ESMO E-Learning: Metastatic Urothelial Carcinoma Systemic Second-Line Therapy: The Platinum-Refractory Setting

In this E-Learning module the authors elaborate systemic second-line therapy in patients with platinum-refractory metastatic urothelial carcinoma. The authors provide a comprehensive overview of the results with chemotherapy in second-line, maintenance studies, immune checkpoint inhibitors, targeted therapies such as FGFR inhibitors and antibody drug conjugates, as well as a glimpse into the future treatment landscape.

The authors report that first-line platinum-based chemotherapy has remained the standard of care for more than 30 years, but virtually all patients progress to first-line chemotherapy despite an initial response. Until recently, second-line options have remained scarce. However, the therapeutic scenario in post-platinum metastatic urothelial carcinoma patients has evolved rapidly within the last 5 years.

The authors explain that an ‘old’ era in this field was characterised by mostly single agent cytotoxic chemotherapy, followed by taxanes introduction. It was also featured by non-randomised data, small size trials, heterogenic population and limited efficacy. 

There were no randomised data in this setting until 2006. Vinflunine was the first agent to demonstrate, in a randomised controlled trial, overall survival advantage against best supportive care. Failure of targeted therapies was seen in biomarker unselected population. This era was also characterised by the maintenance concept after first-line response (early second-line treatment).

Thereafter, immune checkpoint inhibitors have superseded chemotherapy with impressive results in a subset of patients, although the lack of predictive biomarkers might limit the success of this treatment option.

Molecular understanding has led to novel targeted therapies in biomarker selected patients. In particular, FGFR inhibitors have shown remarkable activity in a biomarker selected population.

The antibody drug conjugates represent an attractive alternative for all patients, as they do not require biomarker selection. Their preliminary activity appears very promising.

The authors predict that the near future will be characterised by combinations of immuno-oncology drugs and targeted treatments, that biomarker driven studies are ongoing and will hopefully soon refine the treatment for patients with metastatic urothelial carcinoma.