BRAF/MEK Inhibitor Combo Produces Benefits in Advanced Melanoma

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Study Authors: Antoni Ribas, Adil Daud, et al.

Target Audience and Goal Statement:

Oncologists, dermatologists, primary care physicians, internists, family medicine specialists

The goal of this phase Ib expansion study was to report on the 5-year overall survival (OS) and long-term safety profile of the BRAF inhibitor vemurafenib plus the MEK inhibitor cobimetinib in two cohorts of patients with advanced BRAF-mutated melanoma.

Questions Addressed:

• What were the 5-year OS rates for two patient cohorts with BRAF-mutated melanoma treated with vemurafenib plus cobimetinib?
• What was the long-term safety profile of this combination treatment?

Study Synopsis and Perspective:

Long-term survival benefits were seen in a subset of patients with BRAF-mutated metastatic melanoma who were treated with a combination of the BRAF inhibitor vemurafenib plus the MEK inhibitor cobimetinib, according to follow-up data from the phase Ib BRIM7 trial.

Patients with newly diagnosed advanced BRAF V600-mutated melanoma who were BRAF inhibitor-naive had a median OS of 31.8 months and a 5-year OS rate of 39.8%. Patients who progressed during or after first-line vemurafenib had a median OS of 8.5 months and a 3-year OS rate of 14.0%, reported Antoni Ribas, MD, of the University of California Los Angeles, and colleagues in Clinical Cancer Research.

Initial results of the BRIM7 trial demonstrated that 87% of the patients with previously untreated melanoma had an objective response with the drug combination, including six complete responses; the median progression-free survival (PFS) was 13.7 months. In the previously treated cohort, 10 of 66 patients had partial responses, and the median PFS was 2.8 months.

“When this study was initiated, the treatments available yielded long-term benefit at four or five years for only about 10 percent of patients diagnosed with metastatic melanoma. The fact that a subgroup of patients were alive and well at the five-year follow-up mark after this combination treatment is remarkable,” said Ribas in a statement.

This dose-finding phase of the study reported results at 4 and 5 years for the two cohorts: the newly diagnosed and BRAF inhibitor-naive group (n=63) and the previously treated group (n=66). Patients in both cohorts received the same combination of vemurafenib and cobimetinib.

The trial’s primary objectives were maximum tolerated dose, dose-limiting toxicity, tolerability, pharmacokinetic profile of the combination, and determination of phase II/III dosing. Response rate, PFS, and OS were secondary endpoints.

The updated analysis occurred after a median follow-up of 28.8 months for the previously untreated cohort and 8.4 months for the previously treated cohort. All but one patient in each cohort had discontinued treatment, primarily because of disease progression. Just over half of the patients in the untreated cohort had died (34 of 63) compared with 80% of patients who had received single-agent vemurafenib (53 of 66). Median follow-up for all living patients was 47.0 months and 24.0 months in the untreated and previously treated cohorts, respectively.

The 31.8-month median OS in the cohort with untreated disease represented an estimate, as the upper limit of the confidence intervals had yet to be reached (95% CI 24.5-not estimable).

“It is notable that the survival plateaued at 4 and 5 years at 39% in the BRAF inhibitor-naive patients and at 14.0% from 3 years onward in patients who had experienced progression on prior vemurafenib monotherapy,” the authors noted.

With additional follow-up, the combination’s previously reported safety profile had not changed, including no new or unexpected toxicities/adverse events.

This study is one of a series of trials testing the addition of MEK inhibition to a BRAF inhibitor in order to circumvent resistance to BRAF and to reactivate the MAPK signaling pathway seen in studies of BRAF inhibitor monotherapy. “By inhibiting paradoxical MAPK activation, the combination of BRAF inhibitors plus MEK inhibitors decreases some of the toxicities related to BRAF inhibitor monotherapy, as MAPK activation is the mechanistic basis for secondary squamous cell carcinomas and other skin and musculoskeletal toxicities associated with BRAF inhibitor monotherapy,” the authors wrote.

The results added to those from a pooled analysis of two randomized trials of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib in patients with untreated metastatic melanoma, who demonstrated a 5-year progression-free survival (PFS) rate of 19% and a 5-year OS rate of 34%.

The data on the dabrafenib-trametinib combination came from the randomized Combi-v and Combi-d trials. Both studies included patients with previously untreated advanced melanoma. Combi-v compared dabrafenib plus trametinib versus vemurafenib monotherapy. Combi-d compared dabrafenib and trametinib versus dabrafenib alone. The two trials involved a combined total of 563 patients.

As reported at the 2019 American Society of Clinical Oncology (ASCO) meeting, and subsequently in the New England Journal of Medicine, the pooled data yielded a median PFS of 11.1 months. Landmark PFS ranged from 31% at 2 years to 24%, 21%, and 19% in the next 3 years. Patients with elevated lactate dehydrogenase (LDH) at baseline had worse survival. An analysis limited to patients with normal LDH showed landmark PFS of 39% to 25% at years 2 through 5. Patients with normal LDH and fewer than three involved organs had a 5-year PFS rate of 31% with the combination.

The OS analysis showed little change from 4 to 5 years (37% vs 34%, respectively). The subgroup with normal LDH at baseline had a 4-year OS rate of 48% and 5-year OS rate of 43%. For patients with normal LDH and fewer than three involved organs, landmark analyses of OS showed a 75% rate at 2 years, 67% at 3 years, 58% at 4 years, and 55% at 5 years.

Source Reference: Clinical Cancer Research 2019; DOI: 10.1158/1078-0432.CCR-18-4180

Study Highlights and Explanation of Findings:

This phase of the BRIM7 trial adds to the initial results reported in 2014 of 129 patients treated with 10 dosing regimens of the combination therapy in which the maximum tolerated doses and schedules were determined. The first part of the study demonstrated objective responses in 87% of patients who were naive to BRAF inhibitors, including 9% who had complete responses. For patients who started the study after progression on prior vemurafenib monotherapy, 15% had a confirmed objective response.

This extension study reported on the long-term efficacy and safety of the combination therapy, indicating that it resulted in no new toxicities and durable responses in BRAF V600-mutated patients who were followed for 5 years.

With the extended follow-up, the median duration of response improved for the BRAF inhibitor-naive cohort, at 14.3 months, but remained the same in the previously treated group. In the BRAF inhibitor-naive group, the plateau of long-term PFS was 20.3% (95% CI 7.5%-33.1%) at 5 years.

ASCO discussant Paul Chapman, MD, of Memorial Sloan Kettering Cancer Center in New York City, focused on the next steps and unresolved issues raised by the combination studies in his discussion. Can additional favorable-risk subgroups be identified to increase the PFS? Given that a portion of the patients had prolonged complete responses, can treatment stop at some point? What is the best first-line treatment option for patients with BRAF V600-positive melanoma: combined BRAF/MEK inhibition or checkpoint inhibition?

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