Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With <i>KRAS^G12C</i>-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases.

Abstract

<i>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</i> JCO <i>or elsewhere, for which the primary end point has already been reported.</i>Patients with Kirsten rat sarcoma viral oncogene homolog (<i>KRAS</i>)-mutated non-small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without <i>KRAS</i> mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with <i>KRAS^G12C</i>-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 <i>KRAS^G12C</i>-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 <i>KRAS^G12C</i>-mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.