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 or received lung radiation therapy of >30 Gy within 6 months of the first dose of trial treatment. Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. 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 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 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:  Grade 3 or higher irAEs that led to treatment discontinuation of a prior immunotherapy treatment. Myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade. Liver disease (eg, alcoholic hepatitis or non-alcoholic steatohepatitis, drug-related or autoimmune hepatitis, or evidence of hepatic cirrhosis). 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. 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.