First report of overall survival for ipilimumab plus nivolumab from the phase III Checkmate 067 study in advanced melanoma

Monoclonal antibodies targeting the immune checkpoints programmed death-1 (PD-1) and programmed death-ligand-1 (PD-L1) have shown activity leading to approval globally in multiple tumour types. However, even in the context of a relatively sensitive tumour type, melanoma, responses to monotherapy with agents such as nivolumab and pembrolizumab do not exceed 40% [1.Robert C. Schachter J. Long G.V. et al.Pembrolizumab versus ipilimumab in advanced melanoma.N Engl J Med. 2015; 372: 2521-2532Crossref PubMed Scopus (4051) Google Scholar, 2.Weber J.S. D'Angelo S.P. Minor D. et al.Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.Lancet Oncol. 2015; 16: 375-384Abstract Full Text Full Text PDF PubMed Scopus (2014) Google Scholar] and as such there is a need to develop approaches with greater efficacy. An obvious strategy is to enrich for responders through the use of biomarkers that can predict therapeutic efficacy (and toxicity). While PD-L1 expression is approved to guide patient selection in some tumour types, it does not have enough specificity to guide therapy in melanoma patients at present [3.Daud A.I. Wolchok J.D. Robert C. et al.Programmed death-ligand 1 expression and response to the anti-programmed death 1 antibody pembrolizumab in melanoma.J Clin Oncol. 2016; 34: 4102-4109Crossref PubMed Scopus (417) Google Scholar]. Mutational and neoantigen burden [4.Hugo W. Zaretsky J.M. Sun L. et al.Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma.Cell. 2017; 168: 542.Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 5.Turajlic S. Litchfield K. Xu H. et al.Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.Lancet Oncol. 2017; 18: 1009-1021Abstract Full Text Full Text PDF PubMed Scopus (540) Google Scholar] have demonstrated potential in retrospective analyses but will need prospective evaluation. An alternative or complementary strategy to improving therapeutic efficacy is combining checkpoint inhibitors with other agents and a number of such approaches are under investigation in clinical trials. Ipilimumab, a monoclonal antibody targeting CTLA-4, was approved for the treatment of advanced melanoma in 2011. When given as a single-agent at 3 mg/kg in four infusions over 12 weeks, ipilimumab is associated with durable disease control in around 20% of patients [6.Hodi F.S. O'Day S.J. McDermott D.F. et al.Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010; 363: 711-723Crossref PubMed Scopus (11191) Google Scholar]. A strong rationale for combining ipilimumab with nivolumab was provided by preclinical evidence [7.Curran M.A. Montalvo W. Yagita H. Allison J.P. PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors.Proc Natl Acad Sci USA. 2010; 107: 4275-4280Crossref PubMed Scopus (1330) Google Scholar], and early clinical data demonstrated high response rates [8.Postow M.A. Chesney J. Pavlick A.C. et al.Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.N Engl J Med. 2015; 372: 2006-2017Crossref PubMed Scopus (2099) Google Scholar]. The phase III Checkmate 067 study enrolled 945 patients into three arms: single-agent ipilimumab, single-agent nivolumab and the combination of these two agents. The trial was designed and powered to compare single-agent nivolumab and the combination regimen against single-agent ipilimumab, the standard of care at the time the trial was enrolling. Importantly, Checkmate 067 was not designed or powered to compare the two experimental arms with each other. In 2015, it was reported that both experimental arms demonstrated improvements in progression-free survival and response rate in comparison to ipilimumab monotherapy; in an exploratory analysis, the hazard ratio for progression-free survival for a comparison of the combination treatment to nivolumab was 0.74 [9]. The first report on the overall survival for this study was recently published [10.Wolchok J.D. Chiarion-Sileni V. Gonzalez R. et al.Overall survival with combined nivolumab and ipilimumab in advanced melanoma.N Engl J Med. 2017; 377: 1345-1356Crossref PubMed Scopus (2214) Google Scholar]. Response rates, progression-free survival and toxicity were similar to the initial report. The overall survival data demonstrated that both experimental arms were associated with significant improvements in overall survival compared with ipilimumab monotherapy. The hazard ratio for an exploratory comparison between nivolumab monotherapy and the combination treatment was 0.85 (3-year landmark: 52% for nivolumab and 58% for the combination of ipilimumab and nivolumab) and not statistically significant. How should we interpret these overall survival data, what are their broader implications and do they have any immediate implications for our clinical practice? Caution is required when interpreting the overall survival results for the following reasons: (i) the analysis was conducted at a pre-specified, albeit protocol-defined, time point and was not event driven; as such the number of deaths at the time of the analysis was considerably lower than predicted (approximately 25% less) and (ii) the trial was not powered for the comparison between nivolumab and the combination of ipilimumab and nivolumab. The combination of anti-CTLA4 therapy with anti-PD-1/anti-PD-L1 therapy is currently under investigation across a number of solid tumour types in phase III studies. Combination strategies, particularly as approved for the treatment of advanced melanoma (ipilimumab 3 mg/kg plus nivolumab 1 mg/kg 12-week 'induction' followed by single-agent nivolumab 3 mg/kg 'maintenance') can lead to significant toxicity, mainly in the induction phase, in around half of patients [9.Larkin J. Hodi F.S. Wolchok J.D. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma.N Engl J Med. 2015; 373: 1270-1271Crossref PubMed Scopus (557) Google Scholar]. Such regimens must have clear overall survival benefit compared with single-agent sequential approaches because the latter tend to be associated with significantly reduced toxicity. However, registration studies are rarely designed to test sequential versus combination therapy. In our view, there is still a place for the combination of ipilimumab and nivolumab as delivered in Checkmate 067 in patients with advanced melanoma because of its numerically higher and durable response rate and the relative immaturity of the overall survival data. Moreover, patients with melanoma seen in real-world clinical practice such as those with brain metastases and high lactate dehydrogenase are underrepresented in clinical trials, and in both groups, there is evidence to suggest that combination therapy may be preferred upfront over single agent anti-PD-1 therapy [11.Larkin J. Ferrucci F.P. Gonzalez R. et al.Efficacy of nivolumab plus ipilimumab combination in patients with advanced melanoma and elevated serum lactate dehydrogenase a pooled analysis Society for Melanoma Research Boston. 2016; Google Scholar]. However, a very full discussion with patients is required and there are patient groups where combination therapy may be inadvisable such as those with a limited performance status, the frail elderly and those with significant comorbidities. It is also important that only centres with experience of managing immune-related side-effects deliver combination regimens. Predictive factors are currently being elucidated and they are likely to be a helpful guide as to who might derive benefit from combination therapy. These factors include clinical parameters, molecular markers such as tumour expression of PD-L1 and serum lactate dehydrogenase levels. All this will become clearer when more mature survival data from the Checkmate 067 study becomes available. None declared.