CHICAGO- Interim results of the ongoing phase III COMBI-d study reported at the 2014 annual meeting of the American Society of Clinical Oncology (ASCO) show that patients with BRAF V600E/K mutant metastatic melanoma had a significant improvement in progression-free survival (PFS) when the MEK inhibitor trametinib was added to first-line treatment with the BRAF inhibitor dabrafenib (Late Breaking Abstract 9011).
“This is the first melanoma phase III, double-blind, randomized controlled trial with an active control arm,” said Georgina V. Long, BSc, PhD, MBBS, of the Melanoma Institute Australia, Sydney, who reported the findings at a symposium on novel combination therapies for melanoma. Both dabrafenib and trametinib have demonstrated superior PFS and overall response rate (ORR) vs chemotherapy when used as monotherapy in patients with BRAF V600 mutant, metastatic melanoma, she noted, but most patients develop resistance to treatment and experience oncogenic toxicities, including cutaneous squamous cell carcinoma. A phase I/II study of dabrafenib plus trametinib vs dabrafenib alone found that simultaneous inhibition of BRAF and MEK mitigated these effects, however the study involved only 54 patients in each arm, had crossover, and was not blinded, Long explained.
In the present study 423 patients with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma were randomized to receive dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily; n=211) or dabrafenib plus placebo (n=212). The primary endpoint was investigator-assessed PFS. Secondary endpoints were overall survival (OS), ORR, duration of response, and safety. Crossover was prohibited. The study has 95% power and a one-sided Î± = .025 to detect a PFS hazard ratio (HR) of .59.
Median follow-up was 9 months (range, 0-16 months). Median PFS was 9.3 months for the dabrafenib plus trametinib arm vs 8.8 months for the dabrafenib plus placebo arm. Confirmed ORR for the dabrafenib plus trametinib arm was 67%, with a complete response (CR) of 10% vs 51% with a CR of 9% for dabrafenib plus placebo (P = .0015). The interim OS HR was .63 (95% CI: .42 -.94; P = .023), in favor of dabrafenib plus trametinib (40 vs 55 deaths). An updated OS analysis is planned at 70% death events. Long said PFS will also be updated.
Rates of adverse events (AEs) were similar for both arms, said Long, although more patients in the dabrafenib plus trametinib arm had AEs that led to dose modifications. The combination also resulted in an increased incidence (51% vs 28%) and severity (grade 3, 6% vs 2%) of pyrexia compared with dabrafenib plus placebo. Long said she educates patients regarding the potential for pyrexia and advises them to stop medication for two days if they experience a second event. She said in her experience she has not found premedication or dose reduction helpful, although corticosteroids may be indicated for a small number of recalcitrant patients.
AEs considered BRAF inhibitor related occurred more frequently in patients who received dabrafenib plus placebo. Squamous cell carcinoma was observed in 2% of patients in the combination arm vs 9% in the dabrafenib plus placebo group; hyperkeratosis occurred in 3% of patients in the combination arm vs 32% in the dabrafenib plus placebo group.
“This clinical data from the COMBI-d study has the potential to be highly controversial,” commented Jason J. Luke, MD, medical oncologist at the Dana-Farber Cancer Institute, Boston. He said the initial clinical trials showed that combining the two agents is more effective than either agent alone, but the data became less convincing as researchers followed patients further. “From a scientific perspective, the combination of a BRAF and a MEK inhibitor make sense, but it is not without side effects,” said Luke, who noted the significant increase in the rate of pyrexia experienced by patients treated with the combination. “Interestingly, some of the other BRAF and MEK inhibitors being explored in this setting do not induce this same side effect.”
Trametinib is currently approved for use as a single-agent and in combination with dabrafanib for treatment of patients with unresectable or metastatic melanoma with BRAF V600E/K mutations, as detected by an FDA-approved test. Dabrafanib is approved as a single-agent for treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test, and in combination with trametinib. Both agents are marketed by GlaxoSmithKline.