Nivolumab With or Without Ipilimumab in Patients With Recurrent or Metastatic Merkel Cell Carcinoma: A Nonrandomized, Open-Label, International, Multicenter Phase I/II Study

Merkelcell.org Summary

Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer that often spreads beyond its starting point. Immunotherapy, which helps the immune system fight cancer, has improved survival for people with metastatic MCC, but only about half of patients experience durable benefit. This study tested whether combining two immunotherapy drugs, nivolumab and ipilimumab, would work better than using nivolumab alone.

Among 68 patients, 25 received only nivolumab, while 43 got both drugs. The study found no major difference in how well patients responded – 60% of patients responded well to nivolumab alone, compared to 58% for those who got both drugs. However, patients who had never received MCC treatment before were more likely to have a better response than whose disease progressed on other prior therapy, regardless of the group they were in. The cancer returned after an average of 21 months in the nivolumab-only group, compared to 8.5 months in the combination group. Patients receiving both drugs also had more side effects.

These findings suggest that adding a second immunotherapy drug may not always improve outcomes and can lead to more side effects. However, because patients in the combination group were generally older and had more advanced disease, their outcomes may have been worse regardless of treatment. A larger, more controlled study is needed to better understand whether combination therapy is more effective than a single drug.

Abstract

Purpose: Approximately 50% of patients with advanced Merkel cell carcinoma (MCC) have primary or acquired resistance to PD-(L)1 blockade, which may be overcome using combination immune checkpoint inhibition (ICI) with anti-cytotoxic T lymphocyte antigen-4 antibody. We present results from the recurrent/metastatic MCC cohort in CheckMate 358, a nonrandomized, multicohort, phase I/II study of nivolumab (NIVO) with or without ipilimumab (IPI) in virus-associated cancers (ClinicalTrials.gov identifier: NCT02488759).

Methods: ICI-naïve patients with recurrent/metastatic MCC and 0-2 previous systemic therapies were administered NIVO monotherapy at 240 mg once every 2 weeks or combination therapy with NIVO 3 mg/kg once every 2 weeks + IPI 1 mg/kg once every 6 weeks. The primary end point was objective response. Secondary end points included duration of response (DOR), progression-free survival (PFS), and overall survival (OS).

Results: Sixty-eight patients received NIVO (n = 25) or NIVO + IPI (n = 43). The objective response rate (95% CI) and median DOR (95% CI), respectively, were 60% (38.7 to 78.9) and 60.6 months (16.7 to not applicable [NA]) with NIVO and 58% (42.1 to 73) and 25.9 months (10.4 to NA) with NIVO + IPI. The median PFS (95% CI) and OS (95% CI), respectively, were 21.3 (9.2 to 62.5) and 80.7 (23.3 to NA) months with NIVO and 8.4 (3.7 to 24.3) and 29.8 (8.5 to 48.3) months with NIVO + IPI. The incidence of grade 3/4 treatment-related adverse events was 28% with NIVO and 47% with the combination.

Conclusion: This nonrandomized study showed frequent and durable responses with both NIVO and NIVO + IPI in patients with ICI-naïve advanced MCC. However, it did not show improvement in efficacy with the combination, thus contradicting previous study reports that had suggested clinical benefit with combination ICI. A randomized trial of NIVO + IPI versus NIVO monotherapy is warranted.