The goal of this trial is to learn about the antibody GEN1042 when it is used alone and when it is used together with another antibody cancer drug, pembrolizumab (with or without chemotherapy), for treatment of participants with certain types of cancer.

This is an open-label, multicenter phase 1/2 study designed to assess the safety, pharmacokinetics, pharmacodynamics and anti-tumor activity of GEN1042 administered as a monotherapy or in combination in participants with metastatic or locally advanced solid tumors.

Participants will receive either GEN1042 alone, GEN1042 with pembrolizumab, or GEN1042 with pembrolizumab and chemotherapy. All participants will receive active drug; no one will receive placebo.

This trial has 2 parts. The purpose of the first part is to find out if GEN1042 is safe and to find out the best doses of GEN1042 to use. The purpose of the second part is to give GEN1042 to more participants to see how well the dose(s) of GEN1042 selected in the first part work against cancer with GEN1042 when given alone or in combination with pembrolizumab or in combination with pembrolizumab and chemotherapy.

Trial details include:

• The average trial duration will be about 2 years and 4 months.
• The treatment duration will be up to 2 years (when GEN1042 is combined with pembrolizumab).
• The visit frequency will be weekly at first and lessening over time until visits are only once every 3 weeks.

A long-term extension phase (LTEP) has been added to allow continued access to trial treatment for up to 2 years from the individual participant's Cycle 1 Day 1 visit.

Key Inclusion Criteria:

Monotherapy - Dose Escalation and Dose Expansion Parts

• Participants with non-CNS solid tumors that is metastatic or unresectable and for whom there is no available standard therapy.
• Participants with a confirmed diagnosis of relapsed or refractory, advanced and/or metastatic melanoma, NSCLC, or CRC and for whom there is no available standard therapy

Combination Therapy - Dose Expansion Part

• Participants with unresectable Stage III or Stage IV melanoma with no prior systemic anticancer therapy for unresectable or metastatic disease. Primary ocular or mucosal melanoma is excluded.
• Participants with Stage IV metastatic or recurrent NSCLC with no prior systemic anticancer therapy, no actionable mutation.
• Participants with recurrent or metastatic HNSCC with no prior systemic therapy administered in the recurrent or metastatic setting.
• Participants with confirmed metastatic PDAC with no previous radiotherapy, surgery, chemotherapy, or investigational therapy for the treatment of metastatic disease.

General (all phases):

• Must be age ≥ 18 years of age on the day of signing informed consent, or the legal age of consent in the jurisdiction in which the trial is taking place.
• Measurable disease according to RECIST 1.1
• Eastern Cooperative Oncology Group (ECOG) 0-1
• Normal or adequate liver, renal, cardiac and bone marrow function

Key Exclusion Criteria:

Monotherapy - Dose Escalation and Dose Expansion Parts

• Treatment with an anti-cancer agent (within 21 days or after at least 5 half-lives of the drug, whichever is shorter), prior to GEN1042 administration
• Radiotherapy within 14 days prior to first GEN1042 administration
• Toxicities from previous anti-cancer therapies that have not resolved

Combination Therapy - Dose Expansion Part

• Has received prior systemic cytotoxic chemotherapy, biological therapy, OR major surgery within 3 weeks or at least 5 half-lives of the drug (whichever is shorter) of the first dose of trial treatment.
• Radiotherapy within 14 days of start of trial treatment or received lung radiation therapy of > 30 Gy within 6 months of the first dose of trial treatment.

General (all phases)

• Participants has an active, known, or suspected autoimmune disease.
• History of non-infectious pneumonitis that required steroids or currently has pneumonitis.
• History of ≥ grade 3 allergic reactions to monoclonal antibody (mAb) therapy
• Participants with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first treatment.

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