FDA accepts NDA for adagrasib for non-small cell lung cancer

The FDA is evaluating adagrasib for the treatment of patients with non-small cell lung cancer with tumors that carry 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 have already received at least 1 systemic treatment.1

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

Additionally, 98.3% of patients received adagrasib after being treated with chemotherapy and immunotherapy. The safety and tolerability of adagrasib was found to be consistent with what has been previously reported for its use in patients with advanced NSCLC.

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

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

Researchers in the KRYSTAL-1 trial sought to enroll up to 565 patients with solid tumors bearing a kras G12C mutation, with unresectable or metastatic disease, and who have no treatment available with curative intent or standard care options available.3

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

In the phase 1b dose extension and combination trial, adagrasib was evaluated as monotherapy in patients with colorectal cancer (n=2); in patients with solid tumors and brain metastases; in treatment-naïve NSCLC patients; in patients with NSCLC who have previously received 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 phase 2 of the trial, adagrasib was evaluated as monotherapy in a cohort of patients with NSCLC; a cohort of CRC patients; a cohort of patients with solid tumors; and a cohort of treatment-naïve patients with kras G12C– and STK11– Mutated NSCLC. The primary endpoint of the Phase 2 trial is ORR per RECIST v1.1 criteria, and a key secondary endpoint is safety.

As of the June 15, 2021 data close, the results of the phase 1/1b trial evaluating adagrasib at a dose of 600 mg twice daily in 19 patients with kras The G12C-mutated NSCLC found that adagrasib achieved an investigator-assessed ORR of 58%.

At a median follow-up of 17.3 months and a median treatment duration of 9.5 months, the median DOR was 12.6 months. 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 and differentiated treatment options for patients with kras Cancers with G12C mutation,” Charles Baum, MD, PhD, President, Founder and Head of Research and Development at Mirati Therapeutics, Inc, said in the release. “We look forward to working with the FDA as we review our application and potentially provide a new option for patients with NSCLC.”

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

The references

  1. The U.S. Food and Drug Administration (FDA) is accepting 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 February 15, 2022. https://prn.to/3HWi0oJ
  2. Mirati Therapeutics announces the first positive Phase 2 results for investigational adagrasib in patients with KRAS G12C-mutated advanced non-small cell lung cancer. Press 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 in combination with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) carrying a KRASG12C mutation. Anne Onc. 2021;32(supplement 5):S1283-S1346. doi:10.1016/announce/announce741

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