in case of Grade ≥3abnormal liver function tests, additional liver function tests will be done every 2-3 days untilrecovery to baseline value. Tusamitamab ravtansine was permanently discontinued in case ofdrug induced Grade 4 liver enzyme increase. For stopping rules for docetaxel administration,current product leaflet was followed. Grade ≥3 increase events were reported as adverse eventsof special interest (AESI). Peripheral neuropathy

[0988] Patients with a known history of peripheral neuropathies and / or patients takingmedications (e.g., prior anti-tubulin, platinum, and / or taxanes treatments) known to causeperipheral neuropathies were at high risk of developing neuropathy. Peripheral neuropathiespotentially present as signs and symptoms of sensory (paresthesia, dysesthesias, pain, and change in proprioception), motor (weakness), and neural dysfunctions. Gastrointestinal toxicity

[0989] Based on the clinical observation in TED13751 study, the following side effects have beenobserved regardless of causality: abdominal pain, colitis, constipation, diarrhea, dry mouth, erosive colitis (including ulcerative and hemorrhagic), nausea, stomatitis, and vomiting.

[0990] The monitoring of patients for GI toxicities relied on careful evaluation by routine historyand physical examination, and standard laboratory examination. Close surveillance of any signs and symptoms was required with additional routine blood hematology workup, Hemoglobin, hematocrit, WBC with differential, platelet counts, whenever indicated. As 1 case of Grade 4 erosive colitis reported, it was recommended to close surveillance of any diarrhea event withfurther exams when clinically indicated. Treatment was per patient condition based on investigatordiscretion. Adverse Events and Serious Adverse Events Adverse event of special interest

[0991] An adverse event of special interest (AESI) was an AE (serious or non-serious) of scientificand medical concern specific to the Sponsor’s product or program, for which ongoing monitoringand immediate notification by the Investigator to the Sponsor is required. Such events required further investigation in order to characterize and understand them. Adverse events of specialinterest were added, modified, or removed during a study by protocol amendment.^ Pregnancy of a female subject entered in a study as well as pregnancyoccurring in a female partner of a male subject entered in a study with IMP / NIMP; -Pregnancy occurring in a female participant entered in the clinical trial or in afemale partner of a male participant entered in the clinical trial. It was qualified asan SAE only if it fulfilled one of the seriousness criteria.- In the event of pregnancy in a female participant, IMP was discontinued.- Follow-up of the pregnancy in a female participant or in a female partner of amale participant is mandatory until the outcome was determined.Grade ≥3 keratopathy / keratitis ^Bundle branch blocks or any conduction defects^ Grade ≥3 liver enzyme increased (symptomatic or asymptomatic)^ Symptomatic overdose (serious or nonserious) with IMP / NIMP- An overdose (accidental or intentional) with the IMP / NIMP is an event suspectedby the Investigator or spontaneously notified by the participant and defined as at least 30% above the intended administered dose at each cycle expressed in unit per body surface. PHARMACOKINETICS

[0992] For patients treated with tusamitamab ravtansine during the main study phase, samples ofapproximately 1 mL were collected for measurement of plasma concentrations of tusamitamabravtansine during Cycle 1 at predose (within 48 hours before Start of Infusion), end-of-infusion (EOI; ±10 min), and at D3 (i.e., whenever between 24 hours and 72 hours after administration), at predose (within 24 hours before infusion) from Cycle 2 to Cycle 7, then every 6 cycles (i.e., Cycles13, 19, 25, etc). At Cycle 3, in addition to the predose sample, an EOI+1 hour (±10 minutes)sample were collected. Instructions for the collection and handling of biological samples wereprovided by the Sponsor. The actual date and time of each sample was recorded. These sampleswere tested by the Sponsor's designee. Pharmacokinetic sampling times are summarized in Table3.

[0993] Data from plasma concentrations of tusamitamab ravtansine were used for population PKanalysis by non-linear mixed effects modeling. Data from previously conducted studies were added for model development. This analysis involved an estimation of inter-patient PK variability,the determination of the population PK parameters estimates and the quantitative evaluation of potential effect of patient characteristics on the main PK parameters. Empirical Bayesian estimation of individual exposure parameters such as maximum concentration (Cmax), trough concentration (Ctrough) and area under the curve (AUC) were also performed. Those individual exposure parameters were then investigated as predictive factors for clinical outcomes includingsafety and efficacy endpoints, if possible. PHARMACODYNAMICS Circulating CEA

[0994] Circulating CEA levels collected at baseline and during the treatment and follow-up periodat the time of laboratory assessment as close as to tumor assessment (and no more than 1-2 weeks) until disease progression was assessed using local testing. Venous blood samples ofapproximately 3 mL (volume may change depending on local laboratory assay) were collected formeasurement at the local laboratory. Circulating CEA were collected during the crossovertusamitamab ravtansine treatment every 4 cycles (i.e., end of C4, C8, etc.) at the time of routinesafety lab assessment, before the next cycle. GENETICS

[0995] A 20 mL blood sample corresponding to about 10 mL of plasma for tumor cfDNA isolationand an additional 2 mL blood sample for germline DNA was collected at pre infusion of Cycle 1Day 1 from participants to perform the required genetic tests (unless not allowed by localauthorities). Samples were planned to be transferred to a centralized laboratory for cfDNA / DNAextraction and mutational profiling of key cancer genes to understand the significance of existing or acquired mutation during tusamitamab ravtansine treatment.

