Importance of BRAF Testing Grows as Options Expand in Melanoma

Michael Postow, MD

Evolution of Immunotherapies

The landscape of treatment options for patients with advanced and/or metastatic melanoma continues to expand, with immunotherapies and targeted therapies, as well as combinations thereof, gaining approval in recent years. As such, it is becoming increasingly important to understand the patient-specific oncogenic drivers as a means of selecting treatments. The current National Comprehensive Cancer Network (NCCN) guidance recognizes the importance of BRAF testing for patients with metastatic disease.¹ As clinical experience grows with new agents, combinations, and sequences of therapy, the use of molecular profiling in metastatic melanoma is likely to become an essential means of choosing among treatment options.Patients with metastatic or unresectable melanoma are now candidates for first-line systemic therapy with anti-PD-1 receptor antibodies (category 1 recommendation) as monotherapy (pembrolizumab and nivolumab), but targeted therapies are preferred in BRAF-mutated disease, in cases where an early response is clinically desirable.1 Other options include the nivolumab/ ipilimumab (anti-CTLA-4) combination.¹

Recent phase III results reported in The New England Journal of Medicine demonstrated that the use of nivolumab, an anti-PD-1 agent, either alone or in combination with ipilimumab, an anti— CTLA-4 agent, significantly improved median progression-free survival (PFS) compared with ipilimumab alone.²

As a result, a range of treatment options now exists for patients with BRAF-mutation—positive disease.¹

Evolution of BRAF-Targeted Therapy

Current NCCN guidance recommends considering targeted therapies for patients with BRAF-mutant melanoma with symptomatic disease, or who progress on immunotherapies.¹

Vemurafenib was the first targeted therapy to become available for patients with metastatic melanoma, and was shown to improve overall and progression-free survival (PFS) over conventional chemotherapy (dacarbazine), the standard of care at the time.3 Vemurafenib is currently approved for use in patients with BRAF-mutation—positive melanoma, as determined by an FDA-approved test (Cobas).⁴

Subsequently, a second BRAF inhibitor dabrafenib, became available for use after it was shown to also improve PFS compared with dacarbazine. ⁵ Adverse events (AEs) associated with these BRAF-targeted therapies include skin toxicities, which were observed in a sizable proportion of patients.^3,5-7

Combination Therapies

It now appears that these toxicities stemmed from a paradoxical activation of the MAP kinase pathway by these agents, and these observations, in addition to patients’ propensity to develop resistance to monotherapy, have more recently paved the way for their use in combination with MEK-directed agents in patients with BRAF-mutation— positive disease.^8-11Recent phase III trials have established the clinical feasibility of using BRAF inhibitors and MEK inhibitors in combination, and the FDA has approved two such regimens for clinical use based on late-stage clinical trial results. In mid-November, the FDA granted full approval to the combination of dabrafenib and trametinib for patients with unresectable or metastatic BRAF-mutated melanoma, based on an extension in median overall survival (OS) from two phase III studies. The agency had given the regimen a green light on an accelerated approval basis pending confirmatory trials in January 2014.

In the COMBI-v trial, median OS was extended by 7.6 months with dabrafenib and trametinib compared with single-agent vemurafenib (25.6 months vs 18 months, respectively).10 In the COMBI-d trial, median OS was improved by 6.4 months with a combination of the two drugs compared with dabrafenib alone (25.1 months vs 18.7 months, respectively).¹¹ Moreover, across both studies, the combination was found to induce fewer AEs compared with either agent alone.

Also in November, the FDA approved the combination of vemurafenib and cobimetinib as a treatment for patients with BRAF-positive metastatic or unresectable melanoma, based on an extension in progression-free survival (PFS) in the phase III coBRIM study.

In updated findings presented at the 2015 Society for Melanoma Research Congress, treatment with the combination of vemurafenib and cobimetinib improved OS by 4.9 months compared with vemurafenib alone for patients with BRAF mutation-positive advanced melanoma.¹²

BRAF Testing: Impact on Treatment Decisions

The median OS was 22.3 months with the combination compared with 17.4 months with vemurafenib alone, representing a 30% reduction in the risk of death (HR, 0.70; 95% CI, 0.55-0.90; P = .005).The rapid and impressive response rates that have been observed with targeted therapies, particularly in combination, thus support the use of BRAF testing in metastatic melanoma, in accordance with treatment guidelines, to determine whether or not this set of treatment options applies to a given patient.¹

The efficacy of immunotherapy appears to be largely independent of BRAF mutational status, including the recent nivolumab/ipilimumab combination.² Thus, at present, BRAF testing does not impact treatment decisions with this other line of therapy for malignant melanoma. Jedd D Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service and Lloyd J. Old Chair for Clinical Investigation at Memorial Sloan Kettering Cancer Center (MSK) agrees that BRAF testing is important to guide targeted treatment but is not necessary for immunotherapy.

Michael Postow, MD, an assistant attending physician in the Melanoma and Immunotherapeutics Service at MSK, emphasizes that that the issue of optimal sequencing of targeted therapies and immunotherapies remains a very active area of research.

“Since BRAF mutations are very common in melanoma (approximately 50%), BRAF testing of tumors remains an important part of the management of patients with metastatic melanoma. Additional research is still needed to determine the best sequence of BRAF inhibitors and immunotherapy for patients with BRAF-mutant melanoma,” Postow said.

References

1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Melanoma. www.nccn.org. Accessed October 29, 2015.
2. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(1): 23-34.
3. Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med. 2011;364:2507-2516.
4. Zelboraf (Vemurafenib) Prescribing Information, Genentech USA, Inc.
5. Hauschild A, Grob JJ, Demidov L, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358-365.
6. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600—mutant advanced melanoma treated with vemurafenib. N Engl J Med. 2012;366:707-714.
7. Larkin J, Del Vecchio M, Ascierto PA, et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014;15:436-444.
8. Oberholzer PA, Kee D, Dziunycz P, et al. RAS mutations are associated with the development of cutaneous squamous cell tumors in patients treated with RAF inhibitors. J Clin Oncol. 2012;30: 316-321.
9. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N Engl J Med. 2012;366:207-215.
10. Robert C, Karaszewska B, Schachter J, et al. Two year estimate of overall survival in COMBI-v, a randomized, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (Vem) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma. Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 3301.
11. 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).
12. Ascierto PA, McArthur GA, Dréno B, et al. coBRIM: a phase 3, double-blind placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAF V600 mutation—positive patients with unresectable locally advanced or metastatic melanoma. J Trans Med. 2015;13(suppl 1):O4. doi:10.1186/1479-5876-13-S1-O4
13. Sullivan R, LoRusso P, Boerner S, Dummer R. Achievements and challenges of molecular targeted therapy in melanoma. Am Soc Clin Oncol Educ Book. 2015:177-186.