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

Inclusion criteria :

- Metastatic disease progression fulfilling both of the following 2 criteria:

1. Having progressive disease during or after platinum-based chemotherapy (at least
2 cycles). Maintenance therapy following platinum-based chemotherapy is not
considered as a separate regimen. Adjuvant/neoadjuvant treatment for a patient
who had a relapse with metastatic disease during or within 6 months of completing
treatment will be considered as first-line treatment.

AND

2. Having progressive disease during or after 1 immune checkpoint inhibitor
(anti-PD1/PD-L1); this could be given as monotherapy or in combination with
platinum-based chemotherapy (whatever the order).

- Participants with carcinoembryonic antigen-related cell adhesion molecule (CEACAM) 5
expression of ≥2+ in archival tumor sample (or if not available, fresh biopsy sample)
involving at least 50 % of the tumor cell population as demonstrated prospectively by
central laboratory via immune histochemistry (IHC).

- At least one measurable lesion by RECIST v1.1.

- Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

- A female participant who agrees to use effective contraceptive methods during and for
at least 7 months after the last dose of study intervention.

- A male participant who agrees to use effective contraception methods during and for at
least 4 months after the last dose of study intervention

- Signed informed consent

Exclusion criteria:

Participants are excluded from the study if any of the following criteria apply:

- Patients with untreated brain metastases and history of leptomeningeal disease.

- Significant concomitant illnesses that would impair the patient's participation in the
study or interpretation of the results.

- History within the last 3 years of an invasive malignancy other than the one treated
in this 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.

- Non-resolution of any prior treatment related toxicity to < grade 2 according to NCI
CTCAE V5.0, except for alopecia, vitiligo and active thyroiditis controlled with
hormonal replacement therapy

- History of known acquired immunodeficiency syndrome (AIDS) related illnesses or known
HIV disease requiring antiretroviral treatment, or unresolved viral hepatitis

- Previous history of and/or unresolved corneal disorders. The use of contact lenses is
not permitted.

- Radiographic evidence of major airway or blood vessel invasion or intratumor
cavitation

- History of uncontrolled hereditary or acquired arterial thrombotic disorder or history
of aneurism.

- Major surgery within 28 days prior to Day 1/first IMP infusion,. Postoperative
bleeding complications or wound complications from a surgical procedure performed in
the last 2 months.

- History of gross hemoptysis within 2 months before the first administration of study
intervention.

- Clinically relevant congestive heart failure (CHF; NYHA II-IV, or LVEF less than 50%)
or symptomatic or poorly controlled cardiac arrhythmia.

- Any arterial thrombotic event within 6 months before the first administration of study
intervention.

- Uncontrolled arterial hypertension (systolic ≥150 mmHg or diastolic ≥90 mmHg) despite
standard medical management.

- Serious or nonhealing wound, skin ulcer, or bone fracture within 28 days before the
first administration of study intervention.

- Gastrointestinal (GI) perforation and/or fistulae within 6 months prior to first
administration of study intervention.

- Significant bleeding disorders, vasculitis, or Grade 3-4 gastrointestinal (GI)
bleeding within 3 months before the first administration of study intervention.

- Bowel obstruction, history or presence of inflammatory enteropathy or extensive
intestinal resection Crohn's disease, ulcerative colitis, or chronic diarrhea.

- Medical condition requiring concomitant administration of a medication with a narrow
therapeutic window and metabolized by CYP450 or a strong CYP3A inhibitor

- Concurrent treatment with any other anticancer therapy

- No more than 1-line previous chemotherapy in metastatic setting

- Prior treatment with ramucirumab or docetaxel

- Prior therapy targeting CEACAM5 or maytansinoid treatment (DM1 or DM4 antibody-drug
conjugate)

- Contraindication to use of corticosteroid premedication

- Current therapeutic anticoagulation with warfarin, low-molecular-weight heparin, or
similar agents. Patients receiving prophylactic, low-dose anticoagulation therapy are
eligible

- Previous enrollment in this study, current participation in any other clinical study
involving an investigational study treatment, or any other type of medical research

- Poor bone marrow, liver or kidney functions

- Urine dipstick or routine analysis indicating proteinuria of 2+ or higher, unless a 24
hour urine collection demonstrates <1000 mg of protein.

- Sensitivity to any of the study interventions, or components thereof, or drug or other
allergy that, in the opinion of the Investigator, contraindicates participation in the
study.Most important exclusion criteria for potential participants

Triplet cohort exclusions

- History of active autoimmune disease that has required systemic treatment in the past
2 years.

- History of allogeneic tissue/solid organ transplantation.

- Active infection requiring IV systemic therapy within 2 weeks prior to first study
intervention administration or active tuberculosis.

- Interstitial lung disease or history of pneumonitis that has required oral or IV
steroids.

- Symptomatic herpes zoster within 3 months prior to screening.

- Significant allergies to humanized monoclonal antibodies.

- Any radiation therapy to lung >30 Gy within 6 months of first study intervention
administration.

- Has received or will receive a live vaccine within 30 days prior to the first study
intervention administration.

- Thyroid-stimulating hormone (TSH) out of normal limits. If TSH is not within normal
limits at baseline, the subject may still be eligible if T3 and free T4 are within the
normal limits

The above information is not intended to contain all considerations relevant to a patient's
potential participation in a clinical trial.