TiNivo-2 Data Underscore Challenges With ICI Retreatment in Advanced RCC

Toni Choueiri, MD

Data from the phase 3 phase 3 TiNivo-2 trial (NCT04987203) added to the body of evidence discouraging immune checkpoint inhibitor (ICI) rechallenge in patients with advanced renal cell carcinoma (RCC) who experienced disease progression on or after a prior ICI-containing regimen, according to Toni Choueiri, MD.

Findings presented at the 2024 ESMO Congress showed that the combination of tivozanib (Fotivda) and nivolumab (Opdivo) did not improve clinical outcomes vs tivozanib monotherapy.

There was not a statistically significant difference in progression-free survival (PFS) between the combination and monotherapy arms (stratified HR, 1.10; 95% CI, 0.84-1.43; P = .49). Specifically, data from the primary analysis of centrally reviewed PFS in the intent-to-treat population determined that the median PFS in the combination arm was 5.7 months (95% CI, 4.0-7.4) vs 7.4 months in the monotherapy arm (95% CI, 5.6-9.2). PFS was the primary end point of the phase 3 study. Patients were randomly assigned 1:1 to the tivozanib plus nivolumab arm (n = 171) or tivozanib monotherapy arm (n = 172).

In an interview with OncLive^®, Choueiri detailed the design of the phase 3 TiNivo-2 trial, findings associated with the combination vs the monotherapy arms, and the determined safety profiles.

Choueiri is director of the Lank Center for Genitourinary Oncology at Dana Farber Cancer Institute, co-leader of the Kidney Cancer Program at Dana-Farber/Harvard Cancer Center, and the Jerome and Nancy Kohlberg Chair and Professor of Medicine at Harvard Medical School in Boston, Massachusetts.

OncLive: What was the design of the phase 3 TiNivo-2 trial?

Choueiri: TheTiNivo-2 trial was a phase 3 study that asked the question of [whether] rechallenge with immunotherapy—[meaning] PD-1 [and] PD-L1 inhibitors—[is feasible] in metastatic RCC. The design included the TKI, tivozanib, in both arms, and nivolumab, a PD-1 inhibitor, [was added in the experimental arm]. [Enrolled] patients should have experienced disease progression on a prior PD-1 inhibitor.

This is a soaring question in the field of kidney cancer and solid tumors in general. We had a [data from the phase 3 CONTACT-03 trial (NCT04338269) reported in 2023] that showed adding atezolizumab (Tecentriq) to a TKI [cabozantinib (Cabometyx)] as a rechallenge does not at all improve clinical outcomes.

However, in TiNivo-2, the difference was that we had a PD-1 inhibitor, and the last therapy was not always an immune checkpoint inhibitor.

What key efficacy findings from TiNivo-2 were reported at the 2024 ESMO Congress?

The study was dead negative. PFS, overall survival, [and objective response rates were similar in both arms, although I would also say that the dose of tivozanib in the combination arm was lower because of earlier studies showing an increased risk of grade 3/4 hypertension.

[TiNivo-2] is the second study of ICI rechallenge, published 1 year apart, showing that rechallenging with an ICI, at least in metastatic RCC, should be discouraged outside some specific situations, such as if [there was] a long duration from a prior ICI—[however], these patients were not included in TiNivo-2.

What was the safety profile for this combination of tivozanib and nivolumab and was there anything clinically relevant?

We didn’t see a [difference] in safety or toxicity between arms. The combination arm had the lower dose of tivozanib, [and in that group] we saw increased [rate] of pruritus, and that's related to nivolumab. Besides that, [we saw] the typical adverse effect [AE] profile of VEGF inhibitors, such as fatigue, diarrhea, and gastrointestinal AEs.

Reference

Choueiri TK, Motzer RJ, Beckermann K, et al. Tivozanib–nivolumab vs tivozanib monotherapy in patients with renal cell carcinoma (RCC) following 1 or 2 prior therapies including an immune checkpoint inhibitor (ICI): results of the phase III TiNivo-2 study. Ann Oncol. 2024;35(suppl 1): S1261-S1262. doi:10.1016/j.annonc.2024.08.2316