AACR 2020 – Does the dosing schedule of BRAF and MEK inhibitor combinations influence resistance?

  • Elena Riboldi — Agenzia Zoe
  • Univadis
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  • In patients with BRAFV600E/K melanoma, continuous dosing with the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib yields superior PFS compared with intermittent dosing.

Why this matters

  • BRAF and MEK inhibitor combinations induce rapid response in the majority of BRAF mutated melanoma patients, but acquired resistance is common.
  • Preclinical data suggested that continuous exposure to BRAF inhibitors could lead to the development of resistant cells and that intermittent dosing could prolong drug sensitivity.

Study design

  • The phase II S1320 trial enrolled 245 patients with advanced BRAFV600E/K melanoma.
  • All patients received continuous dabrafenib and trametinib for 8-weeks, then patients without disease progression were randomized to continuous (n=105) or intermittent (n=101; 3-week-off, 5-week-on) dosing of both drugs.
  • Responses were assessed at 8-week intervals.
  • Funding: NIH/NCI.

Key results

  • The median PFS was longer with continuous therapy vs intermittent therapy (9.0 vs. 5.5 months from randomization; HR 1.36, 80%CI 1.10-1.66, P=.063).
  • The median OS was 29.2 months from randomization in both arms; an improvement in post-progression survival was observed with intermittent therapy.
  • The toxicity in the two arms was similar despite decreased drug exposure in the intermittent arm.


  • The study was not powered to detect differences in OS.

Expert commentary

From Charles L. Sawyers, Chair, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY: “Preclinical data was compelling. Why did the clinical trial fail? There are two possible explanations. It is possible that, by enrolling all comers, a beneficial signal which might have been restricted to the BRAF amplified patients could have been missed. The second point is that the toxicity that we are hoping to see with ERK rebound requires very rapid drug withdrawal. Trametinib, the MEK inhibitor used in this trial, has a very long half-life (4-5 days), maybe the ERK rebound was not seen.”

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