[0996] Fragmented cfDNA is released from the tumor in the plasma and can readily be extractedand analyzed for mutation of common cancer genes. Subtractive mutation analysis was performed with germline DNA data to identify tumor specific somatic genetic aberrations. Mutationprofiling analysis was performed and the potential correlation of specific mutation(s) with clinicaloutcomes were assessed.

[0997] List (not exhaustive) of the genes that could be mutated is: AKT1, ALK, BRAF, CDKN1B,CDKN2A, CDKN2D, EGFR, ESR1, FGFR4, HER2, HRAS, KRAS, MDM2, MED1, MET, NRAS, PIK3CA, PTEN, RB1, RET, ROS1, TP53. BIOMARKERS CEACAM5 expression in tumor tissue samples

[0998] At prescreening, determination of CEACAM5 positivity in tumors were performed by IHCon FFPE slides collected from the most recent available tumor samples or if not available from afresh biopsy. The tumor tissue samples were from primary tumor biopsy or metastatic site, butbone lesions were avoided, wherever possible. The level of CEACAM5 expression in tumortissues at prescreening was determined centrally using an in vitro diagnostic medical deviceprovided by a third party. CEACAM5 IHC 769 assay is a qualitative immunohistochemical assay using monoclonal mouse anti-CEACAM5, Clone 769 intended for use in the detection of CEACAM5 protein in FFPE non-squamous NSCLC tissue using EnVision FLEX visualizationsystem on Dako Omnis platform. Analysis was performed in a central laboratory and was used toassess clinical validity of IHC assay to select patients with CEACAM5 high expression.

[0999] For the analysis, at least 5 × 4 µm slides from FFPE tissue block (i.e., archive tumor tissueat diagnosis, archive tumor tissue at surgery, or most recent tumor sample) were required.

[1000] The positivity of CEACAM5 was defined by IHC with membrane staining at ≥2+ intensityof ≥50% of tumor cells. IMMUNOGENICITY

[1001] For patients treated with tusamitamab ravtansine during the main study phase, bloodsamples of approximately 6 mL were collected for measurement of antitherapeutic antibodies(ATAs) against tusamitamab ravtansine in plasma collected from all participants at predoseCycles 1, 2, 3, and 7, and then every 6 cycles (i.e., at predose Cycles 13, 19, 25,). It was requiredto collect the ATA samples at the same time of PK sampling of respective cycles. Additionally,blood samples were also collected at the final visit from participants who discontinued studyintervention or were withdrawn from the study (end-of-treatment (EOT). These samples were tested by the Sponsor's designee or the sponsor himself.

[1002] Plasma samples were screened for antibodies binding to tusamitamab ravtansine and thetiter of confirmed positive samples were reported. Other analyses were performed to verify thestability of antibodies to tusamitamab ravtansine and / or further characterize the immunogenicity of tusamitamab ravtansine by evaluating for their ability to neutralize the activity of tusamitamab ravtansine. Table 3 summarizes sample collection times for immunogenicity assessments. PATIENT-REPORTED OUTCOMES

[1003] Participants completed electronic patient-reported outcomes (ePROs) at predose on Day 1of Cycle 1 (up to within 3 days), then on Day 1 of every 2 docetaxel Cycles, or every 3 tusamitamab ravtansine Cycles (i.e., every 6 weeks) at the end of treatment visit and one more time at first follow-up visit. Completed questionnaires (ePROs) were always considered source document and werefiled accordingly. Participants completed ePROs in clinic (ePRO devices could not be taken home)and prior to having any tests and to any discussion of their progress with healthcare personnel atthe site. The instruments were given to the participant in the appropriate language for the site. Thetime estimated to complete the EORTC QLQ-C30 and the EORTC QLQ LC13 is approximately 10to 15 minutes. There was no ePRO assessment during the crossover tusamitamawb ravtansinetreatment phase. EORTC QLQ-C30

[1004] The EORTC QLQ-C30 (C30) was a validated, self-administered, 30-item, cancer specifichealth related quality of life (HRQOL) questionnaire. The C30 was a secondary endpoint in thisstudy. The recall period for the C30 was the past week. The C30 assessed global healthstatus / health-related quality of life (GHS / QoL), functioning, symptoms, and financial difficulties dueto disease or treatment related to cancer. For the GHS / QoL scale and the five functional scales(physical, role, emotional, cognitive, and social) higher scores indicated better GHS / QoL or function(higher scores better). C30 also assessed symptoms commonly reported by cancer patients andfinancial difficulties due to disease or treatment. For the three C30 symptom scales (fatigue, nausea & vomiting, and pain), five symptom items (dyspnea, insomnia, appetite loss, constipation, diarrheaand perceived financial difficulties item); lower scores indicated fewer symptoms / difficulties (lowerscores better). Items on the C30 were scored using the C30 scoring algorithms which standardized the raw scores to a 0-100 range. EORTC QLQ-LC13

[1005] The EORTC QLQ-LC13 (LC13) is the lung cancer module of the C30. The LC13 was asecondary endpoint in this study. The recall period for the LC13 was the past week. The LC13assessed lung-cancer-associated symptoms (cough, dyspnea, pain, hemoptysis) and side-effectsfrom conventional chemotherapy and radiotherapy (sore mouth, hair loss, dysphagia andneuropathy) that can impact the HRQOL of lung cancer patients. The EORTC QLQ-LC13contained 13 items. Items on the LC13 were scored using the LC13 scoring algorithms whichstandardized the raw scores to a 0-100 range. Lower scores indicated lowersymptomology / symptom burden (lower scores better). Results

[1006] Based on the Phase 3 CARMEN LC03 study comparing treatment between tusamitamabravtansine and docetaxel, it was found that there was no difference in survival (progression freesurvival and overall survival) between docetaxel and tusamitamab ravtansine. See for exampleFIG. 4 and FIG. 5 that show Kaplan-Meier plots for progression free survival. FIG. 7 shows theKaplan-Meier plot for progression free survival based on CEACAM5 expression of 90%. FIG. 6,shows progression free survival based on CEACAM5 terciles.

