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Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2

Alain P Algazi1, Megan Othus2, Adil I Daud3

  • 1University of California, San Francisco, San Francisco, CA, USA. alain.algazi@ucsf.edu.

Nature Medicine
|October 6, 2020
PubMed

Insights

Intermittent dosing of BRAF and MEK inhibitors did not improve progression-free survival in BRAF V600 melanoma patients. Continuous therapy showed better outcomes than intermittent schedules.

Area of Science:

  • Oncology
  • Clinical Trials
  • Melanoma Research

Background:

  • Preclinical models suggested intermittent BRAF inhibitor therapy could delay resistance in BRAF V600 melanoma.
  • Acquired resistance remains a significant challenge in BRAF-mutant melanoma treatment.

Purpose of the Study:

  • To evaluate if intermittent dosing of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) improves progression-free survival (PFS) in metastatic BRAF V600 melanoma.
  • To compare continuous versus intermittent dosing strategies for BRAF/MEK inhibition in melanoma.

Main Methods:

  • A randomized, open-label, phase 2 clinical trial (S1320) involving 206 patients with metastatic BRAF V600 melanoma.
  • Patients received an 8-week lead-in of continuous dabrafenib and trametinib.
  • Non-progressing patients were randomized to continuous or intermittent (3 weeks off, 5 weeks on) dosing of both agents.

Main Results:

  • Continuous dosing resulted in a statistically significant improvement in post-randomization progression-free survival compared to intermittent dosing (median 9.0 vs. 5.5 months).
  • The initial hypothesis that intermittent dosing would improve PFS was not supported by the trial data.
  • No significant differences were observed in overall survival or treatment-associated toxicity between the two arms.

Conclusions:

  • Intermittent dosing of dabrafenib and trametinib did not improve progression-free survival in patients with metastatic BRAF V600 melanoma.
  • Continuous dosing of BRAF and MEK inhibitors appears more effective for PFS in this patient population.
  • Further research may be needed to optimize treatment schedules for BRAF-mutant melanoma.

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