Mirati’s KRAS-blocking Lung Cancer Drug Clears Safety Hurdle in Combination Study

Mirati Therapeutics said this week that its KRAS-targeting cancer drug adagrasib combined with another immunotherapy was well-tolerated by lung cancer patients, STAT recently reported.

Summary of Clinical Results

• The KRYSTAL-7 and KRYSTAL-1 trials represent the largest dataset evaluating a KRAS^G12C inhibitor in combination with a PD-1/L1 checkpoint inhibitor as a first-line treatment for patients with NSCLC harboring a KRAS^G12C mutation.
• 75 patients were enrolled and evaluable for safety with a median follow-up of 3.5 months (duration of treatment: 2 months). Treatment-related adverse events (TRAEs) 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 (ALT)/ aspartate transaminase (AST) were consistent with either agent as a monotherapy with Grade 3 TRAEs being highest grade and total incidence of Grade 3 liver function test (LFT) 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 (n=53), adagrasib and pembrolizumab demonstrated promising preliminary clinical activity across all PD-L1 subgroups with an objective response rate (ORR) 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 (with a median follow-up of 19.3 months) reported an ORR of 57% and a disease control rate (DCR) 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-naïve NSCLC with a manageable safety profile and encouraging clinical activity,” says Pasi A. Jänne, MD, PhD, Dana Farber Cancer Institute, in a statement.”Across all evaluated cohorts, liver-related TRAEs were predominantly low grade and occurred early in treatment, with limited new onset after 3 months.”