Combining Denosumab and Pembrolizumab in Advanced Renal Cell Carcinoma
The combination of the RANKL inhibitor denosumab (Xgeva, Prolia) and the checkpoint inhibitor pembrolizumab (Keytruda) yielded a 31% objective response rate in patients with clear-cell renal cell carcinoma (ccRCC) who had previously progressed on VEGFR-targeted tyrosine kinase inhibitor (TKI) therapy. According to results from the phase 2 KEYPAD trial published in Clinical Genitourinary Cancer, the study recorded a median progression-free survival of 7.5 months among the 59 enrolled participants.
Did you know? While denosumab is primarily known for treating osteoporosis or managing bone-related side effects in cancer patients, researchers are currently exploring its capacity to target RANKL expression, which is often linked to poorer clinical outcomes in various solid tumors.
Efficacy and Clinical Outcomes in the KEYPAD Trial
The multicenter KEYPAD trial (NCT03280667) evaluated the feasibility of pairing immunotherapy with RANKL inhibition. Patients received 200 mg of pembrolizumab every three weeks, combined with 120 mg of denosumab administered on days 1, 8, and 22 of the first cycle, and then every three weeks thereafter. Treatment continued until disease progression, unacceptable toxicity, or a 24-month cap.
Of the 59 patients, 23 presented with bone metastases. Among this subgroup, 29% achieved a partial response, while 21% maintained stable disease. The study authors noted that these outcomes were comparable to those observed in patients without bone involvement. While the objective response rate of 31% was below the researchers’ ambitious predefined threshold, the trial demonstrated that the combination regimen was both safe and feasible for use in a pretreated patient population.
Safety Profile and Study Limitations
Data from the 16 Australian study sites indicated that disease progression was the primary reason for treatment discontinuation, occurring in 58% of patients. Adverse events led to discontinuation in 22% of cases. At the time of the data cutoff, two patients remained on the therapy.
The trial faced recruitment hurdles, failing to reach its goal of 70 participants. Investigators attributed this shortfall to the COVID-19 pandemic and changing reimbursement landscapes for immunotherapy options in Australia. Because the study was a single-arm, pragmatic cooperative group design, the authors cautioned that efficacy comparisons with other regimens should be interpreted with care. Notably, the study did not collect overall survival or post-protocol treatment data.
Future Directions for RANKL Inhibition
The potential for RANKL inhibition to enhance immunotherapy efficacy remains an active area of research. Investigators involved in the KEYPAD trial are currently conducting translational analyses on blood and tissue samples collected during the study. These efforts aim to identify specific biomarkers that may predict which patients are most likely to benefit from the addition of denosumab to checkpoint blockade.
Pembrolizumab remains a cornerstone of RCC management, currently approved for first-line use in combination with axitinib, as well as adjuvant therapy for patients at high risk of recurrence following nephrectomy. Integrating therapies like denosumab represents a strategy to overcome resistance in the post-TKI setting.
Frequently Asked Questions
What is the primary role of denosumab in cancer treatment?
Denosumab is an FDA-approved RANKL inhibitor typically used to increase bone mass or treat bone-related complications in patients receiving cancer therapy. Researchers are investigating its use as a potential therapeutic agent to improve immunotherapy responses.
What were the main findings of the KEYPAD trial?
The trial found that combining pembrolizumab and denosumab in pretreated ccRCC patients resulted in a 31% objective response rate and a median progression-free survival of 7.5 months.
Are there limitations to the KEYPAD trial results?
Yes. The trial was a single-arm study that did not reach its full enrollment target, and it did not collect data on overall survival or post-protocol treatments. Comparisons to other studies should be made with caution.
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