High dose interleukin-2 in combination with anti-programmed cell death protein 1 to overcome immune checkpoint inhibitor resistance in metastatic melanoma and renal cell carcinoma.

To assess the combination of high dose interleukin 2 (HD IL2) and nivolumab in patients with checkpoint inhibitor-refractory melanoma or renal cell carcinoma (RCC), we performed a single-arm, Simon two-stage phase II trial for patients with unresectable stage III or IV melanoma or any histology RCC. The primary endpoint was overall response rate (ORR); secondary endpoints were adverse events and progression-free survival (PFS), defined as time to radiographic or clinical progression, whichever occurred first. Five patients enrolled, three with melanoma and two with RCC. Median age at registration was 47 (35-77) years. Two patients (40%) had treated or asymptomatic brain metastases, and one (20%) had liver metastases. Median prior lines of systemic therapy per patient were 3 (2-5). Patients completed a median of 1 (0.5-3) treatment cycle, involving two admissions for HD IL2 administration and two doses of nivolumab. ORR was 20%. Median PFS was 1.4 (0.8-45.0) months. Time to next therapy for each living patient was 2.5 and 45.6 months for local modalities, and 2.0, 2.3, and 45.9 months for systemic therapies. Adverse events reflected the known toxicity of HD IL2. One treatment-related death occurred, leading to trial termination. The combination of HD IL2 and nivolumab resulted in a durable response in one of five patients with PD-1-refractory advanced melanoma or RCC. Use of HD IL2 remains limited by its toxicity; augmented IL2 formulations and administration strategies are needed. ClinicalTrials.gov ID: NCT03889782 (Registered 6/16/2019; https://clinicaltrials.gov/study/NCT03889782 ).