[1007] Similar results are shown between tusamitamab ravtansine and docetaxel for overallsurvival. FIG.9 shows the Kaplan-Meier plot for overall survival based on CEACAM5 expression of 90%. FIG.8 shows overall survival based on CEACAM5 terciles.

[1008] Finally, docetaxel as used in other clinical trials was compared with the docetaxel arm ofthe CARMEN LC03 study. As can be seen in FIG.10, docetaxel showed a better overall responserate (ORR) compared to the other clinical trials using docetaxel as well as better progression free survival and overall survival.Example 2 - Tusamitamab Ravtansine vs Docetaxel in Patients with Previously TreatedAdvanced Non-squamous NSCLC: Summary of Phase 3 CARMEN-LC03 Results

[1009] CARMEN-LC03 (NCT04154956) was a Phase 3 open-label, randomized, pivotal,multicenter study evaluating tusamitamab ravtansine (tusa rav; a CEACAM5-directed antibody- drug conjugate) versus docetaxel in patients with advanced non-squamous NSCLC previously treated with platinum-based chemotherapy and immunotherapy (in combination or sequential),whose tumors highly expressed CEACAM5. Here we present results from the prespecified final progression-free survival (PFS) and first interim overall survival (OS) analyses.

[1010] Methods: Adult patients were randomized 1:1 to intravenously receive either tusa rav 100mg / m2once every 2 weeks or docetaxel 75 mg / m2once every 3 weeks. Patients with CEACAM5 positivity (assessed by immunohistochemistry) of ≥ 2+ intensity involving ≥50% of tumor cells were included in the study. Multiple primary endpoints were PFS and OS. Key secondary endpoints were objective response rate (ORR), health-related quality of life (HRQoL), duration of response and safety.

[1011] Results: As of 22 September 2023, 194 patients were randomized to receive tusa rav andall patients received treatment; 195 were randomized to docetaxel of which 177 received treatment, 61 patients (n=36 tusa rav and n=25 docetaxel) remained on treatment. Most patients received 1 or 2 prior lines of therapy, had a median age of 64 years and majority were males (59.6%). Median follow-up was 7.4 and 18.1 months for PFS (by Independent Radiologic Committee [IRC]) and OS, respectively. Median PFS as per IRC -for tusa rav and docetaxel was 5.4 vs 5.9 months, respectively (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 0.86-1.51; p=0.820). Median OS (60% Information Fraction) of tusa rav vs docetaxel was 12.8 vs 11.5;HR=0.85 (95% CI [0.64–1.11]; p=0.112). Similar ORR was observed with tusa rav and docetaxel.Time to deterioration of disease related symptoms / physical functioning / role functioning were numerically prolonged with tusa rav (Figure 11). Grade≥ 3 treatment-related adverse events (TEAE) and treatment-related serious AEs, TEAE leading to discontinuation and dose reduction were lower with tusa rav, however dose delay was more frequently required for tusa rav, mainly due to corneal events. The incidence and severity of ocular AEs were consistent with previous studies of tusa rav, and no treatment-related sudden death was reported. Conclusions:

[1012] There was no statistical difference between tusa rav and comparator docetaxel in theFinal pre-specified PFS or interim OS analyses likely due to the unprecedented mediansurvival associated with docetaxel observed in this trial. CEACAM5 directed therapy didresult in a more favorable safety profile and electronic patient-reported outcomes.Example 3 - Exploratory analyses of Tusamitamab Ravtansine vs Docetaxel in PreviouslyTreated Non-squamous NSCLC patients: CARMEN-LC03

[1013] CARMEN-LC03 was a phase 3, open-label, randomized (1:1), multicenter study thatevaluated tusamitamab ravtansine (tusa rav), an antibody-drug conjugate with a microtubule- destabilizing payload (DM4), vs docetaxel in patients with advanced non-squamous non-small cell lung cancer (NSCLC) previously treated with chemotherapy and immunotherapy and whose tumors highly expressed CEACAM5 (defined as ≥2+ intensity in ≥50% of tumor cells assessed by immunohistochemistry [IHC]). The primary analysis showed that tusa rav did not improve progression-free survival (PFS), showed a trend towards improved overall survival (OS), favorable safety, toxicity profile, and patient-reported outcomes (PROs). Here we present results from post-hoc exploratory analysis of PFS and OS.

[1014] Methods: Patients were randomized to receive tusa rav 100 mg / m2 Q2W IV or docetaxel75 mg / m2Q3W IV. The two primary endpoints of PFS and OS were analyzed by stratified Cox regression model to estimate the hazard ratio (HR) and 95% confidence interval (CI) of tusa rav versus docetaxel in all randomized participants (intent-to-treat [ITT] population). Post-hoc exploratory analyses were performed for several subgroups of interest, including different cut-offfor CEACAM5-IHC expression, actionable genomic alterations (AGA), and prior taxane use (usingunstratified Cox-regression model).

