ASCO 2019: Infigratinib in Upper Tract Urothelial Carcinoma vs Urothelial Carcinoma of the Bladder and Association with Comprehensive Genomic DNA Results

Chicago, IL (UroToday.com) FGFR3 mutations occur in approximately 20% of locally advanced and metastatic urothelial cancers.1 To date, clinical development of FGFR inhibitors for the treatment of urothelial cancer has yielded the recent FDA approval of an orally available FGFR inhibitor erdafitinib for the treatment of platinum-refractory metastatic urothelial cancer, and a number of other agents are being investigated in this setting as well.  Infirgratinib is an orally available small molecule FGFR1-3 inhibitor. Nazli Dizman, MD, presented a correlative analysis of a urothelial cancer expansion cohort of a phase I clinical trial2 in platinum-refractory or platinum-ineligible patients. The present study focused on the genomic underpinnings of response to FGFR inhibition and the detection of circulating cell-free DNA.

Investigators observed differing response rates between patients with upper tract primaries relative to patients with bladder primaries. They hypothesize that differences in the somatic mutational landscape between upper tract and lower tract tumors may explain the observed difference in response to FGFR targeted therapy. Specifically, of 67 evaluable patients, 59 had lower tract primaries, among whom infigratinib achieved a modest 22.0% response rate. However, among the 8 patients with upper tract primaries – noting the limitations of the small sample size – investigators identified 3 PRs and 1 CR for an overall response rate of 50.0%
ASCO 2019 tab 3 efficacy summary
Sequencing of the FGFR3 gene identified a predominance of the R248C mutation among upper tract tumors in which it comprises 50% of the FGFR3 alterations relative to just 12% of the lower tract primaries. Furthermore, the majority (59%) of lower tract tumors harbored the S249C relative to just 38% of upper tract primaries.

ASCO 2019 fig 1 UCB vs UTUC
Commensurate with the higher objective response rate, patients with upper tract primaries achieved significantly longer progression-free (8.5 months versus 3.7 months) and overall survival (21.8 months versus 3.7 months) relative to patients with bladder primary bladder cancer.
ASCO 2019 fig 2 progression free survival graph
Finally, investigators sought to further characterize the mutational landscape of these tumors utilizing circulating cell-free DNA. In particular, it was noted that lower tract tumors exhibit a higher variant allelic frequency, perhaps alluding to distinct tumor biology. Finally, the variant allelic frequency was significantly higher in tumor tissue relative to in circulating cell-free DNA, suggesting differences between the metastasizing cell populations relative to the bulk tumor.
ASCO 2019 fig 6 variants of UCB vs UTUC
Given the impressive response rate to infigratinib among patients with upper tract urothelial carcinoma, a phase III adjuvant trial is planned.

Presented by:  Nazli Dizman, MD, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA

Written by: Michael Lattanzi, MD, Internal Medicine Resident, Department of Medicine, NYU School of Medicine, @MikeLattanzi at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Ross JS, Wang K, Khaira D, Ali SM, Fisher HA, Mian B, Nazeer T, Elvin JA, Palma N, Yelensky R, Lipson D. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016 Mar 1;122(5):702-11.
  2. Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, Wolf J, Dittrich C, Keam B, Delord JP, Schellens JH. Efficacy of BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated advanced urothelial carcinoma with FGFR3 alterations. Cancer discovery. 2018 Jul 1;8(7):812-21.
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