30 Sep Melanoma: Combination BRAF and MEK Inhibition Improved Outcomes
Medical Research: Could you provide some background on this project? Why did you decide to do this research project? What prior work led up to this latest paper?
Dr. Long: Pre-clinically, we had data that showed that the combination of BRAF inhibitor + MEK inhibitor
- Decreased skin proliferative toxicity seen with BRAF inhibitors alone (seen as hyperproliferative lesions in rats)
- and delayed the emergence of resistance I.e. The tumours in the mice reduced in size more, and stayed reduced for longer.We then confirmed this concept in a randomised phase 2 study, although it was not powered for a definitive progression free survival (PFS_ difference like a phase 3 trial is, we saw a strong difference in response rate and in PFS, yet there were only 54 patients per arm.
Medical Research: Can you explain the methodology used in your paper? Why did you decide to adopt this approach?
Dr. Long: It is a phase 3 PLACEBO controlled randomised trial – the only definitive method to prove one drug treatment is more efficacious over another.
Medical Research: What were the most significant findings? How do they relate to what was already known about this subject?
Dr. Long: The progression free survival and response rate were statistically significantly improved with the combination of dabrafenib (a BRAF inhibitor) and trameinib (aMEK inhibitor) over the BRAF inhibitor alone (dabrafenib + PLACEBO) in patients with metastatic melanoma. The combination resulted in a 25% reduction in the risk of progression compared with dabrafenib alone (HR for progression 0.75, p0.03). The data is too immature for an ‘overall survival’ analysis, but at this early stage we saw an amazing separation of the survival curves with the combination being much better. The hazard ratio for death was 0.63 and p 0.02 in favor of the combination, but the p value had not yet crossed the very very conservative ‘stopping’ boundary we used. We set the stopping boundary conservatively as we want to be sure there is a benefit before stopping a clinical trial. The trial is continuing, and we will be re-analyzing the overall survival with more mature results in 2015. The difference we see now in overall survival is occurring when there have not been too many deaths on trial, so I am expecting it to be significant when we do the final analysis in 2015.
The sister trial, which has more mature data (COMBI-V – same combination of dabrafenib + trametinib versus a different BRAF inhibitor called vemurafenib) showed a MATURE and statistically significant overall survival improvement with the combination. The sister trial is not published, but will be presented this weekend at ESMO conference 2014.
Medical Research: How do you plan to take this work forward? What are the implications for future research?
Dr. Long: We are conducting phase 1 (first in humans trials) of this combination dabrafenib and trametinib with other targeted drugs and immunotherapies (I.e. triple combinations) to try to increase the complete responses and durable responses. The USA has approved the combination of dabranfieb and trameitnib for use in metastatic melanoma, and I hope other countries follow. We now have overwhelming evidence of effect. With the dabrafenib and trametenib combination, it is very well tolerated, and the quality of life is MUCH higher on the combination versus the BRAF inhibitor alone (we are presenting the quality of life data form COMBI-D at the ESMO conference this weekend)
Medical Research: In particular, what do you see as the potential clinical implications for patients with cancer?
- Firstly, dabrafenib + trametenib improves clinical outcomes – survival and responses.
- Secondly, it is well-tolerated, and provides a higher quality of life than when dabrafenib is administered alone in melanoma patients.
Georgina V. Long, M.D., Ph.D., Daniil Stroyakovskiy, M.D., Helen Gogas, M.D., Evgeny Levchenko, M.D., Filippo de Braud, M.D., James Larkin, M.D., Claus Garbe, M.D., Ph.D., Thomas Jouary, M.D., Axel Hauschild, M.D., Ph.D., Jean Jacques Grob, M.D., Ph.D., Vanna Chiarion Sileni, M.D., Celeste Lebbe, M.D., Mario Mandalà, M.D., Michael Millward, M.D., Ana Arance, M.D., Ph.D., Igor Bondarenko, M.D., Ph.D., John B.A.G. Haanen, M.D., Ph.D., Johan Hansson, M.D., Ph.D., Jochen Utikal, M.D., Ph.D., Virginia Ferraresi, M.D., Nadezhda Kovalenko, M.D., Ph.D., Peter Mohr, M.D., Volodymyr Probachai, M.D., Dirk Schadendorf, M.D., Ph.D., Paul Nathan, M.D., Caroline Robert, M.D., Antoni Ribas, M.D., Ph.D., Douglas J. DeMarini, Ph.D., Jhangir G. Irani, M.A., Michelle Casey, Ph.D., Daniele Ouellet, Ph.D., Anne-Marie Martin, Ph.D., Ngocdiep Le, M.D., Ph.D., Kiran Patel, M.D., and Keith Flaherty, M.D.
September 29, 2014DOI: 10.1056/NEJMoa1406037