[1015] Results: As of September 22, 2023, 194 patients were randomized to tusa rav and 195to docetaxel. Median age was 64 years; 59.6% were male. In patients without AGAs (that needed immunotherapy) and no prior taxanes (overlapping mechanism of action with tusa rav payload), OS favored tusa rav versus docetaxel with a HR (0.71 [0.52–0.98]), while PFS was not affected (HR=1.04 [0.75–1.45]). Both PFS (HR=0.87 [0.60–1.26]) and OS (HR=0.71 [0.49–1.03]) favoredtusa rav in participants with CEACAM5 ≥2+ in ≥80% tumor cells compared to population withCEACAM5 ≥2+ in 50–79% tumor cells (PFS: HR=1.38 [0.92–2.07], and OS: HR=1.01 [0.69– 1.50]). Dividing patients into terciles of CEACAM5 expression showed that patients with >90% achieved the greatest benefit (PFS, OS, and PROs) with tusa rav. Further analysis revealed that median OS substantially improved with increasing CEACAM5 expression, irrespective of treatment. In the post-hoc exploratory analyses, the greatest relative clinical benefit with tusa rav was observed among patients with CEACAM5 ≥90%, median OS (tusa rav vs docetaxel) was18.63m vs 15.24m, respectively (HR=0.65 [0.39–1.07]) See Figure 12.

[1016] Conclusions: These exploratory analyses identify patients likely to derive clinical benefitfrom tusa rav and suggest a previously unknown prognostic role for CEACAM5 in NSCLC. Additional research is needed to corroborate these findings.EMBODIMENTS OF THE DISCLOSURE

[1017] Embodiment 1 : a method of treating cancer in a subject, the method comprising: selectingthe subject for treatment if the subject is bearing a tumor that expresses CEACAM5 in at leastabout 50% of its tumor cells; administering to the subject an effective amount of a microtubule-targeting agent, thereby treating cancer in the subject.

[1018] Embodiment 2 : the method of any of the preceding embodiments, where the microtubule-targeting agent is a taxane, a maytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[1019] Embodiment 3 : the method of any of the preceding embodiments, wherein themicrotubule-targeting agent is a taxane selected from the group consisting of docetaxel,cabazitaxel, nab-paclitaxel, and paclitaxel.

[1020] Embodiment 4 : the method of any of the preceding embodiments, wherein themicrotubule-targeting agent is a vinca-alkaloid selected from vinblastine, vinorelbine, orvincristine.

[1021] Embodiment 5 : the method of any of the preceding embodiments, wherein themicrotubule-targeting agent is an auristatin selected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[1022] Embodiment 6 : the method of any of the preceding embodiments, wherein the subjectwas previously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor, or any combination thereof.

[1023] Embodiment 7 : the method of any of the preceding embodiments, wherein the platinum-based chemotherapies comprise cisplatin, oxaliplatin or carboplatin.

[1024] Embodiment 8 : the method of any of the preceding embodiments, wherein the check-point inhibitors comprise a PD-1 inhibitor, a PD-L1 inhibitor or combination thereof.

[1025] Embodiment 9 : the method of any of the preceding embodiments, wherein the cancer isselected from the group consisting of colorectal cancer, gastric cancer, gastroesophageal junctioncancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[1026] Embodiment 10 : the method of any of the preceding embodiments, wherein the cancer islung cancer.

[1027] Embodiment 11 : the method of any of the preceding embodiments, wherein the lungcancer is non-small cell lung cancer (NSCLC).

[1028] Embodiment 12 : the method of any of the preceding embodiments, wherein the NSCLCcomprises adenocarcinoma or squamous-cell carcinoma.

[1029] Embodiment 13 : the method of any of the preceding embodiments, wherein the NSCLCis non-squamous-cell carcinoma.

[1030] Embodiment 14 : the method of any of the preceding embodiments, wherein selecting thesubject for treatment if the subject is bearing a tumor that expresses CEACAM5 in at least about 90% of its tumor cells.

[1031] Embodiment 15 : the method of any of the preceding embodiments, wherein theCEACAM5 expression is measured by immunohistochemistry (IHC) or CEACAM5 gene expression levels.

[1032] Embodiment 16 : the method of any of the preceding embodiments, wherein the cancerexpresses CEACAM5 with moderate or high intensity as determined by immunohistochemistry.

[1033] Embodiment 17 : the method of any of the preceding embodiments, wherein theCEACAM5 expression comprises ≥2+ intensity in ≥50% of cells, the intensity measured by immunohistochemistry.

[1034] Embodiment 18 : the method of any of the preceding embodiments, wherein theCEACAM5 gene expression is determined by measuring levels of CEACAM5 mRNA.

[1035] Embodiment 19 : the method of any of the preceding embodiments, wherein themicrotubule targeting agent is an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[1036] Embodiment 20 : the method of any of the preceding embodiments, wherein the payloadis a maytansinoid.

[1037] Embodiment 21 : the method of any of the preceding embodiments, wherein themaytansinoid is selected from the group consisting of Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine(DM4).

[1038] Embodiment 22 : the method of any of the preceding embodiments, wherein the ADCcomprising the anti-CEACAM5 antibody is covalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[1039] Embodiment 23 : the method of any of the preceding embodiments, wherein themicrotubule targeting agent is tusamitamab ravtansine.

[1040] Embodiment 24 : the method of any of the preceding embodiments, wherein themicrotubule targeting agent is not tusamitamab ravtansine.

[1041] Embodiment 25 : the method of any of the preceding embodiments, wherein themicrotubule targeting agent is administered at a dose from about 20 mg / m2to about 200 mg / m2.

[1042] Embodiment 26 : the method of any of the preceding embodiments, wherein themicrotubule targeting agent is docetaxel.

[1043] Embodiment 27 : the method of any of the preceding embodiments, wherein themicrotubule targeting agent is administered intravenously.

