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New combination treatment brings hope to patients with advanced bladder cancer

by Medical Xpress
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Response, duration of treatment, follow-up, and percentage change in tumor size by FGFR3, programmed cell death 1 ligand 1 (PD-L1), and resistance alteration (PI3K and RAS) expression status. Data are presented for all treated patients (A) and for patients who received rogaratinib 600 mg twice daily (B; the dashed lines indicate thresholds for partial response and progressive disease, according to Response Evaluation Criteria in Solid Tumors, version 1.1). In relation to percentage change in tumor size, no FGFR3 fusions were detected. Three patients did not have complete values for tumor size at all postbaseline assessments and were excluded from the analysis. One patient achieved a 48% reduction in target lesion, corresponding to a partial response, but reported progressive disease in nontarget lesions on first scan; therefore, best overall response was determined as progressive disease. Credit: JAMA Oncology (2024). DOI: 10.1001/jamaoncol.2024.3900

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, published in JAMA Oncology, show the 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 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 Comprehensive Cancer Center.

The (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 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 ,” said Sweis.

Previous clinical studies with an FGFR inhibitor, rogaratinib, demonstrated that the treatment is tolerable and could shrink tumors in patients. 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.

FORT-2 is a phase 1b/2 non-randomized clinical trial conducted in 30 centers across Asia, Europe and North America. 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 FGFR3 gene alteration in most patients treated with this , the objective response rate in this subgroup was 53%, indicating that positive therapeutic effect was not dependent on the PD-L1 expression or FGFR3 gene status.

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

More information:
Randy F. Sweis et al, Rogaratinib Plus Atezolizumab in Cisplatin-Ineligible Patients With FGFR RNA-Overexpressing Urothelial Cancer, JAMA Oncology (2024). DOI: 10.1001/jamaoncol.2024.3900

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New combination treatment brings hope to patients with advanced bladder cancer (2024, September 19)
retrieved 19 September 2024
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