ESMO 2014: BRAF/MEK Inhibitor Combinations Impressive in Melanoma Trials


Key Points

  • In the phase III COMBI-v trial, dabrafenib plus tremetinib improved survival by 31%, compared with vemurafenib monotherapy, and reduced the risk of progression by 44%. 
  • In the CoBRIM study, cobimetinib plus vemurafenib reduced the risk of progression by 49%, compared to vemurafenib alone.
  • The combinations were very well tolerated, with a low rate of serious adverse events, and less skin toxicity than was seen with vemurafenib alone.

For advanced/metastatic melanoma patients with BRAF mutations, two pathway inhibitors are much better than one, according to studies presented at the ESMO 2014 Congress that demonstrated improved progression-free and overall survival for regimens combining a BRAF inhibitor with an inhibitor of the MEK protein.

“The two combination trials presented here today are compelling. We have at least two combination therapies that look beneficial,” commented Jeffrey S. Weber, MD, of Moffitt Cancer Center in Tampa, at an ESMO press briefing. Dr. Weber presented a separate study of nivolumab vs chemotherapy in previously treated patients, showing that 95% of responders to the immunotherapy were still in remission at 24 weeks.

The combination of a BRAF inhibitor and a MEK inhibitor appears to mitigate the emergence of disease resistance that occurs with BRAF inhibition alone, as well as the occurrence of cutaneous toxicity. The COMBI-V (Abstract LBA4_PR) and coBRIM (Abstract LBA5_PR) studies, both in previously untreated BRAF mutation-positive patients and presented at the ESMO Presidential Symposium, supported these concepts.

COMBI-v: Dabrafenib Plus Trametinib

The COMBI-v trial compared the combination of the BRAF inhibitor dabrafenib (Tafinlar) (150 mg twice daily) plus the MEK inhibitor trametinib (Mekinist) (2 mg/d) with vemurafenib (Zelboraf) monotherapy (960 mg twice daily) in 704 treatment-naive patients with the BRAF V600 mutation. Overall survival was the primary endpoint of the study.

“The Data Monitoring Committee recommended stopping the study based on an interim analysis that demonstrated an overall survival benefit that crossed the prespecified efficacy stopping boundary for the combination,” Caroline Robert, MD, of the Institut Gustave Roussy, Paris, announced at a press briefing. “We saw a significant improvement in all endpoints.”

The preplanned interim analysis showed a 31% reduction in mortality among patients on the combination, and a 44% reduction in the risk of progression, compared to vemurafenib monotherapy.

After a median follow-up of 11 months, median overall survival was 17.2 months with vemurafenib alone and was not reached in the dabrafenib/trametinib arm (hazard ratio [HR] = .69; P = .005). “The P value was clearly below the prespecified boundary of P < .0214,” Dr. Robert noted.

Median progression-free survival was 11.4 months for dabrafenib/trametinib and 7.3 months for vemurafenib (HR = 0.56; P < .001), response rates were 64% and 51% (P < .001), and duration of response was 13.8 months vs 7.5 months, respectively.

Patients tolerated the combination well. In fact, grade 3 toxicities were even lower with the combination (48%) than with single-agent vemurafenib (57%). Cutaneous malignancies occurred in 1% vs 18%.

CoBRIM: Vemurafenib Plus Cobimetinib

Vemurafenib (960 mg twice daily) plus the MEK inhibitor cobimetinib (60 mg/d) was compared to vemurafenib alone in the CoBRIM study of 495 treatment-naive patients. The data were presented at the meeting by Grant McArthur, MD, of the Peter MacCallum Cancer Centre in Melbourne, Australia.

The study’s primary endpoint was met when the combination arm achieved a median progression-free survival of 9.9 months, compared to 6.2 months with vemurafenib alone (HR = .51; P < .0001), a 49% reduction in the risk of progression. Response rates were 68% vs 45% (P < .0001), and the interim analysis of overall survival found a 35% reduction in deaths (HR = .65; P < .05), Dr. McArthur reported.

The toxicity profile was consistent with previous trials. Gastrointestinal side effects were more common with the combination, but were primarily grade 1. Photosensitivity reaction was also more common, but hyperkeratosis was significantly less with the two drugs. Most adverse events were comparable between the arms.

“This study provides clear and definitive evidence that cobimetinib combined with vemurafenib results in improved progression-free survival and objective response rates, and our preliminary overall survival analysis is promising,” Dr. McArthur noted at a press briefing. “We are adding a second agent to a very active drug, vemurafenib, and we still get striking results.”

“We anticipate that the combination of a BRAF and MEK inhibitor will become a new standard treatment for advanced BRAF-mutant melanoma,” he said. “The data lay the foundation for the addition of treatments, either in sequence or in further combination, to obtain even better results.”

For full disclosures of the study authors, view the study abstracts at

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