This is a multicenter, randomized, open-label, international, Phase 3 trial to evaluate the efficacy and safety of acasunlimab in combination with pembrolizumab versus docetaxel (standard of care) in participants with locally advanced (unresectable stage IIIB/C) or programmed death ligand 1 (PD-L1)-positive metastatic non-small cell lung cancer (NSCLC) who have been treated with programmed cell death protein 1 (PD-1)/PD-L1 inhibitor and platinum-containing chemotherapy, administered either in combination or sequentially in the locally advanced (unresectable stage IIIB/C) or metastatic setting.

The goal of this trial is to determine the efficacy and safety of acasunlimab (an experimental antibody also known as GEN1046 or DuoBody® PDL1x4-1BB) in combination with pembrolizumab (an antibody known as KEYTRUDA®) compared to that of docetaxel (a standard of care chemotherapy). During the trial, the participant's quality of life will also be evaluated using industry-standard scales of measurement. To be eligible, participants must have:

1. non-small cell lung cancer that are locally advanced, unresectable stage IIIB/C or has metastasized (spread)
2. tumors that are positive for the PD-L1 protein (a biomarker that may be predictive of response to therapy)
3. been previously treated with a PD-1/PD-L1-inhibitor and a platinum-containing cancer therapy administered in combination or sequentially (irrespective of the order).

Other eligibility criteria will also apply.

Participants will be assigned to 1 of 2 active therapies, also known as treatment arms, as follows:

• Acasunlimab (100 milligrams [mg]) and pembrolizumab (400 mg) once every 6 weeks (Q6W), or
• Docetaxel 75 milligrams per meter squared (mg/m^2) once every 3 weeks (Q3W).

The estimated trial duration for a participant will vary but may be up to 5 years, consisting of:

• An optional 3-month pre-screening period
• A 28-day screening period
• Up to 2 years of treatment
• A 90-day safety follow-up period
• Post-treatment follow-up.

Key Inclusion Criteria:

• Participant has histologically or cytologically confirmed locally advanced (unresectable stage IIIB/C) or metastatic NSCLC (stage IV) with known subtype.

• Participant has progressed radiographically on or after receiving:

  • One prior line of therapy (PD-1/PD-L1 inhibitor and platinum-based chemotherapy concomitantly) in the locally advanced (unresectable stage IIIB/C) or metastatic disease setting; OR
  • No more than 2 prior lines of therapy (PD-1/PD-L1 inhibitor and platinum-based chemotherapy sequentially, irrespective of the order) in the locally advanced (unresectable stage IIIB/C) or metastatic disease setting.

• Participant must have positive tumor PD-L1 expression (tumor cells ≥1%) determined prospectively on a tumor sample from the locally advanced (unresectable stage IIIB/C) or metastatic setting at a sponsor-designated central laboratory.

• Participant has measurable disease according to RECIST v1.1 as assessed by the investigator at baseline.

• Participant has an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 within 7 days of Cycle 1 Day 1.

• Participant has a life expectancy of ≥3 months.

• Participant must have adequate organ and bone marrow function, per laboratory test results within 7 days of trial treatment.

Key Exclusion Criteria:

• Documentation of known targetable epidermal growth factor receptor (EGFR) sensitizing mutations, anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET), ROS proto-oncogene 1; receptor tyrosine kinase (ROS1) rearrangement, Kirsten rat sarcoma virus (KRAS), B-Raf proto-oncogene (BRAF) mutations, and MET proto-oncogene; receptor tyrosine kinase (MET) exon 14 skipping mutations/MET amplification. NOTE: MET amplification testing is optional based on local availability of the test.

  • Participants with known KRAS/BRAF mutations are eligible for the trial if they do not have access to targeted therapies.

• Participants with newly identified, untreated or unstable or symptomatic central nervous system (CNS) metastases or history of carcinomatous meningitis.

• Prior treatment with docetaxel for NSCLC.

• Prior treatment with a 4-1BB (CD137) targeted agent, any type of antitumor vaccine, autologous cell immunotherapy, or any unapproved immunotherapy.

• Treatment with an anticancer agent within 28 days prior to the first dose of trial treatment.

Note: Other protocol-defined inclusion and exclusion criteria may apply.