Trial Outcomes & Findings for Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Pretreated Patients With NSQ NSCLC (CARMEN-LC04) (NCT NCT04394624)

Last Updated: 2025-06-06

Results Overview

The following AEs occurred during the first 2 cycles of treatment, unless due to disease progression or to a cause obviously unrelated to study drug, were considered DLTs: • Grade 4 neutropenia for 7 or more consecutive days. • Grade 3 to 4 neutropenia complicated by fever. • Grade \>=3 thrombocytopenia. • Elevated urine protein \>=3 gram(g)/24 hour. • Grade 4 non-hematologic AE. • Grade \>=3 keratopathy. • Grade 4 or refractory hypertension. In addition, any other AE that the Investigators and sponsor deemed to be dose limiting, regardless of its grade, was also considered as DLT.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

31 participants

Primary outcome timeframe

From Cycle 1 Day 1 up to Cycle 2 Day 14, approximately 28 days

Results posted on

2025-06-06

Participant Flow

The study was conducted at 10 centers in 5 countries. A total of 37 participants were screened between 31 August 2020 and 03 October 2022, of which 6 were screen failures. Screen failures were mainly due to not meeting the criteria for inclusion. The study was prematurely terminated due to the discontinuation of the overall development of tusamitamab ravtansine (SAR408701) by the sponsor.

A total of 31 participants were enrolled in the study. No participants were enrolled in the triplet cohort due to the early termination of the study.

Participant milestones

Participant milestones
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab Participants received tusamitamab ravtansine 100 milligram per square meter (mg/m\^2) and ramucirumab 8 mg per kilogram (kg) intravenous (IV) infusion every 2 weeks (Q2W) until disease progression, unacceptable adverse event (AE), or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Overall Study STARTED	31	0
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	31	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab Participants received tusamitamab ravtansine 100 milligram per square meter (mg/m\^2) and ramucirumab 8 mg per kilogram (kg) intravenous (IV) infusion every 2 weeks (Q2W) until disease progression, unacceptable adverse event (AE), or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Overall Study Adverse Event	6	0
Overall Study Progressive disease	24	0
Overall Study Not related to COVID-19	1	0

Baseline Characteristics

Tusamitamab Ravtansine (SAR408701) in Combination With Ramucirumab or Ramucirumab and Pembrolizumab in Pretreated Patients With NSQ NSCLC (CARMEN-LC04)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion Q3W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Total n=31 Participants Total of all reporting groups
Age, Continuous	62.7 years STANDARD_DEVIATION 10.1 • n=5 Participants	—	62.7 years STANDARD_DEVIATION 10.1 • n=5 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	—	16 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants	—	15 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	—	0 Participants n=5 Participants
Race (NIH/OMB) Asian	13 Participants n=5 Participants	—	13 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	—	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	—	0 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants	—	18 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	—	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	—	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Cycle 1 Day 1 up to Cycle 2 Day 14, approximately 28 days

Population: DLT-evaluable (Part 1) population included all enrolled participants who received 2 cycles with at least 80% of the intended dose for both tusamitamab ravtansine and ramucirumab at each of the 2 first infusions unless they discontinued the study intervention before the end of Cycle 2 due to a DLT.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=6 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort - Part 1: Number of Participants With Study Drug-Related Dose-Limiting Toxicity (DLT)	0 Participants	—

PRIMARY outcome

Timeframe: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.

The ORR is defined as percentage of participants with confirmed complete response (CR) or partial response (PR) as best overall response (BOR) determined per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. The CR is defined as disappearance of all target lesions. The PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort - Part 2: Objective Response Rate (ORR)	22.6 percentage of participants Interval 9.59 to 41.1	—

PRIMARY outcome

Timeframe: From Cycle 1 Day 1 up to Cycle 1 Day 21

Population: No participants were enrolled in the triplet cohort due to the early termination of the study.

The following AEs occurred during the first cycle of treatment, unless due to disease progression or to a cause obviously unrelated to study drug, were considered DLTs: • Grade 4 neutropenia for 7 or more consecutive days. • Grade 3 to 4 neutropenia complicated by fever. • Grade \>=3 thrombocytopenia. • Elevated urine protein \>=3 g/24 hour. • Grade 4 non-hematologic AE. • Grade \>=3 keratopathy. • Grade 4 or refractory hypertension. In addition, any other AE that the Investigators and sponsor deemed dose limiting, regardless of its grade, was also considered as DLT.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered. No participants were enrolled in the triplet cohort due to the early termination of the study.

