Low-Dose Nivolumab with or without Ipilimumab as Adjuvant Therapy Following the Resection of Melanoma Metastases: A Sequential Dual Cohort Phase II Clinical Trial

SIMPLE SUMMARY: Optimal dosing and duration of adjuvant treatment with PD-1 immune checkpoint inhibitors in melanoma patients have not been established. The investigated low-dose regimen of nivolumab with or without ipilimumab (in a sequential dual-cohort phase II trial), resulted in a 12-months relapse-free survival (RFS) rate and tolerability that was comparable to what has been served with standard dosing of nivolumab or pembrolizumab when patients were matched for stage. The incidence of immune-related adverse events was similar to what has been reported from registration trials in this indication. Immunohistochemical quantification of intra- and peritumoral immune cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Therefore, low-dose regimes of PD-1 blocking monoclonal antibodies deserve further study as cost-effective alternatives for currently approved standard dosing regimens, with baseline immunohistochemical tumor profiling to be further explored as a promising biomarker. ABSTRACT: Background: Optimal dosing and duration of adjuvant treatment with PD-1 and CTLA-4 immune checkpoint inhibitors have not been established. Prior to their regulatory approval we investigated a low-dose regimen of nivolumab with or without ipilimumab in a sequential dual-cohort phase II clinical trial. Methods: Following the complete resection of melanoma metastases, patients were treated with a single fixed dose of ipilimumab (50 mg) plus 4 bi-weekly fixed doses of nivolumab (10 mg) (cohort-1), or nivolumab for 1 year (10 mg fixed dose, Q2w x9, followed by Q8w x4) (cohort-2). Twelve-months relapse-free survival (RFS) served as the primary endpoint. Results: After a median follow-up of 235 weeks for cohort-1 (34 patients), and 190 weeks for cohort-2 (21 patients), the 12-months RFS-rate was, respectively, 55.9% (95% CI, 39–72), and 85.7% (95% CI, 70–100). Treatment-related adverse events occurred in 27 (79%), and 18 (86%) patients, with 3 (9%), and 1 (5%) grade 3 adverse events in cohort-1 and -2, respectively. Immunohistochemical quantification of intra- and peritumoral CD3(+) T cells and CD20(+) B cells, but not PD-1/PD-L1 staining, correlated significantly with RFS. Conclusions: One year of adjuvant low-dose nivolumab could be an effective and economically advantageous alternative for standard dosing, at the condition of further confirmation in a larger patient cohort. A shorter low-dose nivolumab plus ipilimumab regimen seems inferior and less tolerable.