This study will assess the safety and efficacy of VS-7375 alone and in combination with cetuximab or panitumumab and cetuximab plus mFOLFOX in patients with metastatic KRAS G12D - mutated Colorectal Cancer

Inclusion Criteria:

• Histopathology confirmed metastatic CRC

• Measurable disease per RECIST 1.1

• Local testing confirmed KRAS G12D mutation (tissue required for confirmatory central testing)

• ECOG PS=0 or 1

  2L+ patients:

• Must have received at least 1 standard chemotherapy for metastatic colorectal adenocarcinoma

• Have documented disease progression during or following their most recent prior line of therapy

• Have either stable disease, partial response (PR), or complete response (CR) by RECIST v1.1 as the best overall response (BOR) during at least 1 prior systemic therapy.

  1L patients:

• Treatment-naïve or received no more than 1 cycle of standard systemic therapy for metastatic disease.

Exclusion Criteria:

• Have any other documented co-existing common RAS mutation(s)
• Prior anti-cancer Tx within 4 weeks or drug-specific timeline within first treatment dose, whichever shorter
• Major surgery within 4 weeks of first treatment dose
• Radiation therapy (RT) within 1 week of first treatment dose
• Receipt of prior direct RAS inhibitor
• Receipt of more than 1 investigational therapy
• Untreated or symptomatic CNS metastasis
• Receipt of strong CYP3A4 inhibitor/inducer or CYP3A4 sensitive substrates with narrow therapeutic index within 14 days or drug-specific timeline within first treatment dose, whichever is shorter
• Receipt of PPI or H2 blocker within 5 days
• Inability to swallow oral medication
• Other protocol-defined inclusion/exclusion criteria may apply