Key Clinical Summary: 

• Design/Population: The phase 2 HCRN GU 2444 trial evaluated neoadjuvant pembrolizumab with response-adapted management in patients with muscle-invasive bladder cancer who were ineligible for or declined cisplatin-based chemotherapy.
• Key Outcomes: A subset of patients achieved clinical complete response after neoadjuvant therapy and were able to avoid cystectomy, with encouraging early outcomes and no observed metastatic recurrences in responders at follow-up.
• Clinical Relevance: These findings support a feasible, individualized bladder preservation strategy using immunotherapy and stringent restaging, with ctDNA showing promise as a tool to guide treatment selection.

Jonathan Anker, MD, PhD, Mount Sinai Medical Center, New York, New York, discusses results from the phase 2 HCRN GU 2444 study evaluating a response-adapted bladder preservation strategy among cisplatin-ineligible patients with muscle-invasive bladder cancer. 

Neoadjuvant pembrolizumab followed by stringent clinical restaging enabled a subset of patients to achieve clinical complete response and avoid cystectomy. Early outcomes support the feasibility of a personalized, response-guided bladder-sparing approach, with ctDNA emerging as a potential predictive biomarker.

Transcript:

I'm John Anker, I'm a genitourinary medical oncologist from the Icahn School of Medicine at Mount Sinai. We reported at GU-ASCO 2026 the results of the phase 2 study HCRN GU 2444.

A little bit of background, traditionally, the treatment for muscle-invasive bladder cancer is radical cystectomy with or without perioperative systemic therapies. Radical cystectomy is a significant surgery, it's associated with significant morbidities, mortality rate, [and] it particularly elevates with patients of advanced age, which is the median age when we see patients with bladder cancer. When we ask patients with bladder cancer what they want, very often what they say is they like to retain their bladders. We showed previously that when we combine what was systemic chemotherapy with PD-1 blockade, that was in this previous study, GU 16257, and perform a clinical restaging assessment, we're able to help patients retain their bladder and achieve very favorable outcomes. 

Many patients with bladder cancer, particularly muscle-invasive bladder cancer, are not able or do not want to receive a cisplatin-based chemotherapy and there are not a lot of biomarkers to further refine this approach so we conducted the phase 2 study, HCRN GU 2444, an investigator-initiated study, looking at muscle-invasive bladder cancer for patients that are not eligible or do not want to receive cisplatin chemotherapy.

Patients underwent maximal resection of the tumor, maximal TRBT, had 2 cycles of every 6-week dosing of intravenous pembrolizumab, and then underwent a clinical, uniform, stringent restaging assessment. Patients that achieved a clinical complete response rate, which was defined as no evidence of disease based on cystoscopy, had resection of any visible tumor, biopsy of where the tumor previously was resected, or biopsies of a predefined template of the bladder, urine cytology, MRI of the bladder, if all those were negative, patients were thought to have achieved a clinical complete response and then got 7 initial cycles of adjuvant pembrolizumab or maintenance pembrolizumab.

If they did not achieve a clinical complete response, they underwent immediate cystectomy or chemoradiation, which is definitive therapy for muscle-invasive bladder cancer, and then were offered 7 additional cycles of adjuvant pembrolizumab. The co-primary end points of the study are clinical complete response rate and the ability of clinical complete response to predict benefit of such an approach.

We enrolled 46 patients, all 46 of those patients underwent clinical restaging and importantly, of those 46 patients, 20 of them, or 43% of them, achieved a clinical complete response and all 20 of those patients were able to omit upfront cystectomy. When we follow those patients now for an 11-month follow-up, and follow-ups ongoing, there have been no metastatic recurrences in that cohort of patients that achieve a clinical complete response. There was only 1 non-muscle invasive local recurrence, a clinical T1 recurrence, that patient to date has an intact bladder. The only patient who had a cystectomy was actually done for a new diagnosis of prostate cancer, the patient had a cystoprostectomy and had no evidence of disease of bladder cancer at that time, had a pathologic complete response in the bladder.

We also reported some data for ctDNA in this cohort. Patients with undetectable baseline ctDNA were much more likely to go on to achieve a clinical response and we did not observe any metastatic recurrences in patients with undetectable baseline ctDNA. Importantly, for patients that achieve a clinical response, an on-treatment time point of ctDNA done at cycle 2, all of those patients had undetectable ctDNA. 

Taken all together, we think it's very feasible, and part of where this field is going is to individualize patient care and to use all of our tools for a uniform and stringent clinical restaging assessment to be able to safely, in an individualized manner, promote a response-guided bladder sparing approach.

Source: 

Anker J, King J, Tripathi A, et al. Phase 2 trial of pembrolizumab (P) with response-guided bladder-sparing in patients with muscle-invasive bladder cancer (MIBC; HCRN GU 20-444). Presented at ASCO GU. February 26-28, 2026. San Francisco, California. Abstract 737.