Mirati Therapeutics announces results from KRYSTAL-7, KRYSTAL-1 trials

Mirati Therapeutics announced preliminary results from the KRYSTAL-7 Phase 2 trial and KRYSTAL-1 Phase 1b cohort evaluating adagrasib concurrently combined with pembrolizumab in patients for the treatment of first-line NSCLC harboring a KRASG12C mutation across all PD-L1 subgroups. These data are the first to demonstrate the tolerability and feasibility of a concurrent combination regimen of a KRASG12C inhibitor and a PD-1/L1 checkpoint inhibitor. The KRYSTAL-7 and KRYSTAL-1 trials represent the largest dataset evaluating a KRASG12C inhibitor in combination with a PD-1/L1 checkpoint inhibitor as a first-line treatment for patients with NSCLC harboring a KRASG12C mutation. 75 patients were enrolled and evaluable for safety with a median follow-up of 3.5 months. Treatment-related adverse events were Grade 1-2 (39%), Grade 3 (40%) and Grade 4 (4%); there were no Grade 5 TRAEs observed. TRAEs led to discontinuation of both adagrasib and pembrolizumab in 2 patients and only pembrolizumab in 2 patients; there were no patients who discontinued only adagrasib due to a TRAE. Increases in alanine transaminase/ aspartate transaminase were consistent with either agent as a monotherapy with Grade 3 TRAEs being highest grade and total incidence of Grade 3 liver function test increases of 9%. Median time from onset to an increase in ALT and AST was 26 and 37 days, respectively and only 1 patient experienced new onset treatment-related ALT/AST increase after 3 months. Of patients who were clinically evaluable and received at least one on-study scan, adagrasib and pembrolizumab demonstrated promising preliminary clinical activity across all PD-L1 subgroups with an objective response rate of 49%. In a subset of response-evaluable patients enrolled at least 6 months prior to the data cutoff date, 6 of 26 clinical responses occurred at second on-study scan or later, and the ORR was 56%. 7 evaluable patients enrolled in the KRYSTAL-1 Phase 1b cohort reported an ORR of 57% and a disease control rate of 100%. The four patients who responded maintained response for over nine months while two continued to receive treatment and remain in response beyond 18 months. Safety in the KRYSTAL-1 Phase 1b cohort was consistent with what has been observed in KRSTYAL-7 and demonstrated a manageable safety profile with no Grade 4-5 TRAEs. "Initial results across all cohorts suggest the concurrent combination of adagrasib and pembrolizumab may provide a chemotherapy-free option for treatment-naive NSCLC with a manageable safety profile and encouraging clinical activity," said Pasi A. Janne, MD, PhD, Dana Farber Cancer Institute. "Across all evaluated cohorts, liver-related TRAEs were predominantly low grade and occurred early in treatment, with limited new onset after 3 months."