Dr Hall on the Feasibility of ICI Continuation and Rechallenge Strategies in Second-Line Metastatic RCC

There is nuance in certain clinical scenarios, but for most patients currently treated with first-line immunotherapy-based regimens, continuing the same immune checkpoint inhibitor beyond progression does not appear to provide additional benefit."

Evan T. Hall, MD, MPhil, an oncologist at the University of Washington and Fred Hutchinson Cancer Center, provided insight into the clinical rationale and evolving evidence surrounding immune checkpoint inhibitor (ICI) continuation and rechallenge strategies in the later-line treatment of metastatic renal cell carcinoma (RCC).

In contemporary clinical practice, most patients with metastatic RCC receive frontline combination regimens containing PD-1 or PD-L1 inhibitors, either in the form of two immuno-oncology agents or an ICI combined with the TKI. As a result, determining the value of ICI continuation beyond progression—or reinitiating therapy after prior response—has become a central question in the post–first-line setting. Hall outlined data from two pivotal randomized phase 3 trials—CONTACT-03 (NCT04338269) and TiNivo-2 (NCT04987203)—that evaluated ICI-based approaches following progression on prior immunotherapy.

CONTACT-03 examined the addition of atezolizumab (Tecentriq) to cabozantinib (Cabometyx) in patients with advanced RCC previously treated with ICIs. The trial did not meet its primary end point of progression-free survival (PFS) improvement, and no benefit in overall survival (OS) was observed. Similarly, the TiNivo-2 trial assessed tivozanib with or without nivolumab in a similar patient population, again showing no incremental advantage with the addition of nivolumab. These findings, Hall explained, support the conclusion that routine continuation an ICI agent after disease progression does not confer meaningful clinical benefit.

However, Hall emphasized that certain patient subgroups may warrant more individualized consideration. For example, patients who previously experienced a durable response to ICI and have since relapsed after an extended treatment-free interval may still derive benefit from ICI rechallenge. Importantly, these scenarios were not explicitly stratified in either CONTACT-03 or TiNivo-2, leaving a gap in the data to guide optimal therapy sequencing in such settings.

Additionally, Hall discussed the limited but notable potential for alternative ICI approaches, including the use of ipilimumab (Yervoy), a CTLA-4–targeting agent, in patients who have not received it previously. Although not formally supported by randomized studies in this context, anecdotal evidence suggests clinical benefit in select cases, particularly those with immunogenic tumor features, he concluded.