The primary objective of the study is to evaluate the safety, tolerability, dose-limiting toxicity (DLT) and pharmacokinetics (PK) of acasunlimab (also known as GEN1046) administered as monotherapy or in combination with pembrolizumab in Japanese study participants with malignant solid tumors.

Key Inclusion Criteria:

• Participant must have a histologically-confirmed non-central nervous system (CNS) solid tumor that is metastatic or unresectable and for whom there is no available standard therapy likely to confer clinical benefit; or a participant who is not a candidate for such available therapy and for whom, in the opinion of the investigator, experimental therapy with acasunlimab or acasunlimab in combination with pembrolizumab may be beneficial.
• Asian race and Japanese ethnicity.
• Have measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Have Eastern Cooperative Oncology Group (ECOG) 0-1.
• Have an acceptable hematological status.
• Have acceptable liver function.
• Have an acceptable coagulation status.
• Have acceptable renal function.
• Should provide a tumor tissue sample (formalin-fixed paraffin-embedded [FFPE] blocks/slides) from archival tissue or fresh biopsy collected before C1D1, preferably derived from advanced disease stage.

Key Exclusion Criteria:

• Have uncontrolled intercurrent illness, including but not limited to:

  • 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 evidence of autoimmune disease.
  • History of irAEs that led to prior checkpoint treatment discontinuation.
  • Prior history of myositis, Guillain-Barré syndrome, or myasthenia gravis of any grade.
  • History of chronic liver disease or evidence of hepatic cirrhosis.
  • Evidence of interstitial lung disease.
  • History of non-infectious pneumonitis that has required steroids or currently has pneumonitis.
  • History of 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 trial treatment.
  • Serious, non-healing wound, skin ulcer (of any grade), or bone fracture.

• Any history of intracerebral arteriovenous malformation, cerebral aneurysm, new (younger than 6 months) or progressive brain metastases or stroke.

• Prior therapy:

  • Radiotherapy: Radiotherapy within 14 days prior to the first dose of trial treatment. Palliative radiotherapy will be allowed.
  • Treatment with an anti-cancer agent (within 28 days or after at least 5 half-lives of the drug, whichever is shorter), prior to trial treatment administration.

• Toxicities from previous anti-cancer therapies that have not adequately resolved.

Note: Other protocol specified inclusion/exclusion criteria may apply.