This is an exploratory, signal-finding, randomized, placebo-controlled, blinded, multi-center phase 2b trial of the anti-GDF-15 antibody Visugromab (CTL-002) at two different dose levels plus Nivolumab with Docetaxel versus Visugromab at the higher dose plus Nivolumab with placebo versus double-placebo with Docetaxel, in participants that receive second-line treatment for non-squamous NSCLC after failure of prior first-line treatment including a CPI (checkpoint inhibitor).

The trial consists of 3 Parts: an open-label Safety Run-in part (Part A) followed by a subsequent randomized phase 2b part with 4 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:

• Participants must have histologically or cytologically confirmed diagnosis of stage IV non-squamous NSCLC.
• Participants must have demonstrated absence of actionable mutations (e.g. EGFR, ALK, among others) that suggest/require treatment with available targeted agent.
• Participants must have failed one line of prior systemic treatment for metastatic NSCLC containing an approved anti PD (L)1 checkpoint inhibitor (CPI). The minimum treatment duration on this regimen must have been 12 weeks exposure for the CPI with no documented progression in this period. Failure of the prior line of systemic treatment for metastatic NSCLC must have occurred under ongoing CPI treatment. Discontinuation of the prior CPI and line of treatment due to AEs, or any other reason than progression/relapse does not permit enrollment.
• Participants must have measurable disease determined by the local site Investigator by their assessment per RECIST v1.1.
• Participants must have life expectancy of at least 3 months as assessed by the Investigator.
• Participants must have ECOG performance status ≤1.

Main Exclusion Criteria:

• Participants must not have received more than one line of prior systemic treatment for advanced/metastatic NSCLC.
• Participants must not have a prior malignancy requiring treatment.
• Participants must not have a 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 must not have any active autoimmune disease that has required systemic treatment in past 3 months before planned treatment start (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).
• Participants must not have interstitial lung disease or a history of (non-infectious) pneumonitis that required systemic steroids or current pneumonitis.

Throughout the randomized part of the trial, participants, Investigators, trial-assigned site staff (except for the pharmacists), the CRO (except for the unblinded clinical monitoring team), and imaging vendor will remain blinded to the information of which participant is receiving which IMP in Treatment Arms A, B and D, treatment assignment to the chemotherapy-free Arm C will be open label. Sponsor staff may be unblinded on an as needed basis.