The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of RMC-5127 as a monotherapy and in combination with either daraxonrasib or cetuximab in adults with KRAS G12V-mutant solid tumors.

This is an open-label, multicenter, Phase 1/1b study of RMC-5127 in adults with advanced KRAS G12V-mutant solid tumors to evaluate the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity. The study consists of three arms: RMC-5127 monotherapy arm, RMC-5127 plus daraxonrasib combination arm, and RMC-5127 plus cetuximab combination arm. All arms consist of two parts: Part 1- dose exploration and Part 2- dose expansion. Both parts of the monotherapy arm may include Food Effect Cohorts.

Inclusion Criteria:

• At least 18 years old and has provided informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Pathologically documented, locally advanced or metastatic KRAS G12V-mutated solid tumor malignancy.
• Received and progressed or been intolerant to prior standard therapy (including targeted therapy) appropriate for tumor type and stage.
• Measurable per RECIST v1.1
• Adequate organ function (bone marrow, liver, kidney, coagulation).
• Able to take oral medications.

Exclusion Criteria:

• Primary central nervous system (CNS) tumors
• Prior therapy with KRAS G12V inhibitor or direct RAS-targeted therapy (eg. degraders and/or inhibitors).
• Any conditions that may affect the ability to take or absorb study drug.
• Major surgery within 28 days prior to receiving study drug(s).
• Patient is unable or unwilling to comply with protocol-required study visits or procedures.