Photo Credit: Nemes Laszlo

The clinical outcomes of tivozanib/nivolumab versus tivozanib monotherapy in patients with metastatic advanced renal cell carcinoma (RCC) who had progressed after one to two lines of therapy, including an immune checkpoint inhibitor (ICI), suggest that rechallenging patients with ICIs may not be beneficial in advanced RCC. Furthermore, tivozanib monotherapy shows promise as an effective option in the post-ICI setting.

The phase 3 TiNivo-2 study (NCT04987203) is a multicenter, randomized, open-label trial conducted with patients with advanced RCC, who had progressed during or after one-two previous lines of treatment (at least 1 being an ICI). Between November 2021 and June 2023, 343 participants were randomly assigned to receive either tivozanib (0.89 mg/day, orally) with nivolumab (480 mg every 4 weeks, intravenously) or tivozanib monotherapy (1.34 mg/day, orally). Randomization was stratified by prior treatment type (ICI or non-ICI) and risk category based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC). The primary endpoint was progression-free survival (PFS), measured from randomization until disease progression or death, whichever occurred first. Toni Choueiri, MD, from the Dana Farber Cancer Institute at Harvard University, in Boston presented the results, which were simultaneously also published in The Lancet^1,2.

With a median follow-up of 12 months, the median PFS was 5.7 months in the tivozanib/nivolumab arm and 7.4 months in the tivozanib monotherapy arm (HR 1.10; 95% CI 0.84–1.43; P=0.49). In participants whose most recent treatment was an ICI (n=244), the median PFS was 7.4 months for the combination therapy and 9.2 months for monotherapy. In those treated with non-ICI therapies previously, PFS was 3.7 months in both groups. The median overall survival was 17.7 months in the combination therapy group compared with 22.1 months in the tivozanib monotherapy group (HR 1.0). Serious AEs were reported in 32% of the participants in the combination group and 37% in the monotherapy group, with one treatment-related death occurring in the tivozanib group.

These results suggest that rechallenging patients with ICIs may not be beneficial in advanced RCC, because the addition of the PD-1 inhibitor nivolumab to tivozanib did not result in improved clinical outcomes in patients with metastatic RCC whose disease progressed on or after prior ICI treatment. This trial confirms and expands key conclusions from CONTACT-03 and suggests that ICI rechallenge should be generally discouraged regardless of treatment sequence. Nevertheless, Prof. Choueiri concluded that “TiNivo-2 is a negative study, but I strongly believe it’s important. It is practice-changing, and it should make us think twice now… The results support tivozanib monotherapy at 1.34 mg as a second-line therapy option in patients following progression on previous ICI therapy.”

Medical writing support was provided by Dr Rachel Giles.
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