Phase 1 Clinical Trial of Trametinib and Ponatinib in Patients With NSCLC Harboring KRAS Mutations

Abstract

Introduction 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 1 dose escalation study of trametinib and ponatinib was conducted in patients with advanced NSCLC with KRAS mutations. A standard 3-plus-3 dose escalation was done. Patients were treated with the study therapy until intolerable toxicity or disease progression. Results A total of 12 patients with KRAS-mutant NSCLC were treated (seven at trametinib 2 mg and ponatinib 15 mg, five at trametinib 2 mg and ponatinib 30 mg). Common toxicities observed were rash, diarrhea, and fever. Serious adverse events potentially related to therapy were reported in five patients, including one death in the study and four cardiovascular events. Serious events were observed at both dose levels. Of note, 75% (9 of 12) were assessable for radiographic response and no confirmed partial responses were observed. The median time on study was 43 days. Conclusions In this phase 1 study, in patients with KRAS-mutant advanced NSCLC, combined treatment with trametinib and ponatinib was associated with cardiovascular and bleeding toxicities. Exploring the combination of MEK and FGFR1 inhibition in future studies is potentially warranted but alternative agents should be considered to improve safety and tolerability.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

“…The failure of MEKi in NSCLC is due to multiple mechanisms, including secondary MEK mutations 11 , immune escape 12 , reactivation of the MAPK pathway by RAF dimerization 13 , or compensatory induction of RAS-related pathways 14 , 15 , 16 , which inevitably leads to the development of therapy resistance and disease recurrence. These molecular discoveries have successfully promoted the clinical application of MEKi in combination with other targeted interventions 17 , 18 . However, it is difficult to restore the sensitivity of KRAS -mutant NSCLC cells to MEKi.…”

Ponatinib sensitizes myeloma cells to MEK inhibition in the high-risk VQ model

“…H23 cells were highly susceptible to Tra and Pon combination treatment 33 , similar as what we observed in the VQ model. However, in a phase I clinical of KRAS mutant non-small cell lung cancer patients, it was found that combination Tra/Pon treatment was associated with cardiovascular (CV) and bleeding toxicities 34 . CV side effects of this combo treatment are not unsurprising, as Pon was temporarily withdrawn by the US Food and Drug Administration in 2013 for heart failure and other CV side effects before being returned with additional safety warnings and restrictions 35 .…”

RAS‐targeted cancer therapy: Advances in drugging specific mutations

“…In contrast, trametinib appears to inhibit the proliferation of KRAS mutant A549 cells effectively by impairing the RAF–MEK interaction 180 . However, its resistance still exists in KRAS mutant NSCLC, which is caused by compensatory activation of FGFR1 181 . As a result, MEK inhibitors are increasingly used in combination with other inhibitors to avoid drug resistance due to the feedback regulatory mechanism induced by their use alone.…”