SEQUENTIAL ENDOLUMINAL GEMCITABINE AND CABAZITAXEL WITH SYSTEMIC PEMBROLIZUMAB FOR RECURRENT NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF THE UPPER AND LOWER URINARY TRACTS

Ian McElree; Ryan L. Steinberg; Sarah L Mott; Vignesh T. Packiam; Michael A. O'Donnell

doi:10.1016/j.urolonc.2024.01.180

Sequential intravesical gemcitabine and docetaxel (Gem/Doce) has shown over 50% 2-year high-grade (HG) recurrence-free survival (RFS) in patients with BCG-unresponsive non-muscle invasive bladder cancer. Based on mechanism of action in other cancer types, recurrences may be secondary to upregulation of p-glycoprotein drug efflux pumps from prolonged taxane exposure. In addition, occult disease of the prostatic urethra and upper tracts may be less accessible to topical therapies. Cabazitaxel is a taxane with reduced efflux pump affinity and sustained efficacy in the setting of docetaxel resistant prostate cancer. Pembrolizumab (Pembro), an anti PD-1 immunotherapy, was FDA approved for BCG-unresponsive CIS and may have efficacy throughout the urinary tract due to systemic administration. We report outcomes of patients treated with sequential endoluminal Gem/Cabaz and concurrent intravenous pembro (GCP) for patients with high-risk docetaxel unresponsive NMIUC with clinically localized disease who refused or were poor candidates for surgery. We retrospectively reviewed 22 patients (27 treated units; 21 lower tract, and 6 upper tract) treated with GCP at the University of Iowa, Holden Comprehensive Cancer Center, from August 2020 to February 2023. Patients received 6 weekly endoluminal 50 cc instillations of sequential 1 g Gem (90 minutes) and 5 mg Cabaz (90 minutes) with concomitant intravenous Pembro (200/400mg q3/6 weeks, respectively). Maintenance treatment was administered every 3-6 weeks until disease progression or unacceptable toxicities. The primary outcome was RFS defined as no disease on bladder/upper tract wash cytology or for-cause biopsies. Progression events included development of muscle-invasive or metastatic disease and any death due to bladder cancer. Adverse events (AEs) were reported per CTCAE v.5. Median (IQR) follow-up was 23 (13-28) months. Patients had a median of 4 prior endoluminal inductions and 41 prior taxane instillations. Stage at induction was CIS or positive cytology in 20, TaHG in 2, T1HG in 2, TaHG + CIS in 2, and T1HG + CIS in 1. Among all treated units, 23 (85%) were disease-free at 3-month follow-up. The 6, 12, and 24-month RFS rates were 85%, 73%, and 39%, respectively (Figure 1). The 2-year cystectomy-free, progression-free, and cancer-specific survival rates were 62%, 77%, and 100%, respectively. In total, 19/22 (86%) patients experienced an AE and 3/22 (14%) had a Grade 3 AE including stone formation, ciprofloxacin-resistant UTI, and pneumatosis intestinalis. Most common AEs were bladder pain/dysuria (10), UTI (9), and bladder spasms (7). All patients tolerated a full induction course, although 8 (36%) stopped maintenance treatment due to side effects. Patients received a median of 9 maintenance treatments. Sequential gemcitabine and cabazitaxel with pembrolizumab (GCP) shows efficacy in a heavily pretreated HG NMIUC cohort, though treatment toxicity was limiting in some patients. Given the growing indications and number of patients treated with taxane-containing treatment regimens, a study evaluating this combination is underway in patients with NMIUC after disease progression on docetaxel-containing regimens.

SEQUENTIAL ENDOLUMINAL GEMCITABINE AND CABAZITAXEL WITH SYSTEMIC PEMBROLIZUMAB FOR RECURRENT NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF THE UPPER AND LOWER URINARY TRACTS

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