Brief Report: Phase I clinical trial of trametinib and ponatinib in patients with non-small cell lung cancer harboring KRAS mutations

Abstract Background Somatic KRAS mutations occur in 25% of patients with NSCLC. Treatment with MEK inhibitor monotherapy has not been successful in clinical trials to date. Compensatory activation of FGFR1 was identified as a mechanism of trametinib resistance in KRAS mutant NSCLC, and combination therapy with trametinib and ponatinib was synergistic in in vitro and in vivo models. This study sought to evaluate this drug combination in patients with KRAS mutant NSCLC. Methods A phase I dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. Standard 3+3 dose escalation was employed. Patients were treated with study therapy until intolerable toxicity or progression of disease. Results 12 patients with KRAS mutant NSCLC were treated (7 at trametinib 2 mg /ponatinib 15mg, 5 at trametinib 2 mg /ponatinib 30mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in 5 patients including one death on study, and 4 cardiovascular events. Serious events were observed at both dose levels. Seventy-five percent (9/12) were evaluable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. Conclusion In this phase I study in patients with KRAS mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring combination MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.