Integrated efficacy and safety exposure response (ER) analysis of tivozanib (TIVO) for the treatment of renal cell cancer (RCC).

461 Background: TIVO is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) approved in the US for treatment of patients with RCC following ≥2 prior systemic therapies. The approved TIVO monotherapy starting dose is 1.34 mg once daily on days (D) 1-21 Q28D, with allowable dose modifications to manage adverse events. In the randomized TiNivo-2 trial, the addition of NIVO 480 mg to TIVO 0.89 mg D1-21 Q28D (lower dose of TIVO was studied given assumed risk of hypertension [HTN]) did not improve outcomes compared with TIVO 1.34 mg D1-21 Q28D. There was a trend toward worse progression-free survival (PFS) in the combination arm. Methods: Using a predeveloped population pharmacokinetic (PK) model, existing ER models based on Tivo-1 and Tivo-3 studies were augmented to characterize the relationship between TIVO at clinically relevant exposures and central reviewer–based PFS, tumor size (TS) reduction, and safety endpoints. TiNivo-2 trial results were integrated to update the PK and ER models for PFS (Cox proportional hazard), TS (sum of longest diameters longitudinal model), and HTN (logistic regression) and to simulate the ER-based risk/benefit profile of TIVO. Results: The visual predictive check of the PK model on TiNivo-2 PK data confirmed that the dose-proportional TIVO PK is unaffected by concurrent NIVO. The PFS range of 5.6-9.7 months and TS reduction models, with a range of −7.02% to −23.8%, showed a significant relationship with TIVO exposure (Table). Concurrent NIVO did not add discernible benefit to TIVO at the dose of 0.89 mg. An ER modeling analysis between maximum concentration and HTN showed that the predicted HTN incidence was similar between TIVO 1.34 mg and TIVO 0.89 mg (41.3% vs 38.8% for any-grade HTN; 23.8% vs 21.5% for grade ≥3 HTN). An effect term for NIVO in the ER model for HTN was nonsignificant. Conclusions: The efficacy ER models predicted that TIVO 1.34 mg would provide greater antitumor activity than the 0.89-mg dose, while the predicted HTN incidence (any grade and grade ≥3) was comparable at the 0.89- and 1.34-mg doses. The TIVO monotherapy dose selection of 1.34 mg is important, based on the ER analysis and its safety profile. The results from the TiNivo-2 data set further confirmed that re-challenge with immunotherapy does not add benefit and optimal dosing of TKI provides the highest clinical benefit. Clinical trial information: NCT04987203 . Efficacy endpoint TIVO average concentration, ng/mL n Observed value,combined studies (range) PFS 13.9-38.4 192 5.6 months PFS 38.4-47.9 191 7.3 months PFS 47.9-62.0 191 9.1 months PFS 62.0-177 191 9.7 months CFB TS 13.9-38.4 176 −7.02% (−16% to 1.93%) CFB TS 38.4-47.9 173 −11.7% (−21.3% to −2.05%) CFB TS 47.9-62.0 185 −17.3% (−26.4% to −8.27%) CFB TS 62.0-177 183 −23.8% (−33.5% to −14.1%) CFB, change from baseline.

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