Pembrolizumab and Denosumab in Clear-Cell Renal-Cell Carcinoma.

BACKGROUND: Anti-PD1 immune checkpoint inhibitors (ICI) are effective in clear-cell renal-cell carcinoma (ccRCC). Preliminary data suggest inhibition of Receptor Activator of Nuclear Factor-κB Ligand (RANKL) signaling may potentiate ICI efficacy. We evaluated the activity and safety of the RANKL-inhibitor denosumab with pembrolizumab in people with pretreated advanced ccRCC. METHODS: This single-arm, multi-center phase 2 trial enrolled participants with metastatic or unresectable ccRCC progressing on or after VEGFR-targeted tyrosine kinase inhibitor (TKI) therapy. Participants received pembrolizumab 200 mg IV every 3 weeks plus denosumab 120 mg SC on days 1, 8 and 22, then 3-weekly until disease progression, unacceptable toxicity, or a maximum of 24 months. Primary endpoint was objective tumor response (ORR). Secondary endpoints: median progression free survival (PFS), progression-free survival rate at 6 months (PFS6m), duration of response (DOR), and adverse events (AE). RESULTS: 59 participants were recruited: male (81%), International Metastatic Database Consortium favorable risk (48%), at least one prior VEGFR-TKI in all participants, 2 or more in 16%. At a median follow-up of 40 months, the ORR was 31% (all partial; 95%CI 20%-45%). Median DOR was 17 months. Median PFS was 7.5 months and PFS6m rate was 53% (95%CI, 39%-65%). Immune-related grade ≥ 3 AEs were reported in 21% of participants; study treatment was discontinued for toxicity in 22%. One participant suffered G3 osteonecrosis of the jaw, and 1 died of myositis attributed to study treatment. CONCLUSION: The combination of denosumab and pembrolizumab is safe in pretreated clear cell renal carcinoma, with activity meriting further investigation.