Non–small cell lung cancer micrograph.

The FDA has granted accelerated approval to adagrasib (Krazati™, Mirati Therapeutics, Inc.) for treatment of adult patients with kirsten rat sarcoma viral oncogene homologue (KRAS) G12C–mutated locally advanced or metastatic non­–small cell lung cancer (NSCLC). Patients should have received one prior line of systemic therapy. Adagrasib is a rat sarcoma virus (RAS) guanosine triphosphatase (GTPase) family inhibitor.

"Adagrasib (MRTX849), a potent, orally available, small molecule covalent inhibitor of KRASG12C, irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state," wrote Pasi Jänne, Director of the Lowe Center for Thoracic Oncology, Dana-Farber, Harvard Cancer Center, and colleagues, in their published results of the KRYSTAL-1 trial (NCT03785249), on which approval was based. "Adagrasib has favorable pharmacokinetic properties, including a long half-life (23 hours), dose dependence, and central nervous system (CNS) penetration."

Safety and efficacy were evaluated in the phase 1/2, multicenter, single-arm, open-label trial, in which 112 patients with KRAS G12C-mutated, locally advanced or metastatic NSCLC received a 600 mg adagrasib tablet orally, twice daily until disease progression or unacceptable toxicity. Patients included in this study had disease progression during or after previous platinum-based chemotherapy, given simultaneously or back-to-back with an immune checkpoint inhibitor.

At a median follow-up of 12.9 months, the primary end points measured were objective response rate, assessed by RECIST v1.1 and blinded independent central review, and duration of response. Objective response rate was 43% with a median duration of response of 8.5 months.

The most common adverse events in ≥20% of patients were diarrhea, nausea, fatigue, vomiting, musculoskeletal pain, hepatotoxicity, renal impairment, dyspnea, edema, decreased appetite, cough, pneumonia, dizziness, constipation, abdominal pain, and corrected QT (QTc) interval prolongation. The most common laboratory abnormalities in ≥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.

"In this phase 2 cohort, adagrasib led to durable clinical benefit in patients with previously treated, advanced KRASG12C–mutated NSCLC," concluded Dr. Jänne and colleagues. "Adagrasib continues to be evaluated as monotherapy and in combination with other therapies in NSCLC and in other advanced solid cancers within the KRYSTAL-1 study."

The recommended dosage for adagrasib is a 600 mg tablet orally, twice daily until disease progression or unacceptable toxicity.

Resources

Jänne P, Riely G, Gadgeel S, et al (2022). Adagrasib in non–small cell lung cancer harboring a KRASG12C mutation. N Engl J Med, 387:120-131. DOI:10.1056/NEJMoa2204619

Clinicaltrials.gov (2022). Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. NLM identifier: NCT03785249.

US Food and Drug Administration (2022). FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc?utm_medium=email&utm_source=govdelivery

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