Dual therapy shows potential in melanoma

Two studies presented in the ESMO melanoma session yesterday point to the growing promise of dual blockade strategies in treatment of metastatic melanoma.

The BRAF inhibitor vemurafenib 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 (DTIC). 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, Dr Georgina Long and colleagues, from Westmead Hospital, Sydney, Australia, reported on a phase 2 study combining darafenib, an inhibitor of mutated BRAF 600, with trametinib, 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. We hoped that by combining both drugs we would see significant delays in the emergence of resistance that would impact patients’ lives,” explained Dr Long.

In the study, 162 melanoma patients with BRAF V600 mutations were randomised 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 2mg trametinib.

Results show progression-free survival (PFS) was 9.4 months for patients receiving dabrafenib plus tramentinib 2 mg versus 5.8 months for patients receiving dabrafenib alone (HR 0.39, 95% CI 0.25 – 0.62; p<0.0001). Furthermore, the confirmed response rate was 76% for patients receiving dabrafenib plus tramentinib 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, she added, can easily be prevented with corticosteroids.

“Importantly, the combination also decreased the rate of the cutaneous toxicities compared with dabrafenib monotherapy, particularly the oncogenic cutaneous toxicity of squamous cell carcinoma,” said Dr Long.

In the second study, Dr 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 tumour size from baseline ranging from 25% to 60%. The discussant Reinhard Dummer, from Zurich, Switzerland, commented that it was remarkable that every single patient showed a response. He added that he had never seen such striking response rates before in his career.
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 particular patient received low levels of the MEK inhibitor,” said Dr Gonzalez.