Gemcitabine, Cisplatin, Plus Nivolumab in Patients With Muscle-invasive Bladder Cancer With Selective Bladder Sparing (GU-16-257)

Icahn School of Medicine at Mount Sinai/Hoosier Cancer Research Network
Study Design: 
This is a single arm, phase II study in which cisplatin-eligible patients with cT2-T4aN0M0 urothelial cancer are treated with TURBT followed by four cycles of gemcitabine/cisplatin and nivolumab and patients reassessed with clinical imaging, cytology, cystoscopy, and biopsies and if patients achieved a clinical complete response rate, then offered a four-month adjuvant period of nivolumab instead of radical cystectomy. Clinical complete response rate is defined as normal imaging, normal cytology, and no tumor or low grade Ta urothelial cancer on biopsy.
This trial explores the impact of primary chemo-immunotherapy as a sole-treatment for MIBC without the use of radiotherapy. Therefore, this trial is evaluating the use of systemic therapy for localized disease without the use of definitive local therapy.
The primary endpoints are clinical complete response rate (cT0 or cTa) and the ability of clinical complete response to predict pathologic complete response (<pT1) in patients undergoing cystectomy and 2 year metastasis-free survival (MFS) in patients pursuing surveillance. Secondary endpoints include the impact of baseline genomic alterations from TURBT (ERCC2, FANCC, RB1, ATM, and tumor mutation burden) on performance of clinical complete response for predicting MFS.
TURBT alone for MIBC has been shown in some series to show excellent response rates and in this study the rates of clinical complete response are lower than historical TURBT series and certainly lower than in studies with definitive local therapy using chemoradiation or radical cystectomy. Furthermore, genomic alterations known to correlate with response to chemoimmunotherapy may not function as biomarkers as they may not correlate with clinical response in all patients.
Overall, 76 patients were enrolled and 64 (84%) completed imaging. Thirty-one (48%) of the 64 patients achieved a complete response and 30 of the 31 patients chose adjuvant immunotherapy instead of radical cystectomy. However, 8 of the 31 patients developed a local recurrence and six of them underwent cystectomy and only one patient had >T2N0 disease. Of note, among the patients without complete response who underwent immediate cystectomy (n=28), 32% had ypTanyN+ disease. Finally, among genomic alterations well described to correlate with response to chemoimmunotherapy, only TMB ? 10 mutations/Mb or mutant ERCC2 were associated with a clinical complete response.