[1044] Embodiment 28 : the method of any of the preceding embodiments, wherein the treatmentresults in a favorable clinical prognosis and is indicative of a progression free survival and / or an improvement in overall survival rates.

[1045] Embodiment 29 : use of CEACAM5 for predicting a response of a subject having a cancerto a treatment with an effective amount of a microtubule-targeting agent, wherein said usecomprises measuring an expression of CEACAM5 in isolated tumor cells from said subject andwherein an expression measured in at least about 50% of said isolated tumor cells is predictiveof a cancer responsive to said treatment.

[1046] Embodiment 30 : use of CEACAM5 for selecting a subject for a cancer treatment, saidtreatment being an effective amount of a microtubule-targeting agent, wherein said use comprisesmeasuring an expression of CEACAM5 in isolated tumor cells from said subject and selectingsaid subject for said treatment if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[1047] Embodiment 31 : use of a kit for in vitro prognosing and / or in vitro predicting a responseof a subject having a cancer to a treatment of cancer comprising a microtubule-targeting agent,wherein the kit comprises: (a) means for measuring, in isolated tumor cells obtained from saidsubject, an expression of CEACAM5, (b) means for comparing the expression measured in (a) with a reference value, wherein said reference value is an expression of CEACAM5 in at leastabout 50% of tumor cells, and wherein an expression measured in(a) above the reference valueis indicative that said subject will respond to said treatment.

[1048] Embodiment 32 : a microtubule-targeting agent for use in treating a cancer in a subject inneed thereof, said use comprising measuring an expression of CEACAM5 in isolated tumor cells from said subject and administering said microtubule-targeting agent to said subject if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[1049] Embodiment 33 : a method for screening a candidate agent for treating cancer, the methodcomprising at least the steps of: a) measuring a cell viability of cells before contacting said cellswith said candidate agent, said cells express CEACAM5 in at least about 50% of isolated tumorcells, b) measuring a cell viability of the cells after contacting said cells with said candidate agent,said cells expressing CEACAM5 in at least about 50% of isolated tumor cells, c) wherein adecrease of cell viability measured at step b) compared to the cell viability measured step a) is indicative of a candidate agent active for treating cancer with a microtubule-targeting agent.

[1050] Embodiment 34 : a method for predicting a response of a subject having a cancer to atreatment with an effective amount of a microtubule-targeting agent, said method comprising atleast a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject,wherein an expression measured in at least about 50% of said isolated tumor cells is predictiveof a cancer responsive to said treatment, wherein the microtubule-targeting agent is not tusamitamab ravtansine.

[1051] Embodiment 35 : a method for diagnosing and treating a subject having a cancer with aneffective amount of a microtubule-targeting agent, the method comprising at least a step ofmeasuring an expression of CEACAM5 in isolated tumor cells from said subject, and a step ofadministering said microtubule-targeting agent if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[1052] Embodiment 36 : a method for selecting a treatment of cancer for a subject having acancer, said method comprising at least a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject, and a step of selecting a treatment of cancer comprising a microtubule-targeting agent if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[1053] Embodiment 37 : a method for classifying a subject diagnosed with cancer into a patientcohort, said method comprising at least: a step of measuring an expression of CEACAM5 inisolated tumor cells from said subject, and a step of classifying said subject into a patient cohort characterized as responding to microtubule-targeting agent if an expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells.

[1054] Embodiment 38 : a microtubule-targeting agent for use in a treatment of a cancer in asubject having a cancer, said use comprising, prior to said treatment, identifying said subject as a responder to said a treatment of cancer comprising a microtubule-targeting agent by measuring an expression of CEACAM5 in isolated tumor cells from said subject, wherein an expression of CEACAM5 measured in at least about 50% of said isolated tumor cells is indicative that said subject is a responder to said treatment.

[1055] Embodiment 39 : a method of determining clinical prognosis of a subject having a cancerto a treatment of cancer comprising a microtubule-targeting therapy, said method comprising atleast: a step of measuring an expression of CEACAM5 in isolated tumor cells from said subject,and a step of classifying the subject as having a favorable clinical prognosis to said treatment ifthe expression of CEACAM5 is measured in at least about 50% of said isolated tumor cells, and optionally wherein the favorable clinical prognosis is indicative of a progression free survival and / or of an overall survival rates improvement.

[1056] Embodiment 40 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-39, wherein the microtubule-targeting agent is a taxane, a maytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

[1057] Embodiment 41 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-40, wherein the microtubule-targeting agent is a taxane selected from the group consisting of docetaxel, cabazitaxel, nab-paclitaxel, and paclitaxel.

[1058] Embodiment 42 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-41, wherein the microtubule-targeting agent is a vinca-alkaloid selected from vinblastine, vinorelbine or vincristine.

[1059] Embodiment 43 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-42, wherein the microtubule-targeting agent is an auristatin selected from monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

[1060] Embodiment 44 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-43, wherein the subject waspreviously treated with a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor, or any combination thereof.

[1061] Embodiment 45 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-44, wherein the platinum-basedchemotherapies comprise cisplatin, oxaliplatin or carboplatin.

[1062] Embodiment 46 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-45, wherein the check-point inhibitorscomprise a PD-1 inhibitor, a PD-L1 inhibitor, or a combination thereof.

[1063] Embodiment 47 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-46, wherein the cancer is selectedfrom the group consisting of colorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroidcancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer (e.g., cholangiocarcinoma), prostate cancer, and skin cancer.

[1064] Embodiment 48 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-47, wherein the cancer is lungcancer.

