This is according to a review of the recent therapeutic advances and ongoing clinical trials in metastatic urothelial carcinoma.
“Survival in the metastatic setting is 12-15 months with cisplatin-based combination chemotherapy, but only 3-6 months if left untreated,” wrote Srikala S. Sridhar, MD, of the University of Toronto, and colleagues. Their report is in Therapeutic Advances in Medical Oncology. “More recently, with the advent of immunotherapy, antibody-drug conjugates, and targeted agents, the treatment landscape has changed significantly, with overall survival now approaching two years.”
Both the incidence and mortality from bladder cancer have risen over the past few decades. Around 5% of patients are metastatic at presentation, but nearly half of patients with muscle-invasive bladder cancer will eventually relapse and develop metastatic disease.
For first-line treatment in metastatic urothelial carcinoma, cisplatin-based chemotherapy remains the preferred option with response rates up to 72%, but durability is an issue with most patients experiencing disease progression. In patients with locally advanced or metastatic disease, who are not eligible for cisplatin-based chemotherapy and whose tumors express PD-L1, or patients who are not eligible for any platinum-based regimen regardless of PD-L1 status, the immune checkpoint inhibitors atezolizumab and pembrolizumab have received accelerated Food and Drug administration approval. More recently, pembrolizumab gained full FDA approval for use in patients not eligible to receive platinum-based chemotherapy.
While phase 3 studies are evaluating chemotherapy combined with atezolizumab or pembrolizumab, the results have not been promising. Moreover, the decreased survival observed in the immunotherapy-alone arms of these trials led the FDA to issue a warning that single agent immunotherapy should be used only in patients who are not eligible for cisplatin-based therapy and have PD-L1 expression, or in those not eligible for any platinum-based regimens regardless of PD-L1 expression.
“More intensive treatment in metastatic urothelial carcinoma is not always better,” the authors wrote. “Some of the reasons for this could be that chemotherapy and immunotherapy are targeting a similar population of cells, or that chemotherapy and immunotherapy are antagonistic on some level.”
Maintenance strategies are considered standard of care for other advanced solid tumors. In patients with bladder cancer without disease progression after a first line platinum-based chemotherapy, maintenance avelumab, an anti PD-L1, has shown an overall survival of 21.4 months versus 14.3 months with best supportive care, a finding that the authors described as “practice changing.” Meanwhile, a separate trial showed increased progression-free survival with maintenance pembrolizumab, but no increased overall survival.
For second-line treatment, immunotherapy is currently the standard of care in patients with disease progression during or after platinum-based chemotherapy. While the efficiency of five anti PD-1 and PD-L1 antibodies has been reported in the second-line setting, pembrolizumab is the only immune checkpoint inhibitor to receive full FDA approval. Atezolizumab, nivolumab, avelumab, and durvalumab have received accelerated approval.
“In urothelial carcinomas, PD-1 appears to have an advantage over anti PD-L1 in the second-line setting, but in the maintenance setting, it seems to be the opposite,” the authors wrote.
Erdafitinib is the only fibroblast growth factor receptor (FGFR) inhibitor approved for locally advanced or metastatic urothelial carcinoma, progressing on platinum-based chemotherapy. The oral potent tyrosine kinase inhibitor of FGFR 1-4 is approved for use only in patients with susceptible FGFR3 gene mutations or FGFR2/3 gene fusions. Despite being approved for second-line treatment, erdafitinib is used mainly in third-line treatment after progression on immunotherapy.
The antibody drug conjugates sacituzumab govitecan and enfortumab vedotin, which have gained accelerated FDA approval, provide other options for patients with metastatic urothelial carcinoma resistant to chemotherapy and checkpoint inhibitors. As these antibody drug conjugates have different mechanisms of action and toxicity profiles, they could be used in the same patient throughout the disease course, but further research is needed. Meanwhile, many chemotherapy options, including docetaxel, gemcitabine, ifosfamide, and pemetrexed, have been tested in metastatic urothelial carcinoma with some response after platinum-based treatment.
“A number of studies evaluating promising therapeutic strategies are still ongoing and will hopefully provide information for some important unanswered questions and further guide treatment sequencing in advanced urothelial carcinoma,” the authors wrote.
They declared that there are no conflicts of interest.
