Coordinated Pembrolizumab and High Dose IL-2 (5-in-a-Row Schedule) for Therapy of Metastatic Clear Cell Renal Cancer

INTRODUCTION: The ligation of the interleukin-2 (IL-2) receptor and immune checkpoint blockade may each alter lymphocytes, thereby inducing regression in various cancers. Single agent objective response rates of 14% to 25% have been reported for usual schedule 14-dose-in-a-row IL-2 therapy of metastatic clear cell renal cancer (ccRCC), with a notable subset of responses being durable. Pembrolizumab yielded a 33% response rate in patients with metastatic ccRCC. PATIENTS AND METHODS: This study addressed the safety and feasibility of the combination of IL-2 and pembrolizumab in the treatment of metastatic ccRCC. Subjects were treated with four 9-week blocks of therapy, receiving pembrolizumab every 3 weeks in all blocks and receiving 4 courses of 5-planned-doses high dose IL-2 in each of blocks 2 and 3. Safety was monitored by a Pocock boundary of study suspension and re-evaluation if exceeding a 15% dose limiting toxicity rate at α = 0.05. The Simon 2-stage design tested for an alternative hypothesis response rate of at least a 45% vs. a null hypothesis rate of less than 20%, with α = 0.10 and 90% power RESULTS: No accrual suspension for safety was triggered. The objective response rate was 70% (19/27, 95% CI: 0.50-0.86). Nine patients responded after pembrolizumab alone and ten responded after the addition of IL-2. At a minimum follow-up of 23 months, 9 of the responding patients had no disease progression requiring additional treatment. CONCLUSION: The combination of 5-planned-dose-schedule high dose IL-2 and pembrolizumab is feasible, with a high response rate, justifying further exploration of this dual immune treatment of metastatic ccRCC.