Abstract CT209: Adagrasib (ADA) as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring <i>KRAS</i> G12Cand <i>STK11</i> mutations: KRYSTAL-1 phase 2 cohort
Authors: Marcelo V. Negrao, Kai He, Edwin Yau, Alexander I. Spira, Melissa L. Johnson, Shirish M. Gadgeel, Pasi A. Jänne, Joshua K. Sabari, Muhammad K. Riaz, Erin L. Schenk, Jamal Misleh, Harris A. Ahmad, Nicolas Brand, Marzana Chowdhury, Laura J. Eccles, Gregory J. Riely
Journal: Cancer Research (2025)

Abstract Background: STK11 mutations are common in KRAS-mutated NSCLC and produce an immunosuppressive phenotype leading to poor clinical outcomes with anti-PD-1/PD-L1 therapy. KEAP1 mutations, which commonly co-occur with STK11 mutations, also negatively impact anti-PD-1/PD-L1 efficacy. KEAP1 co-mutations and, to a lesser extent, STK11 co-mutations reduce the efficacy of ADA, a KRASG12C inhibitor, in previously treated advanced KRAS G12C-mutated NSCLC. However, the impact of KRAS G12C/STK11 co-mutations, with or without concurrent KEAP1 mutations, on the efficacy of ADA as first-line treatment remains unknown. Therefore, in a phase 2 cohort of KRYSTAL-1 (NCT03785249) we evaluated first-line ADA for advanced KRAS G12C/STK11-mutated NSCLC. Methods: KRYSTAL-1 is a multicohort phase 1/2 study evaluating ADA in pts with advanced KRAS G12C-mutated solid tumors. In the phase 2 cohort E, pts with advanced KRAS G12C/STK11-mutated NSCLC received ADA 600 mg orally BID as first-line systemic treatment. KRAS G12C/STK11 mutations were detected in tumor tissue or circulating tumor DNA using a local or central sponsor-approved test. The primary endpoint was objective response rate (ORR) per blinded independent central review (BICR). Secondary endpoints included progression-free survival (PFS) per BICR, overall survival (OS), and safety. Results: As of April 30, 2024, 35 pts with KRAS G12C and STK11 mutations were enrolled. Median age was 64 years, 66% were female, and 31%/69% had ECOG PS 0/1. ORR among 33 evaluable pts was 30.3% (95% confidence interval [CI], 15.6-48.7) and disease control rate was 66.7%. With a median follow-up of 7.9 months, median PFS was 4.8 months (95% CI, 2.6-13.9) and median OS was 12.3 months (95% CI, 4.9-19.1). Median PFS was shorter in pts with concurrent KEAP1 mutations (n=8; 5.5 months; 95% CI, 0.5-not estimable [NE]) compared with those without KEAP1 mutations (n=21; 8.4 months; 95% CI, 1.4-NE). The safety profile of ADA among all 35 pts was consistent with previous studies, with treatment-related adverse events leading to treatment discontinuation in two pts (5.7%) and dose modification in 18 pts (51.4%). Conclusions: ADA was well tolerated and showed efficacy as first-line therapy for pts with advanced NSCLC harboring KRAS G12C and STK11 mutations, particularly in the absence of KEAP1 co-mutations. These results suggest that ADA monotherapy may be a reasonable first-line therapy option for pts with KRAS G12C/STK11-mutated NSCLC who are not candidates for standard first-line therapies. First-line ADA is being evaluated in combination with pembrolizumab or with pembrolizumab and chemotherapy in the KRYSTAL-7 (NCT04613596) and KRYSTAL-17 (NCT05609578) trials, respectively, in pts with advanced KRAS G12C-mutated NSCLC. Citation Format: Marcelo V. Negrao, Kai He, Edwin Yau, Alexander I. Spira, Melissa L. Johnson, Shirish M. Gadgeel, Pasi A. Jänne, Joshua K. Sabari, Muhammad K. Riaz, Erin L. Schenk, Jamal Misleh, Harris A. Ahmad, Nicolas Brand, Marzana Chowdhury, Laura J. Eccles, Gregory J. Riely. Adagrasib (ADA) as first-line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC) harboring KRAS G12Cand STK11 mutations: KRYSTAL-1 phase 2 cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT209.