In KRYSTAL-1, adagrasib for NSCLC has a 43% response rate

Phase 2 results for adagrasib, a KRAS G12C inhibitor, showed promise for treating patients previously treated for KRAS G12C-mutated non-small cell lung cancer (NSCLC), with no new signals safety has been observed.

Adadagrasib selectively binds to KRAS G12C and renders it inactive, making the drug potentially useful for several tumor types. The Food and Drug Administration has already accepted a new drug application for the use of adagrasib in NSCLC based on the results of this study, called KRYSTAL-1 (NCT03785249).1 The results, presented at the 2022 annual meeting of the American Society of Clinical Oncology, were also published in the New England Journal of Medicine.2

Alexander I. Spira, MD, PhD, FACP, director of the Virginia Cancer Specialists Research Institute and Phase I trial program, presented the results on behalf of the KRYSTAL-1 researchers. He said the trial took place under extraordinary circumstances. “I would like to thank the patients and their families for making this trial possible. [and]most importantly all of the clinical study teams and investigators especially at all of the sites doing this trial at the height of the pandemic and frankly one of the toughest times I have ever been involved in research clinical.
Among the first 116 patients in the study, 98.3% had already received both chemotherapy and immunotherapy. Spira said 112 patients were evaluable and similar to the NSCLC population – 65% of patients were female, the median age was 64, and 96% were current or former smokers.

Of the evaluable patients, 43% responded to adagrasib and the disease control rate was 80%. According to Spira, the overall response rate (ORR) was 51% when calculated without including patients who received scans too early or left the study. The duration of response was 8.5 months (95% CI, 6.2 to 13.8). The results also showed the following:

  • The median PFS was 6.5 months (95% CI, 4.7-8.4).
  • As of January 15, 2022 (median follow-up, 15.6 months), median OS was 12.6 months (95% CI, 9.2-19.2).
  • Among those with previously treated central nervous system metastases, the intracranial ORR was 33.3% (95% CI, 18.0-51.8).

Spira said most patients were able to tolerate the drug, although 52% had dose reductions; 7% stopped treatment. Treatment-related adverse events were observed in 97.4% of patients; 52% of patients had grade 1 or 2. Two patients died.

A phase 3 study, KRYSTAL-12 (NCT04685135), is already underway and will compare the efficacy of adagrasib to docetaxel, Spira noted. The main completion date is set for August 2023.3

1. The United States Food and Drug Administration (FDA) accepts Mirati Therapeutics’ New Drug Application for adagrasib for the treatment of previously treated KRASG12C-mutated non-small cell lung cancer. Press release. Mirati Therapeutics, Inc. February 15, 2022. Accessed June 20, 2022.
2. Jänne PA, Riely GJ, Gadgeel SM, et al. Adadagrasib in non-small cell lung cancer harboring a KRASG12C mutation. N Engl J Med. Published online June 3, 2022. doi:10.1056/NEJMoa2204619
3. Phase 3 study MRTX849 (adagrasib) vs docetaxel in patients with advanced non-small cell lung cancer with KRAS G12C (KRYSTAL-12) mutation. Updated June 9, 2022. Accessed June 20, 2022.

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