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) signalling 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-centre phase 2 trial enrolled participants with metastatic or unresectable ccRCC progressing on or after VEGFR-targeted tyrosine kinase inhibitor (TKI) therapy. Participants received pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg 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 tumour 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 favourable risk (48%), at least one prior VEGFR-TKI in all participants, two 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 one 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. Micro-abstract We tested the RANKL inhibitor denosumab in combination with pembrolizumab in 59 people with VEGFR TKI pre-treated advanced clear-cell renal-cell carcinoma. We observed a 31 % objective response rate, median progression-free survival of 7.5 months and a 53 % six-month PFS rate, comparing favourably against historical reports, with little additional toxicity; G3+ adverse events occurred in 21 % (no new safety signals).