Adagrasib in Advanced Solid Tumors Harboring a KRAS Mutation
Tanios S Bekaii-Saab1, Rona Yaeger2, Alexander I Spira3,4,5
1Department of Medical Oncology and Hematology, Mayo Clinic, Scottsdale, AZ.
Purpose:
Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRAS-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRAS 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 KRAS mutation.
Methods:
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 KRAS-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.
Results:
As of October 1, 2022, 64 patients with KRAS-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.
Conclusion:
Adagrasib demonstrates encouraging clinical activity and is well tolerated in this rare cohort of pretreated patients with KRAS-mutated solid tumors.
Insights
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.
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.
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