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.
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).
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.
The combination of denosumab and pembrolizumab is safe in pretreated clear cell renal carcinoma, with activity meriting further investigation.
Clinical genitourinary cancer. 2026 May 27 [Epub ahead of print]
Carole A Harris, Danka S Zebic, Michelle F Morris, Tom Ferguson, Jeffrey C Goh, Andrew J Martin, Craig Underhill, David W Pook, Laurence Krieger, Ganessan Kichenadasse, Abhishek J Joshi, Shalini Subramaniam, Alison Zhang, Anthony M Joshua, Guy C Toner, Paul A Vasey, Prashanth Prithviraj, Martin R Stockler, Ian D Davis, Craig Gedye
Department of Medical Oncology, St George Hospital, New South Wales, Australia; The George Institute for Global Health, UNSW Sydney, New South Wales, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Department of Medical Oncology, Sunshine Coast University Hospital, Queensland, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Department of Medical Oncology, Fiona Stanley Hospital, Perth, Western Australia, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Department of Medical Oncology, Royal Brisbane and Women's Hospital, Herston, Queensland, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Australia; Border Medical Oncology Research Unit, Murray Valley Private Hospital, Wodonga, Victoria, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Monash Health, Monash Cancer Centre, Bentleigh East, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., GenesisCare North Shore, Sydney, New South Wales, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Department of Medical Oncology, Townsville University Hospital, Douglas, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia; Cancer Service, Macquarie University Hospital, North Ryde, New South Wales, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Australia; Kinghorn Cancer Centre, St Vincents Hospital Sydney, Sydney, New South Wales, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Australia and Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, The University of Melbourne, Victoria, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Icon Cancer Centre, Wesley Medical Centre, Auchenflower, Queensland, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Ballarat Oncology and Haematology Services, Ballarat, Victoria, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., NHMRC Clinical Trials Centre, University of Sydney, New South Wales, Australia; Department of Medical Oncology, Concord Repatriation General Hospital, Sydney, New South Wales, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Monash University Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia; Department of Medical Oncology, Box Hill Hospital, Eastern Health, Box Hill, Victoria, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia., Icon Cancer Centre Adelaide, South Australia, Australia; The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group, Sydney, New South Wales, Australia. Electronic address: .