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Adagrasib in Advanced Solid Tumors Harboring a KRAS Mutation.

Tanios S Bekaii-Saab1, Rona Yaeger2, Alexander I Spira3,4,5

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Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
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Adagrasib shows promising results in patients with rare KRAS G12C-mutated solid tumors. This targeted therapy demonstrated clinical activity and was well-tolerated in pretreated individuals, offering a new option for these difficult-to-treat cancers.

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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.