Adagrasib Shows Durable Benefit in KRAS-Mutated NSCLC

Pam Harrison

June 04, 2022

Adagrasib, an investigational drug that acts as a KRASG12C inhibitor, has shown durable clinical benefit in patients with previously treated, advanced non-small cell lung cancer (NSCLC) with tumors with KRAS G12C mutations.

"KRAS G12C mutations occur in over 10% of patients with NSCLC, remain difficult to target, and outcomes for this patient population have remained poor," co-investigator Joshua Sabari, MD, assistant professor of medicine, Perlmutter Cancer Center at NYU Langone, New York City, said in a statement.

"Our patients benefited clinically from this agent and it appears to have improved overall survival (OS) compared to historical outcomes with docetaxel, a standard-of-care chemotherapy regimen, in the second-line setting," he added.

New data on adagrasib were presented at the American Society for Clinical Oncology 2022 annual meeting and simultaneously published in the New England Journal of Medicine.

Adagrasib (developed by Mirati) is currently awaiting approval from the US Food and Drug Administration as a treatment for patients with NSCLC harboring the KRAS G12C mutation who have received at least one prior systemic therapy. This would be an accelerated approval based on overall response data from the KRYSTAL-1 study detailed below. The company has an ongoing confirmatory Phase 3 trial, KRYSTAL-12, evaluating adagrasib versus docetaxel in patients previously treated for metastatic NSCLC with a KRAS G12C mutation.

If approved, adagrasib would be the second in this class of agents. The first KRASG12C inhibitor for use in lung cancer was sotorasib (Lumakras), approved by the US Food and Drug Administration in May 2021.  

Sabari noted that there are several differences between the two drugs. Adagrasib has CNS penetration and is the first KRASG12C inhibitor to demonstrate clinical activity in patients with KRAS G12C-mutated NSCLC with untreated active CNS metastases.

Published Clinical Data

The results published in the New England Journal of Medicine are from the company-funded KRYSTAL-1 clinical trial, which had the primary endpoint of objective response rate.

It was conducted in patients with KRAS G12C-mutated NSCLC who had previously received treatment with at least one platinum-containing chemotherapy regimen and checkpoint inhibitor therapy either sequentially or concurrently.

Patients were treated with oral adagrasib 600 mg twice a day until disease progression, unacceptable toxicity, or death.

On October 15, 2021, the data cutoff date, a total of 116 patients had received at least one dose of adagrasib. At a median follow-up of 12.9 months, the confirmed objective response rate was 42.9% among 112 patients with measurable disease at baseline. One patient achieved a complete response: 42% achieved a partial response, and disease stabilized for a minimum of 6 weeks in over 36% of the group.

Only 5.4% of patients had progressive disease as their best overall response, investigators note. Among those patients who responded to twice-daily KRASG12C inhibition, the median time to response was 1.4 months and the median duration of response was 8.5 months. As of the data cutoff date, one third of the group were still receiving treatment, the authors note.

Median progression-free survival (PFS) was 6.5 months and median overall survival (OS) was 11.7 months. With a longer median follow-up of 15.6 months, median OS was 12.6 months and the estimated OS at 1 year was close to 51%.

"The majority of treatment-related adverse events were low-grade, started early in treatment, and quickly resolved after occurrence," Sabari noted.

Grade 1-2 treatment-related adverse events occurred in 53% of patients while 45% had grade 3-4 treatment-related adverse events, and there were two fatal grade 5 treatment-related adverse events. The same events led to a dose reduction in 52% of the group overall and dose interruption in 61%, while in 7% of patients, treatment-related adverse events led to discontinuation of the drug.

CNS Metastases

At baseline, some 42 patients had evidence of central nervous system (CNS) metastases. At a median follow-up of 15.4 months, an intracranial-confirmed objective response was achieved in one third of this subgroup overall while median duration of the intracranial response was 11.2 months. Again, within the same subgroup, the median PFS was 5.4 months.

As Sabari noted, CNS metastases from KRAS mutant NSCLC are common. "Adagrasib demonstrated encouraging and durable CNS-specific activity in patients with KRAS G12C -mutant NSCLC and active, untreated CNS metastases," he said.

The study was funded by Mirati Therapeutics.

ASCO 2022. Presented June 3, 2022. Abstract 9002.

N Engl J Med. Published online June 3, 2022. Full text

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