Dr. Spira on the CNS Activity of Adagrasib in NSCLC

Supplements And Featured Publications, Addressing the Unmet Needs in KRAS G12C–Mutated Solid Tumors, Volume 1, Issue 1

Alexander I. Spira, MD, PhD, FACP, discusses the activity of adagrasib in patients with non–small cell lung cancer and central nervous system metastases.

Alexander I. Spira, MD, PhD, FACP, research institute director, Thoracic and Phase 1 Trial Program, Virginia Cancer Specialists Research Institute, Virginia Cancer Specialists, clinical assistant professor, Johns Hopkins University, discusses the activity of adagrasib (MRTX 849) in patients with non–small cell lung cancer (NSCLC) and central nervous system (CNS) metastases.

The phase 2 KRYSTAL-1 trial (NCT03785249) evaluated adagrasib in patients with advanced/metastatic NSCLC whose tumors harbored KRAS G12C mutations, with or without CNS metastases. Data presented at the 2022 ASCO Annual Meeting showed that among 33 patients with treated, stable CNS metastases, the intracranial overall response rate was 33%, including a complete response rate of 15%, a partial response of 18%, and a stable disease rate of 52%.

An analysis of patients with active, untreated CNS metastases at baseline (n = 25), also presented the 2022 ASCO Annual Meeting, showed that patients who received adagrasib at 600 mg twice daily had durable CNS-specific activity. At a median follow-up of 6.6 months, 19 patients have radiographically evaluable disease for intercranial ORR—15 with target lesions and 4 with nontarget lesions only. Among all evaluable patients the intercranial ORR was 32% comprising a 16% CR rate and a 16% partial response rate.

Currently, patients in this population are treated with chemotherapy and immunotherapy in the first or second line. In May 2021, the FDA approved sotorasib (Lumakras) for patients with NSCLC harboring KRAS G12C mutations who have received at least 1 prior systemic therapy, Spira explains.

However, adagrasib represents another potential tool in this armamentarium, and this is the first agent to display evidence of any CNS activity in the patient population, which is a differentiator from sotorasib and other treatments, Spria adds. Patients in this population often present with CNS metastases or progress to the brain, so this agent could help fulfill an unmet need, Spira concludes.