Jeffrey S. Weber, MD, PhD
Favorable long-term phase II results of the combination of dabrafenib (Tafinlar) plus trametinib (Mekinist) in patients with BRAF
V600-mutant melanoma were presented at the 2017 ASCO Annual Meeting, demonstrating that the regimen had 4-year and 5-year overall survival (OS) rates of 30% and 28%, respectively.1
In the open-label trial, patients with BRAF
V600-mutant melanoma were randomized 1:1:1 to receive dabrafenib plus 1 mg/day of trametinib, dabrafenib plus 2 mg/day trametinib, or dabrafenib alone (n = 54 each). Forty-five patients in the dabrafenib-alone arm crossed over to receive the combination as of October 13, 2016.
The data showed that OS with dabrafenib/trametinib continued to remain superior to dabrafenib monotherapy. The progression-free survival (PFS) curve for dabrafenib/trametinib also remained stable, with 4-year and 5-year rates both at 13%. At the 5-year landmark, 1 patient who received dabrafenib/trametinib went from a partial response to a complete response.
Additional encouraging findings presented at the meeting focused on the impact of this combination in BRAF
-mutant patients with melanoma who harbor brain metastases. An analysis of the phase II COMBI-MB trial results showed that dabrafenib plus trametinib achieved an intracranial response (IR) rate of 58% in melanoma that metastasized to the brain.2
The median duration of response (DOR), 6.5 months, was generally shorter than that observed in patients with melanoma who did not have brain metastases.
Patients in cohort A (n = 76) were asymptomatic for brain metastases, had an ECOG performance status of 0 or 1, and had not received prior local therapy. Cohorts B through D were considered exploratory due to their small sizes (n = 16, 16, and 17, respectively). Moreover, all patients received 150 mg of dabrafenib twice daily plus 2 mg of trametinib daily.
In cohort A, 29 of 44 patients (66%) experienced a survival event. The median DOR was 6.5 months (95% CI, 4.9-10.3), and the 6-month OS rate was 63% (95% CI, 45%-76%) in this cohort. In cohort A, 44 patients showed an overall response (95% CI, 46-69). The cohort’s overall median DOR was 6.5 months (95% CI, 4.9-10.3), and the 6-month rate was 57% (95% CI, 41-71).
The PFS in the overall study cohort was 5.6 months (95% CI, 5.3-7.4). Also, preliminary data showed that 44 patients experienced a survival event and the median OS was 10.8 months (95% CI, 8.7-19.6).
Aside from dabrafenib/trametinib, the combination regimen of nivolumab (Opdivo) plus ipilimumab (Yervoy) generated excitement in a phase II trial, in which more than 40% of patients with melanoma who had brain metastases achieved objective IRs when treated with the combination.3
The response rate increased to 50% for patients with previously untreated melanoma, and one-fifth of patients with untreated disease had IRs to treatment with nivolumab alone.
Jeffrey S. Weber, MD, PhD, deputy director and co-director of the Melanoma Program, Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center, discussed both pivotal studies for dabrafenib/trametinib in patients with melanoma and any unanswered questions that remain after the extensive 5-year follow-up in an interview with OncLive
during the 2017 ASCO Annual Meeting.
OncLive: Can you discuss the 5-year follow-up results with the dabrafenib/trametinib combination in melanoma presented at the 2017 ASCO Annual Meeting?
The gist of the presentation that I made was that our study was the longest-term follow-up with any BRAF/MEK inhibitory combination trial done. This was a randomized phase II portion of a larger phase I/II trial, part C, in which 50 or so patients per arm were randomized to get the BRAF/MEK inhibitor combination, dabrafenib/trametinib, at the standard dose of dabrafenib 150 mg twice daily by mouth and then trametinib at either 2 mg or 1 mg once daily by mouth versus the control arm of dabrafenib alone, which was then an FDA-approved treatment at the 150-mg daily standard dose.
The long-term follow-up suggest that of the patients free of progression at 4 and 5 years, it plateaued between 10% and 15%. Some of those patients will be free of progression—which includes a handful of patients who actually stayed on treatment beyond 5 years—or patients who came off treatment for various causes, such as the investigator’s choice or the patient’s decision not to continue, or toxicity. And they never progressed.
If you look at the survival curve, there does appear to be a plateau at year 5, in that the 4-year survival was 30% and the 5-year survival was 28%. It does appear that past year 3, there is a plateau on that survival curve. This implies that it’s a tail on the curve that you traditionally see with immunotherapy, but here you are seeing it with targeted therapy.