This was a strategic business decision. There were no safety concerns contributing to this decision.

The purpose of this study is to evaluate the safety and tolerability of INCB099280 in combination with adagrasib and to establish the MTD or identify RDE(s) for the combination of INCB099280 and adagrasib.

Inclusion Criteria:

• KRASG12C-mutated solid malignancy determined by a sponsor-approved assay using either tumor tissue or ctDNA.

• Histologically confirmed malignant solid tumor with locally advanced and/or metastatic disease.

  • Only participants with NSCLC will be enrolled into Part 2 Cohort A.
  • Only participants with CRC will be enrolled into Part 2 Cohort B.

• Part 1: Disease progression on or after at least 1 prior systemic treatment.

• Part 2 (Cohort A - NSCLC): Received an anti-PD-(L)1-containing regimen and platinum based chemotherapy regimen either concurrently or sequentially

• Part 2 (Cohort B - CRC): Received at least 1 line of systemic therapy that includes the combination of fluoropyrimidine-based chemotherapy (in combination with oxaliplatin and/or irinotecan) and either a vascular endothelial growth factor-targeting monoclonal antibody or an anti-epidermal growth factor receptor monoclonal antibody (if RAS wild type). Participants with MSI-H/dMMR CRC must also have received a prior immune checkpoint inhibitor approved for this indication.

• Measurable disease according to RECIST v1.1.

• Eastern Cooperative Oncology Group performance status of 0 or 1.

• Estimated life expectancy > 3 months.

• Willingness to avoid pregnancy.

Exclusion Criteria:

• Known additional malignancy that is progressing or requires active treatment.
• Central nervous system (CNS) metastases requiring treatment and/or leptomeningeal disease.
• Part 2 only: Prior treatment with an approved or investigational agent targeting KRASG12C.
• Toxicity from prior therapy that has not recovered to protocol-defined limits.
• Received thoracic radiation of > 30 Gy within 6 months of the first dose of study treatment.
• Participation in another interventional clinical study.
• History or evidence of interstitial lung disease, including noninfectious pneumonitis.
• Presence of gastrointestinal condition that may affect drug absorption.
• Active autoimmune disease requiring systemic treatment, including corticosteroids exceeding a daily dose of 10 mg of prednisone or equivalent.
• Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy exceeding a daily dose of 10 mg of prednisone or equivalent.
• Active infection requiring systemic therapy.
• History of organ transplantation, including allogeneic stem cell transplantation.
• Receipt of systemic antibiotics within 28 days of the first dose of study treatment.
• Probiotic usage is prohibited during screening and throughout the study treatment period.
• Received a live vaccine within 28 days of the planned start of study drug.
• Laboratory values outside the Protocol-defined ranges.

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Incyte shares data with qualified external researchers after a research proposal is submitted. These requests are reviewed and approved by a review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. The trial data availability is according to the criteria and process described on https://www.incyte.com/our-company/compliance-and-transparency

Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.

Data from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.incyteclinicaltrials.com website. For approved requests, the researchers will be granted access to anonymized data under the terms of a data sharing agreement.