Two drugs are better than one: GSK's melanoma combo improves PFS at Phase II
This article was originally published in Scrip
Combining two novel GlaxoSmithKline drugs, the selective BRAF inhibitor dabrafenib, and the selective MAPK kinase (MEK) inhibitor trametinib, significantly improved progression-free survival in a Phase II study in melanoma, new data presented at ESMO and published in the New England Journal of Medicine show.
Both products are currently awaiting approval as single agents in the US for unresectable/metastatic melanoma with BRAF V600 mutations, while dabrafenib has additionally been filed in the EU, and a filing for trametinib is due there shortly.
If approved, the two GSK products will mark a further broadening of the treatment options for melanoma patients, who in the US have seen the approval of both Roche/Daiichi Sankyo's Zelboraf (vemurafenib) and Bristol-Myers Squibb's antibody Yervoy (ipilimumab) in the last year or so.
BRAF – also the target for Zelboraf – is a key new target in melanoma drug development but like all cancer therapies, the development of resistance is a concern and the new study is part of a broader approach to testing promising drugs combinations earlier in the development process.
About half of patients who are treated with BRAF or MEK inhibitors have disease progression within six to seven months after the initiation of treatment, and several mechanisms mediating resistance to BRAF inhibitors through MAPK reactivation have been described. "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 researcher Dr Georgina Long of Westmead Hospital in Sydney, Australia.
In the study, 162 melanoma patients with BRAF V600 mutations were randomised to receive either 150mg of dabrafenib twice daily; 150mg of dabrafenib twice daily plus 1mg trametinib once-daily; or 150mg dabrafenib twice daily plus 2mg trametinib once-daily.
Progression-free survival was 9.4 months for patients receiving dabrafenib plus trametinib 2mg compared with 5.8 months for patients receiving dabrafenib alone (HR 0.39, 95% CI 0.25 – 0.62; p<0.0001). meanwhile,="" the="" confirmed="" response="" rate="" was="" 76%="" for="" patients="" receiving="" dabrafenib="" plus="" 2mg="" trametinib="" compared="" with="" 54%="" for="" dabrafenib="" monotherapy="" (p="">
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 and 26% in the monotherapy group. But Dr Long said this could 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. The incidence of these BRAF-inhibitor induced hyperproliferative skin lesions, another primary endpoint, was 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (p=0.09).
In the NEJM paper, the researchers led by Dr Keith Flaherty of the Massachusetts General Hospital Cancer Center wrote that they currently, had very little insight into the mechanisms of resistance for this combination regimen. "It is critical to determine whether resistance is mediated by reactivation of the MAPK pathway or by MAPK-independent compensatory signalling pathways that have been described previously in preclinical models of melanoma with BRAF mutations."
However, they concluded that the combination of dabrafenib and trametinib warrants further evaluation as a potential treatment for metastatic melanoma with BRAF V600 mutations and other cancers with these mutations. Two randomised Phase III trials are now underway in metastatic melanoma.