ESMO2012: BRAF and MEK inhibitor combination therapy of melanoma drug resistance can be delayed

BRAF and MEK drug combination therapy for the treatment of melanoma, a breakthrough occurred during the exposing of acquired resistance for more ideas. BRAF inhibitors and MEK inhibitor combination therapy appears promising new data notifications to, BRAF inhibitors delay occurs during resistance exists only in metastatic melanoma. First, the two trials focused on the use combination therapy to slow the BRAF-half of this gene in melanoma mutations appeared - inhibitor development of drug resistance. Test results were published in 2012 in Vienna at the European Society for Medical Oncology ESMO Conference.

Use BRAF targeted therapies early trials, the drug can stimulate the patient's immune indications to rapidly shrinking melanoma tumor. However, for many patients, this beneficial effect is of short duration, since the resistance of tumor cells.

According to information from the Israeli Weizmann Institute of Science, is the 2012 ESMO meeting basic science and translational research projects approach President-Yossef Yarden professors say, these studies illustrate, in a recent laboratory study, only to find that certain tumors An important milestones: the presence of certain mutations in tumors exposed a fatal weakness, such as metastatic melanoma BRAF mutation is its Achilles heel.

Two trials used alone BRAF inhibitor-dabrafenib and joint use of MEK1 / 2 inhibitor trametinib to compare the efficacy of

From Westmead Hospital and the Australian Institute of melanoma Georgina Long, PhD, and colleagues reported, dabrafenib and trametinib joint use of these two drugs on the 162 have BRAF V600 mutation in patients with melanoma progression-free survival, response speed and response duration to provide a clinically significant improvement on.

In this study, some patients given 150mg dabrafenib 2 times / day; some patients dabrafenib2 times / day plus 1mg trametinib 1 times / day; some patients dabrafenib 2 times / day plus 2mg trametinib 1 times / day. Combination therapy using a drug to make a separate 5.8-month progression-free survival was extended to 9.4 months, which means that 60% improvement. In the simultaneous use of two large doses of the drug in patients, 41% of patients in the treatment within 12 months after the start of the tumor without any progress, compared with monotherapy group only 9% of patients after starting treatment 12 months without any progress in the tumor. 

According to reports, fever and chills, etc. The incidence of adverse events in the combination therapy group were 71% and 58%, while dabrafenib monotherapy group, the incidence was 26% and 17%. In the combined treatment group were 35% and 42% of patients had dose reductions and dose interruption, by contrast, dabrafenib monotherapy groups, respectively 4% and 6%.

dabrafenib / trametinib The most common grade 3 + adverse event was neutropenia and hyponatremia, and respectively 11% and 7% of patients had both symptoms. Combined group hyperproliferative skin lesion incidence than alone dabrafenib group is much lower; cutaneous squamous cell carcinoma incidence rates were 7% and 19%; skin papilloma incidence rates were 4% and 15%; hyperkeratosis incidence rates were 9% and 30%.

Stage IB research is about vemurafenib MEK inhibitor GDC-0973 with the joint use of

According to information from the University of Colorado Cancer Center, Denver's Rene Gonzalez, MD, and colleagues reported that a one study shows, MEK inhibitor GDC-0973 in combination with vemurafenib is safe.

BRAF inhibitors can produce higher response rates and may improve melanoma patients with BRAF mutation survival. One of the mechanisms of resistance is to activate the MAPK pathway. Preclinical models show that, compared with BRAF inhibitors used alone, the combination BRAF and MEK inhibition can be delayed acquired resistance. According to Dr. Gonzalez mentioned, beginning downstream from BRAF inhibition of this pathway to bottom, and with the MEK inhibitor GDC-0973 in combination, in theory, this can be overcome or delay resistance mechanisms and may improve treatment outcomes.

This study was not designed to assess the efficacy. However, early research data is indeed a minority of patients showed tumor reduction. According to Dr. Gonzalez mentioned on the basis of these preliminary results is premature to evaluate the efficacy, further research is needed in order to be evaluated.
All patients most commonly reported adverse events were diarrhea (54.5%), rash (50.0%), nausea (38.6%), fatigue / weakness (34.1%), liver function abnormalities (25.0%) and photosensitivity / sunburn (25.0 %). And the most common treatment-related grade ≥ 3 adverse events were diarrhea, rash, increased creatine phosphokinase and liver function abnormalities, the incidence rates were 6.8%, 6.8%, 6.8% and 4.5%. Only one patient develop into squamous cell carcinoma.