In the third and final presidential symposium at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid, Spain, Bristol-Myers Squibb (BMS) provided a planned interim analysis of the Phase III CheckMate-236 trial. CheckMate-236 is evaluating Opdivo (nivolumab) in patients with resected Stage IIIB/C and IV melanoma, regardless of BRAF mutation status.
The Phase III CheckMate-238 trial included 906 patients with stages IIIB, IIIC, and IV melanoma that has been completely resected and had more than a 50% risk of relapse over five years. Patients were randomised 1:1 to receive Opdivo 3m/kg intravenously (IV), taken every two weeks, or to Yervoy 10mg/kg, taken every three weeks for four doses, followed by 10mg/kg every 12 weeks. The primary endpoint was relapse free survival (RFS).
Opdivo met its primary endpoint, showing a statistically significant improvement RFS of 35% (HR 0.65; 97.6% CI: 0.51 to 0.83; p <0.0001) compared with Yervoy. Another key milestone was at a minimum follow-up of 18 months, the rate of RFS for the Opdivo and Yervoy groups were 66% (95% CI: 61.8 to 70.6) and 53% (95% CI: 47.8 to 57.4), respectively. At the time of this analysis, median RFS had not yet been reached for either group.
The RFS benefit was similar across pre-specified patient subgroups, comprising BRAF V600 mutation-positive and BRAF wildtype patients. In addition, fewer treatment-related adverse events of Grade 3/4 were seen and the rates of treatment discontinuation due such events were significantly lower with Opdivo in comparison to Yervoy. Future evaluation of the outcomes of CheckMate-238 will have to ascertain whether patients who have received adjuvant therapy respond in the same way if re-treated at a later stage.
The CheckMate-238 study is paradigm-shifting. However, Opdivo was not the only regimen set to revolutionise post-surgery treatment in melanoma. Presented alongside CheckMate-238 at ESMO 2017, the Phase III COMBI-AD trial of Novartis’ BRAF/MEK combo Tafinlar (dabrafenib) and Mekinist (trametinib) boasted equally impressive RFS improvements in adjuvant treatment for patients with BRAF V600 mutation-positive melanoma. Coupled to the resounding message at the oncology meeting that interferons should no longer be used (unless indicated for ulcerated melanoma), the lucrative adjuvant space is there for the taking for PD-1/PD-L1-based and BRAF/MEK combination treatments. As such, the two new regimens look set to transform the adjuvant space and the two trials are heralded as landmarks for the treatment of melanoma.
The adjuvant melanoma space will continue to shape up over the coming months. It is still to be determined whether certain prognostic factors, such as metastases in fewer than three organ sites and lower baseline lactate dehydrogenase, can indicate which patients derive the most benefit from either of the two treatments. Opdivo will be indicated for all-comers, regardless of BRAF mutation status, whereas Tafinlar + Mekinist will receive an indication for patients with BRAF V600 mutation-positive melanoma, approximately half of the patient population. The race to become the go-to treatment for this subset of patients is on, not unlike the one that has already transpired in the advanced melanoma setting.
Results clearly hinted at the most likely outcomes in the adjuvant melanoma space. Opdivo will usurp Yervoy in the US as adjuvant therapy in completely resected stage III/IV melanoma and will become the first available immuno-oncology agent in this setting in Europe.
With results from a Phase III trial with Merck & Co’s Keytruda (pembrolizumab) in adjuvant melanoma also eagerly awaited, the opportunity for adjuvant anti-PD-1 to be established as a standard of care for high-risk melanoma in the near future is attainable.