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

Abstract

PURPOSE Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAFV600-mutant metastatic melanoma. METHODS SECOMBIT is a randomized, three-arm, noncomparative phase II trial (ClinicalTrials.gov identifier: NCT02631447 ). Patients with untreated, metastatic BRAFV600-mutant melanoma from 37 sites in nine countries were randomly assigned to arm A (encorafenib [450 mg orally once daily] plus binimetinib [45 mg orally twice daily] until progressive disease [PD] -> ipilimumab plus nivolumab [ipilimumab 3 mg/kg once every 3 weeks and nivolumab 1 mg/kg once every 3 weeks × four cycles -> nivolumab 3 mg/kg every 2 weeks]), arm B [ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib], or arm C (encorafenib plus binimetinib for 8 weeks -> ipilimumab plus nivolumab until PD -> encorafenib plus binimetinib). The primary end point was overall survival (OS) at 2 years. Secondary end points included total progression-free survival, 3-year OS, best overall response rate, duration of response, and biomarkers in the intent-to-treat population. Safety was analyzed throughout sequential treatment in all participants who received at least one dose of study medication. RESULTS A total of 209 patients were randomly assigned (69 in arm A, 71 in arm B, and 69 in arm C). At a median follow-up of 32.2 (interquartile range, 27.9-41.6) months, median OS was not reached in any arm and more than 30 patients were alive in all arms. Assuming a null hypothesis of median OS of ≤ 15 months, the OS end point was met for all arms. The 2-year and 3-year OS rates were 65% (95% CI, 54 to 76) and 54% (95% CI, 41 to 67) in arm A, 73% (95% CI, 62 to 84) and 62% (95% CI, 48 to 76) in arm B, and 69% (95% CI, 59 to 80) and 60% (95% CI, 58 to 72) in arm C. No new safety signals emerged. CONCLUSION Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAFV600-mutant melanoma.

Immunotherapy for Melanoma: The Significance of Immune Checkpoint Inhibitors for the Treatment of Advanced Melanoma

“…As described above, ICIs are currently among the most promising therapies to induce long-acting anti-tumor effects, even in BRAFV600 mutated melanomas [ 1 , 2 , 3 , 4 , 26 , 94 ]. Indeed, recent phase II/III clinical studies of the treatment of patients with BRAFV600-mutated advanced melanoma suggested that ICIs are promising for the induction of long-term, anti-melanoma effects [ 26 , 94 ].…”

Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC)

“…The phase III DREAMseq trial demonstrated superior OS and ORR when patients with stage III-IV BRAF- mutant melanoma received ipilimumab plus nivolumab followed by dabrafenib plus trametinib at disease progression compared with the inverse sequence, 113 and the phase II SECOMBIT trial also found favorable survival outcomes with an immunotherapy-first sequence. 152 The INSIGNIA trial (EA5163/S1709) is studying whether pembrolizumab alone as a first-line treatment followed by pemetrexed and carboplatin with or without pembrolizumab after disease progression is superior to induction with pembrolizumab, pemetrexed and carboplatin followed by pembrolizumab and pemetrexed maintenance for the treatment of stage IV NSCLC. Future studies should continue to address the effect of sequencing.…”

Triple Combination of Immune Checkpoint Inhibitors and BRAF/MEK Inhibitors in BRAFV600 Melanoma: Current Status and Future Perspectives

“…The phase 2 SECOMBIT trial randomly assigned patients to encorafenib/binimetinib followed by ipilimumab/nivolumab upon disease progression (arm A), to the converse sequence (arm B) and to encorafenib/binimetinib for 8 weeks followed by a treatment switch to ipilimumab/nivolumab until disease progression (arm C) [ 42 ]. The primary endpoint of the study was the OS rate at two years, and the secondary endpoints included PFS and total PFS, defined as the time to second progression.…”

“…Similarly, a recent study of 1764 patients with advanced melanoma from a nationwide registry confirmed the prolonged mPFS and mOS in BRAF -mutant melanoma compared with NRAS -mutant and double wild-type melanoma [ 64 ]. Prospective data on disease outcomes with sequential targeted therapy and ipilimumab/nivolumab support frontline treatment with ICIs over targeted therapy [ 42 , 45 ].…”

“…Despite preclinical data supporting the immunomodulatory effects of BRAF/MEK inhibitors in the tumor microenvironment, clinical and preclinical data suggest that this effect might be transient and that acquired resistance to BRAF/MEK inhibitors is suggestive of a cross-resistance to ICIs as well [ 43 ]. Notably, 8-week induction treatment with encorafenib/binimetinib in arm C of the SECOMBIT study resulted in a clinical benefit [ 42 ]. In addition, combined treatment with BRAF/MEK inhibitors can provide rapid symptomatic relief in patients with a high tumor burden and symptomatic disease at baseline [ 8 ].…”