A phase I/II study of talazoparib and axitinib in patients with advanced clear cell renal cell carcinoma.
Authors: Kotecha Ritesh R. , Doshi Sahil D , Knezevic Andrea , Jacobi Rachel , Aggen David H , McHugh Deaglan Joseph , Shah Neil J. , Carlo Marie Isabel , Keegan Niamh M. , Gayadin Yogini , Chaim Joshua , Feldman Darren R. , Motzer Robert J. , Voss Martin H 
Published: July 2024

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Background: Targeting the VEGF pathway is a backbone therapeutic for patients with advanced clear cell renal cell carcinoma (ccRCC). Tumor and tissue hypoxia may also lead to DNA repair suppression and PARPs are key regulators of DNA damage and genomic maintenance which interact with HIF proteins. Pairing a potent VEGFR TKI with a selective PARP inhibitor (PARPi) may lead to improved outcomes in ccRCC patients. Methods: This was a phase I/II, investigator-initiated, single-center, open-label study (NCT04337970) of talazoparib plus axitinib in previously treated ccRCC patients. In the phase Ib dose escalation, patients must have been previously treated with a PD-1/PD-L1 inhibitor with no maximum lines of prior therapy, and those in dose expansion were required to have prior treatment with a PD-1/PD-L1 inhibitor and prior VEGFR TKI, with a maximum of 2 prior lines of therapy. Patients received escalating doses of talazoparib (0.5 mg, 0.75 mg and 1 mg daily) with axitinib (5 mg twice daily) in a 3+3 design, with primary endpoint of safety and tolerability. After establishing the recommended phase II dose (RP2D), a dose expansion cohort enrolled patients in a Simon two-stage design with a primary endpoint of objective response (ORR), and secondary endpoints including progression-free survival (PFS). Results: From 2020-2023, 23 ccRCC patients were enrolled and treated on study. In the dose escalation, 15 patients enrolled across all 3 dose levels and there were 2 observed DLTS (1 in dose levels 2 and 3). Both DLTs was due to a lack of minimum exposure to study drugs during cycle 1 due to treatment-related toxicities. The maximum tolerated dose and RP2D established was 1 mg talazoparib daily with axitinib 5 mg twice daily. In the phase II dose expansion portion, an additional 9 patients were enrolled to evaluate preliminary efficacy. In total, 13/14 patients treated at the RP2D discontinued therapy due to progressive disease. The objective response rate (ORR) was 7% (90% CI 0, 30), with 1 patient achieving a partial response and 12 patients achieving stable disease (86%). With a median follow-up of 13.2 months (R: 6.6 -29), the median PFS was 6.1 months (95% CI 3.5, 8.4) and median overall survival (OS) was 27 months (95% CI 12- NE). Across the study, 13 (56%) patients had at least one treatment-emergent AE of grade 3+, and 9 (39%) patients had at least one treatment-related AE of grade 3+. Most common grade 3+ AEs included diarrhea, nausea, and anemia. Conclusions: This is the first clinical study evaluating combination PARPi and VEGFR TKI in metastatic ccRCC patients. This study established the RP2D and MTD of combination talazoparib and axitinib and demonstrated a tolerable safety profile across all dose escalation cohorts. The study did not meet the pre-defined efficacy threshold for further enrollment per Simon stage two design. Exploratory efforts to evaluate this treatment approach with tissue biomarker data remain ongoing. Clinical trial information: NCT04337970 .