TiNivo-2: Tivozanib-Nivolumab Combination Fails to Improve PFS in Advanced RCC Compared to Tivozanib Monotherapy

The phase 3 TiNivo-2 trial evaluated the combination of tivozanib and nivolumab versus tivozanib monotherapy in patients with advanced clear-cell renal cell carcinoma (RCC) who had progressed following one or two prior therapies, including an immune checkpoint inhibitor (ICI).

For the study, Toni K. Choueiri, MD, of Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues aimed to determine whether adding the PD-1 inhibitor nivolumab to tivozanib, a selective vascular endothelial growth factor receptor tyrosine kinase inhibitor, could improve progression-free survival (PFS) in this challenging patient population.

Patients with advanced RCC (n=343) were randomized to receive either tivozanib (0.89 mg once daily) plus nivolumab or tivozanib monotherapy (1.34 mg once daily). The primary endpoint was PFS as assessed by independent radiology review (IRR), with secondary endpoints including overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), and safety. The trial aimed for ≥80% power to detect a 50% improvement in PFS, with a targeted sample size of 343 patients and 220 events.

Baseline characteristics were balanced between the two groups. The study did not meet its primary endpoint, as the combination of tivozanib and nivolumab failed to show a statistically significant improvement in PFS compared to tivozanib monotherapy. The median IRR-assessed PFS was 5.7 months for the tivozanib-nivolumab combination versus 7.4 months for tivozanib alone (hazard ratio 1.10; 95% CI, 0.82-1.43).

For patients who had received ICI therapy immediately prior (n=244), the median PFS was 7.4 months for the combination and 9.2 months for tivozanib monotherapy. In patients whose most recent therapy was not ICI-based, both groups had a median PFS of 3.7 months.

Median OS was 17.7 months for the tivozanib-nivolumab group versus 22.1 months for the monotherapy group. The best ORR was nearly identical between the two groups: 19.3% in the combination arm and 19.8% in the monotherapy arm.

The safety profile was consistent across both treatment arms. Grade 3 or higher adverse events (AEs) occurred in 60% of patients, with the most common AE being hypertension, reported in 22% of patients in both arms. Deaths related to treatment occurred in 7 (4.2%) patients in the combination arm and 5 (2.9%) patients in the monotherapy arm, with one treatment-related death in the tivozanib arm.

The TiNivo-2 trial concluded that the combination of tivozanib and nivolumab did not improve clinical outcomes compared to tivozanib monotherapy for advanced RCC patients previously treated with ICI therapy. This suggests that sequential ICI combinations may not offer additional benefit in this setting, and tivozanib monotherapy at 1.34 mg daily remains a viable second-line option following ICI progression.