It is an exciting time to be a melanoma specialist! At the ESMO Presidential Symposium three potentially practice changing papers were presented:
1. ESMO 2014. LBA3_PR: A phase 3 randomized, open-label study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy
2. ESMO 2014. LBA4_PR: COMBI-v - A randomised, open-label, phase III study comparing the combination of dabrafenib (D) and trametinib (T) with vemurafenib (V) as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/K mutation-positive cutaneous melanoma
3. ESMO 2014. LBA5_PR: A phase 3, double-blind, placebo-controlled study of vemurafenib versus vemurafenib + cobimetinib in previously untreated BRAFV600 mutation-positive patients with unresectable locally advanced or metastatic melanoma (NCT01689519)
The superiority of dual blockade with a braf and MEK inhibitor in Stage IV brafV600 positive melanoma were confirmed in two Phase III trials; COMBI-v comparing dabrafenib and trametinib versus vemurafenib alone and COBRIM comparing vemurafenib and cobemetinib versus vemurafenib monotherapy. In COMBI -v which was stopped early, the preliminary analysis showed a median overall survival of17.2 months in the vemurafenib arm vs. NR with the combination (HR 0.69; P=.005). PFS was also significant (7.3 months for vemurafenib and 11.4 months with the combination HR 0.56; p<0.01).
COBRIM reached its primary endpoint of PFS. The combination arm achieved a PFS of 9.9 months versus 6.2 months with vemurafenib monotherapy (p=0.51; p<.0001). An interim analysis of OS showed a reduction in deaths (HR=0.65; p<0.05). Interestingly, the toxicity profile in both trials favoured the combination arm.
Although the endpoints of these Phase III Trials were different, the results were similar, both trials showed similar Hazard Ratios for PFS and OS. Both combinations appear to be superior to monotherapy and likely will become a new standard of treatment for braf mutated Stage IV melanoma.
Just as exciting was LBA3 - a phase 3 randomized, open-label study of nivolumab (anti PD-1; BMS-936558; ON0-4538) versus investigator's choice chemotherapy (ICC) in patients with advanced melanoma after prior anti-CTLA-4 therapy. 405 patients were randomized after progression on ipilimumab 2:1 to either nivolumab or investigator choice chemotherapy (dacarbazine or carboplatin/paclitexel). Co primary endpoints were ORR and OS. Preliminary results showed patients assigned to the nivolumab arms had a superior ORR of 32% vs. 11 % in the chemotherapy arm as well as a lower toxicity. The responses to nivolumab were also of a longer duration. This trial adds to the growing evidence that immune checkpoint blockade will have a major role in the treatment of metastatic melanoma. We await the survival data with great interest.
CARE Faculty Perspective: Overall these three trials have added extensively to our treatment options available for patients with stage IV melanoma. Gone are the days when our treatment options for these patients were slim and none. We now have the braf and MEK inhibitors as well as the immune checkpoint inhibitor ipilimumab. With this new information presented at ESMO we will soon be able to add combination braf/MEK blockade and PD-1 inhibition to that as well.
Ralph Wong, MD