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Dual blockade strategy in treatment of metastatic melanoma: Dabrafenib plus Trametinib, Vemurafenib plus GDC-0973


The BRAF inhibitor Vemurafenib ( Zelboraf ) represents a new standard of care for metastatic melanoma patients with BRAF V600 mutations after showing improved progression free and overall survival in comparison with Dacarbazine. In many cases, however, benefits have proved short-lived as cancer cells develop resistance. Such observations have led to the initiation of new studies exploring treatment strategies targeting multiple signalling pathways at once.

In the first study, Georgina Long and colleagues, from Westmead Hospital, Sydney, Australia, reported on a phase 2 study combining Dabrafenib, an inhibitor of mutated BRAF 600, with Trametinib ( Mekinist ), a selective MEK inhibitor.
The rationale behind adding the MEK inhibitor was that it blocks the same MAP kinase pathway as the BRAF inhibitor, but lower down. Researchers hope that by combining both drugs they would see significant delays in the emergence of resistance that would impact patients’ lives.

In the study, 162 melanoma patients with BRAF V600 mutations were randomized 1:1:1 to receive either Dabrafenib 150 mg twice daily; Dabrafenib 150 mg twice daily plus once-daily 1 mg Trametinib; or Dabrafenib 150 mg twice daily plus once-daily 2 mg Trametinib.

Results have shown progression-free survival ( PFS ) was 9.4 months for patients receiving Dabrafenib plus Trametinib 2 mg versus 5.8 months for patients receiving Dabrafenib alone ( hazard ratio, HR=0.39; p less than 0.0001 ). Furthermore, the confirmed response rate was 76% for patients receiving Dabrafenib plus Trametinib 2 mg versus 54% for Dabrafenib monotherapy ( p=0.026 ).

Pyrexia ( fever above 38.5°C ) and chills were the most common adverse events reported, occurring in 71% and 58% of patients respectively receiving dual therapy. But the fever can easily be prevented with corticosteroids.
The combination also decreased the rate of the cutaneous toxicities compared with Dabrafenib monotherapy, particularly the oncogenic cutaneous toxicity of squamous cell carcinoma.

In the second study, Rene Gonzalez and colleagues, from the University of Colorada at Denver, Aurora, USA, explored the strategy of combining Vemurafenib with the MEK inhibitor, GDC-0973, in patients with unresectable or metastatic BRAF V600 melanoma mutations.

In the phase 1 dose escalation study, patients received Vemurafenib 720 mg or 960 mg BID continuously, with GDC-0973 used at doses of 60 mg, 80 mg or 100 mg QD, with a varying regimen of 14 days on / 14 days off; 21 days on and 7 days off and continuously.
Results for individual patients showed decreases in tumor size from baseline ranging from 25% to 60%.
The most common adverse events were diarrhoea ( 54.5% ), rash ( 50% ), nausea ( 38.6% ), fatigue/ asthenia ( 34.1% ), liver function abnormality ( 25.0% ) and photosensitivity / sunburn ( 25% ). Only one patient developed cutaneous squamous cell carcinoma, but this patient received low levels of the MEK inhibitor. ( Xagena )

Source: European Society for Medical Oncology ( ESCO ) Meeting, 2012

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