KO-2806 Monotherapy and Combination Therapies in Advanced Solid Tumors

Inclusion Criteria:

1. At least 18 years of age.
2. Histologically or cytologically confirmed advanced solid tumors

1. Arm #1 (KO-2806 monotherapy): Patients who have progressed on, or are refractory to, standard of care (SOC) treatments with advanced solid tumors, specifically: HRAS-mutant and/or amplified tumors (any solid tumor type); HRAS overexpression (only for HNSCC tumors); KRAS and/or NRAS, and/or HRAS-mutant and/or amplified NSCLC or CRC; KRAS-mutant and/or amplified PDAC
2. Arm #2 (Combination): Patients who have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic RCC with predominantly clear cell subtype; non-clear cell RCC patients who are either treatment-naïve or have received any prior systemic treatment for locally advanced and metastatic RCC.
3. Arm #3 (Combination): Patients who have received at least 1 prior systemic therapy including available approved SOC treatments for KRAS G12C-mutant locally advanced or metastatic NSCLC, CRC, or PDAC.
4. Arm #4 (Combination): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
5. Arm #5 (Cabozantinib monotherapy): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
6. Arm #6 (Cabozantinib rollover to combination): Patients must be cabozantinib-naïve and have received at least 1 prior systemic therapy with IO-based treatment for locally advanced or metastatic ccRCC, but no more than 3 prior systemic anticancer therapies.
7. Arm #7 (Combination): Patients who have received at least 1 prior systemic therapy including available approved SOC treatments for KRAS G12C-mutant locally advanced or metastatic NSCLC
8. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
9. Karnofsky Performance Status of 70 or higher with no clinically significant deterioration over the previous 2 weeks.
10. Acceptable liver, renal, endocrine, and hematologic function.

* Other protocol-defined inclusion criteria may apply.

Exclusion Criteria:

1. Any use of anticancer therapy within 14 days or 5 half-lives (whichever is shorter) of Cycle 1 Day 1.
2. Prior treatment with an FTI or HRAS inhibitor.
3. Major surgery, other than local procedures, within 28 days prior to Cycle 1 Day 1, without complete recovery.
4. Spinal cord compression, leptomeningeal disease, or clinically active CNS metastases.
5. Toxicity (excluding alopecia) from prior therapy that has not been completely resolved to baseline at the time of consent.
6. Active or prior documented autoimmune or inflammatory disorders within the past 5 years prior to Cycle 1 Day 1 (with exceptions).
7. Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
8. Inability to swallow, impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the trial drugs.
9. Inadequate cardiac and/or vascular function, including receipt of treatment for unstable angina, myocardial infarction, and/or cerebrovascular attack within the prior 6 months, mean QTcF ≥470 ms, or Class II or greater congestive heart failure.
10. Other invasive malignancy within 2 years.

* Other protocol-defined exclusion criteria may apply.