1. Starting treatment with nivolumab/ipilimumab rather than dabrafenib/trametinib resulted in an improvement in 2-year overall survival (72% vs 52%)
2. The incidence of adverse events grade 3 or higher was relatively similar across all arms, although the events themselves differed.
Evidence Rating Level: 1 (Excellent)
Study Rundown: BRAF-mutant melanoma uses the MAP kinase pathway to drive cell proliferation, and it has been shown that BRAF/MEK inhibitor combinations (such as dabrafenib/trametinib) have led to several improved outcomes. Checkpoint inhibitor immunotherapy (such as nivolumab/ipilimumab) had also been shown to be effective, but there was no consensus as to the optimal sequence of therapies for new patients. This study investigated the optimal treatment sequence between nivolumab/ipilimumab (arm A) and dabrafenib/trametinib (arm B) followed by swapping treatments for arms C (dabrafenib/trametinib) and D (nivolumab/ipilimumab) for those who had disease progression. The primary endpoint was 2-year overall survival (OS), and secondary endpoints included 3-year OS, objective response rate (ORR), duration of response (DoR), progression-free survival (PFS) and safety. 2-year OS favored starting on nivolumab/ipilimumab (71.8%) vs dabrafenib/trametinib (51.5%). This difference was considered clinically meaningful and patients on dabrafenib/trametinib were given the option to switch to nivolumab/ipilimumab without the need for disease progression. 3-year OS followed a similar pattern, 66.2% (arm A) vs 42.8% (arm B). PFS also favored nivolumab/ipilimumab followed by dabrafenib/trametinib compared with the opposite, with 11.8 months (arm A), 8.5 months (arm B), 9.9 months (arm C), and 2.9 months (arm D). ORR was similar in arms A, B, and C, but lower in D meaning nivolumab/ipilimumab appeared less effective after progression on dabrafenib/trametinib. The incidence of adverse events grade 3 or higher was relatively similar across all arms. The strengths of this study included longer follow-up time. Limitations to this study included a small sample size, and the inclusion of only healthy participants. Overall, for patients diagnosed with BRAF positive melanoma, starting therapy with nivolumab/ipilimumab followed by dabrafenib/trametinib led to improved outcomes.
In-Depth [randomized controlled trial]: This study enrolled 265 patients, who were otherwise healthy, with histologically confirmed unrespectable stage III or IV melanoma with a BRAFV600E/K mutation into a two-arm, two-step, open-label, randomized phase 3 trail. Patient were initially assigned to nivolumab/ipilimumab (arm A, 133 patients) or dabrafenib/trametinib (arm B, 132) in step 1 and then at disease progression (defined by RECISTv1.1) enrolled in step 2 with alternate therapy, dabrafenib/trametinib (arm C, 27) or nivolumab/ipilimumab (arm D, 46). Initial patient characteristics were balanced but arm B had more BRAFV600K and less BRAFV600E mutation tumors than arm A. Median follow-up time was 27.7 months. 2-year OS rate followed a biphasic curve with 71.8% (95%CI, 62.5-79.1) for patients starting in arm A and 51.5% (95%CI, 41.7-60.4) for patients starting arm B (p = 0.010). Given this difference, arm B was given the option to switch to arm D without the need for disease progression. 3-year OS followed a similar pattern, 66.2% in those starting in arm A and 42.8% in those starting in arm B. Median PFS also followed a biphasic pattern with 11.8 months (95%CI, 5.9-33.5) for arm A, 8.5 months (95%CI, 6.5-11.3) for arm B, 9.9 months (95%CI, 8.3-20.8) for arm C, and 2.9 months (95%CI, 2.6-8.9) for arm D. ORR was similar for both arms in step 1 (46% in arm A, and 43% in arm B), but showed a difference for step 2 with 47.8% (95%CI, 26.8-69.4) in arm C vs 29.6% (95%CI, 12.7-47.2) in arm D. Median DoR was longer in arm A than arm B. The incidence of adverse events grade 3 or higher was relatively similar across all arms (59.5% in arm A, 53.1% in arm B, 53.8% in arm C, and 50% in arm D), with more immune related events occurring in arms A/D and more fevers, leukopenia, and hyponatremia in arms B/C. Overall, this study found that starting therapy with nivolumab/ipilimumab compared to dabrafenib/trametinib resulted in improved outcomes for BRAF positive melanoma.
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