Introduction:
The recent FDA approval of fibroblast growth factor receptor (FGFR)3 kinase inhibitors for use in metastatic urothelial carcinoma has increased interest in targeted therapy for bladder cancer. Additionally, FGFR3 alterations may be associated with lower response rates to immune checkpoint inhibition. It is known that FGFR3 mutations are more commonly identified in the non-muscle invasive bladder cancer (NMIBC) tumors. FGFR3 altered NMIBC tumors tend to be less likely to progress but their response to intravesical Bacillus Calmette-Guerin (BCG) immunotherapy is unknown. We sought to examine NMIBC tumors with FGFR3 alterations and determine the response of these tumors to BCG therapy. While assessing response, we will also identify any associated co-mutations that may be predictive genomic biomarkers of BCG response in these tumors.
Methods:
We identified treatment naïve high-grade NMIBC patients enrolled on a prospective IRB-approved protocol for which targeted exon capture sequencing (MSK-IMPACT) was performed on pretreatment tumor DNA and matched germline DNA in a CLIA-certified laboratory and who were subsequently treated with intravesical BCG. Analysis of those tumors harboring a FGFR3 alterations was performed to compare response to BCG. Genomic alterations beyond FGFR3 were correlated to those who were BCG refractory versus BCG relapsing and those without any recurrence. Identified FGFR3 alterations were further evaluated for recurrence-free survival with Kaplan-Meier curves as they correlated to type of alteration (fusion vs hotspot).
Results:
One-hundred nineteen patients with high-grade NMIBC who underwent BCG treatment were identified with fifty-one containing a FGFR3 alterations (43%). Thirty-nine patients (76%) were cTaHG and twelve (24%) were cT1HG at diagnosis. No patient with cTis contained a FGFR3 alteration. At a median 60-month (IQR 32-75) follow-up, 20 patients (39%) did not have a high-grade recurrence while 8 patients (16%) were deemed BCG refractory and 23 (45%) were BCG relapsing. Rate of progression was very low with only four patients (8%) with stage progression and only one patient to muscle-invasive disease. Assessment of the entire cohort for genomic alterations identified significant co-occurrence of FGFR3 mutations with cell cycle genes including CDKN2A (p=0.03) and MDM2 (p=0.03) and no FGFR3 mutated tumor contained an ERBB2 mutation. In Figure 1, we assessed the genomic alterations in the three responses to BCG for FGFR3 altered tumors. In an analysis of the types of FGFR3 alterations, we did identify four FGFR3-TACC3 and one FGFR3-TNIP2 fusions, but majority of the mutations were S249C hotspot mutations (n=34) and the remaining hotspot mutations in R248C, Y373C and K650E. Figure 2 demonstrates the recurrence-free survival of these FGFR3 alterations compared to FGFR3 wild-type.
Conclusion:
FGFR3 alterations are relatively common in NMIBC where the standard of care is BCG immunotherapy. While FGFR3 altered NMIBC tumors have historically been associated with a favorable prognosis, our data demonstrates that FGFR3 altered tumors are associated with high recurrence rates similar to wild-type tumors. Given these findings further testing of FGFR3 altered tumors with FGFR3 inhibitors in the NMIBC setting are warranted. In this era of recurrent BCG shortages, patients with FGFR3 altered NMIBC tumors may benefit from the use of novel intravesical or systemic targeted agents and clinical trials of FGFR3 kinase inhibitors in NMIBC are currently underway.
Funding: This work was supported by the Sidney Kimmel Center for Prostate and Urologic Cancers, the Michael and Zena Wiener for Therapeutics Program in Bladder Cancer, Pin Down Bladder Cancer, Cycle for Survival, the Marie-Josee and Henry R. Kravis Center for Molecular Oncology, NIH/NCATS Grant Number UL1-TR002384, the National Cancer Institute Cancer Center Core Grant Number P30-CA008748 and by SPORE in Bladder Cancer P50-CA221745.
RESPONSE OF FGFR3 ALTERATIONS IN HIGH-GRADE NON-MUSCLE INVASIVE BLADDER CANCER TREATED WITH INTRAVESICAL BACILLUS CALMETTE-GUERIN THERAPY
Category
Bladder Cancer > Non-Muscle Invasive Bladder Cancer
Description
Poster # / Podium #7
Oral Abstract Session
12/6/2019
1:15 PM - 2:00 PM
Presented By: Timothy Clinton
Authors:
Timothy Clinton
Nima Almassi
Shawn Dason
Victor McPherson
Aditya Bagrodia
Aleksandra Walasek
Michal Wiseman
Michael Berger
Nikolaus Schultz
Guido Dalbagni
David Solit
Gopa Iyer
Hikmat Al-Ahmadie
Bernard Bochner
Eugene Pietzak