Combination Immunotherapy Shows Increased Survival and Antitumor Activity in Bladder Cancer Cases: Study
Findings from the international FORT-2 clinical trial showed that a combination treatment including immunotherapy is safe and tolerable in patients with locally advanced or metastatic bladder cancer. The results, which were recently published in JAMA Oncology, show potential to broaden the number of patients with bladder cancer who could benefit from immunotherapy, an approach that harnesses a patient's own immune system to fight cancer.
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 protein 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 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,” said Sweis.
In pre-clinical cancer models, the combination of FGFR inhibitor and a programmed cell death ligand 1 (PD-L1) inhibitor showed increased survival and antitumor activity, suggesting clinical utility of this combination.
It is the first clinical trial to evaluate the safety, tolerability and the 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,” said Sweis.
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,” said Sweis.
Reference: Sweis RF, Gajate P, Morales-Barrera R, et al. Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer: The FORT-2 Phase 1b Nonrandomized Clinical Trial. JAMA Oncol. Published online September 19, 2024. doi:10.1001/jamaoncol.2024.3900
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