A Phase 1b/2 Study of Talazoparib and Axitinib in Patients with Advanced Clear-cell Renal Cell Carcinoma.

Abstract

Inactivation of the VHL gene leads to HIF accumulation, angiogenesis, and genomic instability. In this phase 1b/2 study, we assessed the safety and antitumor activity of axitinib combined with talazoparib in treatment-refractory clear-cell renal cell carcinoma (ccRCC). Patients received escalating doses of talazoparib with a fixed standard dose of axitinib in a 3 + 3 design. This was followed by a dose expansion phase in a separate cohort. The primary endpoints were determination of the recommended phase 2 dose (RP2D) and the objective response rate. From 2020 to 2023, 23 patients with ccRCC were enrolled: 15 in the dose escalation cohort and eight in the dose expansion cohort. The RP2D was identified as talazoparib 1 mg daily with axitinib 5 mg twice daily. At the RP2D, 13/14 patients discontinued treatment because of disease progression. Median progression-free survival was 6.1 mo (95% confidence interval 3.5-8.4). Thirteen patients (56%) experienced at least one grade 3+ treatment-emergent adverse event (AE), while nine (39%) experienced at least one treatment-related grade ≥3 AE, of which diarrhea, nausea, and anemia were the most common. This is the first report on a VEGFR-targeted tyrosine kinase inhibitor combined with a PARP inhibitor for ccRCC. While our results demonstrate the safety of this strategy, the combination did not meet a predefined efficacy threshold for continued evaluation. This trial is registered on Clinicaltrials.gov as NCT04337970.