FDA Grants Accelerated Approval to Adagrasib for KRAS-G12C-Mutated NSCLC


Adagrasib (Krazati; Mirati Therapeutics, Inc) approved for adults with KRAS-G12C-mutated locally advanced or metastatic non-small cell lung cancer as determined by an FDA-approved test.

The FDA has granted accelerated approval to adagrasib (Krazati; Mirati Therapeutics, Inc) for adults with KRAS-G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC), as determined by an FDA-approved test, who were administered at least 1 prior systemic therapy. The accelerated approval for this indication was based on objective response rate (ORR) and duration of response (DOR), with continued approval contingent upon verification and description of a clinical benefit in a confirmatory trial.

Adagrasib is an investigational, highly selective, KRAS-G12C inhibitor that is optimized to sustain target inhibition. Previous studies of adagrasib have shown that the drug has a long half-life, extensive tissue distribution, and is well tolerated.

“The FDA approval of Krazati is a positive development for thousands of patients with KRAS-G12C mutations, including the approximately 14% of patients with NSCLC adenocarcinomas histology that harbor a KRAS-G12C mutation. Mirati is thrilled to make Krazati available in a tablet formulation to patients in the US with advanced NSCLC who have progressed beyond a first-line treatment for the historically difficult-to-treat KRAS mutation,” said David Meek, chief executive officer, Mirati Therapeutics, Inc, in a press release. “We look forward to continuing to advance our Krazati development program including several monotherapy and combination studies in KRAS-G12C-mutated solid tumors.”

The FDA based the approval of adagrasib on its positive benefit-risk profile from the phase 2 registration-enabling cohort of the KRYSTAL-1 study. The trial evaluated adagrasib 600 mg capsules administered orally twice daily in 116 patients with KRAS-G12C-mutated advanced NSCLC who were previously administered a platinum-based regimen and an immune checkpoint inhibitor. Primary efficacy endpoints were confirmed ORR and DOR as determined by blinded independent central review (BICR) and according to response evaluation criteria in solid tumors (RECIST v1.1).

In the KRYSTAL-1 study, adagrasib produced an ORR of 44% (95% CI: 34-53), with 80% (95% CI: 71-87) of patients achieving disease control, and a median DOR of 8.5 months (95% CI: 6.2-13.8). A pooled efficacy analysis (n=132) including phase 1/1b NSCLC and registrational phase 2 NSCLC cohorts from the KRYSTAL-1 study of adagrasib as a single agent at 600 mg capsules orally twice daily showed an ORR of 44% and a disease control rate of 81% based on BICR. Further, adagrasib produced a median DOR of 12.5 months (95% CI, 7.3-NE) and median overall survival (OS) of 14.1 months (94% CI, 9.2-19.2).

The investigators noted that although KRAS-G12C is the most common KRAS mutation in patients with NSCLC, there are limited options for this condition.

“KRAS-G12C in NSCLC is an area of high unmet need and new treatment options offer patients and our community new hope for survivorship,” Bonnie J. Addario, co-founder and board chair of the GO2 Foundation for Lung Cancer, said in a press release. “I’m pleased that patients have options, there’s more awareness of this disease and we are all focused on improving the journeys of people living with KRAS-G12C-mutated NSCLC.”

The safety of adagrasib was analyzed in a pooled population of 366 patients with NSCLC and other solid tumors as a single agent at 600 mg orally twice daily in KRYSTAL-1 and KRYSTAL-12. The most commonly reported (≥ 25%) adverse events (AEs) were nausea, diarrhea, vomiting, fatigue, musculoskeletal pain, hepatotoxicity, renal impairment, edema, dyspnea, and reduced appetite. AEs that led to permanent discontinuation of adagrasib were reported in 13% of patients.

“The approval of Krazati offers an effective therapy for patients with advanced NSCLC harboring the KRAS-G12C mutation. The positive ORR and DOR results, as observed in previously treated patients with NSCLC harboring the KRASG12C mutation, demonstrate the effectiveness of KRAZATI as an option for these difficult-to-treat patients,” Shirish M. Gadgeel, MD, chief of the Division of Hematology and Oncology, Department of Internal Medicine, Henry Ford Cancer Institute/Henry Ford Health System, said in a press release.


Mirati Therapeutics Announces U.S. FDA Accelerated Approval of KRAZATI™ (adagrasib) as a Targeted Treatment Option for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation. Mirati Therapeutics. News release. December 12, 2022. https://www.multivu.com/players/English/8999051-mirati-therapeutics-fda-accelerated-approval-of-krazati-adagrasib/

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