44Overview of tivozanib (tivo) safety in phase 3 clinical trials in patients with metastatic renal cell carcinoma (mRCC)

Abstract Background Tivo is a potent and highly selective VEGFR inhibitor designed to optimize VEGF blockade and minimize off-target toxicities. In TiNivo-2, patients with mRCC who had previous exposure to ICI, were randomized to receive study treatment as 2 L or 3 L with Tivo alone at 1.34 mg, or at 0.89 mg in combination with the ICI nivolumab (nivo).[1] The addition of nivo to tivo in second line (2 L) or third-line treatment (3 L) did not improve outcomes, and tivo monotherapy showed activity as a 2 L treatment in the post ICI setting. In TIVO-3, randomized patients had at least two previous systemic treatments and received tivo or sorafenib. We carried out a safety review of tivozanib monotherapy in these 2 randomized trials in the context of populations that had been previously exposed to VEGFR-TKI and ICI treatment. Methods The safety profile of tivo monotherapy was evaluated in these two phase 3 trial cohorts that consisted of the tivo monotherapy arms of TiNivo-2 (N = 171), and TIVO-3 (N = 173).[2] Results Patient baseline characteristics of the two tivo monotherapy cohorts showed some differences, most notably in the distribution of previous exposure to VEGFR target therapy and ICIs: in TIVO-3, exposure to two prior VEGFR-TKI was 45%, to prior ICI plus VEGFR-TKI was 27%, and to a prior VEGFR-TKI plus other agent was 28%. Whereas inTiNivo-2, exposure to prior ICI was 100% (71% as the most recent line of therapy), while exposure to VEGFR-TKI was: none 31%, one 56% and two 13%. Additionally, 94% of TIVO-3 participants were white, compared with 62% of those in TiNivo-2. The incidence of grade 3-4 TEAEs and serious AEs was lower in TiNivo-2, however there was consistency in the incidence of any cause TEAEs, as well as those leading to death or treatment modifications in both cohorts (Table 1). For TEAEs ≥Grade 3, hypertension was the most common, occurring in approximately 20% of patients in each cohort; while the incidence of all other TEAEs ≥Grade 3 was lower, they also occurred at similar rates in each cohort (Table 1). Conclusions Here, results show that tivo has a manageable safety profile across phase 3 trials. The better tolerability of tivo in the TiNivo-2 study vs TIVO-3 is driven in part by more patients enrolled in the earlier lines of treatment (2 L).1. Choueiri et al. Lancet 20242. Rini et al. Lancet Oncol 2020