Introduction: Sequential intravesical Gemcitabine and Docetaxel (Gem/Doce) has shown over 50% 2-year high-grade (HG) recurrence free survival in patients with BCG-unresponsive non-muscle invasive bladder cancer. Subsequent recurrences may be due to overexpression of p-glycoprotein drug efflux pumps induced by prolonged Doce exposure. Cabazitaxel (Cabaz) has reduced efflux pump affinity and retains efficacy following Doce resistance in prostate cancer. We report outcomes of patients treated with sequential endoluminal Gem/Cabaz and intravenous Pembrolizumab (GCP) for patients with high-risk Doce-unresponsive NMIUC who refused or were poor candidates for cystectomy.
Methods: This is a retrospective analysis of 14 patients (18 treated units; 14 lower tract, 4 upper tract) who were treated with GCP from September 2020 to July 2021 with at least 3-month evaluation. Patients received 6 weekly endoluminal 50 cc instillations of sequential 1g Gem (90 minutes) and 5mg Doce (90 minutes) with concomitant intravenous Pembro (200/400mg q3/6weeks respectively). Maintenance treatment was administered every 2-4 weeks until disease progression or unacceptable toxicities. The primary outcome was complete response (CR) at 3 month evaluation, defined as no disease on cystoscopy, bladder/upper tract wash cytology or for-cause biopsies. We also evaluated tolerability and adverse events.
Results: Median follow-up was 6 months. Prior treatments included BCG in 93%, Gem/Doce in 100%, and additional Doce containing regimens in 79% of patients. Considering treated units, 79% presented with positive cytology or biopsy proven CIS, 7% with HG Ta and 14% with HG T1 disease. One patient did not start Pembro due to fatigue. At first evaluation, 12/14 (86%) patients and 16/18 (89%) treated units had CR. In those with at least 6 months of post-treatment evaluation, 7/10 (70%) patients and 9/12 (75%) treated units remained disease-free. Two patients recurred with positive cytology or CIS at 5 and 6 months, respectively. One patient was found to have muscle invasive bladder cancer at 3-months and underwent cystectomy (pTisN2). Three patients developed cystitis requiring dose modification of endoluminal agents and 2 patients stopped Pembro due to hepatitis and arthralgias.
Conclusions: GCP shows promising early efficacy in heavily pretreated patients with high-risk NMIUC. The ~33% of patients requiring dosing adjustments may reflect determination of optimal dosing. Prospective evaluation of this regimen is underway.
Source of Funding: This work was supported by the John & Carol Walter Family Foundation and the Carver College of Medicine.