The combination of denosumab (Xgeva) and pembrolizumab (Keytruda) produced an objective response rate (ORR) of 31% (95% CI, 20%-45%) in patients with vascular VEGFR TKI–pretreated advanced clear cell renal cell carcinoma (ccRCC), according to findings from the phase 2 KEYPAD trial (ANZUP 1601; NCT03280667) published in Clinical Genitourinary Cancer.¹
Eighteen partial responses (PRs) were reported among 58 evaluable participants, with no complete responses (CRs). At a median follow-up of 40 months, the 6-month progression-free survival (PFS) rate was 53% (95% CI, 39%-65%) and the median PFS was 7.5 months (95% CI, 4-11). The disease control rate (DCR) at 6 months was 57% (95% CI, 43%-70%), the median time to response was 2.7 months, and the median duration of response (DOR) was 17 months (95% CI, 8.3-30).
"Whilst meaningful clinical responses were observed in 31% of participants, this was less than the predefined level of interest of 40% or more, and comparable to other studies of immunotherapy after VEGFR-TKI," the study authors wrote in the publication.
KEYPAD Trial of Pembrolizumab Plus Denosumab in ccRCC: Key Findings
- Confirmed ORR was 31% (18/58; all PRs, no CRs), exceeding the null hypothesis threshold of 25% but not the 40% threshold of interest.
- The 6-month PFS rate was 53% and median PFS was 7.5 months, comparing favorably with historical second-line immunotherapy trials in ccRCC following VEGFR-TKI.
- Grade 3 or higher AEs occurred in 64% of participants; irAEs of any grade occurred in 32%, most commonly pneumonitis (n = 6), myocarditis (n = 3), and colitis (n = 3).
How was KEYPAD designed?
KEYPAD was a single-arm, multicenter phase 2 trial conducted at 16 Australian sites that enrolled adults with histologically confirmed, unresectable or metastatic ccRCC that had progressed on or after VEGFR-TKI therapy, an ECOG performance status of 0 to 2, and adequate organ function; prior treatment with denosumab or an immune checkpoint inhibitor was exclusionary.1,2
Participants received pembrolizumab at 200 mg intravenously every 3 weeks plus denosumab at 120 mg subcutaneously on days 1, 8, and 22, and then every 3 weeks until disease progression, unacceptable toxicity, or a maximum of 24 months.
The trial used a Simon 2-stage minimax design targeting 70 participants, but enrollment closed at 59 between December 2017 and July 2022 because of COVID-19–related accrual disruption and the emergence of other standard therapies.
Of the enrolled population, 81% were male, the median age was 67 years (range, 60-72), and 48% had International Metastatic Database Consortium favorable-risk disease; all participants had received at least 1 prior VEGFR-TKI, and 16% had received 2 or more prior lines of therapy.
The primary end point was investigator-assessed ORR per RECIST 1.1 criteria; secondary end points included 6-month PFS rate, 6-month DCR, DOR, and time to first skeletal-related event (SRE).
What was the safety profile of pembrolizumab plus denosumab?
Grade 3 or higher adverse effects (AEs) occurred in 38 of 59 participants (64%), and immune-related AEs (irAEs) of grade 3 or higher occurred in 12 participants (21%).
Any-grade AEs occurred in 58 of 59 participants (98%), most commonly fatigue (53%), pain (29%), and rash (27%); grade 3 or higher AEs occurred in 64%, most frequently elevated lipase (14%), colitis (7%), lung infection (7%), and hyperglycemia (7%). IrAEs occurred in 19 participants (32%), with grade 3 or higher irAEs in 12 (21%); the most clinically significant were pneumonitis, myocarditis, and colitis. Denosumab-attributed toxicities were reported in 2 participants, including 1 grade 3 hypocalcemia and 1 grade 3 osteonecrosis of the jaw.
Serious AEs occurred in 40 participants (68%), most commonly infections (17%) and cardiac disorders (12%). Three participants died during the study, including 1 treatment-related death attributed to myositis. Ten SREs were observed, with a 25th-percentile time to SRE of 37 months; median and 75th-percentile times could not be estimated because of the low event rate. Treatment was discontinued for AEs in 22% of participants, and the median treatment duration was 8.1 months.
The study authors concluded that the denosumab-pembrolizumab combination was feasible and safe, with no new safety signals beyond those expected from either agent alone, and that ongoing translational analyses of blood and tissue collected during KEYPAD may help identify which patients are most likely to benefit from RANKL inhibition added to checkpoint blockade.
References
- 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
- Denosumab and pembrolizumab in clear cell renal carcinoma (KEYPAD). ClinicalTrials.gov. Updated March 29, 2023. Accessed August 14, 2026. https://clinicaltrials.gov/study/NCT03280667
