Systemic treatment with chemotherapy plus immunotherapy may allow patients with muscle-invasive bladder cancer (MIBC) to avoid radical cystectomy, according to the results of a phase 2 study. However, at least one expert cautions that patient selection is key to the approach, which may not be applicable to a wider group of patients.
The investigator-initiated study, which was published in Nature Medicine, is among the first prospective trials to test transurethral resection of bladder tumor, along with cisplatin-based chemotherapy, as a bladder-sparing approach in MIBC. Cystectomy is the current standard treatment for MIBC but comes with significant morbidity and mortality risks.
The new trial is also presumed to be the first to uniformly assess performance characteristics of clinical complete response (cCR) as a tool for patient selection, using this strategy.
“This is the first study to test this specific concept in this manner,” lead author Matthew Galsky, MD, co-director of the Center of Excellence for Bladder Cancer at the Tisch Cancer Institute at Mount Sinai in New York City, told OBR. “Certainly, we need more data to know if this should be a standard treatment for [MIBC].”
The study enrolled 76 patients. Of these, 72 received four cycles of gemcitabine, cisplatin, and nivolumab, followed by clinical restaging. One patient did not undergo restaging because of the development of metastatic disease. Three patients who received a cystectomy had done so after developing cerebrovascular accident, deep venous thrombosis, or increased creatinine.
cCR was achieved in 43% of patients. Higher likelihood of a cCR was associated with lower baseline clinical T stage; however, some patients with cT2–T4 disease did achieve cCR.
Patients with a cCR were allowed to proceed with additional immunotherapy without cystectomy. Of the 33 participants who achieved a cCR, only one chose to undergo immediate cystectomy. About 70% of patients who opted for additional immunotherapy had no evidence of recurrence after two years.
Dr. Galsky touched on the results of the CheckMate901 study, which investigated the combination of gemcitabine-cisplatin chemotherapy with or without nivolumab in the metastatic setting. He said that the trial’s significance aligns with his research, suggesting a potential benefit for chemotherapy and immunotherapy in bladder cancer.
“We have the same regimen now showing in the metastatic setting and improvement in progression for survival and overall survival,” Dr. Galsky said. “So, all of this data is sort of associated and coming together.”
Arlene O. Siefker-Radtke, MD, professor of genitourinary medical oncology at the University of Texas MD Anderson Cancer Center in Houston, agrees that there remains an unmet need for patients who wish to retain their bladders. However, she suggested that patient selection has an effect on outcomes and is the challenge with these trials.
“Therefore, one should be cautious in extrapolating these outcomes and performing cross-trial comparisons,” Dr. Siefker-Radtke, who is unaffiliated with the study, told OBR.
She added that 72% of the patients who had a cCR came from the group with only cT2 disease. In contrast, just 27% of patients with bulkier disease burden with at least cT3b disease had a cCR, with relapses more common in this latter group of patients. “This remains an experimental and controversial topic, which cannot be recommended as a standard of care,” Dr. Siefker-Radtke said. “Unfortunately, the biomarkers that were tested did not inform us on a group of patients who would benefit from this approach.”
Patient selection has a major effect on clinical outcomes. More work is needed before this can be recommended for all patients with MIBC, Dr. Siefker-Radtke said.
“There is a clear wish by patients to keep their bladders as long as they possibly can do so safely,” Dr. Siefker-Radtke said. “More work is needed to determine how to best select patients for this preservation strategy.”
Dr. Galsky reported relationships with several companies, including Janssen, Lilly, and Merck.
Dr. Siefker-Radtke reported relationships with numerous companies.
Commentary
Noah Taylor, MD
Radiation oncologist, Evansville Cancer Center, The US Oncology Network
This is promising data, but in reality, in this trial only 30% of patients are without cystectomy at 2 years, with many to most of those remaining patients expected to recur by 5 years.
Bladder-sparing protocols using radiation therapy that have been performed for more than 25 years achieve 80% to 90% pathological CR rate (more than double that of this regimen), with the majority of patients cystectomy-free long term, and have proven equivalent survival to cystectomy in randomized trials.
The more prudent trial design would be to incorporate immunotherapy and chemotherapy with radiation therapy for the best chance of avoiding cystectomy and the best chance to prove equivalent five-year survival to neoadjuvant chemotherapy followed by planned cystectomy.
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