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Potential breakthrough for bladder cancer: Netherlands trials

After 40 years of treating metastatic bladder cancer with chemotherapy as a primary treatment, scientists now offer a new approach using immunotherapy combinations, with the outcomes of two studies presented at the European Society for Medical Oncology (ESMO) conference in Madrid potentially going to revolutionise the landscape of bladder cancer treatment.

Traditionally, cisplatin-based chemotherapy has been the standard treatment for bladder cancer patients who are able to tolerate this drug. However, responses have been limited, and durable outcomes rare.

Over the past years, two phase three clinical trials studied the effects of combining immunotherapy with either chemotherapy or a new drug, enfortumab vedotin, to treat bladder cancer (more exact: urothelial carcinoma).

With success, both studies show a significant increase in both overall survival as well as progression-free survival.

Medical oncologist Michiel van der Heijden from the Netherlands Cancer Institute (NKI) said: “These results mark a milestone in bladder cancer research, providing the first evidence of a survival benefit of combination therapy involving immune checkpoint inhibitors over chemotherapy.

“This is an exciting development in our field, as these findings will thoroughly change the treatment landscape for advanced bladder cancer.”

Combining therapies

The CheckMate 901 trial investigated a new combination of the drugs nivolumab and gemcitabine-cisplatin and compared this to treatment with only chemotherapy. The results demonstrated that patients treated with both drugs showed a 22% reduction in the risk of death compared with patients only treated with chemotherapy.

The findings also showed that the combination of nivolumab and chemotherapy led to a significant improvement in progression-free survival vs chemotherapy alone.

The results were published in the New England Journal of Medicine.

During this ESMO presidential session, the results of another phase three trial in the same treatment line were presented, featuring a novel combination of an antibody-drug conjugate with immune checkpoint inhibition, using Enfortumab Vedotin + pembrolizumab.

This study found a statistically significant and clinically meaningful improvement in overall survival and progression-free survival as well. These results will be published in a scientific journal at a later time.

Both treatments are yet to be registered and approved in the Netherlands for health insurance coverage, meaning that they will not yet be readily available.

In the US, the Enfortumab Vedotin + pembrolizumab is already available for a subgroup of bladder cancer patients, based on a phase two study.

Study details

Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma

Michiel van der Heijden, Guru Sonpavde, Thomas Powles, Matthew Galsky, et al.

Published in New England Journal of Medicine on 9 November 2023


No new agent has improved overall survival in patients with unresectable or metastatic urothelial carcinoma when added to first-line cisplatin-based chemotherapy.

In this phase 3, multinational, open-label trial, we randomly assigned patients with previously untreated unresectable or metastatic urothelial carcinoma either to receive intravenous nivolumab (at a dose of 360 mg) plus gemcitabine–cisplatin (nivolumab combination) every three weeks for up to six cycles, followed by nivolumab (at a dose of 480 mg) every four weeks for a maximum of 2 years, or to receive gemcitabine–cisplatin alone every three weeks for up to six cycles. The primary outcomes were overall and progression-free survival. The objective response and safety were exploratory outcomes.

A total of 608 patients underwent randomisation (304 to each group). At a median follow-up of 33.6 months, overall survival was longer with nivolumab-combination therapy than with gemcitabine–cisplatin alone (hazard ratio for death, 0.78; 95% confidence interval [CI], 0.63 to 0.96; P=0.02); the median survival was 21.7 months (95% CI, 18.6 to 26.4) as compared with 18.9 months (95% CI, 14.7 to 22.4), respectively. Progression-free survival was also longer with nivolumab-combination therapy than with gemcitabine–cisplatin alone (hazard ratio for progression or death, 0.72; 95% CI, 0.59 to 0.88; P=0.001). The median progression-free survival was 7.9 months and 7.6 months, respectively. At 12 months, progression-free survival was 34.2% and 21.8%, respectively. The overall objective response was 57.6% (complete response, 21.7%) with nivolumab-combination therapy and 43.1% (complete response, 11.8%) with gemcitabine–cisplatin alone. The median duration of complete response was 37.1 months with nivolumab-combination therapy and 13.2 months with gemcitabine–cisplatin alone. Grade 3 or higher adverse events occurred in 61.8% and 51.7% of the patients, respectively.

Combination therapy with nivolumab plus gemcitabine–cisplatin resulted in significantly better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitabine–cisplatin alone.


NEJM article – Nivolumab plus Gemcitabine–Cisplatin in Advanced Urothelial Carcinoma (Open access)


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