Contrary to prior clinical trials, researchers have revealed that metastatic urothelial cancer patients with fibroblast growth factor receptor (FGFR) mutations respond equally well to immunotherapy as patients without the mutation. Their findings highlight the value of using real-world data when evaluating patient response to treatments.
Urothelial cancer immunotherapy
Globally, urothelial cancer is the tenth most common cancer. Cancer Research UK estimates that the five-year survival rate is around 52.6% for all urothelial cancer stages. For stage 4 urothelial cancer, when the tumour has metastasised to other body parts, the number plunges to about 10%.
In the last decade, several new treatments have been approved for urothelial cancer. Notably, the FDA recently approved enfortumab vedotin, an immune checkpoint blockade (ICB) immunotherapy. ICB enhances the ability of T cells to kill cancer cells by blocking their inhibitory receptors and subsequently preventing their transition into an inactive state.
Previous preclinical research has demonstrated that fibroblast growth factor receptor (FGFR)–mutated urothelial cancers have fewer T cells than cancers without the mutation. Since tumours with low T cell levels tend to respond poorly to ICB, it was postulated that patients with the mutation would display little response to ICB and should thus not receive the treatment. However, around 17-32% of urothelial cancer patients harbour mutations in FGFR family members. This means that ICB is unavailable to the many patients in need.
There have been conflicting results from prior studies investigating whether the presence of FGFR mutations influence the response of metastatic urothelial cancer patients to ICB treatment. Furthermore, these findings were based on clinical trial data and have thus not been validated with real-world data.
Response to ICB
In this study, researchers at the Lineberger Comprehensive Cancer Centre evaluated clinical outcomes of 17 urothelial cancer patients with the FGFR3 mutation and 83 patients without. The patients were treated with ICB within the University of North Carolina hospital system from 2014 to 2018. Unlike clinical trials, this real-world dataset included patients with poor performance status and poor prognosis. Their findings have been published in the British Journal of Cancer.
Researchers revealed that patients with the mutations responded equally as well as patients without the mutations. There was no significant difference in overall or progression-free survival between ICB-treated patients with or without FGFR3-mutated tumours. Similarly, median duration of response, binary response rates and clinical benefit rates were not significantly different between the two patient groups.
Immunogenomics of FGFR3-mutated urothelial cancer
To investigate the functional characteristics of the immune cells in FGFR3-mutated tumours, whole transcriptomic profiles were obtained for 89 tumour samples that had adequate RNA quantity and quality for RNA-seq.
In line with previous studies, the FGFR3-mutated tumours were depleted of T cells. Yet, there was no difference observed in T cell receptor clonality between FGFR3-mutated and wild-type tumours, indicating similar antigen-driven immune responses.
The researchers further demonstrated that ICB response was determined by the balance of immune activation and suppressor signals, irrespective of FGFR3 state. They developed a linear model to determine expected levels of suppressor gene signatures for a given activation gene signature score. Applying the model to each wild-type tumour revealed that non-responding patients displayed a higher level of suppressive signals.
Altogether, these findings revealed that despite harbouring lower numbers of T cells, FGFR3-mutated tumours have lower levels of immunosuppressive signatures compared to FGFR3 wild-type tumours. This makes the tumours responsive to ICB treatment.
Summary
Contrary to prior clinical trials, this study demonstrated that metastatic urothelial cancer patients, with and without FGFR3 mutations in their tumours, responded equally well to ICB treatment. These findings open the door to a potentially life-saving treatment for patients with mutated tumours, who may previously have been denied ICB owing to their genetic profiles. Crucially, this work demonstrated the importance of using real-world datasets, as opposed to clinical trial data, to accurately evaluate the response to treatments in stratified patients.
Image credit: rawpixel.com – Freepik
