Dr Tan on the Ongoing Investigation of Adaptive Treatment Intensification Strategies in RCC

"We don’t know when we’re going to reach the primary OS end point [of PDIGREE]. [If and when] we hit that end point, we’re going to learn a lot more about whether this adaptive approach is appropriate. [We’ll also identify whether] we should intensify with IO/TKI therapy after ipilimumab/nivolumab and whether this is feasible.

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 next steps for the investigation of adaptive immunotherapy approaches in previously untreated metastatic renal cell carcinoma (RCC) in the phase 3 PDIGREE/Alliance A031704 trial (NCT03793166).

The ongoing phase 3 PDIGREE trial is evaluating an adaptive approach to treatment intensification in metastatic RCC. This strategy involves escalating therapy with nivolumab (Opdivo) plus cabozantinib (Cabometyx) in subsequent lines of treatment, with the primary goal of improving patient outcomes. The patient population in PDIGREE is distinct from that in the phase 3 CheckMate 214 study (NCT02231749), even though the inclusion and exclusion criteria were relatively similar. Notably, almost half of the participating sites (48.6%) were community-based, which likely contributed to a more varied patient cohort. Regarding safety, the incidence of grade 5 adverse effects, including deaths due to disease progression, similar to those seen in the CheckMate 214 study.

A critical aspect for future understanding revolves around reaching the primary overall survival (OS) end point, Tan asserted. Once this end point is achieved, a significant amount will be learned about the appropriateness and feasibility of this adaptive approach, particularly whether intensifying with immune-oncology (IO) and TKI therapy after initial ipilimumab (Yervoy)/nivolumab is a viable strategy, he explained. Tan acknowledged biases from other trials, such as the phase 3 TiNivo-2 (NCT04987203) and CONTACT-03 (NCT04338269) trials, which suggest against continuing IO/TKI therapy after IO, but emphasized that PDIGREE's adaptive strategy will provide unique insights.

Looking ahead, the trial is also focusing on the identification of new biomarkers, with specimen collection occurring throughout the protocol, Tan explained. Exciting biomarkers under investigation include KIM-1, circulating tumor DNA, and various RNA signatures. These future findings are expected to offer a deeper understanding of patient responses and guide personalized treatment decisions, he concluded.