Targeted Therapy Combinations Still Key in Metastatic Melanoma

Jeffrey S. Weber, MD, PhD

Combinations of targeted therapies continue to advance toward full regulatory approval for patients with metastatic or unresected melanoma, given the substantial benefits seen with these agents. At this time, the FDA is considering two applications for separate combinations of BRAF and MEK inhibiting agents for patients with unresectable or metastatic BRAFV600 mutation-positive melanoma.

“The future of the treatment of melanoma is clearly going to be in combinations, both for targeted therapy and for immunotherapy,” said Jeffrey S. Weber, MD, PhD, who recently joined the NYU Langone Medical Center. “Already, there is an FDA-approved combination therapy that is targeted; that is dabrafenib and trametinib. There are new combinations coming up, mainly concerning CDK 4/6 and MEK inhibitors in NRAS-mutated but BRAF wild-type melanoma, which is an unmet medical need.”

An application for the full approval of dabrafenib/trametinib is currently with the FDA. This submission was based on data from the phase III COMBI-d and COMBI-v studies, which showed an improvement in overall survival (OS) for the combination versus single-agent BRAF inhibition. Additionally, an application for the combination of vemurafenib and cobimetinib is currently pending a decision from the agency, based on the phase III coBRIM study. The FDA is scheduled to make a decision on both applications within the next two weeks.

“There is a new BRAF/MEK combination with vemurafenib and cobimetinib. This looks very promising,” said Weber. “The initial data from a randomized trial of vemurafenib and cobimetinib versus vemurafenib alone was presented at ESMO and published in The New England Journal of Medicine. It looks very impressive. In many ways, the data are probably comparable to the existing dabrafenib and trametinib data that led to the FDA approval a year ago of that doublet.”

In a final analysis of the COMBI-d trial presented at the 2015 ASCO Annual Meeting,¹ the combination of dabrafenib and trametinib demonstrated a median OS of 25.1 months compared with 18.7 months with dabrafenib alone (HR, 0.71; 95% CI, 0.55-0.92; P = .011). The 2-year OS rate with the combination was 51% versus 42% with the single-agent.

Median progression-free survival (PFS) was 11.0 months with the combination compared with 8.8 months for dabrafenib plus placebo (HR, 0.67; 95% CI, 0.53-0.84; P <.001). The ORR was 69% versus 53%, for the combination and single-agent, respectively. The complete response rate was 16% in the combination arm compared with 13% for dabrafenib. Duration of response was 12.9 and 10.6 months in the combination and monotherapy arms, respectively.

"Dabrafenib and trametinib are terrific drugs given as frontline therapy for BRAF-mutated patients," said Weber.

All-grade adverse events (AEs) occurred in 97% of patients in each arms; however, treatment-related AEs were lower in the combination arm (87% vs 90%). Treatment-related grade 3 AEs occurred in 30% of patients with the single-agent versus 32% with the combination. Discontinuation of treatment due to AEs occurred in 11% of patients with the combination versus 7% for the monotherapy.

In a second phase III trial used for the FDA application, COMBI-v, the median PFS with the combination was 11.4 versus 7.3 months with vemurafenib (HR, 0.56; P <.001).² The ORR was 64% with the combination versus 13% for vemurafenib alone. The median duration of response was 13.8 months compared with 7.5 months with vemurafenib.

The 1-year OS rate was 72% versus 65% for the combination and monotherapy, respectively. The median OS in the combination arm was not reached compared with 17.2 months with vemurafenib (HR, 0.69; P = .002).

“Anyone who has used these drugs in detail knows that there is a cadre of long-term survivors who get complete responses to the dabrafenib and trametinib combination and who have been on them for 4 or 5 years,” said Weber. “Maybe they are cured, just like maybe a lot of those immunotherapy patients who are on [those therapies] for 5 years and are cured.”

For the currently unapproved combination of vemurafenib and cobimetinib, the data are still in flux. In fact, the FDA extended the review for the combination in order to review updated data from the pivotal coBRIM study that were presented at the 2015 ASCO Annual Meeting.³ In the updated findings, median PFS with the combination of vemurafenib and cobimetinib was 12.25 versus 7.20 months with vemurafenib plus placebo (HR, 0.58; 95% CI, 0.46-0.72).

The ORR was 69.6% versus 50%, for cobimetinib and placebo, respectively. The absolute difference in ORR between the two arms was 19.64% (95% CI, 10.95-28.32). The complete response rate in the combination arm was 15.8% versus 10.5% with vemurafenib and placebo. The median duration of response was 12.98 months versus 9.23 months, with cobimetinib and placebo, respectively.

In an earlier analysis of the study published in The New England Journal of Medicine,⁴ the most frequently reported adverse events (AEs) of all grades reported in the cobimetinib arm versus the control arm included diarrhea (57% vs 28%), nausea (39% vs 24%), photosensitivity (28% vs 16%), increased ALT (24% vs 18%), increased AST (22% vs 13%), increased CPK (30% vs 3%), vomiting (21% vs 12%), and serous retinopathy (20% vs <1%).

“The most significant change in the targeted sphere is the fact that BRAF/MEK is now the treatment of choice upfront for patients with aggressive, high-disease burden, BRAF-mutated disease. There is no question there,” Weber said. “Now, we are into triple combinations. First, it is the single drug vemurafenib, and then it is the dabrafenib and trametinib combination. Now, who knows? It’s going to be either triple therapy with targets, or a combination of targeted and immunotherapy.”

At this time, there are numerous studies continuing to explore combinations for patients with metastatic melanoma. These trials continue to push toward a curative approach.

"There must be 20 combination trials that are coming along in phases I and II. All of them will shed significant light on what the best leads are for double and triple therapies," Weber concluded.

References

1. Long GV, Stroyakovsky DK, Gogas H, et al. COMBI-d: a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma. J Clin Oncol. 2015;33 (suppl; abstr 102).
2. Robert C, Karaszewska B, Schachter J, et al. COMBI-v: A randomised, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: ESMO Congress 2014; September 26-30, 2014; Madrid, Spain. Abstract LBA4.
3. Larkin JMG, Yan Y, McArthur GA, et al. Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma. J Clin Oncol. 2015;33 (suppl; abstr 9006).
4. Larkin JMG, Ascierto PA, Dréno B, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371(20):1867-1876.