[1065] Embodiment 49 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-48, wherein the lung cancer is non-small cell lung cancer (NSCLC).

[1066] Embodiment 50 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-49, wherein the NSCLC comprisesadenocarcinoma or non-squamous-cell carcinoma.

[1067] Embodiment 51 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-50, wherein the subject is at leastabout 18 years old.

[1068] Embodiment 52 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-51, wherein the CEACAM5expression is measured by immunohistochemistry (IHC) or CEACAM5 gene expression levels.

[1069] Embodiment 53 : he method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-52, wherein the cancer expressesCEACAM5 with moderate or high intensity as determined by immunohistochemistry.

[1070] Embodiment 54 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-53, wherein the CEACAM5 isexpressed in at least about 90% of tumors.

[1071] Embodiment 55 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-54, wherein the CEACAM5expression comprises ≥2+ intensity in ≥50% of cells, the intensity measured by immunohistochemistry.

[1072] Embodiment 56 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-55, wherein the CEACAM5 geneexpression is determined by measuring levels of CEACAM5 mRNA.

[1073] Embodiment 57 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-56, wherein the microtubule targetingagent is an antibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule destabilizing payload.

[1074] Embodiment 58 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-57, where the payload is amaytansinoid.

[1075] Embodiment 59 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-58, wherein the ADC is tusamitamabravtansine

[1076] Embodiment 60 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-59, where the maytansinoid isselected from the group consisting of Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine(DM4), and Soravtansine (DM4).

[1077] Embodiment 61 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-60, wherein the ADC comprisingthe anti-CEACAM5 antibody is covalently attached via a cleavable or non-cleavable linker to the microtubule-targeting agent.

[1078] Embodiment 62 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-61, wherein the microtubule targetingagent is administered at a dose from about 20 mg / m2to about 200 mg / m2.

[1079] Embodiment 63 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-62, wherein the microtubule targetingagent is docetaxel.

[1080] Embodiment 64 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-63, wherein the microtubule targetingagent is administered intravenously.

[1081] Embodiment 65 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-64, wherein the microtubule targetingagent is tusamitamab ravtansine.

[1082] Embodiment 66 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-65, wherein the microtubule targetingagent is not tusamitamab ravtansine.

[1083] Embodiment 67 : the method, the microtubule-targeting agent for use, the use ofCEACAM5, or the use of a kit of any one of embodiments 29-66, wherein the treatment results ina favorable clinical prognosis and is indicative of a progression free survival and / or an improvement in overall survival rates.

[1084] Embodiment 68 : a method of treating cancer in a subject, the method comprising: (a)selecting the subject for treatment if the subject is bearing a tumor that expresses CEACAM5 inat least about 50% of its tumor cells; (b) administering to the subject an effective amount oftusamitamab ravtansine, such that the subject exhibits improved Quality of Life with respect to apatient who has been administered docetaxel.

[1085] Embodiment 69 : the method of embodiment 68, wherein the Quality of Life is assessedaccording to the quality of life (HRQOL) questionnaire.

[1086] Embodiment 70 : the method of embodiment 68, wherein the subject expressesCEACAM5 in at least about 90% of its tumors.

[1087] Embodiment 71 : the method of embodiments 68-70, wherein the cancer is lung cancer.

[1088] Embodiment 72 : the method of any one of embodiments 68-71, wherein the lung canceris non-small cell lung cancer (NSCLC).

[1089] Embodiment 73 : the method of any one of embodiments 68-72, wherein the NSCLCcomprises adenocarcinoma or squamous-cell carcinoma.

[1090] Embodiment 74 : the method of any one of embodiments 68-73, wherein the NSCLC isnon-squamous-cell carcinoma.

[1091] Embodiment 75 : a method of treating cancer in a subject, the method comprising: (a)selecting the subject for treatment if the subject is bearing a tumor that expresses CEACAM5 inat least about 50% of its tumor cells; (b) administering to the subject an effective amount oftusamitamab ravtansine, such that the subject exhibits reduced adverse events (AEs) with respectto a patient who has been administered docetaxel.

[1092] Embodiment 76 : the method of embodiment 75, wherein the AEs are Grade ≥3, all gradetreatment-related AES or Grade ≥3 treatment-related AEs.

[1093] Embodiment 77 : the method of embodiment 75, wherein the subject expressesCEACAM5 in at least about 90% of its tumors.

[1094] Embodiment 78 : the method of any one of embodiments 75-77, wherein the cancer islung cancer.

[1095] Embodiment 79 : the method of embodiments 75-78, wherein the lung cancer is non-smallcell lung cancer (NSCLC).

[1096] Embodiment 80 : the method of any one of embodiments 75-79, wherein the NSCLCcomprises adenocarcinoma or squamous-cell carcinoma.

[1097] Embodiment 81 : the method of any one of embodiments 75-80, wherein the NSCLC isnon-squamous-cell carcinoma.

[1098] Embodiment 82 : a method of treating cancer in a subject, the method comprising: (a)selecting the subject for treatment if the subject is bearing a tumor that expresses CEACAM5 at≥2+ intensity in at least about 80% of its tumor cells; (b) administering to the subject an effectiveamount of tusamitamab ravtansine, such that the subject exhibits improved survival with respectto a patient who has been administered docetaxel.

[1099] Embodiment 83 : the method of any of the previous embodiments, wherein the subjectexpresses CEACAM5 in at least about 90% of its tumor cells.

[1100] Embodiment 84 : the method of any of the previous embodiments, wherein the subject isintravenously administered tusamitamab ravtansine at 100 mg / m2once every 2 weeks.

