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. 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. ![]() Unlike the SECOMBIT trial, DREAMSeq did not include a sandwich arm. 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). 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). ![]() The DREAMSeq study was a phase 3 trial with 265 enrolled patients from 2015 to 2021. 8Īnother recently published trial by Atkins et al was similarly designed to look at the question of immunotherapy and targeted therapy sequencing. 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. 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. The sandwich arm C did not show any survival or response benefit over arm B. 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 OS end point was met for all arms, with 2-year and 3-year OS reported in the TABLE. Secondary end points included PFS, 3-year OS, best overall response rate, and duration of response (DOR). 8īaseline characteristics were similar in the 3 arms. 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. In arm B, patients received immunotherapy with ipilimumab plus nivolumab until PD followed by targeted therapy with encorafenib plus binimetinib. This was followed by nivolumab monotherapy every 2 weeks. 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. In arm A, patients received targeted therapy followed by immunotherapy. Patients (N = 209) were randomly assigned 1:1:1 into 1 of 3 arms ( FIGURE 1 8). The SECOMBIT trial was a randomized, open-label, phase 2 study that took place from 2016 to 2019. Two recently published trials, SECOMBIT (NCT02631447) and DREAMSeq (NCT02224781), aimed to investigate an answer to this question. Optimal therapy sequencing for BRAF V600–mutated melanoma has been a long-standing question since the advent of the aforementioned FDA approvals. Immunotherapy and Targeted Therapy Sequencing ![]() 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%. 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. 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. 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. 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). Approximately 50% of melanoma cases contain activating mutations in BRAF, with a majority (90%) occurring at the V600 location. Constitutive activation of this pathway may lead to cancer cell growth and proliferation. For patients with BRAF V600–mutated disease, immunotherapy and targeted therapy present different but effective treatment options.īRAF is a potent oncogene that plays a critical role in the MAPK pathway. Melanoma treatment has progressed dramatically in the past decade.
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