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Sequencing of Checkpoint or BRAF/MEK Inhibitors on Brain Metastases in Melanoma
Paolo A Ascierto1, Mario Mandalà2,3, Pier Francesco Ferrucci4
1Department of Melanoma, Cancer Immunotherapy and Development Therapeutics, Istituto Nazionale Tumori - IRCCS Fondazione "G. Pascale," Napoli, Italy.
Background:
The impact of the order of treatment with checkpoint inhibitors or BRAF/MEK inhibitors on the development of brain metastases in patients with metastatic unresectable BRAFV600-mutant melanoma is unknown. The SECOMBIT trial examined the impact of the order of receipt of these treatments in such patients.
Methods:
In this three-arm trial, we reviewed patients without brain metastases who received the BRAF/MEK inhibitors encorafenib and binimetinib until they had progressive disease followed by the immune checkpoint inhibitors ipilimumab and nivolumab (arm A); or treatment with ipilimumab and nivolumab until they had progressive disease followed by encorafenib and binimetinib (arm B); or treatment with encorafenib and binimetinib for 8 weeks followed by ipilimumab and nivolumab until they had progressive disease followed by retreatment with encorafenib arm binimetinib (arm C).
Results:
Brain metastases were discovered during the trial in 23/69 patients in arm A, 11/69 in arm B, and 9/68 in arm C. At a median follow-up of 56 months, the 60-month brain metastases-free survival rates were 56% for arm A, 80% for arm B (hazard ratio [HR] vs. A: 0.40, 95% confidence interval [CI] 0.23 to 0.58), and 85% for arm C (HR vs. A: 0.35, 95% CI 0.16 to 0.76).
Conclusions:
In patients with unresectable metastatic melanoma, the treatment sequence of immune checkpoint inhibition followed by BRAF/MEK inhibitors was associated with longer periods of new brain metastases-free survival than the reverse sequence. A regimen in which immune checkpoint inhibition was sandwiched between BRAF/MEK inhibition also appeared to be protective against brain metastases. (ClinicalTrials.gov number NCT02631447.).
Insights
For BRAF V600-mutant melanoma, starting with immune checkpoint inhibitors then BRAF/MEK inhibitors, or sandwiching them, significantly reduced brain metastases compared to the reverse order.
Area of Science:
- Oncology
- Melanoma Research
- Clinical Trials
Background:
- The optimal sequencing of BRAF/MEK inhibitors and immune checkpoint inhibitors for metastatic unresectable BRAF V600-mutant melanoma is not well-defined.
- Brain metastases are a significant concern in this patient population.
Purpose of the Study:
- To investigate the impact of different treatment sequences of BRAF/MEK inhibitors (encorafenib and binimetinib) and immune checkpoint inhibitors (ipilimumab and nivolumab) on the development of brain metastases.
- To compare brain metastases-free survival rates across distinct treatment arms.
Main Methods:
- A three-arm clinical trial (SECOMBIT) involving patients with metastatic unresectable BRAF V600-mutant melanoma without pre-existing brain metastases.
- Arm A: BRAF/MEK inhibitors followed by immune checkpoint inhibitors.
- Arm B: Immune checkpoint inhibitors followed by BRAF/MEK inhibitors.
- Arm C: Sequential BRAF/MEK inhibitors, immune checkpoint inhibitors, and then re-treatment with BRAF/MEK inhibitors.
Main Results:
- At 56 months median follow-up, 60-month brain metastases-free survival rates were 56% (Arm A), 80% (Arm B), and 85% (Arm C).
- Patients receiving immune checkpoint inhibitors before BRAF/MEK inhibitors (Arm B) or in a sandwiched regimen (Arm C) had significantly lower rates of developing brain metastases compared to Arm A.
- Hazard ratios (vs. Arm A) for brain metastases were 0.40 (Arm B) and 0.35 (Arm C).
Conclusions:
- Sequencing immune checkpoint inhibitors before BRAF/MEK inhibitors is associated with improved brain metastases-free survival in BRAF V600-mutant melanoma.
- A treatment strategy involving immune checkpoint inhibition sandwiched between BRAF/MEK inhibitor therapies also demonstrates protective effects against brain metastases.
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