Each therapy presents a different but effective treatment option.
Melanoma treatment has progressed dramatically in the past decade. For patients with BRAF V600–mutated disease, immunotherapy and targeted therapy present different but effective treatment options.
Prior Treatment Approvals
BRAF is a potent oncogene that plays a critical role in the MAPK pathway. Constitutive activation of this pathway may lead to cancer cell growth and proliferation. Approximately 50% of melanoma cases contain activating mutations in BRAF, with a majority (90%) occurring at the V600 location.1
There are currently 3 approved BRAF/MEK inhibitor (BRAF/MEKi) combinations: encorafenib (Braftovi; Pfizer) and binimetinib (Mektovi; Pfizer), dabrafenib (Tafinlar; Novartis) and trametinib (Mekinist; Novartis), and vemurafenib (Zelboraf; Genentech) and cobimetinib (Cotellic; Genentech). All 3 combinations have shown improved progression-free survival (PFS), overall survival (OS), and objective response rates compared with BRAF inhibitor alone in BRAF-mutated metastatic melanoma.2-5 In 2018, the combination of encorafenib plus binimetinib was approved by the FDA based on findings from the COLUMBUS trial (NCT01909453), which showed a median PFS of 14.9 months compared with 7.3 months with binimetinib alone.2 Likewise, results from the COMBI-v (NCT01597908) and COMBI-d (NCT01584648) studies showed statistically significant improvements in PFS and OS with combination dabrafenib and trametinib compared with BRAF inhibitor monotherapy.4,5
On the other end of the treatment spectrum, combination immunotherapy with CTLA-4 and PD-1 inhibitors ipilimumab (Yervoy; Bristol Myers Squibb) and nivolumab (Opdivo; Bristol Myers Squibb) was approved by the FDA in part based on results from the CheckMate 067 study (NCT01844505).6 In the group with BRAF V600–mutated disease, OS at 5 years was 60%.7
Immunotherapy and Targeted Therapy Sequencing
Optimal therapy sequencing for BRAF V600–mutated melanoma has been a long-standing question since the advent of the aforementioned FDA approvals. Two recently published trials, SECOMBIT (NCT02631447) and DREAMSeq (NCT02224781), aimed to investigate an answer to this question.
The SECOMBIT trial was a randomized, open-label, phase 2 study that took place from 2016 to 2019. Patients (N = 209) were randomly assigned 1:1:1 into 1 of 3 arms (FIGURE 18).
In arm A, patients received targeted therapy followed by immunotherapy. Specifically, they received the BRAF/MEKi combination of encorafenib plus binimetinib until progressive disease (PD) followed by combination ipilimumab and nivolumab once every 3 weeks for 4 cycles. This was followed by nivolumab monotherapy every 2 weeks.
In arm B, patients received immunotherapy with ipilimumab plus nivolumab until PD followed by targeted therapy with encorafenib plus binimetinib. Finally, in arm C, investigators used a sandwich approach with an 8-week BRAF/MEKi targeted therapy induction phase followed by combination immunotherapy until PD. This was followed by targeted therapy.8
Baseline characteristics were similar in the 3 arms. The primary end point was OS at 2 years. Secondary end points included PFS, 3-year OS, best overall response rate, and duration of response (DOR). The OS end point was met for all arms, with 2-year and 3-year OS reported in the TABLE.8 Patients in arm B (immunotherapy followed by targeted therapy) had a numerically higher overall response rate of 45% compared with those treated in arm A (targeted therapy followed by immunotherapy), who had an overall response rate of 26%. The sandwich arm C did not show any survival or response benefit over arm B.
In the SECOMBIT trial, Atkins et al concluded that sequential immunotherapy and targeted therapy provided clinically meaningful survival benefits for patients with BRAF V600–mutated melanoma. However, it is important to note that this trial was a noncomparative study, meaning that the arms were not formally compared by any statistical test.8
Another recently published trial by Atkins et al was similarly designed to look at the question of immunotherapy and targeted therapy sequencing. The DREAMSeq study was a phase 3 trial with 265 enrolled patients from 2015 to 2021.9
In step 1 of the trial, patients were randomly assigned to arm A (combination of ipilimumab and nivolumab) or arm B (combination of dabrafenib and trametinib). After experiencing disease progression, patients were enrolled in step 2 alternate therapy: arm C (dabrafenib and trametinib) or arm D (ipilimumab and nivolumab) (FIGURE 29). Unlike the SECOMBIT trial, DREAMSeq did not include a sandwich arm.
