A Study to Evaluate INCB099280 in Participants With Select Solid Tumors Who Are Immune Checkpoint Inhibitor Naive

Inclusion Criteria:

1. Immunotherapy naive and without access to approved and/or available immune checkpoint inhibitor (ICI) therapy.
2. Measurable disease per RECIST v1.1.
3. One of the following disease settings:

1. Unresectable or metastatic Child-Pugh Class A hepatocellular carcinoma (HCC) not eligible for surgical and/or locoregional therapy and have not received prior systemic therapy or had disease progression following primary therapy.
2. Unresectable or metastatic cutaneous melanoma and have not received more than 1 previous systemic therapy for advanced disease.
3. Unresectable Stage III PD-L1-positive (TPS ≥ 50% using the Dako PD-L1 IHC 22C3 assay) non-small cell lung cancer (NSCLC) without actionable molecular biomarkers and have not received prior systemic therapy and where chemoradiation is contraindicated; in addition, able to provide fresh or archival tumor tissue for central confirmation of PD-L1 expression.
4. Stage IV PD-L1-positive (TPS ≥ 50% using the Dako PD-L1 IHC 22C3 assay) NSCLC without actionable molecular biomarkers and have not received prior systemic therapy; in addition, able to provide fresh or archival tumor tissue for central confirmation of PD-L1 expression.
5. Relapsed or Stage IV clear cell renal cell carcinoma (RCC) after having received 1 prior systemic therapy for relapsed or Stage IV disease.
6. Cisplatin-ineligible, locally advanced or Stage IV urothelial cancer (UC) and have not received prior systemic therapy for locally advanced or Stage IV UC and able to provide fresh or archival tumor tissue for central confirmation of PD-L1 expression using the Dako PD-L1 IHC 22C3 assay.
7. Advanced or metastatic microsatellite instability high (MSI-H) or deficient mismatch repair (dMMR) (as determined by an approved assay) solid tumors and able to provide fresh or archival tumor tissue for central confirmation of MSI-H or dMMR.
8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
9. Life expectancy > 3 months.
10. Willingness to avoid pregnancy or fathering children.

Exclusion Criteria:

1. Known history of an additional malignancy.
2. Central nervous system (CNS) metastases requiring treatment and/or leptomeningeal disease.
3. Toxicity from prior therapy that has not recovered.
4. Prior receipt of an PD-1, anti-PD-L1, or anti-PD-L2 agent or treatment with an immune modulator (eg, CTLA-4, GITR, LAG3, TIM3, OX40, ICOS, IL-2, 4-1BB, CAR-T cell).
5. Received thoracic radiation within 6 months of the first dose of study treatment.
6. Participation in another interventional clinical study while receiving INCB099280.
7. Impaired cardiac function or clinically significant cardiac disease.
8. History or evidence of interstitial lung disease including noninfectious pneumonitis.
9. Presence of gastrointestinal conditions that may affect drug absorption.
10. Any autoimmune disease requiring systemic treatment in the past 5 years.
11. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy at a daily dose exceeding 10 mg of prednisone or equivalent.
12. Active infection requiring systemic therapy.
13. History of organ transplantation, including allogeneic stem cell transplantation.
14. Receipt of systemic antibiotics within 28 days of first dose of study treatment.
15. Probiotic usage is prohibited during screening and throughout the study treatment period.
16. Received a live vaccine within 28 days of the planned start of study drug.
17. Laboratory values outside the Protocol-defined ranges.

Other protocol-defined Inclusion/Exclusion Criteria may apply.