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Alan Tan, MD, discusses the clinical significance and next steps for evaluating the relative safety of IO vs IO/TKI regimens in ccRCC.
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"We've come a long way with all of these IO combinations. It's now about gaining experience with the combinations and selecting which patients are more appropriate [candidates] for IO/IO vs more appropriate to try to rescue from clinical deterioration or primary progressive disease with an IO/TKI regimen."
Alan Tan, MD, an associate professor of medicine in the Division of Hematology Oncology at Vanderbilt University Medical Center and genitourinary oncology and melanoma specialist at Vanderbilt-Ingram Cancer Center, discussed the clinical significance of early findings from step 1 of an analysis of the phase 3 PDIGREE trial (Alliance A031704; NCT03793166), as well as next steps for evaluating the relative safety profiles of immuno-oncology (IO) vs IO/TKI regimens, before choosing ipilimumab (Yervoy) plus nivolumab (Opdivo) as treatment for patients with metastatic clear cell renal cell carcinoma (ccRCC).
Early data from step 1 of the analysis were presented at the 2025 ASCO Annual Meeting. The interim analysis included 1,111 patients treated across over 500 academic sites in the United States. PDIGREE is an adaptive trial designed to evaluate the optimal sequencing of immunotherapy and targeted therapy in patients with previously untreated metastatic ccRCC, using overall survival (OS) as the primary end point.
The step 1 data reflected the safety and tolerability of dual immune checkpoint blockade in a real-world multicenter setting. Grade 3 or 4 treatment-related adverse effects were consistent with the known toxicity profile of ipilimumab and nivolumab, including gastrointestinal events, hepatic transaminase elevation, dermatologic reactions, and endocrinopathies. Importantly, this interim analysis does not speak to the primary OS outcome; the step 1 data release was reviewed and approved by the Alliance Data and Safety Monitoring Board.
Tan emphasized that these findings underscore the importance of patient selection for dual immunotherapy (IO/IO) vs immunotherapy plus tyrosine kinase inhibitor (IO/TKI) combinations. While IO/IO regimens may offer long-term benefit for some patients, others may require the disease control afforded by TKIs to mitigate clinical deterioration or overcome primary resistance to checkpoint blockade. As clinical experience with these regimens expands, appropriate upfront selection remains a critical challenge, he stated.
The trial’s primary endpoint—3-year OS—has not yet been reached. Once mature, these data are expected to provide key insights into the value of an adaptive approach based on initial response to ipilimumab/nivolumab, particularly whether escalation to IO/TKI in nonresponders is effective and feasible, Tan explained. He noted the relevance of ongoing questions raised by prior trials in ccRCC, which have prompted debate about continued IO strategies beyond progression.
In the longer term, translational analyses from PDIGREE are expected to inform biomarker-driven treatment selection. The trial includes serial biospecimen collection for exploratory analyses of candidate biomarkers such as KIM-1, circulating tumor DNA, and RNA-based immune signatures, which may guide future personalized approaches in metastatic RCC, Tan concluded.
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