An AE is any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study drug, whether or not considered related to the study drug. A SAE is defined as any untoward medical occurrence that, at any dose: results in death or life-threatening or requires inpatient hospitalization or prolongation of existing hospitalization or results in persistent disability/incapacity or congenital anomaly/birth defect. TEAE is defined as AEs that develop, worsen, or become serious during the treatment period.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Any treatment-emergent SAE	7 Participants	—
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) Any TEAE	31 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered. Only those participants with data collected are reported. No participants were enrolled in the triplet cohort due to the early termination of the study.

Blood samples were collected to determine the hematology laboratory clinically significant abnormalities.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology Anemia	19 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology White blood cell decreased	8 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology Neutrophil count decreased	8 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology Lymphocyte count decreased	11 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology Eosinophilia	12 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology Platelet count decreased	21 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology International normalized ratio increased	2 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Hematology Activated partial thromboplastin time prolonged	11 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Blood samples were collected to determine the clinically significant abnormalities in metabolism.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Metabolism Hypoglycemia	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Metabolism Hypoalbuminemia	16 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Metabolism Total protein: <Lower limit of normal	3 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Metabolism Total protein: >Upper limit of normal	4 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Blood samples were collected to determine the clinically significant abnormalities in electrolytes.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes Hyponatremia	15 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes Hypernatremia	2 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes Hypokalemia	7 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes Hyperkalemia	9 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes Hypocalcemia	6 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrolytes Hypercalcemia	5 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Blood samples were collected to determine the renal function laboratory clinically significant abnormalities.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Renal Function	10 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Blood samples were collected to determine the liver function laboratory clinically significant abnormalities.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function Alanine aminotransferase increased	19 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function Aspartate aminotransferase increased	21 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function Alkaline phosphatase increased	12 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function Blood lactate dehydrogenase increased	26 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Liver Function Total bilirubin increased	6 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

A single 12-lead ECG was recorded using an ECG machine that automatically calculates the heart rate and measures PR, QRS, and QT intervals.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) Heart Rate: >90 beats per minute (bpm)	22 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) Heart Rate: >90 bpm and increase from baseline >=20 bpm	13 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) Heart Rate: >100 bpm	14 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) Heart Rate: >100 bpm and increase from baseline >=20 bpm	8 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) Heart Rate: >120 bpm	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) PR Interval: >200 milliseconds (msec)	4 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) PR Interval: >200 msec and increase from baseline >=25%	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) PR Interval: >220 msec	2 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) PR Interval: >220 msec and increase from baseline >=25%	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QRS Interval: >110 msec	6 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QRS Interval: >110 msec and increase from baseline >=25%	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QRS Interval: >120 msec	2 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QT Interval: >500 msec	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QTcF Prolongation: >450 msec	8 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QTcF Prolongation: >480 msec	2 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QTcF Prolongation: >500 msec	1 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QTcF Prolongation: Increase from baseline [30-60] msec	9 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Electrocardiogram (ECG) QTcF Prolongation: Increase from baseline >60 msec	2 Participants	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Urine samples were collected to determine the clinically significant abnormalities in urine.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis Urine Protein: +	12 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis Urine Protein: Negative	8 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis Urine Protein: ++	3 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis Urine Protein: +++	2 Participants	—
Number of Participants With Potentially Clinically Significant Abnormalities: Urinalysis Urine Protein: ++++	1 Participants	—

SECONDARY outcome

Timeframe: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered. Only responders (participants with CR or PR with confirmation of response by investigator) were analyzed in this outcome measure.

The DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) determined per RECIST v1.1 or death from any cause, whichever occurs first. The PD is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=7 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort: Duration of Response (DOR)	11.07 months Interval 3.647 to Upper limit of 95% confidence interval was not calculable due to insufficient number of participants with events at study closure.	—

SECONDARY outcome

Timeframe: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.

The PFS is defined as the time from the first study drug administration to the date of the first documented disease progression or death due to any cause, whichever comes first.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort: Progression-Free Survival (PFS)	5.95 months Interval 5.355 to 9.101	—

SECONDARY outcome

Timeframe: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks

Population: All-treated population included all enrolled participants exposed to the study treatment, regardless of the amount of treatment administered.

The DCR is defined as the percentage of participants who achieved confirmed CR, confirmed PR or stable disease (SD) as per RECIST v1.1. The SD is defined as neither sufficient shrinkage from the baseline study to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort: Disease Control Rate (DCR)	83.9 percentage of participants Interval 66.27 to 94.55	—

SECONDARY outcome

Timeframe: Tumor assessments performed at baseline, and every 8 weeks +/-7 days thereafter, approximately 130 weeks

Population: No participants were enrolled in the triplet cohort due to the early termination of the study.

