Inclusion Criteria:

* Prior systemic therapy, diagnoses and disease setting as follows:

* For Part 1 (dose escalation), and no history of treatment with anti-CTLA-4 or anti-PD-(L)1 therapy and one of the following,

1. Unresectable or metastatic cutaneous melanoma, or
2. Unresectable of metastatic Child-Pugh Class A NDD not eligible for surgical and/or locoregional therapy, or
3. Intermediate or poor-risk advanced clear cell RCC, or
4. MSI-H or dMMR metastatic CRC and able to provide fresh or archival tumor tissue for central confirmation of MSI-H or dMMR.
5. For Part 2 (dose expansion), IO treatment -naïve, e.g., no prior receipt of an anti PD-1, anti-PD-L1 or PD-L1, anti-CTLA-4, GITR, LAG3, TIM3, OX-40, IL-2, 4-1BB or other immune modulator, and have not received prior systemic therapy and one of the following,

1. Unresectable or metastatic Child-Pugh Class A HCC not eligible for surgical and/or locoregional therapy, or
2. Intermediate - or poor-risk advanced clear cell RCC.
3. ECOG performance score of 0 or 1.
4. Life expectancy > 3 months, in the opinion of the investigator.
5. Histologically confirmed solid tumors with measurable disease per RECIST v1.1.

1. Exception: HCC may be diagnoses based on cross-sectional multiphasic imagining using the AASLD criteria.
2. 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. Received thoracic radiation within 6 months of the first dose of study treatment.
5. Participation in another interventional clinical study while receiving INCB099280.
6. Impaired cardiac function of clinically significant cardiac disease.
7. History of evidence of interstitial lung disease including non-infections pneumonitis.
8. Presence of gastrointestinal condition that may affect drug absorption
9. Any autoimmune disease requiring systemic treatment in the past 5 years.
10. Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy at a daily dose exceeding 10 mg of prednisone or equivalent
11. Active infection requiring systemic therapy.
12. History of organ transplantation, including allogeneic stem cell transplantation.
13. Receipt of system antibiotics within 28 days of first dose of study treatment.
14. Probiotic usage is prohibited during the screening and throughout the study treatment period.
15. Received a live vaccine within 28 days of planned start of study drug.
16. Laboratory values outside the Protocol-defined ranges.

Other protocol-defined Inclusion/Exclusion Criteria may apply.