KRAS G12C mutated NSCLC

Mirati Therapeutics revealed results from the registration-enabling Phase II cohort of the KRYSTAL-1 study evaluating adagrasib 600 mg BID in patients with non-small cell lung cancer (NSCLC) harboring the KRASG12C mutation who have received at least one prior systemic therapy, cohort A (Abstract # 9002)

Adagrasib (irreversibly and selectively binds to KRAS G12C) is being tested in a registrational trial, including NSCLC patients harboring the G12C mutation. The multi-expansion study evaluates the efficacy and safety of adagrasib in patients with advanced solid tumors with KRAS G12C mutation. Data from cohort A includes patients who have previously received platinum-based chemotherapy and anti-PD-1 or PD-L1therapy.

As of October 15, 2021, a total of 116 patients with KRASG12C-mutated NSCLC had been treated (median follow-up, 12.9 months); 98.3% had previously received both chemotherapy and immunotherapy. Of 112 patients with measurable disease at baseline, 48 (42.9%) had a confirmed objective response. The median duration of response was 8.5 months, and the median progression-free survival was 6.5 months. As of January 15, 2022, the median overall survival was 12.6 months. Among 33 patients with previously treated, stable central nervous system metastases, the intracranial confirmed objective response rate was 33.3%. Treatment-related adverse events occurred in 97.4% of the patients- grade 3 or higher in 44.8% — and resulted in drug discontinuation in 6.9% of patients.

KOL insights

“Based on these data, the [new drug application] for adagrasib has been accepted and is under review for accelerated approval in the US, and the [marketing authorization applications] has been recently submitted to the European Medicines Agency.” –Expert Opinion


KRAS mutations have long been considered resistant to drug therapies representing the true unmet need for patients with certain types of cancers. Last year, this patient segment finally received its first targeted therapy, LUMAKRAS (sotorasib). The encouraging results from the KRYSTAL-1 adagrasib represent a significant step toward the future; more patients now will get a personalized treatment approach. Although Amgen was licensed for KRASG12C NSCLC patients last spring by winning the race to the market, Mirati always had a chance to catch up if it could provide improved efficacy and safety evidence. Still, those hopes also seem to be diminishing now. LUMAKRAS had recorded a lower objective response rate in the data released at last year's ASCO conference from a similar population, but the duration of response (DoR) for LUMAKRAS was more than two and a half months longer than adagrasib at 11.1 months, and the disease control rate was same at 80%. Also, as of the data cutoff of Jan 15, adagrasib recorded 12.6 months, just barely beating the LUMAKRAS’ 12.5 months. However, adagrasib is being considered by the FDA, with the decision date expected in mid-December, which still puts Mirati long behind Amgen (about 19 months). Because KRAS G12C mutation continues to multiply, researchers anticipate that pharmacological inhibition may be required in the long run. As a result, agdagrasib was modified to include a lengthy half-life (23 hours) and the ability to penetrate the central nervous system. The results are encouraging, but, overall, anti-KRAS remains disappointing compared to other targeted therapies in NSCLC.

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