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 PD-L1 tumor expression score of TPS ≥1% assessed by a central 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, ROS1, or ALK mutations or gene rearrangements.
• Treatment with an anti-cancer agent within 28 days prior to GEN1046 administration.
• Any investigational agent for the treatment of stage 4 NSCLC.
• Radiotherapy within 14 days prior to first GEN1046 administration. If a subject received radiation therapy of >30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
• Chronic systemic immunosuppressive corticosteroid doses, ie, prednisone >10 mg daily or a cumulative dose >150 mg prednisone within 14 days before the first GEN1046 administration.
• Subject has contraindications to the use of pembrolizumab per local prescribing information.
• Ongoing or active infection requiring intravenous treatment with anti-infective therapy that has been administered <2 weeks prior to first dose.
• 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 GEN1046.
  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.