Durable Benefits With Melanoma Combinations

A subset of patients with metastatic melanoma obtained long-term survival benefits from combined BRAF/MEK inhibition, follow-up data from an early-phase trial showed.

The benefits were most pronounced for patients with newly diagnosed disease treated with vemurafenib (Zelboraf) and cobimetinib (Cotellic). Median overall survival (OS) was 31.8 months and 5-year OS was 39.8%. Patients who progressed during or after first-line vemurafenib had median OS of 8.5 months and 3-year OS of 14.0%.

Initial results from the phase Ib BRIM7 trial showed that 87% of patients with previously untreated disease had an objective response with the combination, reported Antoni Ribas, MD, of the University of California Los Angeles, and colleagues in Clinical Cancer Research.

"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," Ribas said in a statement. "The fact that a subgroup of patients were alive and well at the five-year follow-up mark after this combination treatment is remarkable."

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

Investigators in the multicenter BRIM7 trial enrolled two cohorts of patients with BRAF V600-mutant melanoma: Those with newly diagnosed unresectable or metastatic disease (n=63) and patients whose disease progressed with first-line vemurafenib monotherapy (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.

A previously reported analysis of BRIM7 demonstrated the safety and tolerability of the combination. The results showed that 55 of 63 patients with untreated melanoma had objective responses with the combination therapy, including six complete responses, and the median PFS was 13.7 months. In the previously treated cohort, 10 of 66 patients had partial responses and median PFS was 2.8 months

The updated analysis occurred after a median follow-up of 28.8 months for the previously untreated cohort and 8.4 months for patients who received single-agent vemurafenib in first line. 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) as 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.

The pooled analysis data of 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 with vemurafenib monotherapy. Combi-d compared dabrafenib and trametinib with 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 of 31% with the combination.

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

ASCO invited discussant Paul Chapman, MD, of Memorial Sloan Kettering Cancer Center in New York City, focused on next steps and unresolved issues raised by the combination studies. 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 BRAFV600-positive melanoma: combined BRAF/MEK inhibition or checkpoint inhibition?

Comment