Thursday, November 17, 2016

BRAF/MEK combined with immunotherapy!!!


I thought this was a very informative article regarding BRAF inhibitors, MEK inhibitors...what we've learned and where research is looking with those drugs.

Combination therapy with BRAF and MEK inhibitors for melanoma: latest evidence and place in therapy.  Eroglue and Ribas.  Ther Adv Med Onc. Jan 2016.

 Treatment with BRAF inhibitors such as vemurafenib or dabrafenib in patients with advanced BRAFV600 mutated melanoma has shown objective tumor responses in approximately half of the patients. However, the duration of responses is limited in a majority of these patients, with progression-free survival rates around 6 months due to tumor progression from development of acquired resistance. Preclinical studies have suggested that concurrent inhibition of the BRAF kinases and MEK of the mitogen-activated protein kinase (MAPK) pathway could decrease MAPK-driven acquired resistance, resulting in longer duration of responses, higher rate of tumor responses, and a decrease in the cutaneous toxicities observed from paradoxical MAPK pathway activation with BRAF inhibitor monotherapy. This review provides an overview of the currently available clinical trial data on BRAF and MEK inhibitors together and in combinations with other therapeutic agents.

The article goes on to report:  "About one half of melanoma patients carry the BRAF V600E mutation.  BRAF inhibitors illicit 48-59% response rates in those patients. However, duration of response is limited in most patients with a median PFS of 5-7 months “although a minority can last for over 5 years”.  BRAF inhibitors combined with MEK inhibitors improved things further with decreased side effects and increased PFS, amounting to 11-12 months depending on the combo.  It also reviews the importance of intermittent dosing as opposed to continuous therapy with BRAFi in order to delay resistance.  Other drugs combined with BRAF/MEK , like heat shock protein 90 (HSP90) inhibitors, like XL88 can overcome resistance.  There are also plans for additional studies using a triple therapy approach.

BRAF/MEK has provided response rates of up to 70% in trials but with limited durability of that response, researchers are looking at combining those drugs with checkpoint inhibitors like ipi, anti-PD1, or anti-PD-L1.  When dabrafenib, trametinib and ipi were combined patients experienced colitis with perforation.  So that arm was stopped, though the ipi and dabrafenib arm is ongoing.  Another trial is currently looking at dabrafenib, trametinib and anti-PD-L1 (MEDI4736).  So far, the ratties are demonstrating a 69% ORR and 16 of 18 patients have an ongoing response."

 Here's a link to the whole paper:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4699264/ 

Hope that helps, for what it's worth - c

2 comments:

  1. Very hopefully, thank you Celeste

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  2. Sounds like the side effects are better than high dose ipi alone

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