Adagrasib in Advanced Solid Tumors Harboring a KRAS Mutation

Area of Science:

• Oncology
• Molecular targeted therapy
• Genomics in cancer treatment

Background:

• KRAS G12C mutations are common drivers in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC).
• These mutations are less frequent in other solid tumors, representing an unmet need for targeted therapies.
• Adagrasib is an established KRAS G12C inhibitor with proven efficacy in NSCLC and CRC.

Purpose of the Study:

• To evaluate the clinical activity and safety of adagrasib in patients with advanced solid tumors harboring KRAS G12C mutations, excluding NSCLC and CRC.
• To assess objective response rate, duration of response, progression-free survival (PFS), and overall survival.
• To determine the safety profile and tolerability of adagrasib in this specific patient population.

Main Methods:

• Phase II cohort of the KRYSTAL-1 study (NCT03785249).
• Adagrasib 600 mg orally twice daily administered to patients with KRAS G12C-mutated advanced solid tumors (excluding NSCLC/CRC).
• Primary endpoint: objective response rate. Secondary endpoints: duration of response, PFS, overall survival, and safety.

Main Results:

• 63 patients treated with a median follow-up of 16.8 months; median of 2 prior lines of therapy.
• Objective response rate of 35.1% (20/57) among patients with measurable disease, including responses in pancreatic (33.3%) and biliary tract (41.7%) cancers.
• Median PFS of 7.4 months; 96.8% experienced treatment-related adverse events (TRAEs), with 27.0% having grade 3-4 TRAEs, and no grade 5 TRAEs or treatment discontinuations due to TRAEs.

Conclusions:

• Adagrasib exhibits encouraging clinical activity in a rare cohort of pretreated patients with KRAS G12C-mutated solid tumors.
• The drug is well-tolerated in this population, with no treatment discontinuations due to adverse events.
• These findings support adagrasib as a potential therapeutic option for patients with KRAS G12C-mutated solid tumors beyond NSCLC and CRC.