Dr Tan on the Rationale for Evaluating an Adaptive Immunotherapy Strategy in Previously Untreated RCC

"The rationale [for PDIGREE] was having an IO doublet as first-line therapy. [We wanted to know if] there was an adaptive strategy where we can de-escalate patients who already had complete responses and intensify [treatment for] patients who have a partial response."

Alan Tan, MD, an associate professor of medicine in the Division of Hematology Oncology in the Department of Medicine at Vanderbilt University Medical Center, discusses the rationale for evaluating an adaptive immunotherapy approach for patients with previously untreated metastatic renal cell carcinoma (RCC) in the phase 3 PDIGREE/Alliance A031704 trial (NCT03793166)

PDIGREE was conceptualized over a decade ago, predating the current standard of care involving immune checkpoint inhibitor (IO) combinations established in 2018, Tan began. The trial explores an adaptive approach involving the intensification of treatment with nivolumab (Opdivo) plus cabozantinib (Cabometyx) in subsequent [lines of] therapy, and whether this could improve outcomes. 

All patients with International Metastatic RCC Database Consortium intermediate- or poor-risk disease received induction nivolumab plus ipilimumab. At 12 weeks, treatment was adapted based on iRECIST responses: patients with complete responses (CRs) continued nivolumab alone; those with partial responses (PRs) or stable disease were randomized to either continued nivolumab or intensification with nivolumab plus cabozantinib.

From May 2019 to May 2024, 1,111 patients were enrolled. Although the primary end point of overall survival has not yet been met, early analyses from step 1 confirmed that immunotherapy doublets remain the standard of care in this setting. According to Tan, PDIGREE may help refine sequencing strategies and guide therapeutic intensification or de-escalation before radiographic progression, potentially enabling a more individualized approach to managing metastatic RCC.