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Can immunotherapy propel bladder sparing–approaches to prime time?


Several abstracts presented at the 2021 ASCO Annual Meeting highlighted how integrating immune checkpoint inhibitors into bladder-sparing approaches may enhance the efficacy of these strategies in patients with bladder cancer.

“The biggest impact from studies at ASCO this year in the bladder cancer field had to do with bladder-sparing approaches, and the studies really mark a ‘new dawn’ in bladder-sparing approaches in bladder cancer in terms of integrating immune checkpoint blockade with radiation or even without radiation to achieve bladder sparing,” Matthew Galsky, MD, said in an interview with Urology Times during the meeting.

“This is an approach that has, of course, been used for decades—it is a standard of care and there is level 1 evidence for the approach—although it is not practiced as frequently in some parts of the world as others. And it could be that the integration of a new treatment modality into the bladder-sparing arena is a tipping point that is needed to really have the community [as a whole] embrace this as a reasonable option for patients with bladder cancer,” added Galsky, a professor of Medicine and acting chief of the Division of Hematology and Medical Oncology for the Mount Sinai Health System.

The following 3 ASCO abstracts in particular demonstrated the emergence of immune checkpoint inhibitors as a major component of the bladder-sparing treatment paradigm.

Nivolumab, chemotherapy, and TURBT

Findings from the phase 2 HCRN GU16-257 trial showed that combining transurethral resection of the bladder tumor (TURBT) with nivolumab (Opdivo) and chemotherapy is a promising bladder-sparing approach in patients with muscle-invasive bladder cancer (MIBC).1

The study enrolled 76 patients with cisplatin-eligible cT2 to T4aN0M0 clinically localized urothelial bladder cancer.

Patients initially received 4 cycles of gemcitabine plus cisplatin plus nivolumab. Following these 4 cycles, all patients underwent clinical restaging, including MRI/CT of the bladder (unless otherwise contraindicated), urine cytology, and cystoscopy with bladder/prostatic urethral biopsies. Patients with a clinical complete response (CR) could then opt to proceed with cystectomy or proceed without cystectomy and instead receive an additional 4 months of single-agent nivolumab. For patients without a clinical CR, a cystectomy was recommended.

At the time of the data cutoff, 64 patients had completed clinical restaging. Of these patients, 31 (48%) achieved a clinical CR. Thirty of these patients chose not to undergo cystectomy and instead receive an additional 4 months of nivolumab monotherapy. Only 1 patient opted for immediate cystectomy. On surgical pathology, that patient had a low-grade papillary tumor. The remaining 33 patients did not reach a clinical CR and cystectomy was recommended.

All 31 patients who achieved a clinical CR were still alive at the cutoff and, at the time of the data reporting, there were a number of patients who were 12 months out since treatment initiation who had no recurrence and whose bladders remained intact.

Trimodal pembrolizumab-based regimen

An early analysis of pembrolizumab (Keytruda) in combination with gemcitabine and concurrent hypofractionated radiotherapy (RT) for MIBC found that the protocol demonstrated safety and efficacy.2

The phase 2 trial included patients with cT2 to T4aN0M0 MIBC who declined or who were ineligible for cystectomy. Patients had an ECOG performance status of 0 or 1, estimated glomerular filtration rate of more than 30 cc/min, and no contraindications to pelvic RT or pembrolizumab. No perioperative chemotherapy was allowed.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal transurethral resection of the bladder tumor and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m2 and pembrolizumab every 3 weeks for 3 doses. Six patients were enrolled in a safety cohort, and 48 patients were enrolled in an efficacy cohort.

A total of 42 patients (85%) completed all protocol therapy in the study. Twelve patients (25%) had dose reductions of gemcitabine. One patient (2%) discontinued RT/gemcitabine, 3 (6%) discontinued gemcitabine only, and 4 (8%) discontinued pembrolizumab.

Twelve-week complete response was 100% in the safety cohort and 77% in the efficacy cohort.

The investigators reported a 1-year bladder-intact disease-free survival (DFS) rate in the efficacy cohort of 88%. The rate increased slightly to 89% when the safety cohort was added. Metastases-free survival was 85% at 1-year follow-up for the entire cohort.

Durvalumab, tremelimumab, and radiotherapy

The phase 2 IMMUNOPRESERVE-SOGUG trial showed that a regimen combining transurethral resection followed by duel immune checkpoint blockade with durvalumab (Imfinzi) and tremelimumab along with concurrent RT was effective at inducing responses and leading to bladder sparing in patients with localized MIBC.3

The study enrolled 32 patients with clinical stage cT2 to 4aN0M0 disease with an ECOG performance status of 0 to 1 who were either medically ineligible for radical cystectomy or refused to receive the procedure.

All patients received transurethral resection, after which they were administered durvalumab plus tremelimumab. Two weeks following the start of immunotherapy, patients initiated normofractionated external-beam RT. Salvage cystectomy was offered to patients with residual or relapsed MIBC.

Overall, 81% (n = 26) of patients achieved a CR. Two patients did not respond and 4 patients were not evaluable (rejection, clinical impairment, COVID-19–related death, and death related to peritonitis). The 12-month DFS and overall survival rates were 76% and 87%, respectively.

At a median follow-up of 12.7 months (range, 5.3-24.5), the 12-month bladder intact DFS rate was 73%. Two patients received salvage cystectomy (both late, not immediate).


1. Galsky MD, Daneshmand S, Chan KG et al. Phase 2 trial of gemcitabine, cisplatin, plus nivolumab with selective bladder sparing in patients with muscle- invasive bladder cancer (MIBC): HCRN GU 16-257. J Clin Oncol 39, 2021 (suppl 15; abstr 4503). doi: 10.1200/JCO.2021.39.15_suppl.4503

2. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. J Clin Oncol 39, 2021 (suppl 15; abstr 4504). doi: 10.1200/JCO.2021.39.15_suppl.4504

3. Garcia del Muro X, Valderrama BP, Medina A, et al. Phase II trial of durvalumab plus tremelimumab with concurrent radiotherapy (RT) in patients (pts) with localized muscle invasive bladder cancer (MIBC) treated with a selective bladder preservation approach: IMMUNOPRESERVE-SOGUG trial. J Clin Oncol 39, 2021 (suppl 15; abstr 4505). doi: 10.1200/JCO.2021.39.15_suppl.4505

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