Sequencing of Ipilimumab/Nivolumab With Encorafenib/Binimetinib in BRAF-Mutant Metastatic Melanoma

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Paolo A. Ascierto, MD

Paolo A. Ascierto, MD

In a phase II trial (SECOMBIT) reported in the Journal of Clinical Oncology, Paolo A. Ascierto, MD, and colleagues found that sequential immunotherapy and targeted therapy with ipilimumab/nivolumab followed at disease progression by encorafenib/binimetinib was associated with good survival outcomes in previously untreated patients with BRAF V600–mutant metastatic melanoma.

As stated by the investigators, “Limited prospective data are available on sequential immunotherapy and BRAF/MEK inhibition for BRAF V600–mutant metastatic melanoma.”

Study Details

In the open-label noncomparative trial, 209 patients from sites in nine countries were randomly assigned 1:1:1 between November 2016 to May 2019 to receive:

  • Encorafenib at 450 mg once daily plus binimetinib at 45 mg twice daily until disease progression, followed by ipilimumab at 3 mg/kg plus nivolumab at 1 mg/kg once every 3 weeks for four cycles, and then nivolumab at 3 mg/kg every 2 weeks (n = 69)
  • Ipilimumab/nivolumab until disease progression followed by encorafenib/binimetinib (n = 71)
  • A “sandwich” approach consisting of encorafenib/binimetinib for 8 weeks, followed by ipilimumab/nivolumab until disease progression, and then encorafenib/binimetinib (n = 69).

The primary endpoint was overall survival at 2 years. The null hypothesis was a median overall survival of ≤ 15 months, with at least 30 patients in a treatment group remaining alive at 24 months considered a positive result.

Overall Survival

Median follow-up was 32.2 months (interquartile range = 27.9–41.6) months. Median overall survival was not reached in any group, and the lower bounds of the 95% confidence intervals were not estimable. More than 30 patients remained alive in each group. Compared with the null hypothesis, the overall survival endpoint was considered met in all groups, and each strategy achieved a positive result.

Overall survival at 2 and 3 years was 65% (95% confidence interval [CI] = 54%–76%) and 54% (95% CI = 41%–67%) in the encorafenib/binimetinib followed by ipilimumab/nivolumab group,  73% (95% CI = 62%–84%) and 62% (95% CI = 48%–76%) in the ipilimumab/nivolumab followed by encorafenib/binimetinib group, and 69% (95% CI = 59%–80%) and 60% (95% CI = 58%–72%) in the “sandwich” group receiving targeted therapy, then immunotherapy, then targeted therapy.


  • Median overall survival was not reached in any of the treatment groups.
  • Overall survival at 2 years was 65% in the sequential targeted therapy-immunotherapy group, 73% in the immunotherapy-targeted therapy group, and 69% in the “sandwich” strategy group.

Adverse Events

No new safety signals were identified. Grade 3 or 4 adverse events occurred in 39% of patients in the targeted therapy then immunotherapy group, 59% of the immunotherapy then targeted therapy group, and 38% of the “sandwich” strategy group; the most common in the three groups, respectively, were increased creatine kinase (9%), increased transaminases (14%), and increased lipase (12%). Treatment-related adverse events led to discontinuation of treatment in 10%, 10%, and 9% of patients, respectively. No treatment-related deaths were reported.

The investigators concluded, “Sequential immunotherapy and targeted therapy provide clinically meaningful survival benefits for patients with BRAF V600–mutant melanoma.” They noted, “To our knowledge, this study also provided the first prospective data on survival outcomes for the sandwich approach.”

Dr. Ascierto, of Istituto Nazionale Tumori IRCCS Fondazione “G. Pascale,” Napoli, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb and Array Biopharma Inc/Pfizer. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.