Results of phase II randomized study of intermittent versus continuous schedule of vemurafenib plus cobimetinib in BRAF-mutated advanced melanoma.
Authors: Gonzalez-Cao Maria , Mayo de las Casas Clara , Oramas Juana , Berciano-Guerrero Miguel-Angel , De la Cruz Luis , Cerezuela-Fuentes Pablo , Arance Ana Maria , Muñoz-Couselo Eva , Espinosa Enrique , Puértolas Teresa , Diaz Beveridge Robert , Ochenduszko Sebastian , Villanueva Silva Maria Jose , Basterretxea Laura , Bellido Lorena , Rodriguez-Abreu Delvys , Drozdowskyj Ana , Molina Vila Miguel Angel , Lopez-Martin Jose Antonio , Berrocal Alfonso ,   Spanish Melanoma Group (GEM)
Published: June 2021

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Background: Combination of vemurafenib plus cobimetinib is approved for the treatment of BRAF-mutated advanced melanoma. Although patients initially respond to treatment, resistance emerges before 18 months in most cases. One of the key pre-clinical observations that supported an intermittent schedule was that resistant tumors suffer a fitness deficit in the absence of the drug, so modulation of the drug pressure through an intermittent dosing could delay the emergence of resistance. Methods: GEM1501 is a randomized phase 2 study comparing the activity of the combination of vemurafenib 960 mg every 12 h/d plus cobimetinib 60 mg/d in a standard (arm A) versus intermittent schedule (arm B). Arm A: four-week (w) cycles of daily vemurafenib for 4w plus cobimetinib for 3w-on and 1w-off-treatment. Arm B: first three cycles according to the standard schedule, followed by 6w-cycle with 2w-off vemurafenib & 3w-off cobimetinib. Primary endpoint was progression free survival (PFS) and secondary were objective response (OR) and treatment-related adverse events (TAEs). Results: 70 treatment-naïve patients were included. Results in arms A and B: median PFS 16.2 (95%CI 9.5, 24.1) vs 6.9 months (95%CI 5.2, 9.3) (p = 0.079); OR in 25 (71.4%) (8 complete -23%-) vs 21 (60%) patients (5 complete -14%-); G3-4 TAEs 42.8% vs 40.0%, respectively. Analysis of BRAFV600 mutation in tumoral cell free DNA (cfDNA) was performed in serial plasma samples in 41 patients. Twenty-one (51%) patients had detectable BRAFV600 mutation in pretreatment cfDNA (preBRAF+). Significant differences in PFS were found according to preBRAF V600: 8.2 months (95%CI 5.2, 13.6) in preBRAF+ vs non-reached (NR) (95%CI 2.8, NR) in preBRAF- (p = 0.017). In arm A, median PFS was 13.3 months (95% CI 4.6, NR) in preBRAF+ vs NR (95% CI 2.3, NR) in preBRAF-. In arm B, median PFS was 6.2 months (95% CI 0.3-8.3) in preBRAF+ vs NR (95%CI 2.8, NR) in preBRAF- (p = 0.003). BRAFV600 mutation became undetectable in cfDNA after treatment initiation in all preBRAF+ patients. Different kinetic of BRAFV600 mutation in cfDNA was found according to treatment arm. At progression, BRAFV600 reappeared in cfDNA in all (5/5) cases treated in arm B, but only in 50% (3/6) of cases in arm A. NGS analysis of cfDNA at progression suggested different resistance mechanisms. Conclusions: The results of this study do not support the use of an intermittent schedule of vemurafenib plus cobimetinib in advanced melanoma. BRAFV600 detection in pretreatment cfDNA is a prognostic factor of poor survival that it is independent of treatment schedule, although most striking differences favoring continuous arm vs intermittent arm were found in patients with detectable BRAFV600 mutation on pretreatment cfDNA. Further research is required to determine the clinical value of the analysis of resistance mechanisms in cfDNA. Clinical trial information: 2014-005277-36.