The PD-1 blocking antibody nivolumab has activity in melanomas refractory to CTLA-4 blockade.

  • Major finding: The PD-1 blocking antibody nivolumab has activity in melanomas refractory to CTLA-4 blockade.

  • Concept: Nivolumab was similarly effective in ipilimumab-naïve and ipilimumab-refractory patients.

  • Impact: Targeting different immune checkpoint proteins sequentially can lead to clinical responses.

Cancer cells can evade immune detection by activating T-cell inhibitory immune checkpoint proteins. Blockade of immune checkpoint proteins such as cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed death 1 (PD-1) has emerged as a promising approach to increase antitumor immunity and has improved survival in patients with melanoma and other cancers. Ipilimumab, a CTLA-4–blocking monoclonal antibody, has been approved by the FDA to treat melanoma, but it remains unclear if other immune checkpoint antibodies will be effective in ipilimumab-refractory patients. Weber and colleagues report findings from a phase I trial that assessed the safety and tolerability of nivolumab, a monoclonal PD-1–blocking antibody, in patients with ipilimumab-naïve or -refractory melanoma alone or with a peptide vaccine to augment T-cell responses. Assessment of the objective response rate was a secondary endpoint. Fatigue was the most common adverse event, and injection site reactions occurred in patients receiving the vaccine, which had no impact on nivolumab activity. Among 34 ipilimumab-naïve patients, 2 (6%) had a complete response, 6 (18%) had a partial response, and 7 (21%) had stable disease, and of 53 ipilimumab-refractory patients, 14 (26%) had a partial response and 11 (21%) had stable disease. The median duration of response was not reached in either group. Patients with high pre-existing T-cell reactivity to melanoma antigens were less likely to have an objective response than were patients with low or no reactivity. In an unplanned analysis of 12 ipilimumab-naïve patients who received ipilimumab after progression on nivolumab, 2 had a partial response and 2 had a mixed response, suggesting that some nivolumab-refractory tumors also remain sensitive to ipilimumab. Collectively, these results show that sequential use of ipilimumab and nivolumab in melanoma can lead to durable responses with limited toxicity, though future studies are needed to compare sequential with combination treatment.

Weber JS, Kudchadkar RR, Yu B, Gallenstein D, Horak CE, Inzunza HD, et al. Safety, efficacy, and biomarkers of nivolumab with vaccine in ipilimumab-refractory or -naive melanoma. J Clin Oncol 2013 Oct 21 [Epub ahead of print].

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