Pembrolizumab/Denosumab Combo Shows Activity in Pretreated ccRCC

The combination of denosumab (Xgeva) and pembrolizumab (Keytruda) showed antitumor activity in pretreated advanced clear cell renal cell carcinoma (ccRCC), according to results from the phase 2 KEYPAD/ANZUP 1601 trial (NCT03280667) published in Clinical Genitourinary Cancer.

At a median follow-up of 40 months, the confirmed objective response rate (ORR) was 31% (95% CI, 20%-45%), with all responses being partial. Stable disease occurred in 26% (95% CI, 15%-39%) of patients, and progressive disease in 41% (95% CI, 29%-55%). The median time to response was 2.7 months, and the median duration of response was 17 months (95% CI, 8.3-30).

The median progression-free survival (PFS) was 7.5 months (95% CI, 4.0-11.0), with a 6-month PFS rate of 53% (95% CI, 39%-65%), and a 6-month disease control rate of 57% (95% CI, 43%-70%).

Any-grade adverse effects (AEs) occurred in 98% of the 59 patients in the safety analysis, and grade 3/4 AEs occurred in 64%. Immune-related AEs occurred in 32% of patients (grade 3/4, 21%), most notably pneumonitis (n = 6), myocarditis (n = 3), and colitis (n = 3). Ten skeletal-related events occurred; the 25th percentile for time to a skeletal-related event was 37 months (95% CI, 17-not estimable). Treatment was discontinued due to toxicity in 22% of patients; 1 patient developed grade 3 osteonecrosis of the jaw attributed to denosumab, and 1 died of treatment-related myositis.

“KEYPAD is the first study to investigate the combination of PD1 axis-targeted immunotherapy with RANKL inhibition in [RCC],” study author Craig Gedye, BSc (Hons), MBChB, FRACP, PhD, medical oncologist and director of Research at Icon Cancer Centre Adelaide, and coauthors wrote in the publication. “We found no new safety signals compared [with] either agent as monotherapy.”

KEYPAD was a single-arm, multicenter, phase 2 trial enrolling patients with metastatic or unresectable ccRCC that had progressed on or after VEGFR-targeted tyrosine kinase inhibitor (TKI) therapy. Between December 2017 and July 2022, investigators enrolled 59 patients across 16 Australian sites; enrollment closed before reaching the planned target of 70 because of COVID-19–related disruptions and the availability of other standard treatments. One patient lacking a measurable target lesion at baseline was excluded from the efficacy analysis, leaving 58 evaluable patients.

Patients received pembrolizumab 200 mg intravenously every 3 weeks plus denosumab 120 mg subcutaneously on days 1, 8, and 22, followed by every 3 weeks until progression, unacceptable toxicity, or a maximum of 24 months. All patients had received at least 1 prior VEGFR-TKI line, and 16% had 2 or more; 48% had International Metastatic Database Consortium favorable-risk disease.

The primary end point was ORR, defined as the percentage of patients achieving a partial or complete response per RECIST v1.1 guidelines. Secondary end points included 6-month PFS rate, disease control rate at 6 months, ORR at 6 months, time to and duration of response, and time to first skeletal-related event.

The 6-month PFS rate of 53% and the median PFS of 7.5 months in KEYPAD compared favorably with an estimated 6-month PFS rate range of 30% to 46% and median PFS range of 2.7 to 5.6 months across similar second-line immunotherapy trials in metastatic RCC, including the phase 3 CheckMate 025 trial (NCT01668784) of nivolumab (Opdivo) vs everolimus (Afinitor).² Grade 3 or higher treatment-related AEs attributable to pembrolizumab occurred in 25% of KEYPAD patients, compared with 21% in CheckMate 025.³

The authors noted that KEYPAD did not meet its recruitment target because of pandemic-related accrual disruptions and changing immunotherapy availability in Australia during the study; as a single-arm trial, comparisons with other studies should be made cautiously, and overall survival data were outside the trial’s scope.

Reference

1. Harris CA, Zebic DS, Morris MF, et al. Pembrolizumab and denosumab in clear-cell renal-cell carcinoma. Clin Genitourin Cancer. 2026;24(5):102585. doi:10.1016/j.clgc.2026.102585
2. Motzer RJ, Escudier B, George S, et al. Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial. Cancer. 2020;126(18):4156-4167. doi:10.1002/cncr.33033
3. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665