Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRAS G12C -Mutated Non–Small-Cell Lung Cancer Who Have Untreated CNS Metastases

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Patients with Kirsten rat sarcoma viral oncogene homolog ( KRAS)–mutated non–small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without KRAS mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with KRAS G12C -mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249 ; phase Ib cohort), in which adagrasib 600 mg was administered orally, twice daily. Study outcomes included the safety and clinical activity (intracranial [IC] and systemic) by blinded independent central review. Twenty-five patients with KRAS G12C -mutated NSCLC and untreated CNS metastases were enrolled and evaluated (median follow-up, 13.7 months); 19 patients were radiographically evaluable for IC activity. Safety was consistent with previous reports of adagrasib, with grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months. Adagrasib is the first KRAS G12C inhibitor to prospectively demonstrate IC activity in patients with KRAS G12C -mutated NSCLC and untreated CNS metastases, supporting further investigation in this population. Adagrasib achieves promising intracranial activity for untreated brain metastases in NSCLC.