New Drug Application Accepted For Adagrasib In KRAS G12C-Mutation NSCLC


The FDA has accepted a new drug application for adagrasib for the treatment of patients with non-small cell lung cancer harboring KRAS G12C mutation.

A new drug application (NDA) for adagrasib (MRTX849) seeking approval for the treatment of patients with non-small cell lung cancer harboring KRAS G12C mutation who have received at least 1 prior therapy has been accepted for review by the FDA, according to Mirati Therapeutics, Inc.1

The NDA will undergo a traditional FDA review and has been given a Prescription Drug User Fee Act target action date of December 14, 2022.

Adagrasib is an investigational and highly selective oral small-molecule inhibitor used for the treatment of patients with non-small cell lung cancer (NSCLC) harboring the KRAS G12C mutation. Since the KRAS G12C protein regenerates every 24-48 hours, Adagrasib can help treat these cancers as it works to sustain target inhibition.

Data from the patients enrolled in a phase 2 KRYSTAL-01 trial (NCT03785249) was the basis for this decision as findings showed the agent to have promising clinical activity with monotherapy in previously treated patients with advanced or metastatic solid tumors who had a KRAS G12C mutation.

​​"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 cancers," said Charles Baum, MD, PhD, president, founder and head of research and development at Mirati Therapeutics, Inc, in a 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 non-small cell lung cancer."

Eligibility in the study required individuals to have a solid tumor with a KRAS G12C mutation and unresectable or metastatic NSCLC which progressed on or after treatment with a PD-1/PD-L1 inhibitor in combination with or following chemotherapy.2

Across all phases of the trial, patients were current or former smokers (89% and 95%, respectively), had nonsquamous histology (100% and 96%), and had average of 3 (range, 1-9) and 2 (range, 1-9) prior lines of therapy. A majority of patients had previously received PD-1/PD-L1 inhibitor (89% and 92%).

Investigators during the phase 1 looked at once-daily doses of adagrasib ranging from 150, 300, 600, and 1200 mg. 600 mg given twice a day was also examined, which had a clinical benefit rate of 96% in the phase 1/1b trial. This dose progressed to be the recommended phase 2 dose.

While phase 1b looked at adagrasib alone and in combination with pembrolizumab (Keytruda), afatinib (Gilotrif), and cetuximab (Erbitux), the phase 2 portion studied adagrasib monotherapy in patients with NSCLC (n = 61), colorectal cancer, and other solid tumors.

Primary end points of the phase 1b study included safety, maximum-tolerated dose, pharmacokinetic (PK), and the recommended phase 2 dose while the phase 2 portion included ORR.

Secondary end points in the phase 1b portion consisted of ORR, duration of response, progression-free survival, and overall survival while the phase 2 portion examined safety.

Data showed that when adagrasib was given at a dose of 600 mg twice a day, patients achieved an objective response rate (ORR) of 43% and 45% in the trial’s phase 1/1b (n = 14) and phase 1/1b and 2 cohort (n=51). Stable disease was 57% in phase 1/1b, and 51% in phase 1/1b and 2.

In the phase 1/1b population, disease control rate was 100% and 96% in the phase 1/1b and 2 population. Disease progression did not occur in the phase 1/1b cohort but did in 2% of those in phase 2.

PK data also found adagrasib to yield a Cave 2- to 5-fold above the target threshold for the full dosing interval, at 2.63 µg/mL. The Cave PK parameter was best matched to nonclinical antitumor activity. Based on nonclinical studies, extensive volume of distribution was predicted.

Patients treated at the 600-mg, twice-daily dose (n = 110) reported the most common all-grade, treatment-related adverse effects (TRAEs) to include nausea (54%), diarrhea (51%), vomiting (35%), and fatigue (32%). Grade 3/4 TRAEs consisted of fatigue (6%), increased alanine aminotransferase (5%), aspartate aminotransferase (5%), and QT prolongation (3%). Two grade 5 TRAEs were present: pneumonitis, which developed in a patient with recurrent pneumonitis, and cardiac failure. Out of all of the cohorts, TRAEs led to discontinuation in 4.5% of patients.

A phase 3 trial, KRYSTAL-12, is confirmed to evaluate adagrasib versus docetaxel in patients with second-line KRAS G12C mutated NSCLC.

Further exploration of adagrasib will continue with the ongoing KRYSTAL-1 trial as well as in a phase 3 trial, KRYSTAL-12 (NCT04685135), confirmed to evaluate adagrasib versus docetaxel in patients with second-line KRAS G12C mutated NSCLC.

  1. U.S. Food and Drug Administration (FDA) Accepts Mirati Therapeutics' New Drug Application for Adagrasib as Treatment of Previously Treated KRAS G12C-Mutated Non-Small Cell Lung Cancer. News Release. Mirati Therapeutics, Inc.; February 15, 2022. Accessed February 16, 2022.
  2. Riely GJ, Ignatius Ou SH, Rybkin II, et al. KRYSTAL-1: Activity and pre-liminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in pa-tients (pts) with advanced non-small-cell lung cancer (NSCLC) harboring KRASG12C mutation. Presented at: European Lung Cancer Virtual Confer-ence 2021; March 25-27, 2021. Abstract 99O_PR
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