Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRASG12C-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases

Abstract

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.

FIG 1.

Efficacy outcomes for evaluable patients per CNS RECIST v1.1 (n = 19). (A) Waterfall plot of maximum percent tumor change from baseline (only patients with target lesions are shown). (B) Kaplan-Meier graphical representation of intracranial PFS. (C) Swimmer plot showing individual duration of treatment, time to first dose modification, response, clinical outcome, and most commonly administered dose at data cutoff. (D) Kaplan-Meier graphical representation of OS for the full analysis set (N = 25). ^aTime to first dose modification due to any cause, including missed dose, AE, or others. For patients who had a dose modification (reduction or interruption) after initiation of treatment because of an AE, adagrasib could be restarted at the 600 mg twice a day dose following resolution of AEs if deemed appropriate. AE, adverse event; NE, not evaluable; OS, overall survival; PFS, progression-free survival.