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Almost 90% of patients with muscle-invasive bladder cancer (MIBC) remained alive with intact bladders a year after organ-sparing treatment, according to preliminary results from an ongoing study.

The first 54 patients treated with the bladder-sparing protocol had an estimated 1-year bladder-intact disease-free survival (BIDFS) of 89%, including the first six patients, now followed for almost 4 years. The efficacy cohort (48 of the 54) had a 1-year BIDFS of 88%.

The trimodal regimen -- comprising pembrolizumab (Keytruda), surgery, and chemoradiation -- was generally well tolerated, and follow-up will continue toward the primary endpoint of 2-year BIDFS, reported Arjun V. Balar, MD, of NYU Langone Health in New York City, at the American Society of Clinical Oncology (ASCO) virtual meeting.

"This is an early look, the 1-year estimated bladder-intact disease-free survival is 88%, which is quite encouraging," said Balar. "You need longer follow-up to make sure that these data hold up."

"Trimodal bladder preservation therapy is an effective nonsurgical option for patients with muscle-invasive bladder cancer with curative intent," he added. "Pembrolizumab added to hypofractionated bladder radiotherapy and twice weekly gemcitabine is safe and well tolerated and has demonstrated promising efficacy in this early analysis."

Curative-intent therapy for MIBC consists of two strategies: neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy and trimodal bladder preservation therapy. No randomized trials have evaluated the two strategies, but propensity risk-matched cohort analysis have suggested similar disease-specific and overall survival, Balar said. An optimal chemoradiation regimen has yet to be defined.

PD-1 blockade produces durable responses in advanced urothelial cancer and has improved survival, he continued. Preclinical and clinical evidence suggest synergistic activity between PD-1 blockade and chemoradiation. To examine the issue, investigators at five centers enrolled and treated 54 patients with nonmetastatic (cT2-T4N0M0) MIBC. All had declined cystectomy or were ineligible for the bladder-removal surgery.

The study population consisted of a six-patient safety cohort and a 48-patient efficacy cohort. All 54 patients started treatment with pembrolizumab, followed 2 to 3 weeks later by maximal transurethral resection of the bladder tumor. Three to 4 weeks after surgery, patients received 4 weeks of chemoradiation with gemcitabine plus additional pembrolizumab. Tissue specimens were collected before and after the upfront pembrolizumab and 12 weeks after completion of chemoradiation.

The primary endpoint (assessed in the efficacy cohort) was 2-year BIDFS, defined as muscle-invasive recurrence, regional or distant metastasis, need for cystectomy, or death. on bladder-sparing trimodality treatment strategies suggested a 2-year disease control rate of 60%, and the current trial had statistical power to detect a 20% absolute improvement to a 2-year BIDFS of 80%, said Balar. Secondary endpoints included objective response rate at 12 weeks, metastasis-free survival (MFS), overall survival, and safety.

All but six patients in the efficacy cohort completed treatment. One patient discontinued during chemoradiation, three discontinued gemcitabine, and four discontinued because of adverse effects associated with pembrolizumab. Additionally, 12 patients required gemcitabine dose reductions.

The 12-week post-chemoradiation response assessment included tumor specimen, urine cytology, and bladder imaging. The findings showed that five of six patients in the safety cohort had complete responses (CRs), as did 27 of 48 (56%) in the efficacy cohort. Four patients in the efficacy cohort had partial responses, one patient had progressive disease, and 10 were not yet evaluable (as well as the sixth patient in the safety cohort). The three patients in the efficacy cohort missed one or more components of response assessment, and three were no longer on study.

After a median follow-up of 14.6 months, the efficacy cohort had an estimated 1-year BIDFS of 88%. The estimated 1-year MFS was 85%.

The most common grade 1/2 treatment-related adverse events (TRAEs) were fatigue (41.7%), nausea (35.4%), diarrhea (33.3%), urinary urgency (29.2%), maculopapular rash (22.9%), decreased platelet count (22.9%), and anorexia (20.8%). Diarrhea, decreased lymphocyte count, and colitis (4.2% each) were the most commonly reported grade 3/4 TRAEs.

Considerably more research is needed to provide direction in bladder-sparing treatment for MIBC, said ASCO-invited discussant Andrea Necchi, MD, of Vita-Salute San Raffaele University in Milan, Italy.

Optimal sequencing of the components -- as well as the choice of components -- of trimodal therapy has yet to be determined. The search for useful biomarkers continues. Recent studies have used different methods to define CR. The optimal mix of immunotherapy and chemotherapy agents is unclear, and the role of new and emerging classes of systemic therapies has to be considered and explored, he said.

To the extent that CR correlates with BIDFS, a of standard chemoradiation has established a high bar (88% CR) for ongoing evaluations of adding immunotherapy to the therapeutic mix, Necchi continued. Ultimately, phase III trials will be required to point bladder-sparing therapy in the right direction.

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