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Purpose: We investigated the combination of tivantinib, a c-MET tyrosine kinase inhibitor (TKI), and bevacizumab, an anti-VEGF-A antibody. Methods: Patients with advanced solid tumors received bevacizumab (10 mg/kg intravenously every 2 weeks) and escalating doses of tivantinib (120–360 mg orally twice daily). In addition to safety and preliminary efficacy, we evaluated pharmacokinetics of tivantinib and its metabolites, as well as pharmacodynamic biomarkers in peripheral blood and skin. Results: Eleven patients received the combination treatment, which was generally well tolerated. The main dose-limiting toxicity was grade 3 hypertension, which was observed in four patients. Other toxicities included lymphopenia and electrolyte disturbances. No exposure-toxicity relationship was observed for tivantinib or metabolites. No clinical responses were observed. Mean levels of the serum cytokine bFGF increased (p = 0.008) after the bevacizumab-only lead-in and decreased back to baseline (p = 0.047) after addition of tivantinib. Tivantinib reduced levels of both phospho-MET (7/11 patients) and tubulin (4/11 patients) in skin. Conclusions: The combination of tivantinib and bevacizumab produced toxicities that were largely consistent with the safety profiles of the individual drugs. The study was terminated prior to establishment of the recommended phase II dose (RP2D) due to concerns regarding the mechanism of tivantinib, as well as lack of clinical efficacy seen in this and other studies. Tivantinib reversed the upregulation of bFGF caused by bevacizumab, which has been considered a potential mechanism of resistance to therapies targeting the VEGF pathway. The findings from this study suggest that the mechanism of action of tivantinib in humans may involve inhibition of both c-MET and tubulin expression. Trial registration: NCT01749384 (First posted 12/13/2012). [ABSTRACT FROM AUTHOR]

On December 15, 2023, the FDA granted traditional approval to enfortumab vedotin-ejfv plus pembrolizumab (EV + Pembro) for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Substantial evidence of effectiveness was obtained from EV-302/KEYNOTE-A39 (NCT04223856), an open-label, randomized trial evaluating EV + Pembro versus cisplatin or carboplatin plus gemcitabine (Plat + Gem) in patients with previously untreated la/mUC. A total of 886 patients were randomized (1:1) to receive EV 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity plus Pembro 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles or Plat + Gem for up to 6 cycles. Dual primary endpoints were progression-free survival determined by blinded independent central review and overall survival. The median progression-free survival was 12.5 months [95% confidence interval (CI), 10.4-16.6] in the EV + Pembro arm and 6.3 months (95% CI, 6.2-6.5) in the Plat + Gem arm [HR, 0.450 (95% CI, 0.377-0.538); P value < 0.0001]. The median overall survival was 31.5 months (95% CI, 25.4-not estimable) in the EV + Pembro arm and 16.1 months (95% CI, 13.9-18.3) in the Plat + Gem arm [HR, 0.468 (95% CI, 0.376-0.582); P value < 0.0001]. The safety profile of EV + Pembro was similar to that observed in EV-103/KEYNOTE-869 in cisplatin-ineligible patients with la/mUC. This article summarizes the data and the FDA thought process supporting traditional approval of EV + Pembro, as well as additional exploratory analyses conducted by the FDA., (©2024 American Association for Cancer Research.)