FDA Approves Adagrasib for Locally Advanced or Metastatic KRAS G12C+ NSCLC

December 12, 2022

The FDA has granted accelerated approval to adagrasib (Krazati) for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer, as determined by an FDA-approved test, who have received at least 1 prior systemic therapy.

The FDA has granted accelerated approval to adagrasib (Krazati) for the treatment of adult patients with KRAS G12C–mutated locally advanced or metastatic non–small cell lung cancer, as determined by an FDA-approved test, who have received at least 1 prior systemic therapy.¹

The agency simultaneously approved the QIAGEN therascreen KRAS RGQ PCR kit for tissue and the Agilent Resolution ctDx FIRST Assay for plasma as companion diagnostics for adagrasib. If no mutation is detected in a plasma specimen, the tumor tissue should be tested, the FDA stated.

The approval was based on results from the multicenter, single-arm, open-label KRYSTAL-1 trial, (NCT03785249), in which adagrasib elicited an objective response rate (ORR) of 43% (95% CI, 34%-53%) in this patient population, with 80% (95% CI, 71%-87%) of patients achieving disease control. The median duration of response (DOR) was 8.5 months (95% CI, 6.2-13.8).

In a pooled efficacy analysis (n = 132), which included the phase 1/1b NSCLC and registrational phase 2 NSCLC cohorts of the KRYSTAL-1 study, adagrasib elicited an ORR of 44% and a disease control rate of 81% based on blinded independent central review. The median DOR was 12.5 months (95% CI, 7.3–not evaluable). The median overall survival was 14.1 months (94% CI, 9.2-19.2).²

"The FDA approval of [adagrasib] 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," David Meek, chief executive officer, Mirati Therapeutics, Inc., stated in a press release.² "Mirati is thrilled to make [adagrasib] available in a tablet formulation to patients in the United States with advanced NSCLC who have progressed beyond a first-line treatment for the historically difficult-to-treat KRAS mutation."

KRYSTAL-1 enrolled patients with locally advanced or metastatic NSCLC harboring a KRAS G12C mutation who previously received a platinum-based regimen and an immune checkpoint inhibitor. They were required to have an ECOG performance status of 0 or 1 and at least 1 measurable lesion by RECIST v1.1 criteria.

Study participants received oral adagrasib at 600 mg twice daily until disease progression or unacceptable toxicity. Tumor assessments were conducted every 6 weeks.

Confirmed ORR and DOR by BICR assessment and RECIST v1.1 criteria served as the major efficacy outcome measures.

Of 112 patients whose tumors harbored a KRAS G12C mutation, 88% (n = 98) had tissue samples tested retrospectively using the QIAGEN kit. Eighty-nine percent of the 98 patients tested positive for the mutation and 11% (n = 11) did not. Sixty-three percent (n = 71) of the 112 patients had plasma samples tested retrospectively using the Agilent Resolution ctDx FIRST assay. Sixty-six percent (n = 47) of the 71 patients tested positive for the mutation and 34% (n = 24) did not.

In the efficacy population, the median age was 64 years (range, 25-89), 55% were female, and 83% were White. Regarding ECOG performance status, 16% of patients had a status of 0 and 83% had a status of 1. Ninety-seven percent of patients had adenocarcinoma and 89% had metastatic disease. Sites of extrathoracic disease included the bone (42%), brain (30%), adrenals (21%), and liver (21%).

The median number of prior systemic treatments received was 2 (range, 1-7). Moreover, 43%, 35%, 10%, and 12% of patients received 1, 2, 3, or 4 or more prior lines of treatment, respectively. The majority of patients (98%) previously received both platinum and anti–PD-1/PD-L1 therapy.

Regarding safety, the most common adverse events occurring in at least 20% of patients were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and QTc interval prolongation.

The most common laboratory abnormalities occuring in at least 25% of patients were decreased lymphocytes, increased aspartate aminotransferase, decreased sodium, decreased hemoglobin, increased creatinine, decreased albumin, increased alanine aminotransferase, increased lipase, decreased platelets, decreased magnesium, and decreased potassium.

The recommended adagrasib tablet dose is 600 mg orally twice daily until disease progression or unacceptable toxicity.

References

FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. News release. FDA. December 12, 2022. Accessed December 12, 2022. https://bit.ly/3WdCKPs
Mirati Therapeutics announces US 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. News release. Mirati Therapeutics, Inc. December 12, 2022. Accessed December 12, 2022. https://bit.ly/3WtPPod
Adagrasib (Krazati). Prescribing information; Mirati Therapeutics, Inc.; 2022. Accessed December 12, 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf