GU Cancers 2026 | HCRN GU 20-444: pembrolizumab and response-guided bladder-sparing in MIBC

We presented results from the HCRN GU 2444 study. So a little bit of background. So traditionally, the traditional approach for muscle-invasive bladder cancer has been radical cystectomy. And as our treatments evolved, that’s included perioperative therapy, systemic therapy before and then often after the surgery as well. What we know is that radical cystectomy is not a trivial surgery. It involves a permanent urinary diversion. It has significant morbidity, mortality rate, especially in patients of advanced age, which is the population that we typically see with bladder cancer. And we also know from long-term follow-up data that patients with muscle-invasive bladder cancer who have systemic neoadjuvant therapy, a subset of those patients that went on to surgery had a pathological response, meaning no evidence of disease in the bladder at that point. And then long-term follow-up, many of those patients had no further recurrence. So it’s suggestive that those patients, many of whom are likely to have been cured prior to even having undergone the surgery. And so we conducted an initial study, HCRN GU 16257. That was a combination of cisplatin-based chemotherapy and PD-1 blockade following a similar approach as this study for a potential bladder-sparing approach. And we saw very favorable outcomes in patients, and they were able to retain their bladders. And so some limitations to that is that many patients are not eligible for cisplatin, and there’s not a lot of biomarkers to refine that approach. So we conducted HCRN GU 20444, a phase two investigator-initiated study. Patients were eligible with clinical T2 to T3 muscle-invasive bladder cancer, declined or ineligible for cisplatin-based chemotherapy. They went on to have a maximal TURBT followed by two cycles of pembrolizumab, which was at 400 milligrams every six-week dosing. And then importantly, they had a very stringent and uniformly assessed clinical restaging where they had cystoscopy of the bladder. They had resection of any visible tumor. They also had biopsies of the prior site of disease in the bladder as well as a predefined template of the bladder and urine cytology and MRI of the bladder. If all those findings were negative, then they were presumed to have achieved a clinical complete response. And they went on to seven additional cycles of maintenance pembrolizumab. The patients that did not achieve a clinical response for any one of those reasons, they proceeded with upfront either cystectomy or chemoradiation, the standard definitive local therapies for muscle-invasive bladder cancer, and were also offered seven additional cycles of adjuvant pembrolizumab. And the co-primary endpoints of the study were clinical complete response and the ability of clinical CR to predict a benefit from the treatment. And so the results we saw were very promising. We enrolled 46 patients. 20 of those 46, which is 43% of those patients, achieved a clinical complete response. We were very encouraged by that result, given that in our prior study that included both chemotherapy and immunotherapy, we saw the same exact number, 43%. So we were able to achieve the same clinical complete response rate with only single-agent immunotherapy. And then of those 20 patients, all of them were able to omit cystectomy, and we have not seen any metastatic recurrences in that group. One patient underwent a cystectomy for a new diagnosis of prostate cancer, was a cystoprostatectomy, and had actually no evidence of any cancer in the bladder. And then one other patient had a non-muscle-invasive recurrence in the bladder, still has his bladder to date at the latest data lock. So very encouraging results, no metastatic recurrences, and a high rate of patients being able to safely retain their bladders.

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