New combination treatment brings hope to advanced bladder cancer patients

Researchers from the University of Chicago Medicine Comprehensive Cancer Center demonstrated that a combination treatment of fibroblast growth factor receptor (FGFR) inhibitor and programmed cell death ligand 1 (PD-L1) inhibitor is safe and tolerable in newly diagnosed, cisplatin-ineligible, locally advanced or metastatic bladder cancer. Findings from the global FORT-2 trial were recently published in JAMA Oncology.

“The major problem with immunotherapy was it works great for some patients with bladder cancer, but the response rates never exceeded 25% with immunotherapy by itself, and our main focus is to try to understand the resistance to immunotherapy,” said first author Randy Sweis, MD, Assistant Professor at the University of Chicago Medicine. 

The tumor microenvironment (TME) plays a critical role in predicting response to immunotherapy. Tumors with a T-cell-inflamed microenvironment — which are characterized by infiltration of CD8+ T cells, chemokines, a group of proteins that help in migration of immune cells, and an interferon signature — respond well to immunotherapies and are associated with improved survival. In urothelial bladder cancer, increased T cell infiltration has been correlated with longer patient survival.

In many cases, fibroblast growth factor receptor (FGFR) mutations are known to be drivers of bladder cancer development and progression. “In 2016, we published studies showing that the tumors with FGFR3 mutations have no T cell infiltration, which led to the logical conclusion that blocking the FGFR pathway could make more patients responsive to immunotherapy,” Sweis said.

Previous clinical studies with oral pan-fibroblast growth factor receptor inhibitor rogaratinib demonstrated that FGFR inhibitor treatment is tolerable and could shrink tumors in patients. In pre-clinical cancer models, the combination of an FGFR inhibitor and a PD-L1 inhibitor showed increased survival and antitumor activity suggesting this combination could have clinical utility. 

FORT-2 is a phase 1b nonrandomized clinical trial conducted in 30 centers across Asia, Europe and North America. It is the first clinical trial to evaluate the safety, tolerability and recommended phase 2 dose of FGFR inhibitor plus PD-L1 inhibitor in advanced urothelial cancer patients with FGFR mRNA high expression. The study enrolled and treated 37 patients between May 15, 2018 and July 16, 2021.

“By measuring FGFR mRNA gene expression, we found that half of the patients’ tumors have activation of the FGFR pathway, whereas previous studies reported only about 15% using a method that measured only FGFR DNA mutations, suggesting overexpression of FGFR captures all mutations and additional tumors where this pathway is relevant,” Sweis said.

In previous studies, the response rate reported was 23% with PD-L1 inhibitor atezolizumab alone, and 21% with rogaratinib alone; however, by combining the FGFR inhibitor and PD-L1 inhibitor, the response rate increased to 54%. In addition, the responses were achieved quickly, with a median time to response of 2.1 months, and included many durable responses lasting longer than 2 years.  

Despite negative expression for PD-L1 and lack of FGFR3 gene alteration in most patients treated with this combination therapy, the objective response rate in this subgroup was 53%, indicating that positive therapeutic effect was not dependent on PD-L1 expression or FGFR3 gene alteration status.

“The next-generation, more selective FGFR inhibitors are being developed, which should improve tolerability, and combining them with PD-L1 inhibitor may yield better results with fewer side effects,” Sweis said.

The study “Rogaratinib Plus Atezolizumzb in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer – The FORT-2 Phase 1b Nonrandomized Clinical Trial” was funded by Bayer and also supported by the National Cancer Institute.

Additional authors include Pablo Gajate from Ramon y Cajal University Hospital, Madrid, Spain; Rafael Morales-Barrera from Vall d’Hebron University Hospital, Barcelona, Spain; Jai-Lyun Lee from University of Ulsan College of Medicine, Seoul, Republic of Korea; Andrea Necchi from IRCCS San Raffaele Hospital, Milan, Italy; Nicolas Penel from University of Lille, France; Viktor Grunwald from Universitatsklinikum Essen, Germany; Marco Maruzzo from Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Johannes Meran from Krankenhaus der Barmherzigen Bruder, Vienna, Austria; Tatiane Cristine Ishida, Bao from Bayer HealthCare Pharmaceuticals, New Jersey; Yinghui Zhou from Bayer HealthCare Pharmaceuticals, Cambridge, Massachusetts; Peter Ellinghaus from Bayer AG, Wuppertal, Germany; and Jonathan Rosenberg from Memorial Sloan Kettering Cancer Center, New York.