FDA Grants Breakthrough Therapy Designation to Adagrasib for KRAS G12C–Mutated NSCLC

The FDA has granted a breakthrough therapy designation to adagrasib for use as a potential therapeutic option for patients with KRAS G12C–mutated non–small cell lung cancer following previous systemic therapy.

The FDA has granted a breakthrough therapy designation to adagrasib (MRTX849) for use as a potential therapeutic option for patients with KRAS G12C–mutated non–small cell lung cancer (NSCLC) following previous systemic therapy.1

The decision is supported by preliminary findings from the registrational phase 1/2 KRYSTAL-01 trial (NCT03785249), which showed that the agent had durable clinical activity with favorable tolerability in previously treated patients with KRAS G12C–mutated NSCLC.2

Among 51 patients evaluable for activity (14, phase 1/1b; 37, phase 2), 45% achieved an objective response to adagrasib (n =23), with 5 patients experiencing an unconfirmed partial response. Moreover, the disease control rate was 96% (n = 49) in these patients.

Updated data from the trial presented during the 2021 European Lung Cancer Conference demonstrated that when the agent was given at a twice-daily dose of 600 mg resulted in ORRs of 43% and 45% in the phase 1/1b (n = 14) and 2 (n = 51) cohorts, respectively.3

“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 of Mirati Therapeutics, Inc., stated 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.”

The highly selective, potent, oral small molecule inhibitor was developed to sustain target inhibition, a quality that could be significant in the treatment of KRAS G12C–mutated cancers, as the KRAS G12C protein regenerates every 24 to 48 hours. Previous data with shown that the agent has a long half-life, broad tissue distribution, and favorable tolerability.

The multicohort phase 1/2 study enrolled patients with advanced or metastatic solid tumors that harbor a KRAS G12C mutation who have received prior treatment with chemotherapy and anti–PD-1/PD-L1 therapy.

In the phase 1, dose-escalation portion of the trial, investigators evaluated several once-daily doses of adagrasib: 150 mg, 300 mg, 600 mg, 1200 mg, and 600 mg given twice daily. In the dose-expansion portion of the trial, participants received the agent at a twice-daily dose of 600 mg, as it was identified to be the recommended phase 2 dose.

In the phase 1b portion of the research, investigators evaluated adagrasib monotherapy, as well as in combination with pembrolizumab (Keytruda), afatinib (Gilotrif), and cetuximab (Erbitux). In the phase 2 portion, single-agent adagrasib was examined in patients with NSCLC (n = 61), colorectal cancer, and other solid tumors.

The primary end points of the phase 1b portion of the study were safety, maximum-tolerated dose, pharmacokinetics, and the recommended phase 2 dose. ORR was evaluated in the phase 2 portion of the research. Secondary end points in the phase 1b portion was ORR, duration of response, progression-free survival, and overall survival; in the phase 2 portion, investigators also looked at safety.

As of the data cutoff date of August 30, 2020, a total of 79 patients with pretreated NSCLC received the agent; 18 did so in the phase 1/1b portion of the research, and 61 did so in the phase 2 portion. In both phases of the trial combined, 57% of patients were women, 85% were White, and most participants were either current or former smokers (89% and 95%, respectively). Participants received an average of 2 prior lines of therapy (range, 1-9), and 92% had a prior PD-1/PD-L1 inhibitor.

Updated data from the trial showed that the clinical benefit rate achieved with adagrasib in the phase 1/1b portion of the trial was 96%. Five of 6 responders continued to receive treatment after a median follow-up of 9.6 months. Responses had been ongoing for over 11 months in most responders (n = 4). The median time to response was 1.5 months and the median duration of treatment was 8.2 months (range, 1.4 to 13.1+).

Among the 110 patients who received adagrasib at a twice-daily dose of 600 mg, the most frequent all-grade treatment-related adverse effects (TRAEs) comprised nausea (54%), diarrhea (51%), vomiting (35%), and fatigue (32%). TRAEs that were grade 3 or 4 in severity included fatigue (6%), increased alanine aminotransferase (5%), aspartate aminotransferase (5%), and QT prolongation (3%). Two grade 5 TRAEs were also observed: pneumonitis and cardiac failure. Moreover, 4.5% of patients experienced TRAEs that resulted in discontinuation.


  1. Mirati Therapeutics’ adagrasib receives breakthrough therapy designation from US Food and Drug Administration for patients with advanced non-small cell lung cancer harboring the KRAS G12C mutation. News release. June 24, 2021. Accessed June 24, 2021. https://prn.to/2SXZWqe
  2. Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: activity and safety of adagrasib (MRTX849) in advanced/metastatic non–small-cell lung cancer (NSCLC) harboring KRAS G12C mutation. Eur J Cancer. 2020;138(suppl 2):S1-S2. doi:10.1016/S0959-8049(20)31076-5
  3. Riely GJ, Ignatius Ou SH, Rybkin II, 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. Presented at: 2021 European Lung Cancer Conference; March 25-27, 2021; virtual. Abstract 99O_PR