Dr Gadgeel on Adagrasib Monotherapy in KRAS G12C–Mutated NSCLC

Shirish M. Gadgeel, MD, division lead, Hematology/Oncology, associate director, patient experience and clinical care, Henry Ford Cancer Institute, discusses 2-year follow-up data from the phase 1/2 KRYSTAL-1 trial (NCT03785249) in patients with advanced or metastatic non–small cell lung cancer (NSCLC) harboring KRAS G12C mutations, which he presented at the 2023 IASLC World Conference on Lung Cancer.

KRYSTAL-1 is evaluating adagrasib (Krazati) in patients with KRAS G12C–mutated NSCLC at 600 mg twice daily. These 2-year follow-up data are comprised of pooled datasets from the phase 1/1b dose escalation and expansion cohorts, as well as data from phase 2 cohort A.

At a median follow-up of 26.9 months, the median overall survival (OS) was 14.1 months (95% CI, 9.2-18.7), with a 1-year OS rate of 52.8% and a 2-year OS rate of 31.3%. The median progression-free survival (PFS) was 6.9 months (95% CI, 5.4-8.7), with 1- and 2-year PFS rates of 35.0% and 13.9%, respectively. The overall response rate was 43%, and the median duration of response was 12.4 months (95% CI, 7.0-15.1).

No additional safety signals were identified with this long-term follow-up, Gadgeel says. Furthermore, no patients who received adagrasib within 30 days of receiving immunotherapy experienced grade 3 or higher hepatotoxicity, an adverse effect (AE) that is associated with other KRAS G12C inhibitors that are administered after immunotherapy, Gadgeel notes. Additionally, among the patients who received adagrasib for at least 1 year, the incidence of new-onset treatment-related AEs (TRAEs) after 1 year of therapy was low, Gadgeel emphasizes. The most common new-onset TRAEs included gastrointestinal toxicities, fatigue, and increased serum creatinine levels.

This 2-year analysis also assessed the effects of dose modification, defined as either dose interruption or dose reduction, on the efficacy of adagrasib. Among the patients who responded, 60% (n = 33) received adagrasib for more than 1 year, and 22% (n = 12) received the agent for more than 2 years, all of whom underwent dose modifications. Of the patients who underwent dose modifications, the 2-year OS rate was 32.1%. These data demonstrate that dose modification does not affect the efficacy of adagrasib, Gadgeel concludes.