First-Line Adagrasib Active in STK11/KRAS G12C–Mutated NSCLC

ORR appeared to be higher in patients without KEAP1 comutations vs those with KEAP1 mutations.

In a phase 2 cohort of the KRYSTAL-1 trial (NCT03785249), first-line adagrasib (Krazati) produced a clinically meaningful objective response rate (ORR) of 30.3% (95% CI, 15.6%–48.7%) and a disease control rate of 66.7% in patients with advanced non–small cell lung cancer (NSCLC) harboring both KRAS G12C and STK11 mutations, according to data presented at the 2025 AACR Annual Meeting.¹

The ORR appeared numerically higher in patients without KEAP1 comutations (38%) compared with those with KEAP1 mutations (24%). The median progression-free survival (PFS) was 4.8 months (95% CI, 2.6-13.9), and the median overall survival (OS) was 12.3 months (95% CI, 4.9-19.1).

Consistent with prior reports, adagrasib was well tolerated in this first-line setting. These data suggest that adagrasib monotherapy may represent a viable first-line treatment option for this specific patient subgroup, particularly in the absence of KEAP1 comutations, especially for those who may not be ideal candidates for standard first-line regimens.

Background and Study Design

STK11 mutations are frequently observed in KRAS-mutated NSCLC and are associated with an immunosuppressive phenotype and poorer outcomes with anti-PD-1/PD-L1 therapy. KEAP1 comutations, which often coexist with STK11 mutations, further worsen the efficacy of anti-PD-1/PD-L1 agents and have also been shown to reduce the effectiveness of the KRAS G12C inhibitor adagrasib in the second-line setting. However, the impact of KRAS G12C/STK11 comutations, with or without concurrent KEAP1 alterations, on the efficacy of adagrasib as first-line treatment was previously unknown.

To address this, a phase 2 cohort (E) of the KRYSTAL-1 study evaluated first-line adagrasib (600 mg orally twice daily) in patients with advanced KRAS G12C/STK11-mutated NSCLC. KRAS G12C and STK11 mutations were identified using local or central sponsor-approved tests on tumor tissue or circulating tumor DNA.

The FDA previously granted accelerated approval to adagrasib/cetuximab (Erbitux) in June 2024 for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy.²

KRYSTAL-1 is an open-label, nonrandomized, multiple-expansion cohort phase 1/2 trial evaluating the safety and efficacy of the combination of adagrasib and cetuximab in patients with advanced KRAS G12C-mutated solid tumors.³ Enrollment in the study was open to patients with no available treatment options with curative intent or refusing or being ineligible for standard-of-care treatment in phase 1 and 2. Patients must have been receiving previous treatment with fluoropyrimidine, irinotecan, oxaliplatin, and a VEGF/VEGFR inhibitor in phase 2, and are required to have an ECOG performance status of 0 or 1.

For phase 2 of the study, ORR by blinded independent central review per RECIST 1.1 criteria served as the primary end point. Secondary end points included PFS, duration of response (DOR), OS, and safety.³

As of the data cutoff (April 30, 2024), 35 patients with KRAS G12C and STK11 mutations were enrolled. The median age was 64 years, 66% were female, and the majority had an ECOG performance status of 0 or 1.

Additional Phase 2 Cohort Findings

Among 33 evaluable patients, the ORR was 30.3% (95% CI, 15.6-48.7), with a disease control rate of 67%. The ORR was numerically higher in the KEAP1 mutation group vs in the KEAP1 wild-type group (38% vs 24%, respectively). The median DOR was not reached at a median follow-up of 7.8 months.

With a median follow-up of 7.8 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 patients with concurrent KEAP1 mutations (5.5 months) compared with those without (8.4 months; 95% CI, 1.4-not evaluable [NE]). Among 7 patients with PD-L1 expression greater than or equal to 50%, the median PFS was 4.8 months (95% CI, 1.3-NE).

Looking at safety, the safety profile of adagrasib among all 35 patients was shown to be consistent with prior studies, with treatment-related adverse events (TRAEs) leading to treatment discontinuation in 2 patients (5.7%) and dose modification in 18 patients (51.4%). Any-grade TRAEs were seen in 34 patients (97%), with the most common being nausea, diarrhea, and vomiting.

Twelve patients (34%) had grade 3 TRAEs, with the most common being diarrhea and fatigue. Grade 4 TRAEs occurred in 3 patients (9%) and included cerebrovascular accident (n = 1), renal failure (n = 1), and seizure and mental status changes (n =1). Further, there were no grade 5 TRAEs.

Overall, data from this phase 2 cohort of the KRYSTAL-1 study showed adagrasib to be well tolerated, leading to promising efficacy findings when used as a first-line treatment for patients with advanced NSCLC harboring KRAS G12C and STK11 mutations.

The role of first-line adagrasib in KRAS G12C-mutated NSCLC is being further investigated in combination with pembrolizumab (Keytruda) in the KRYSTAL-7 study (NCT04613596) and with pembrolizumab and chemotherapy in KRYSTAL-17 (NCT05609578).¹

Reference

1. Negrao MV, He K, Yau E et al. 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. Cancer Res. (2025) 85 (8_Supplement_2): CT209. doi:10.1158/1538-7445.AM2025-CT209
2. FDA grants accelerated approval to adagrasib with cetuximab for KRAS G12C-mutated colorectal cancer. News release. FDA. June 21, 2024. Accessed June 21, 2024. https://tinyurl.com/3dezap8f
3. Kopetz S, Uboha NV, Klempner SJ, et al. KRYSTAL-1: pooled phase 1/2 efficacy and safety of adagrasib (MRTX849) in combination with cetuximab in patients with metastatic colorectal cancer (CRC) harboring a KRAS G12C mutation. Presented at: 2024 AACR Annual Meeting; April 5-10, 2024; San Diego, CA. Abstract CT013.