The primary end point of the trial was also 2-year OS, with secondary end points of 3-year OS, PFS, overall response rate, and response duration. The 2-year OS for those who started in arm A was 71.8% (95% CI, 62.5-79.1) and 51.5% (95% CI, 41.7-60.4) for those who began in arm B.9 This was comparable to OS results reported in the SECOMBIT trial.8
For those patients who experienced response in step 1, median DOR was longer for those in the arm A immunotherapy group (not reached [NR]; range, 29.3 months-NR) than those in the arm B BRAF/MEKi group (12.7 months; range, 8.2 months-NR). Furthermore, the authors concluded that immunotherapy appeared to be less effective when used after progression on BRAF/MEKi targeted therapy than when used in the first-line setting.9 This trend was also seen in the SECOMBIT study.8
Based on findings from the SECOMBIT and DREAMSeq trials, initiating immunotherapy followed by targeted therapy for metastatic or unresectable BRAF V600– mutated melanoma appears to provide clinical benefit with improved outcomes including OS.8,9 In an article that accompanies the SECOMBIT publication, Chandra et al comment that although the sequence of immunotherapy followed by targeted therapy may provide better outcomes in many patients, this sequence may not be appropriate for all patients. They further explain that a certain subset of patients may present with disease that is rapidly progressive and this population may not have time or the ability to mount an immune response secondary to immunotherapy in the first line. In this situation, starting with BRAF/MEKi targeted therapy or using an approach similar to the SECOMBIT arm C sandwich may be more appropriate.10 Although there remains a great need for the discovery of biomarkers and elucidation of resistance mechanisms to guide therapy selection more optimally, combination immunotherapy should be utilized in the first-line setting for advanced BRAF-mutated melanoma.
1. Ascierto PA, Kirkwood JM, Grob JJ, et al. The role of BRAF V600 mutation in melanoma. J Transl Med. 2012;10:85. doi:10.1186/1479-5876-10-85
2. Dummer R, Ascierto PA, Gogas HJ, et al. Encorafenib plus binimetinib versus vemurafenib or encorafenib in patients with BRAF-mutant melanoma (COLUMBUS): a multicentre, open label, randomised phase 3 trial. Lancet Oncol. 2018;19(5):603-615. doi:10.1016/S1470-2045(18)30142-6
3. Ascierto PA, McArthur GA, Dréno B, et al. Cobimetinib combined with vemurafenib in advanced BRAF(V600)-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. Lancet Oncol. 2016;17(9):1248-1260. doi:10.1016/S1470-2045(16)30122-X
4. Grob JJ, Amonkar MM, Karaszewska B, et al. Comparison of dabrafenib and trametinib combination therapy with vemurafenib monotherapy on health-related quality of life in patients with unresectable or metastatic cutaneous BRAF Val600-mutationpositive melanoma (COMBI-v): results of a phase 3, open-label, randomised trial. Lancet Oncol. 2015;16(13):1389-1398. doi:10.1016/S1470-2045(15)00087-X
5. Long GV, Stroyakovskiy D, Gogas H, et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015;386(9992):444-451. doi:10.1016/S0140-6736(15)60898-4
6. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-1356. Published correction appears in N Engl J Med. 2018;379(22):2185. doi:10.1056/NEJMoa1709684
7. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2019;381(16):1535-1546. doi:10.1056/NEJMoa1910836
8. Ascierto PA, Mandalà M, Ferrucci PF, et al. Sequencing of ipilimumab plus nivolumab and encorafenib plus binimetinib for untreated BRAF-mutated metastatic melanoma (SECOMBIT): a randomized, three-arm, open-label phase II trial. J Clin Oncol. Published online September 1, 2022. doi:10.1200/JCO.21.02961
9. Atkins MB, Lee SJ, Chmielowski B, et al. Combination dabrafenib and trametinib versus combination nivolumab and ipilimumab for patients with advanced BRAF-mutant melanoma: the DREAMseq trial-ECOG-ACRIN EA6134. J Clin Oncol. Published online September 27, 2022. doi:10.1200/JCO.22.01763
10. Chandra S, Choi JS, Sosman JA. Melanoma: does sequencing really matter? J Clin Oncol. Published online September 20, 2022. doi:10.1200/JCO.22.01354
About the Author
Noor Naffakh, PharmD, MS, is a clinical assistant professor of pharmacy practice at the University of Illinois Chicago College of Pharmacy.