This is an exploratory, signal finding, randomized, placebo-controlled, blinded, multi-center Phase 2b trial of the anti GDF-15 antibody Visugromab (CTL-002) versus Placebo, combined with Immunochemotherapy (ICT: Pembrolizumab, Pemetrexed, Carboplatin) in the first-line treatment of participants with newly diagnosed metastatic non-squamous NSCLC. The trial consists of 3 Parts, a non-randomized Safety-run-in part (Part A) and the subsequent randomized Ph2b trial with 2 treatment arms. After the treatment of 15 participants with visugromab at the expansion dose, an interim safety and preliminary efficacy analysis will be conducted (Part B), followed by the treatment of the remaining participants (Part C).

Main Inclusion Criteria:

• Histologically confirmed, newly diagnosed stage IV non-squamous NSCLC.
• Demonstrated absence of actionable mutations (e.g., EGFR, ALK, among others) that suggest/require treatment with available targeted agent.
• Measurable disease determined by the local site Investigator/radiology by their assessment per RECIST v1.1.
• Have not received prior systemic treatment for advanced/metastatic NSCLC. Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of metastatic disease and did not contain any PD 1/PD L1 directed CPI therapy.
• Availability of locally determined PD L1 TPS, determined with a test validated for this purpose, from a tumor tissue biopsy obtained after any potential prior systemic treatment for this disease. Participants with PD-L1 TPS ≥ 50% can only be enrolled in case CPI monotherapy is not clinically indicated.
• Availability of a tissue/histological biopsy for translational research investigations and Informed Consent Form (ICF) for biopsy release for translational research signed by participant. The biopsy has to be obtained after any potential prior systemic treatment for this disease and be available for shipment. A cytological sample is not accepted.
• Age ≥ 18 years on the day of signing the informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
• Adequate organ function (bone marrow, hepatic, renal function and coagulation).

Main Exclusion Criteria:

• Presence of predominantly squamous cell histology or predominantly neuroendocrine histology NSCLC (mixed tumors will be categorized by the predominant cell type) or presence of small cell lung cancer elements (ineligibility independent of percentage).
• Any acute or chronic major tissue injury that may require maintained GDF 15 function for tissue protection as per Investigator assessment (diagnosed with myocardial infarction, or liver, kidney or other major organ failure, all within < 3 months prior to planned treatment start).
• Major surgery (defined as a surgery which requires general anesthetic and/or involves opening of body cavities), within 4 weeks of the first dose of study drug.
• Received potentially curative radiation therapy to the lung that is > 30 Gy within 6 months prior to the first dose of study drug.
• Received or completed any focal radiotherapy for symptoms within 28 days of the first dose of study drug.
• Expected to require any other form of antineoplastic therapy while on trial.
• Clinically active inflammatory bowel disease, active diverticulitis, intra-abdominal abscess, and/or gastrointestinal obstruction.
• Known history of prior malignancy with the exception that the participant has undergone potentially curative therapy with no evidence of that disease recurrence for 5 years since initiation of that therapy.
• Known or detected clinically active central nervous system (CNS) involvement by NSCLC or other tumors, e.g., with symptomatic metastases and/or carcinomatous meningitis. Participants with CNS involvement may be enrolled with mandatory regular imaging of the brain under protocol-defined conditions.
• Have one of the following cardiovascular risk factors: myocardial infarction in the past 3 months before planned treatment start; uncontrolled heart failure; uncontrolled ventricular arrhythmia; QT interval corrected for heart rate using Fridericia's formula interval ≥ 470 ms regardless of sex; peri/myocarditis in the past 3 months before planned treatment start; history of ischemic stroke in the past 3 months before planned treatment start.
• Any active autoimmune that has required systemic treatment in the past 3 months before planned treatment start (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
• Comedication with metformin or metformin-containing antidiabetics in participants with type II diabetes.
• Has interstitial lung disease or a history of non-infectious pneumonitis that required systemic steroids or current pneumonitis.
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial.

Participants, Investigator and Site trial team, Sponsor and Service Providers' trial teams (including Imaging vendor) are blinded