FDA Accepts NDA for Adagrasib for Non-Small Cell Lung Cancer


FDA to evaluate adagrasib for the treatment of patients with non–small cell lung cancer with tumors that have a KRAS G12C mutation.

The FDA has accepted a new drug application (NDA) for adagrasib (MRTX849, Mirati Therapeutics) for the treatment of patients with non–small cell lung cancer (NSCLC) with tumors that have a KRAS G12C mutation and who were previously administered at least 1 systemic therapy.1

The application follows the findings from the phase 2 registration-enabling cohort of the KRYSTAL-1 trial. The study showed that at a median follow-up of 9 months when adagrasib was administered at a twice-daily dose of 600 mg, patients achieved an objective response rate (ORR) of 43% and a disease control rate of 80% based on central independent review.2

Further, 98.3% of patients were administered adagrasib after having been treated with chemotherapy and immunotherapy. The safety and tolerability of adagrasib was found consistent with what was previously reported on its use in patients with advanced NSCLC.

Under the Prescription Drug User Fee Act, the FDA will decide on the application by December 14, 2022.

KRAS mutations have been notoriously hard to target and historically have had limited therapeutic options,” said Pasi A. Jänne, MD, PhD, a KRYSTAL-1 investigator and director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, in a press release. “The KRAS G12C biomarker in particular is associated with poor survival outcomes. The FDA’s review of the adagrasib NDA marks important progress toward potentially providing a new, targeted option for those living with KRAS G12C–mutated NSCLC.”

The KRYSTAL-1 trial researchers sought to enroll up to 565 patients with solid tumors that carry a KRAS G12C mutation, with unresectable or metastatic disease, and who do not have available treatment with curative intent or available standard-of-care options.3

In the phase 1 dose-escalation phase of, adagrasib was analyzed at once-daily doses of 150 mg, 300 mg, 600 mg, and 1200 mg, and a twice-daily dose of 600 mg, which was identified as the dose to be evaluated in the expansion phase of the trial. The primary end points for the phase 1 portion of the trial included safety, maximum-tolerated dose, pharmacokinetics, and recommended phase 2 dose. The secondary end points were ORR per RECIST v1.1 criteria, duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

In the phase 1b dose expansion and combination part of the trial, adagrasib was evaluated as a monotherapy in patients with colorectal cancer (n = 2); in patients with solid tumors and brain metastases; in patients with treatment-naïve NSCLC; in patients with NSCLC previously administered a KRAS G12C inhibitor; in combination with pembrolizumab (Keytruda) in patients with NSCLC; in combination with afatinib (Gilotrif) in patients with NSCLC; and in combination with cetuximab in patients with CRC (n = 32).

In the phase 2 portion of the trial, adagrasib was evaluated as a monotherapy in a cohort of patients with NSCLC; a cohort of patients with CRC; a cohort of patients with solid tumors; and a cohort of treatment-naïve patients with KRAS G12C– and STK11-mutated NSCLC. The primary end point of the phase 2 trial is ORR per RECIST v1.1 criteria, and a key secondary end point is safety.

At a data cutoff of June 15, 2021, results of the phase 1/1b portion of the trial evaluating adagrasib at a twice-daily dose of 600 mg in 19 patients with KRAS G12C–mutated NSCLC found adagrasib achieved an investigator-assessed ORR of 58%.

At a median follow-up of 17.3 months and a median duration of treatment of 9.5 months, the median DOR was 12.6 months. The results showed that 64% of patients were still receiving treatment and continued to experience a response to the agent. Median PFS with adagrasib was 8.3 months and median OS had not yet been reached in these patients.

“The acceptance of our NDA for adagrasib is a significant step forward in Mirati’s ongoing efforts to advance innovative, differentiated treatment options for patients with KRAS G12C–mutated cancers,” said Charles Baum, MD, PhD, president, founder, and head of research and development at Mirati Therapeutics, Inc, in the release. “We look forward to working with the FDA during their review of our application and potentially provide a novel option for patients with NSCLC.”

Detailed results from the cohort supporting the NDA are anticipated to be shared at a medical meeting in the first half of 2022.


  1. US Food and Drug Administration (FDA) accepts Mirati Therapeutics’ new drug application for adagrasib as treatment of previously treated KRASG12C-mutated non-small cell lung cancer. News release. Mirati Therapeutics, Inc.; February 15, 2022. Accessed February 15, 2022. https://prn.to/3HWi0oJ
  2. Mirati Therapeutics announces positive phase 2 topline results for investigational adagrasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer. News release. Mirati Therapeutics, Inc.; September 20, 2021. Accessed February 15, 2022. https://bit.ly/3HWGZYY
  3. Weiss J, Yaeger RD, Johnson ML, et al. KRYSTAL-1: adagrasib (MRTX849) as monotherapy or combined with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Onc. 2021;32(suppl 5):S1283-S1346. doi:10.1016/annonc/annonc741
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