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Published on: February 8, 2018
Fibroblast Growth Factor Receptor 3 Alteration Status and Outcomes on Immune Checkpoint Inhibitors in Patients With
Shilpa Gupta1, Jessica K Lee2, Jerry Mitchell2
1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH.
Purpose:
The use of immune checkpoint inhibitors (ICPIs) has expanded in the treatment of metastatic urothelial carcinoma (mUC), but response rates are variable, highlighting the need for predictive biomarkers. Tumor mutational burden (TMB) has been shown to predict response to ICPI, but Fibroblast Growth Factor Receptor 3 (FGFR3) alterations are common drivers in mUC and there is preclinical and anecdotal evidence that they may predict less favorable outcomes to ICPIs, similar to ALK and ROS1 fusions in lung cancer. We sought to explore the effect of FGFR3 alterations alone and with TMB on response to ICPI in mUC.
Methods:
A total of 1,416 patients with mUC who received hybrid-capture next-generation sequencing (NGS)-based genomic profiling were evaluated for their response to ICPI and chemotherapy based on the presence of FGFR3 alterations and TMB. A nationwide deidentified real-world clinicogenomic database (CGDB) of NGS results linked to deidentified electronic health record-derived clinical data was used to assess treatment patterns and real-world overall survival (rwOS) and real-world progression-free survival (rwPFS).
Results:
Among 819 patients with mUC who received ICPI, there were no significant differences in rwOS or rwPFS between FGFR3-altered (alt) and wild-type (wt) patients. However, among patients with TMB ≥10 mut/Mb, FGFR3-alt patients trended toward longer rwOS and rwPFS than FGFR3-wt patients. Comparing first-line ICPI versus chemotherapy and adjusting for imbalances, patients with TMB ≥10 and FGFR3-alt who received ICPI also trended toward longer rwPFS than patients who received chemotherapy although no significant difference in rwOS was observed.
Conclusion:
While FGFR3 status alone is not predictive of response to ICPI, FGFR3 combined with TMB emerged as a biomarker that may be predictive of response to ICPI in mUC. Further studies involving larger patient populations are warranted to confirm these findings.
Insights
Fibroblast Growth Factor Receptor 3 (FGFR3) alterations combined with tumor mutational burden (TMB) may predict response to immune checkpoint inhibitors (ICPIs) in metastatic urothelial carcinoma (mUC). FGFR3 status alone was not predictive, but its combination with TMB shows promise as a biomarker.
Area of Science:
- Oncology
- Genomics
- Biomarker Discovery
Background:
- Metastatic urothelial carcinoma (mUC) treatment relies on immune checkpoint inhibitors (ICPIs), but response rates vary.
- Tumor mutational burden (TMB) predicts ICPI response, while Fibroblast Growth Factor Receptor 3 (FGFR3) alterations are common in mUC and may indicate poorer ICPI outcomes.
- Predictive biomarkers are crucial for optimizing ICPI therapy in mUC.
Purpose of the Study:
- To investigate the predictive role of Fibroblast Growth Factor Receptor 3 (FGFR3) alterations, alone and in combination with tumor mutational burden (TMB), for immune checkpoint inhibitor (ICPI) response in metastatic urothelial carcinoma (mUC).
Main Methods:
- Utilized a real-world clinicogenomic database (CGDB) of 1,416 mUC patients.
- Assessed treatment response, real-world overall survival (rwOS), and real-world progression-free survival (rwPFS) using hybrid-capture next-generation sequencing (NGS) data.
- Analyzed the impact of FGFR3 alterations and TMB (≥10 mut/Mb) on ICPI and chemotherapy outcomes.
Main Results:
- No significant difference in rwOS or rwPFS was observed between FGFR3-altered and wild-type mUC patients receiving ICPIs.
- In patients with TMB ≥10 mut/Mb, FGFR3-altered status trended towards longer rwOS and rwPFS compared to FGFR3-wild-type patients.
- First-line ICPI treatment for patients with TMB ≥10 and FGFR3 alterations showed a trend towards longer rwPFS versus chemotherapy, though rwOS did not differ significantly.
Conclusions:
- FGFR3 alterations alone do not predict ICPI response in mUC.
- The combination of FGFR3 alterations and TMB (≥10 mut/Mb) may serve as a predictive biomarker for ICPI response in mUC.
- Larger studies are needed to validate these findings and confirm the predictive value of this combined biomarker.
