In a phase II trial reported in The Lancet Oncology, Planchard et al found that combined MAPK pathway inhibition with the BRAF inhibitor dabrafenib (Tafinlar) and the MEK inhibitor trametinib (Mekinist) resulted in a high response rate in patients with BRAF V600E–mutant non–small cell lung cancer (NSCLC). Bruce E. Johnson, MD, of Dana-Farber Cancer Institute, is the corresponding author of this article.
In the study, 57 eligible patients from 30 sites in North America, Europe, and Asia who had pretreated metastatic stage IV BRAF V600E–mutant NSCLC with tumor progression after at least 1 previous platinum-based chemotherapy and who had up to 3 previous systemic anticancer therapies were treated with dabrafenib at 150 mg twice daily plus trametinib at 2 mg once daily in continuous 21-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response.
Overall, 36 patients (63.2%, 95% confidence interval [CI] = 49.3%–75.6%) achieved an investigator-assessed overall response, including a complete response in 2 (4%). The median duration of response was 9.0 months, with responses in 18 of 36 responders ongoing at the time of analysis. The median time to first response was 6 weeks.
The disease control rate was 79.8%. Median progression-free survival was 9.7 months (95% CI = 6.9–19.6 months). Survival data were immature, but 82% of patients were alive at 6 months.
Serious adverse events were reported in 32 of 57 patients (56%), including pyrexia in 16%, anemia in 5%, confusional state in 4%, decreased appetite in 4%, hemoptysis in 4%, hypercalcemia in 4%, nausea in 4%, and cutaneous squamous cell carcinoma in 4%. The most common grade 3 or 4 adverse events were neutropenia in 9%, hyponatremia in 7%, and anemia in 5%. Four patients died during the study due to adverse events considered unrelated to treatment.
The investigators concluded:
Dabrafenib plus trametinib could represent a new targeted therapy with robust antitumour activity and a manageable safety profile in patients with BRAF V600E-mutant NSCLC.
The investigation was funded by GlaxoSmithKline. ■