Efficacy of second line (2L) treatment with tivozanib (Tivo) as monotherapy or with nivolumab (Nivo) in patients (pts) with metastatic renal cell carcinoma (mRCC) previously treated with an immune checkpoint inhibitor (ICI) combination of ipilimumab (Ipi)/Nivo or vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)/ICI in the phase 3 TiNivo-2 study.

4540 Background: In TiNivo-2, the addition of Nivo to Tivo did not prolong progression-free survival (PFS) relative to Tivo alone (Choueiri, Lancet 2024). To assess study outcomes in the context of contemporary treatment sequencing, a subset of pts treated in the 2L who failed 1L Ipi/Nivo or VEGFR-TKI/ICI therapy was evaluated. Methods: Pts were randomized 1:1 to receive Tivo once daily for 21/28 days at either 1.34mg alone or at 0.89 mg with Nivo at 480 mg by IV on day 1 of each 28-day cycle. We characterized PFS, objective response rate (ORR), and best percentage change from baseline in tumor size in two cohorts consisting of pts who did not previously receive adjuvant therapy and who progressed in 1L on Ipi/Nivo, or VEGFR-TKI/ICI therapy. Results: Among the 153 eligible 2L pts, 70 (46%) previously received Ipi/Nivo and 83 (54%) previously received a VEGFR-TKI/ICI regimen (TKI/ICI): axitinib/pembrolizumab (54.2%), cabozantinib/nivolumab (25.3%), axitinib/avelumab (12.0%), and lenvatinib/pembrolizumab (8.4%). Overall, the median follow-up was 11.6 months. More pts with lung metastasis and age <65 years were in the Tivo arm than in the Tivo+Nivo arm in both cohorts. In the Ipi/Nivo cohort, median PFS was 9.2 months (95% CI, 4.5-NR) with Tivo and 9.3 months (95% CI, 7.3-15.3) with Tivo+Nivo. ORR was 32.4% (95% CI, 18.0%-49.8%) with Tivo and 24.2% (95% CI, 11.1%-42.6%) with Tivo+Nivo. In the TKI/ICI cohort, median PFS was 7.4 months (95% CI, 3.7-9.3) with Tivo and 3.9 months (95% CI, 2.1-5.7) with Tivo+Nivo. ORR was 22.0% (95% CI, 10.6%-37.6%) with Tivo and 9.5% (95% CI, 2.7%-22.6%) with Tivo+Nivo. Target tumor size reduction from baseline was observed in both arms (Table). More pts had target tumor reductions (≥30% or ≥50%) in the Tivo arm than in the Tivo+Nivo arm in both cohorts. Of 7 pts with target tumor reduction of ≥50% from Tivo, 6 (85.7%) and 1 (14.3%) were previously treated with axitinib and cabozantinib, respectively. Conclusions: In this TiNivo-2 subgroup analysis, Tivo monotherapy at 1.34 mg daily showed activity in pts who previously received a contemporary 1L mRCC regimen. At this dose of Tivo, substantial tumor size reduction was observed, both after Ipi/Nivo and VEGFR-TKI/ICI regimens. There appeared to be no benefit with the addition of Nivo to Tivo in this context, akin to the results of the parent trial. Clinical trial information: NCT04987203 . Best percentage change in target tumor size. Best % Change from Baseline Prior Treatment ≥30% Reduction ≥50% Reduction Tivo TKI/ICI 30.5% 19.4% Ipi/Nivo 44.4% 27.8% Tivo+ Nivo TKI/ICI 17.5% 2.5% Ipi/Nivo 33.3% 12.1%

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