The Oncology Decoded podcast, co-hosted by Manojkumar Bupathi, MD, MS, executive cochair of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI) and medical oncologist with Rocky Mountain Cancer Centers specializing in solid tumors and genitourinary cancers, and Benjamin Garmezy, MD, associate director of genitourinary research and executive cochair of the Genitourinary Cancer Research Executive Committee at SCRI and medical oncologist at SCRI Oncology Partners specializing in genitourinary cancers, in a recent live session with US Oncology Network and the Pathways Task Force, delved into significant updates that were set to happen at the 2025 American Society of Clinical Oncology (ASCO), focusing on the genitourinary cancer landscape.

Bupathi and Garmezy were joined by John M. Burke, MD, a hematologist and medical oncologist at Rocky Mountain Cancer Centers, and Dhaval R. Shah, MBBS, a medical oncologist from Christiana Care. 

A primary focus of the discussion was the phase 3 KEYNOTE-564 trial (NCT03142334), a pivotal trial for patients with renal cell carcinoma (RCC). This study investigated pembrolizumab (Keytruda) as adjuvant therapy for patients with clear cell RCC who had undergone surgical resection and presented with intermediate-high or high-risk features. 

Garmezy highlighted the “clear separation of the curves” in disease-free survival (DFS), with an HR of 0.68, and a compelling 5% difference in long-term overall survival, signifying a benefit for “about 1 in 20 patients”. Despite about 20% of patients discontinuing treatment due to toxicity, the overall safety profile of pembrolizumab was considered well-tolerated, with no statistically significant difference in quality of life compared with placebo.

Burke provided the panel with his perspective on evaluating such trials. He emphasized the importance of scrutinizing study design flaws, even in “randomized, double-blind, placebo-controlled, phase 3 clinical trials,” which are often seen as the “epitome of great science”. Key questions for consideration include the appropriateness of the control arm (placebo in KEYNOTE-564 was deemed appropriate), the validity of surrogate end points like DFS, and the presence of “informative censoring”—a form of bias that can skew results. Burke noted that informative censoring can occur if patients drop out of a trial due to disappointment with their randomized arm or due to drug toxicity, which can make the treatment arm’s progression-free survival look better than it truly is.

The discussion also touched upon the consistency of KEYNOTE-564’s findings with other trials. Garmezy noted that while pembrolizumab showed positive results, other adjuvant studies involving atezolizumab (Tecentriq), nivolumab (Opdivo), and nivolumab plus ipilimumab (Yervoy) had no significant difference, potentially due to differences in drug type or duration of therapy (6 vs 12 months). Shah affirmed that despite these nuances, the overall survival benefit seen in KEYNOTE-564 justifies the use of adjuvant pembrolizumab for eligible patients, emphasizing adherence to the exact trial criteria.

Beyond kidney cancer, the podcast previewed discussions on the phase 3 NIAGARA trial (NCT03732677) for perioperative bladder cancer and the phase 3 TALAPRO-2 trial (NCT03395197) for first-line metastatic castrate-resistant prostate cancer (mCRPC). Bupathi highlighted the ongoing debate within the Pathways Committees regarding the integration of new data vs established practices, particularly concerning the timeline for new drugs to be incorporated into pathways. Burke clarified that while Pathways guides value-driven decisions, physicians retain the autonomy to prescribe off-pathway regimens, though financial implications might arise. The episode concluded with a look ahead to more data releases, underscoring the dynamic nature of oncology practice and the continuous evaluation of therapies for optimal patient care.

Reference

Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390(15):1359-1371. doi:10.1056/NEJMoa2312695