Pembrolizumab Plus Denosumab Shows Activity in Pretreated Kidney Cancer

Adding the RANKL inhibitor denosumab (Xgeva, Prolia) to pembrolizumab (Keytruda) produced a 31% objective response rate and a median progression-free survival (PFS) of 7.5 months in patients with clear-cell renal cell carcinoma (ccRCC) who had progressed on prior VEGFR-targeted tyrosine kinase inhibitor (TKI) therapy, according to results from the phase 2 KEYPAD trial (NCT03280667) published in Clinical Genitourinary Cancer.¹

The single-arm, multicenter trial conducted across 16 Australian sites, enrolled 59 patients with unresectable or metastatic ccRCC whose disease had progressed during or after VEGFR TKI treatment. Patients received pembrolizumab 200 mg intravenously every 3 weeks plus denosumab 120 mg subcutaneously on days 1, 8, and 22 and then every 3 weeks, continuing until disease progression, unacceptable toxicity, or a maximum of 24 months. The primary end point was objective response rate (ORR) by investigator assessment per RECIST v1.1.

Efficacy Outcomes

Among 58 evaluable patients, 18 (31%; 95% CI, 20%-45%) achieved a confirmed objective response, all partial; no complete responses were observed. Fifteen patients (26%) had stable disease, and 24 (41%) experienced disease progression. Median duration of response was 17 months. At a median follow-up of 40 months, median PFS was 7.5 months (95% CI, 4-11), and the 6-month PFS rate was 53% (95% CI, 39%-65%). The study's investigators had prespecified an ORR of 40% or higher as the threshold of interest; the observed 31% fell below this mark but was described by the authors as comparable to other second-line immunotherapy studies in this setting.

Of 23 patients with bone metastases, 7 (29%) had partial responses and 5 (21%) had stable disease, findings the authors noted were similar to outcomes in patients without bone involvement.

Safety Profile

Any-grade adverse events (AEs) occurred in 58 of 59 patients (98%), most commonly fatigue (53%), pain (29%), and rash (27%). Grade 3 or higher AEs occurred in 38 participants (64%), with elevated lipase (14%), colitis (7%), lung infection (7%), and hyperglycemia (7%) among the most common treatment-related severe events. Immune-related AEs occurred in 19 patients (32%), including grade 3 or higher events in 12 (21%); the most clinically significant were pneumonitis (n = 6), myocarditis (n = 3), and colitis (n = 3). One patient died of treatment-related myositis. Denosumab-specific toxicities were limited to 1 case of grade 3 hypocalcemia and 1 case of grade 3 osteonecrosis of the jaw. Ten skeletal-related events occurred during follow-up, with a relatively low overall incidence in this population.

Treatment was discontinued for disease progression in 58% of patients and for adverse events in 22%. Two patients remained on treatment at the time of data cutoff.

Study Rationale

Denosumab has been approved by the FDA since 2010 for the treatment of osteoporosis or to increase bone mass in patients receiving certain cancer treatments.² Inhibition of RANKL is emerging as a potential cancer therapeutic, as high RANKL expression is associated with poorer outcomes across cancer types.¹ Pembrolizumab is approved for first-line treatment of RCC in combination with axitinib (Inlyta) and as adjuvant therapy as a single agent or in combination with belzutifan (Welireg) for patients at intermediate-high or high risk of recurrence following nephrectomy.³

Trial Limitations

The trial did not reach its planned enrollment target of 70 patients; accrual was affected by the COVID-19 pandemic and by evolving availability and reimbursement of other immunotherapy options in Australia during the study period. As a single-arm trial, the authors cautioned that efficacy and safety comparisons with other studies should be interpreted with caution and noted that overall survival and post-protocol treatment data were not collected as part of this pragmatic cooperative group design.

The authors concluded that the combination of pembrolizumab and denosumab was feasible and safe to deliver in pretreated ccRCC, with clinical activity that, while below the trial's ambitious predefined threshold, merits further investigation. They pointed to ongoing translational analyses of blood and tissue collected during the study as a potential avenue for identifying which patients might benefit most from RANKL inhibition added to checkpoint immunotherapy.

REFERENCES

1. Harris CA, Zebic DS, Morris MF, et al. Pembrolizumab and Denosumab in Clear-Cell Renal-Cell Carcinoma. Clin Genitourin Cancer. 2026 Aug;24(5):102585. doi: 10.1016/j.clgc.2026.102585. Epub 2026 May 27. PMID: 42336709.

2. Prolia® (denosumab). US FDA. Accessed July 17, 2026. https://tinyurl.com/mryy7bkj

3. FDA approves belzutifan with pembrolizumab for adjuvant treatment of renal cell carcinoma. US FDA. June 12, 2026. Accessed June 12, 2026. https://tinyurl.com/ctdeyjpw