Neoadjuvant sorafenib, gemcitabine, and cisplatin administration preceding cystectomy in patients with muscle-invasive urothelial bladder carcinoma: An open-label, single-arm, single-center, phase 2 study

Outcomes of neoadjuvant chemotherapy in patients with muscle-invasive urothelial bladder carcinoma (MIUBC) should be improved. Sorafenib was combined with gemcitabine and cisplatin chemotherapy (SGC) in an open-label, single-arm, phase 2 trial (NCT01222676).

After transurethral resection of the bladder, T2-T4a N0 patients received four cycles of SGC followed by cystectomy. Sorafenib 400mg q12h daily, continuously, was added to standard GC chemotherapy. In a Simon's 2-stage design, the primary endpoint was the pathologic complete response (pT0), assuming H0: ≤0.20 and H1: ≥0.40, with a type I and type II error of 5% and 10%, respectively.

From April 2011 to June 2016, 46 patients were enrolled. Pathologic T0 response was obtained in 20 patients (43.5%, 95% CI: 28.9-58.9); pT ≤ 1 in 25 (54.3%, 95% CI: 39.0-69.1). After a median follow-up of 35 months, the median progression-free survival was not reached (NR, interquartile range: 23.6-NR), nor was median overall survival (interquartile range: 30.3-NR). Hematologic and extrahematologic grade 3 to 4 adverse events occurred in 45.6% and 26.1% of patients, respectively. In 29 samples from responders (pT ≤ 1) and nonresponders, different distribution of missense mutations involved DNA-repair genes, RAS-RAF pathway genes, chromatin-remodeling genes, and HER-family genes. ERCC1 immunohistochemical expression was associated with pT ≤ 1 response (P = 0.047). The absence of a comparator arm prevented us to quantify sorafenib contribution.

SGC combination was active in MIUBC, and the identified molecular features included alterations that may help personalize treatment in MIUBC with new more potent targeted agents, combined with chemotherapy.

Urologic oncology. 2017 Sep 11 [Epub ahead of print]

Andrea Necchi, Salvatore Lo Vullo, Daniele Raggi, Federica Perrone, Patrizia Giannatempo, Giuseppina Calareso, Elena Togliardi, Nicola Nicolai, Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Maurizio Colecchia, Adele Busico, Marzia Pennati, Nadia Zaffaroni, Luigi Mariani, Roberto Salvioni

Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy. Electronic address: ., Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Pharmacy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy., Department of Experimental Oncology and Molecular Medicine (DOSMM), Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.