The phase 3 TiNivo-2 trial, presented at the 2024 ESMO Congress, demonstrated that tivozanib monotherapy outperformed the combination of tivozanib and nivolumab in patients with metastatic renal cell carcinoma (RCC) who had progressed on or after prior immune checkpoint inhibitor (ICI) therapy. The study challenges the practice of ICI rechallenge in this patient population, suggesting that tivozanib monotherapy at 1.34 mg is a more effective second-line treatment option.
The TiNivo-2 study (NCT04987203) was a multicenter, randomized, open-label, phase 3 trial involving 343 patients with advanced RCC across 16 countries. Patients had experienced disease progression during or after one to two prior lines of therapy, including at least one ICI. Participants were randomized 1:1 to receive either tivozanib monotherapy (1.34 mg daily) or a combination of tivozanib (0.89 mg daily) plus nivolumab (480 mg every 4 weeks).
The primary endpoint was progression-free survival (PFS) as assessed by independent radiology review. Secondary endpoints included overall survival (OS), objective response rate (ORR), duration of response (DOR), and safety/tolerability.
PFS Results
The median PFS was 5.7 months (95% CI, 4.0-7.4) in the tivozanib plus nivolumab arm and 7.4 months (95% CI, 5.6-9.2) in the tivozanib monotherapy arm (HR, 1.10; 95% CI, 0.84-1.43; P = .49). Subgroup analyses indicated no benefit from the addition of nivolumab, regardless of whether patients received an ICI as their most recent prior therapy.
Specifically, in patients who received ICI as their most recent therapy, median PFS was 7.4 months with the combination versus 9.2 months with tivozanib monotherapy (HR 1.10, 95% CI 0.80-1.52, P =0.56). For those who received non-ICIs as the most recent therapy, median PFS was 3.7 months in each group (HR 0.95, 95% CI 0.61-1.50, P =0.85).
Overall Survival and Response Rates
Overall survival (OS) data were immature at the time of data cutoff, with 32% of events having occurred. The median OS was 17.7 months (95% CI, 15.1-NR) in the combination arm compared with 22.1 months (95% CI, 15.2-NR) in the tivozanib monotherapy arm (HR, 1.00; 95% CI, 0.68-1.46; P = .9868).
The objective response rate (ORR) was similar between the two arms, with 19.3% (95% CI, 13.7%-26.0%) in the doublet arm and 19.8% (95% CI, 14.1%-26.5%) in the singlet arm. The median duration of response (DOR) was 15.77 months (95% CI, 5.65-NR) with the doublet compared with 9.66 months (95% CI, 3.71-NR) with monotherapy.
Safety Profile
Adverse events (AEs) leading to death occurred in 7 patients in the doublet arm and 5 patients in the tivozanib monotherapy arm. Grade 2 or greater AEs were reported in 61% of patients in the doublet arm and 60% in the singlet arm. Serious AEs occurred in 32% and 37% of patients, respectively. Treatment-emergent AEs leading to discontinuation were observed in 16% and 19% of patients, respectively. The most common AEs were hypertension, fatigue, diarrhea, and nausea.
Implications for Clinical Practice
Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, emphasized that the study results suggest that ICI rechallenge should be generally discouraged in patients with advanced RCC. He also noted that the reduced dose of tivozanib (0.89 mg) in the combination arm, agreed upon with regulatory authorities due to potential hypertension risks, may have impacted the efficacy of the combination therapy.
These findings support the use of tivozanib monotherapy at 1.34 mg as a second-line therapy option for patients with metastatic RCC following progression on prior ICI therapy. Further research is needed to determine the optimal sequencing of therapies in this setting and to explore strategies for improving outcomes after ICI failure.
