70IN - How to overcome resistance in mutation driven therapies combination targeted therapy regimens

Date 01 October 2012
Event ESMO Congress 2012
Session Melanoma therapy: From frustration to enthusiasm
Topics Clinical research
Skin cancers
Basic Scientific Principles
Presenter Keith Flaherty
Authors K.T. Flaherty
  • Developmental Therapeutics, Cancer Center,, Massachusetts General Hospital, MA 02114 - Boston/US


The identification of BRAF mutations in 2002 was the watershed event that turned the attention of the melanoma field to this concept. Seven years passed between the identification of BRAF mutations and the validation of this target in melanoma patients with a potent and specific BRAF inhibitor, PLX4032. As phase II and phase III single-agent trials have established BRAF inhibition as a new standard of care for the BRAF mutated subpopulation, attention now turns to understanding mechanisms of resistance and rational combination approaches. The available evidence regarding acquired resistance mechanisms does not point to an obvious approach for developing second line or salvage therapy for these patients. Current efforts are focused on combining other targeted therapies with BRAF inhibitors in the subgroup of patient who have BRAF mutations to overcome de novo resistance. The spectrum of potential combination therapy regimens is broad. It has been known for several years that BRAF mutations are accompanied by genetic alterations that activate the PI3K pathway and CDK4. Characterizing more than one genetic alteration before selecting such combinations is feasible and an appropriate way to stratify patients for next-generation combination therapy clinical trials. Recent evidence suggests that stromal secreted by the tumor microenvironment confers resistance to BRAF inhibitor therapy and HGF antibodies o small molecule c-met inhibitors represent available investigational agents to combined. Additionally, emerging evidence suggests that BRAF inhibitors induce a secondary immune response and combinations with various active immunotherapies is being pursued. However, the current inability to predict which patients are most likely to benefit from immunotherapy represents a persistent challenge in arriving at a personalized approach with such combinations. Similarly, combination therapy with BRAF inhibitors and anti-apoptotic drugs and agents that target developmental pathways in melanoma show promise but do not have an associated predictive biomarker.


K.T. Flaherty: Consultant - Roche/Genentech, GlaxoSmithKline