Adagrasib Earns FDA Breakthrough Therapy Designation for KRAS G12C+ NSCLC


Based on positive single-agent activity in patients with non–small cell lung cancer harboring a KRAS G12C mutation, adagrasib wins FDA breakthrough therapy designation.

Breakthrough therapy designation has been granted to the investigational, highly selective, oral small molecular inhibitor adagrasib for the treatment of patients with previously treated KRAS G12C–mutant non–small cell lung cancer (NSCLC), according to the company responsible for the agent, Mirati Therapeutics, Inc.1

Data from the phase 1/2 KRYSTAL study (NCT03785249) of adagrasib in patients with chemotherapy- or immune checkpoint inhibitor–pretreated disease supported the designation by the FDA.

“We are pleased to receive this breakthrough therapy designation for adagrasib, which emphasizes the significant need for new treatment options for patients with lung cancer who harbor the KRAS G12C mutation,” Charles M. Baum, MD, PhD, president and chief executive officer, Mirati Therapeutics, Inc, said in a press release. “We look forward to submitting a new drug application for adagrasib in the second half of this year and further advancing adagrasib across a broad development plan with the goal of improving clinical outcomes in patients with KRAS G12C mutated cancers.”

Results of the KRYSTAL study were presented at the European Lung Cancer Virtual Congress 2021 and demonstrated the feasibility of KRAS G12C as an oncogenic target for patients with NSCLC. Patients (n = 79) had mostly received prior treatment with either chemotherapy or a PD-1/PD-L1 inhibitor.2

In 51 response-evaluable patients, 23 (45%) had a partial response and 26 had stable disease. In a sub-population of patients with co-mutations in STK11 (n = 14), the objective response rate (ORR) was 64%, which is considered high for tumors harboring KRAS G12C mutations. Additionally, positive activity associated with STK11 co-mutations are promising since they typically infer worse responses to immune checkpoint inhibition.

“The 45% response rate is unprecedented activity in patients with KRAS G12C–mutant NSCLC,” Myung-Ju Ahn, MD, from Samsung Medical Center at Sungkyunkwan University School of Medicine in Seoul, Korea, said in a press release.3 “A response of this magnitude could not be expected with other chemotherapy or immunotherapy in pre-treated KRAS-mutated patients, suggesting that KRAS G12C is a therapeutic target.”

In a pharmacodynamic and mechanistic biomarker analysis of 3 patients with tumor biopsies before and after therapy, it was revealed that treatment with adagrasib resulted in downregulation of KRAS/MAPK pathway genes. In patients with co-mutations in STK11, low expression of immune transcripts such as CD4 and CD8 were noted at baselines and were increased after adagrasib therapy, which may suggest a potential immune response.

Adagrasib also demonstrated a tolerable safety profile, with common (>20%) treatment-related adverse events including nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased alanine aminotransferase (23%).

Aside from studies of NSCLC, adagrasib has shown single-agent activity in patients with colorectal cancer (CRC), pancreatic cancer, and solid tumors harboring KRAS G12C mutations, with registrational trials in NSCLC and CRC ongoing.


1. Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from u.s. food and drug administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. Mirati Therapeutics. June 24, 2021. Accessed June 25, 2021.

2. Riely G, Ou SI, Rybkin I, et al. KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non-Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation. J Thoracic Oncol. 2021;16(suppl 4):99O_PR.

3. Second drug targeting KRASG12C shows benefit in mutated non-small-cell lung cancer. News release. European Society for Medical Oncology. March 29, 2021. Accessed March 29, 2021.

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