Adagrasib in Advanced Solid Tumors Harboring a <i>KRAS</i>^<i>G12C</i> Mutation.

Abstract

Adagrasib, a KRAS^G12C inhibitor, has demonstrated clinical activity in patients with <i>KRAS</i>^<i>G12C</i>-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). <i>KRAS</i>^<i>G12C</i> mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a <i>KRAS</i>^<i>G12C</i> mutation. In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with <i>KRAS</i>^<i>G12C</i>-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival (PFS), overall survival, and safety. As of October 1, 2022, 64 patients with <i>KRAS</i>^<i>G12C</i>-mutated solid tumors were enrolled and 63 patients treated (median follow-up, 16.8 months). The median number of prior lines of systemic therapy was 2. Among 57 patients with measurable disease at baseline, objective responses were observed in 20 (35.1%) patients (all partial responses), including 7/21 (33.3%) responses in pancreatic and 5/12 (41.7%) in biliary tract cancers. The median duration of response was 5.3 months (95% CI, 2.8 to 7.3) and median PFS was 7.4 months (95% CI, 5.3 to 8.6). Treatment-related adverse events (TRAEs) of any grade were observed in 96.8% of patients and grade 3-4 in 27.0%; there were no grade 5 TRAEs. TRAEs did not lead to treatment discontinuation in any patients. Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with <i>KRAS</i>^<i>G12C</i>-mutated solid tumors.