In a new study entitled “Nivolumab and Ipilimumab versus Ipilimumab in Untreated Melanoma,” researchers showed how combining two immunotherapies — nivolumab and ipilimubad — to treat patients with advanced melanoma significantly improves patients’ responses and survival. The results are part of a Phase 2 clinical trial and were published in the New England Journal of Medicine and recently presented during the Annual Meeting of the American Association for Cancer Research.
In a Phase I Clinical Trial led by Jedd Wolchok at the Memorial Sloan Kettering’s Ludwig Center for Cancer Immunotherapy, researchers showed that dual blockade of immune checkpoints, such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and the programmed death 1 (PD-1) receptor, via Ipilimumab and Nivolumab, respectively, improved overall survival among patients with advanced melanoma. Immune checkpoints refer to inhibitory pathways linked to the immune system with the objective of controlling the duration of an immune response and minimizing collateral tissue damage. However, tumors can hijack immune checkpoints to their advantage and promote tumor immune resistance, particularly against T cell responses.
Ipilimumab and Nivolumab, both approved by US Food and Drug Administration (FDA), target specific immune checkpoints — the former is an antibody against CTLA-4, while the latter targets PD-1, two proteins expressed at the surface of T cells that once activated dampen T cell anti-tumor responses.
As noted by Wolchok in a press release, “It was apparent following that trial that the combination should be tested as a first line therapy for metastatic melanoma. Rationally combined immunotherapies hold great promise for cancer treatment as long as their side effects can be managed.”
In the Phase II Clinical Trial, the team together with researchers at Harvard Ludwig Cancer Center led by Stephen Hodi enrolled 142 patients with advanced melanoma without any prior cancer treatment, with 109 of those patients negative for BRAF gene mutations (BRAF is one of the most common mutated genes in melanoma patients; however, patients harboring wild-type (wt) BRAF have currently very few treatment options). From the WT BRAF cohort of patients, 72 patients received combined therapy of ipilimumab with nivolumab, followed by nivolumab alone; the other 37 patients received ipilimumab plus placebo.
The team observed that while patients receiving combined ipilimumab with nivolumab exihibted a 61% overall objective response rate, with 22% complete response rate, patients treated only with ipilimumab exhibited a response rate of 11%, and no complete response. The same phenotype was observed in mutated BRAF patients. The side effects were more pronounced in the combined therapy group, with 27% patients dying, against 11% in monotherapy. However, as Stephen Hodi noted, “In general, and as might be expected, side effects were more prevalent in patients who received the combination therapy. This is something that will have to be studied further. But we also look forward to following up with the patients who benefitted from the combination therapy to assess the durability of the responses we have observed.”