The goal of this clinical trial is to compare the safety and efficacy (how well the drug works) of acasunlimab (also known as GEN1046) when it is used alone (monotherapy) versus when it is combined with a cancer drug (pembrolizumab) for participants with relapsed/refractory (disease has returned after treatment or did not respond to treatment) non-small cell lung cancer (NSCLC; the most common type of lung cancer).

This trial has 2 parts. The purpose of the first part is to find out if the combination of acasunlimab and pembrolizumab is safe and to find out the best doses to use. The purpose of the second part is to give acasunlimab and pembrolizumab to more participants to evaluate efficacy. In the second part of the trial, participants will be randomized to participate in 1 of the 3 arms of the trial. Randomized means that the participant will be randomly assigned to a treatment arm based on chance; no one chooses their treatment arm.

Participants will receive either acasunlimab alone (100 followed by 500 mg into the vein) or acasunlimab with pembrolizumab (200 or 400 mg into the vein) once every 3 or 6 weeks, depending on which arm the participant is randomized into. All participants will receive active drug; no one will receive placebo.

Trial details include:

• The average trial duration for an individual participant will be about 10 months.
• The average treatment duration for an individual participant will be about 6 months.
• The visit frequency will be weekly at first and lessening over time until visits are only once every 3 weeks.

Key Inclusion Criteria:

• Have signed an informed consent form (ICF)
• Be at least 18 years of age.
• Have histologically or cytologically confirmed diagnosis of stage 4 NSCLC with at least 1 prior line of systemic therapy containing an anti-PD-1/PD-L1 mAb for metastatic disease
• Have a tumor PD-L1 expression result available prior to first treatment demonstrating PD-L1 expression in ≥1% of tumor cells as assessed by a central or local laboratory during screening.
• Have measurable disease per RECIST v1.1.
• Have Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1.
• Have life expectancy of at least 3 months.
• Have adequate organ and bone marrow function as defined in the protocol.

Key Exclusion Criteria:

• Documentation of known EGFR, KRAS, RET, ROS1, BRAF mutations, NTRK gene infusions, RET arrangement, ALK gene rearrangements, high-level MET amplification, or METex 14 skipping. Note: Subjects harboring such mutations, gene rearrangements or amplifications may be enrolled in the trial, if subjects have received prior approved targeted therapy for such mutations, the subject may still be eligible for this trial.

• Treatment with an anti-cancer agent within 28 days prior to acasunlimab administration.

• Any investigational agent (including investigational vaccines).

• Radiotherapy within 14 days prior to first dose of acasunlimab. Note: palliative radiotherapy will be allowed for local pain control under certain conditions.

• Chronic systemic immunosuppressive corticosteroid doses, ie, prednisone >10 mg daily or a cumulative dose >150 mg prednisone within 14 days before the first acasunlimab administration.

• Subject has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.

• Subject has contraindications to the use of pembrolizumab per local prescribing information.

• Subject has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis (interstitial lung disease).

• Ongoing or active infection requiring intravenous treatment with anti-infective therapy or any ongoing systemic inflammatory condition requiring further diagnostic work-up or management during screening.

• Symptomatic congestive heart failure (grade III or IV as classified by the New York Heart Association), unstable angina pectoris, or cardiac arrhythmia.

• Uncontrolled hypertension defined as systolic blood pressure ≥160 mmHg and/or diastolic blood pressure ≥100 mmHg, despite optimal medical management.

• Ongoing or recent (within 6 months) evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments, which may suggest risk for irAEs.

• Subject has a known history of any of the following:

  1. Grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy treatment.
  2. Myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade.
  3. Liver disease (eg, alcoholic hepatitis or non-alcoholic steatohepatitis, drug-related or autoimmune hepatitis, or evidence of hepatic cirrhosis).
  4. Organ allograft (except for corneal transplant) or autologous or allogeneic bone marrow transplant, or stem cell rescue within 3 months prior to the first dose of acasunlimab.
  5. Grade 3 or higher allergic reactions to monoclonal antibody therapy as well as known or suspected allergy or intolerance to any agent given in the course of this trial.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.