The ORR is defined as percentage of participants with confirmed CR or PR as BOR determined per RECIST v1.1.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 4

Population: The Pharmacokinetic (PK) population included all participants from the all-treated population with at least 1 post-baseline PK concentration with adequate documentation of dosing and sampling dates and times. Only participants analyzed and data collected at specific timepoints are reported.

Blood samples were collected for the measurement of Cmax of tusamitamab ravtansine concentrations. Cmax of tusamitamab ravtansine was calculated using non-compartmental method.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=6 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort: Maximum Observed Concentration (Cmax) of Tusamitamab Ravtansine Cycle 1 Day 1	70.0 microgram per milliliter (mcg/mL) Standard Deviation 11.9	—
Doublet Cohort: Maximum Observed Concentration (Cmax) of Tusamitamab Ravtansine Cycle 4 Day 1	82.5 microgram per milliliter (mcg/mL) Standard Deviation 16.3	—

SECONDARY outcome

Timeframe: Day 1 of Cycles 1 and 4

Population: The PK population included all participants from the all-treated population with at least 1 post-baseline PK concentration with adequate documentation of dosing and sampling dates and times. Only participants analyzed and data collected at specific timepoints are reported.

Blood samples were collected for the measurement of AUC0-14d of tusamitamab ravtansine concentrations. AUC0-14d was calculated using the trapezoidal method from time 0 to 14 days and non-compartmental method.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=6 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 14 Days (AUC0-14d) of Tusamitamab Ravtansine Cycle 1 Day 1	312 day*mcg/mL Standard Deviation 71.3	—
Doublet Cohort: Area Under the Plasma Concentration Versus Time Curve From Time 0 to 14 Days (AUC0-14d) of Tusamitamab Ravtansine Cycle 4 Day 1	459 day*mcg/mL Standard Deviation 26.8	—

SECONDARY outcome

Timeframe: Cycle 2 Day 1

Blood samples were collected for the measurement of Ctrough of ramucirumab concentrations. Ctrough was calculated using non-compartmental method.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=24 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Doublet Cohort: Concentration Observed Before Treatment Administration During Repeated Dosing (Ctrough) of Ramucirumab	32481.7 nanogram/mL Standard Deviation 11656.52	—

SECONDARY outcome

Timeframe: From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks

Population: The ATA population included all participants from the all-treated population with at least 1 post-baseline ATA result (negative, positive, or inconclusive). No participants were enrolled in the triplet cohort due to the early termination of the study.

Blood samples were collected to assess the presence of ATA against tusamitamab ravtansine in plasma from all participants. Treatment-emergent ATA is defined as participant with at least 1 treatment-induced/boosted ATA during the treatment period.

Outcome measures

Outcome measures
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 Participants Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150 mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mg IV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Number of Participants With Anti-Therapeutic Antibodies (ATAs) Against Tusamitamab Ravtansine	4 Participants	—

Adverse Events

Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab

Serious events: 7 serious events

Other events: 31 other events

Deaths: 13 deaths

Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab n=31 participants at risk Participants received tusamitamab ravtansine 100 mg/m\^2 and ramucirumab 8 mg/kg IV infusion Q2W until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.	Tusamitamab Ravtansine 100 mg/m^2 + Ramucirumab + Pembrolizumab Participants were planned to receive tusamitamab ravtansine 150mg/m\^2 plus ramucirumab 10 mg/kg and pembrolizumab 200 mgIV infusion every 3 weeks (Q3W) until disease progression, unacceptable AE, or the participant's or investigator's decision to stop the treatment.
Infections and infestations Abscess Limb	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Infections and infestations Pneumonia	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cutaneous T-Cell Lymphoma	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Psychiatric disorders Confusional State	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Respiratory, thoracic and mediastinal disorders Haemoptysis	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Respiratory, thoracic and mediastinal disorders Pleural Effusion	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Respiratory, thoracic and mediastinal disorders Pulmonary Haemorrhage	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Gastrointestinal disorders Colitis Ulcerative	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Hepatobiliary disorders Hepatic Function Abnormal	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
Renal and urinary disorders Renal Impairment	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
General disorders Disease Progression	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.
General disorders Multiple Organ Dysfunction Syndrome	3.2% 1/31 • Number of events 1 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.	— 0/0 • From first dose of study drug (Day 1) up to Day 30 post last dose of study drug, approximately 134 weeks Analysis was performed on all-treated population. No participants were enrolled in the triplet cohort due to the early termination of the study.

Other adverse events

Additional Information

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