FDA Approval Sought for Adagrasib in Previously Treated KRAS G12C–Mutated NSCLC

FDA

The FDA has accepted a new drug application (NDA) for the use of adagrasib (MRTX849) in the treatment of patients with non–small cell lung cancer (NSCLC) whose tumors harbor a KRAS G12C mutation and who have previously received at least 1 prior systemic therapy.¹

The application is supported by findings from the phase 2 registration-enabling cohort of the KRYSTAL-1 trial (NCT03785249). Topline results demonstrated that at a median follow-up of 9 months, and when the agent was given 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

Notably, 98.3% of patients received adagrasib after having received chemotherapy and immunotherapy. The safety and tolerability of the agent proved to be consistent with what has previously been reported on its use in those with advanced NSCLC.

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

“KRAS mutations have been notoriously hard to target and historically have had limited therapeutic options,” Pasi A. Jänne, MD, PhD, a KRYSTAL-1 investigator, and director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, stated 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.”

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

In the phase 1 dose-escalation phase of the research, adagrasib was evaluated at once-daily doses of 150 mg, 300 mg, 600 mg, and 1200 mg, as well as a twice-daily dose of 600 mg, which was identified as the dose to be explored in the expansion phase of the research.

The primary end points for the phase 1 portion of the research included safety, maximum-tolerated dose, pharmacokinetics, and recommended phase 2 dose. The secondary end points included 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 portion of the research, adagrasib was examined as a monotherapy in patients with colorectal cancer (n = 2), in those with solid tumors and brain metastases, in those with treatment-naïve NSCLC, in those with NSCLC who previously received a KRAS G12C inhibitor, in combination with pembrolizumab (Keytruda) in those with NSCLC, in combination with afatinib (Gilotrif) in those with NSCLC, and in combination with cetuximab in those with CRC (n = 32).

In the phase 2 portion of the research, adagrasib was explored 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, findings from the phase 1/1b portion of the trial, which evaluated adagrasib at a twice-daily dose of 600 mg in 19 patients with KRAS G12C–mutated NSCLC, showed that the investigator-assessed ORR achieved with the agent was 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. Notably, 64% of patients were still receiving treatment and continued to experience a response to the agent. The median PFS with adagrasib was 8.3 months, and the 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,” Charles Baum, MD, PhD, president, founder, and head of research and development at Mirati Therapeutics, Inc., added in the press 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.

In the confirmatory phase 3 KRYSTAL-12 trial (NCT04685135), adagrasib is under exploration in combination with docetaxel in patients with advanced NSCLC whose tumors harbor a KRAS G12C mutation.

References

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