[1101] Embodiment 85 : the method of any of the previous embodiments, wherein the subjectexhibits improved survival with respect to a patient who has been intravenously administered docetaxel at 75 mg / m2once every 2 weeks.

[1102] Embodiment 86 : the method of any of the previous embodiments, wherein the subjectexhibits improved progression free survival (PFS) or improved overall survival (OS).

[1103] Embodiment 87 : the method of any of the previous embodiments, wherein the cancer islung cancer.

[1104] Embodiment 88 : the method of any of the previous embodiments, wherein the lung canceris non-small cell lung cancer (NSCLC).

[1105] Embodiment 89 : the method of any of the previous embodiments, wherein the NSCLCcomprises adenocarcinoma or squamous-cell carcinoma.

[1106] Embodiment 90 : the method of any of the previous embodiments, wherein the NSCLC isnon-squamous-cell carcinoma.

Claims

CLAIMS1. A method of treating cancer in a subject, the method comprising:(a) selecting the subject for treatment if the subject is bearing a tumor that expresseshighly positively CEACAM5;(b) administering to the subject an effective amount of a microtubule-targeting agent,thereby treating cancer in the subject; wherein the microtubule-targeting agent is not tusamitamab ravtansine.

2. The method of claim 1, wherein the CEACAM5 expression is measured byimmunohistochemistry (IHC), CEACAM5 gene expression levels or circulating carcinoembryonic antigen (CEA) levels.

3. The method of claim 1 or 2, wherein the method comprises selecting the subject if the tumorexpresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 50% of the tumorcells, the CEACAM5 expression being measured by immunohistochemistry,optionally wherein the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 60% of the tumor cells, optionally wherein the tumor expresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 70% of the tumor cells, optionally wherein the tumor expresses CEACAM5 at an intensity of at least 2+ in greater thanor equal to 80% of the tumor cells, optionally wherein the tumor expresses CEACAM5 at an intensity of at least 2+ in greater thanor equal to 90% of the tumor cells.

4. A method of treating cancer in a subject, the method comprising:(a) selecting the subject for treatment if the subject is bearing a tumor that expressesCEACAM5 at an intensity of at least 2+ in greater than or equal to 80% of the tumorcells, the CEACAM5 expression being measured by immunohistochemistry; (b) administering to the subject an effective amount of a microtubule-targeting agent,thereby treating cancer in the subject.

5. The method of claim 4, wherein the method comprises selecting the subject if the tumorexpresses CEACAM5 at an intensity of at least 2+ in greater than or equal to 90% of the tumor cells.

6. The method of any one of the preceding claims, wherein the microtubule-targeting agent is ataxane, a maytansinoid, a vinca alkaloid, a colchicine, an auristatin, a pironectin, or a gatorbulin.

7. The method of any one of the preceding claims, wherein the microtubule-targeting agent is ataxane selected from the group consisting of docetaxel, cabazitaxel, nab-paclitaxel, and paclitaxel; or wherein the microtubule-targeting agent is a vinca-alkaloid selected from the group consistingof vinblastine, vinorelbine, and vincristine; orwherein the microtubule-targeting agent is an auristatin selected from the group consisting of monomethyl auristatin (MMAE) or monomethyl auristatin F (MMAF).

8. The method of any one of the preceding claims, wherein the subject was previously treatedwith a platinum-based chemotherapy, an immune check point inhibitor, an angiogenesis inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, an aplastic lymphoma kinase (ALK) inhibitor, a receptor tyrosine kinase (ROS1) inhibitor, or any combination thereof, optionally wherein the platinum-based chemotherapies comprise cisplatin, oxaliplatin or carboplatin, optionally wherein the check-point inhibitors comprise a PD-1 inhibitor, a PD-L1 inhibitor or combination thereof.

9. The method of any one of the preceding claims, wherein the cancer is selected from the groupconsisting of colorectal cancer, gastric cancer, gastroesophageal junction cancer, esophageal cancer, lung cancer, uterine cervix cancer, pancreatic cancer, ovarian cancer, thyroid cancer, bladder cancer, endometrial cancer, breast cancer, liver cancer, biliary tract cancer, cholangiocarcinoma, prostate cancer, and skin cancer.

10. The method of any one of the preceding claims, wherein the cancer is selected from the groupconsisting of pancreatic, prostate, colorectal and lung cancer.

11. The method of any one of the preceding claims, wherein the cancer is non-small cell lungcancer (NSCLC), optionally wherein the NSCLC comprises adenocarcinoma or squamous- cell carcinoma.

12. The method of claim 11, wherein the NSCLC is non-squamous-cell carcinoma.

13. The method of any one of claims 1-5 and 8-12, wherein the microtubule targeting agent is anantibody-drug conjugate (ADC) comprising an anti-CEACAM5 antibody conjugated to a microtubule targeting agent.

14. The method of claim 13, wherein the microtubule targeting agent is a microtubule destabilizingpayload.

15. The method of claim 14, wherein the microtubule destabilizing payload is a maytansinoid,optionally wherein the maytansinoid is selected from the group consisting of Ansamitocin, Mertansine, Emtasine (DM1), Ravtansine (DM4), and Soravtansine (DM4).

16. The method of any one of claims 13-15, wherein anti-CEACAM5 antibody is covalentlyattached via a cleavable or non-cleavable linker to the microtubule targeting agent.

17. The method of any one of the preceding claims, wherein the subject exhibits:a) improved Quality of Life, optionally wherein the Quality of Life is assessed accordingto the quality of life (HRQOL) questionnaire, and / orb) improved survival, and / or c) reduced adverse events (AEs), optionally wherein the AEs are Grade ≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs.

