CHMP Advises Against Adagrasib Approval for KRAS G12C–Mutant Advanced NSCLC

The European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) issued a negative opinion on the conditional marketing authorization application (MAA) for adagrasib (Krazati) for the treatment of patients with KRAS G12C–mutated advanced non–small cell lung cancer (NSCLC), according to an announcement from Mirati Therapeutics.¹

CHMP stated that although adagrasib has shown a positive risk-benefit profile, it does not meet certain requirements for a conditional MAA. Mirati disagrees with the opinion and plans to request a formal re-evaluation on the basis that adagrasib meets the requirements for MAA despite there being another conditionally approved KRAS G12C inhibitor. Mirati also stated that adagrasib has a distinct clinical profile, evidenced by its efficacy, potential central nervous system activity, and ability to be combined or used in sequence with other agents, including immune checkpoint inhibitors.

“We remain steadfast in our belief in the potential of adagrasib to provide hope for patients in the European Union,” David Meek, chief executive officer of Mirati Therapeutics, stated in a news release. “We will continue to work closely with the EMA and the CHMP to bring adagrasib to eligible patients. We are committed to delivering therapeutic options for patients living with KRAS G12C–mutated NSCLC in the European Union, as we have in the United States following the accelerated approval of adagrasib in December 2022.”

The MAA was based on the registrational phase 2 KRYSTAL-1 trial (NCT03785249), which evaluated 600 mg of oral adagrasib twice daily in 116 patients with KRAS G12C–mutant advanced NSCLC with prior exposure to platinum-based chemotherapy and an immune checkpoint inhibitor.

Data from the trial served as the basis for the December 2022 FDA accelerated approval of adagrasib in adult patients with KRAS G12C–mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least 1 prior systemic therapy.²

Despite the opinion, Mirati will continue to provide adagrasib to eligible patients in Europe with a KRAS G12C mutation based on individual requests from health care professionals. The company will also continue to supply adagrasib under early access in European Union member states in accordance with applicable laws and regulations.

The CHMP decision will not affect any of Mirati’s clinical trials, including the confirmatory, phase 3 KRYSTAL-12 trial, in which enrollment is progressing as expected. The study is evaluating adagrasib vs docetaxel in previously treated patients with KRAS G12C–mutant metastatic NSCLC. Progression-free survival and interim overall survival data are expected in the first half of 2024.

References

1. Mirati Therapeutics provides update on regulatory review in the European Union of KRAZATI (adagrasib) for the treatment of advanced non-small cell lung cancer (NSCLC) with a KRAS G12C mutation. News release. Mirati Therapeutics, Inc. July 21, 2023. Accessed July 24, 2023. https://ir.mirati.com/press-releases/press-release-details
2. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed July 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc?utm_medium=email&utm_source=govdelivery