Targeted BRAF/MEK Inhibitor Combination Achieves Long-Term Survival in Melanoma

Jeffrey Weber, MD

Jeffrey Weber, MD

More than one-fourth of patients with advancedBRAFV600-mutant melanoma remained alive at 5 years after treatment with the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), long-term follow-up from a randomized trial showed.¹

In the subgroup of patients with normal baseline lactate dehydrogenase (LDH) and fewer than 3 organ sites with metastases, half remained at alive at 5 years. No new safety signals emerged during long-term follow-up, as reported at the 2017 ASCO Annual Meeting in Chicago.

“This is the longest follow-up for any randomized trial evaluating a BRAF inhibitor combined with a MEK inhibitor,” said Jeffrey Weber, MD, a medical oncologist at NYU-Langone Medical Center in New York, who presented the findings during the meeting. “Long-term survival is achievable with dabrafenib-trametinib in patients withBRAFV600-mutant metastatic melanoma, particularly those with favorable baseline factors. “

“These data support the use of dabrafenib and trametinib as a treatment option that can achieve long-term survival inBRAFV600E/K-mutated melanoma,” he added.

Studies of combination therapy with dabrafenib and trametinib have demonstrated superior outcomes versus BRAF inhibitor monotherapy in patients withBRAFV600-mutant metastatic melanoma. Specific baseline factors—LDH levels and number of involved organs—were associated with long-term.

Data on long-term outcomes with the combination remained limited. Follow-up in the randomized, open-label phase II BRF113220 study provided a dataset to examine long-term outcomes. The trial compared the combination (2 groups assigned to different doses of trametinib) against dabrafenib alone in patients with unresectable stage IIIc/IVBRAFV600-mutant metastatic melanoma. The trial demonstrated significant improvement in progression-free survival (PFS) with the combination.²

Weber reported updated findings after a median follow-up of 66.5 months. The trial initially involved 162 patients. Key baseline characteristics included presence of a V600E mutation in about 85% of patients, LDH above the upper limit of normal (ULN) in 40% to 50%, and involvement of 3 or more organs in 50% to 63% of patients across the 3 treatment arms. About one-fourth of patients had prior exposure to immunotherapy, and about 20% had received previous chemotherapy.

The updated analysis showed that 35 of the original 162 patients remained alive, including 5 who crossed over from monotherapy to the combination at progression. Weber said 29 of the 35 remained in active follow-up. Records showed that 106 of the 162 patients received subsequent anticancer therapy including targeted therapies (44%), immunotherapy (38%, including anti—PD-1/PD-L1 therapy in 17%), radiotherapy (19%), surgery (20%), and chemotherapy (17%).

Dabrafenib plus the higher dose of trametinib led to an overall response rate of 76% (95% CI, 62%-87%) as compared with 50% (95% CI, 36%-64%) in the patients who received dabrafenib with a lower dose of trametinib, and 54% (95% CI, 40%-67%) in those who received dabrafenib alone. Median duration of response was 10.5 to 11.1 months with combination therapy versus 5.6 months with dabrafenib alone. Median PFS was 9.4 (95% CI, 8.6-16.6) and 9.2 (95% CI, 6.5-11.0) months in the combination arms and 5.8 (95% CI, 4.6-7.4) months with dabrafenib monotherapy. Overall survival (OS) was 25.0, 22.5, and 20.2 months across the treatment arms, respectively.

LDH level and number of metastatic sites had significant associations with PFS and OS. Patients with LDH ≤ULN had a 36-month PFS of 47%, declining to 25% at 45 and 60 months. Patients with higher LDH levels had PFS of 8% at all 3 time points. Patients with fewer than 3 metastatic sites had OS of 74% at 36 months, 57% at 48 months, and 51% at 60 months. For patients with more metastatic sites, OS at the same 3 time points were 58%, 42%, and 31%.

Treatment-related adverse events (AEs) occurred in a similar proportion of patients in all 3 treatment groups. The incidence of grade 3/4 treatment-related AEs was higher in the 2 combination arms (42% to 43%) versus with the dabrafenib monotherapy (25%). Rates of discontinuation associated with adverse events were 16%, 7%, and 2% across the 3 groups, respectively.

The most common AEs with the combination were pyrexia, diarrhea, nausea, vomiting, arthralgia, and rash. The most common grade 3/4 AEs in the combination arms were pyrexia (7%; 11%), nausea (4%; 7%), vomiting (2%; 7%), and secondary squamous cell skin cancer (5%; 2%), which also occurred in 11% of patients in the dabrafenib monotherapy group.

References:

1. Long GV, Eroglu Z, Infante JR, et al. Five-year overall survival (OS) update from a phase II, open-label trial of dabrafenib (D) and trametinib (T) in patients (pts) with BRAF V600-mutant unresectable or metastatic melanoma (MM).J Clin Oncol.2017;35(suppl; abstr 9505).
2. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.N Engl J Med.2012;367(18):1694-1703. doi: 10.1056/NEJMoa1210093.