Treatment of melanoma has switched gears after immune checkpoint inhibitor (ICI) therapies were first introduced in 2011. Currently, the combination of anti-programmed cell death protein 1 (PD-1) inhibitor nivolumab (Opdivo) and anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor ipilimumab (Yervoy) is the most aggressive treatment regimen available for advanced metastatic melanoma. This combination demonstrated a 52% 5-year survival rate in the Phase III CheckMate-062 study, establishing it as a standard of care in frontline treatment of melanoma. Despite the treatment benefits, ICIs are commonly associated with a high risk of colitis, liver disease and kidney injury as well as other immune-related adverse events. During the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program, held 29 May – 2 June, some prominent presentations in the melanoma field highlighted the efforts to reduce or optimise the use of ICIs with the intention to spare patients from excessive toxicities. The evidence from these studies suggest sometimes “less is more”, however, determining for which patient populations less treatment will be better is another question that needs to be answered.
A Phase II dose-sparing study presented by Michael A. Postow, MD (abstract #10003) demonstrated that half of the recommended 4-dose treatment with Opdivo + Yervoy combination could be sufficient to provoke an anti-cancer immune response. According to the presented study, after 6 weeks and two doses of Opdivo + Yervoy, 41 out of 60 patients had tumour shrinkage or no growth and thereafter switched to maintenance therapy with Opdivo alone. Interestingly, none of the remaining patients who have continued treatment with the combination after the six-week assessment had tumour shrinkage or subsequent radiological response at the end of 12-week treatment. Although this presentation highlighted that a shorter than the recommended duration of treatment with ICIs could generate similar responses, it would be critical to demonstrate that this approach could also generate durable responses that result in comparable survival benefits as well.
A caveat to personalising the length of ICI treatment based on the level of immune response is the lack of sensitive tools for assessing drug activity on the tumour level. Tumour-associated autoantibodies produced by cancer cells are increasingly considered as viable blood-based biomarkers for early detection of various types of cancers and could also be used for predicting safety and efficacy of drug treatment. Hassel et al (abstract # 10011) presented results from a trial that aimed to understand the use of autoantibodies in predicting clinical outcome. The study assessed tumour samples from advanced melanoma patients who had received ICI treatment. From a wide range of autoantibodies, the study achieved identifying those that were most frequently correlated with the risk of immune-related adverse events as well as the probability of treatment response.
In the upcoming years, optimising the use of ICIs will be crucial in the treatment of melanoma, given the foresight of new doublet and triplet combinations formed around an ICI foundation entering global markets. Currently, the knowledge of how to optimally benefit from ICI-based therapies is still growing, and with the support of new biomarkers such as autoantibodies, physicians and regulators could provide safer guidance to using ICIs without compromising efficacy in melanoma.