18. The method of claim 4 or 5, wherein the microtubule targeting agent is tusamitamabravtansine.

19. The method of claim 18, wherein the subject exhibits:a) improved Quality of Life, optionally wherein the Quality of Life is assessed accordingto the quality of life (HRQOL) questionnaire, and / orb) improved survival, and / orc) reduced adverse events (AEs), optionally wherein the AEs are Grade ≥3, all grade treatment-related AES or Grade ≥3 treatment-related AEs with respect to a patient who has been administered docetaxel.

20. The method of any one of claims 1-12, wherein the microtubule targeting agent is docetaxel.

21. The method of any one of the preceding claims, wherein the microtubule targeting agent isadministered at a dose from about 20 mg / m2to about 200 mg / m2, optionally wherein the microtubule targeting agent is administered intravenously.

22. The method of any one of the preceding claims, wherein the treatment results in a favorableclinical prognosis and is indicative of a progression free survival and / or an improvement in overall survival rates.

23. A method for predicting a response of a subject having a cancer to a treatment with aneffective amount of a microtubule-targeting agent, said method comprising at least a step of measuring an expression of CEACAM5 in a biological sample from said subject, wherein ahighly positive expression of CEACAM5 in said biological sample is predictive of a cancer responsive to said treatment.

24. Use of CEACAM5 as a biomarker for predicting a response of a subject having a cancer to atreatment with an effective amount of a microtubule-targeting agent, wherein said use comprises measuring an expression of CEACAM5 in a biological sample from said subject and wherein a highly positive expression of CEACAM5 in said biological sample is predictiveof a cancer responsive to said treatment.

25. A method of determining clinical prognosis of a subject having a cancer to a treatment ofcancer comprising a microtubule-targeting therapy, said method comprising at least: (i) a step of measuring an expression of CEACAM5 in a biological sample from saidsubject, and (ii) a step of classifying the subject as having a favorable clinical prognosis to saidtreatment if the expression of CEACAM5 is highly positive,optionally wherein the favorable clinical prognosis is indicative of a progression free survival and / or of an overall survival rates improvement.

26. Use of CEACAM5 as a biomarker for selecting a subject for a cancer treatment, said treatmentbeing an effective amount of a microtubule-targeting agent, wherein said use comprises measuring an expression of CEACAM5 in a biological sample from said subject and selectingsaid subject for said treatment if the expression of CEACAM5 is highly positive in saidbiological sample.

27. A method for diagnosing and treating a subject having a cancer with an effective amount of amicrotubule-targeting agent, the method comprising at least a step of measuring an expression of CEACAM5 in a biological sample from said subject, and a step of administeringsaid microtubule-targeting agent if the expression of CEACAM5 is highly positive in saidbiological sample.

28. A microtubule-targeting agent for use in treating a cancer in a subject in need thereof, saiduse comprising measuring an expression of CEACAM5 in a biological sample from said subject and administering said microtubule-targeting agent to said subject if the expression ofCEACAM5 is highly positive in said biological sample.

29. A microtubule-targeting agent for use in a treatment of a cancer in a subject, said usecomprising, prior to said treatment, identifying said subject as a responder to said treatment of cancer comprising a microtubule-targeting agent by measuring an expression of CEACAM5 in a biological sample from said subject, wherein a highly positive expression of CEACAM5 is indicative that said subject is a responder to said treatment.

30. A method for selecting a treatment of cancer for a subject having a cancer, said methodcomprising at least (i) a step of measuring an expression of CEACAM5 in a biological sample from saidsubject, and (ii) a step of selecting a treatment of cancer comprising a microtubule-targetingagent if the expression of CEACAM5 is highly positive in said biological sample.

31. A method for classifying a subject diagnosed with cancer into a patient cohort, said methodcomprising at least:(i) a step of measuring an expression of CEACAM5 in a biologic sample from saidsubject, and (ii) a step of classifying said subject into a patient cohort characterized as respondingto microtubule-targeting agent if the expression of CEACAM5 is highly positive insaid biological sample.

32. The method, the microtubule-targeting agent for use, or the use of CEACAM5 of any one ofclaims 23-31, wherein the expression of CEACAM5 is highly positive if said expressionconsists of at least 2+ intensity in greater than or equal to 50% of the biological sample, theexpression being measured by immunohistochemistry, wherein the microtubule-targeting agent is not tusamitamab ravtansine.

33. The method, the microtubule-targeting agent for use, or the use of CEACAM5 of any one ofclaims 23-31, wherein the expression of CEACAM5 is highly positive if said expressionconsists of at least 2+ intensity in greater than or equal to 80% of the biological sample, theexpression being measured by immunohistochemistry.

34. The method, the microtubule-targeting agent for use, or the use of CEACAM5 of claim 33,wherein the microtubule targeting agent is tusamitamab ravtansine.

35. The method, the microtubule-targeting agent for use, or the use of CEACAM5 of any one ofclaims 23-34, wherein the biological sample consists of isolated tumor cells.

36. A method for screening a candidate agent for treating cancer, the method comprising at leastthe steps of: a) measuring a cell viability of cells before contacting said cells with said candidate agent, said cells expressing highly positively CEACAM5, b) measuring a cell viability of the cells after contacting said cells with said candidate agent, said cells expressing highly positively CEACAM5, c) comparing the cell viabilities measured at step a) and b), wherein a decrease of cellviability measured at step b) compared to the cell viability measured step a) is indicative of a candidate agent active for treating cancer with a microtubule-targeting agent.