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

Chicago, IL (UroToday.com) Infigratinib (BGJ398) is a potent and selective FGFR1–3 inhibitors with significant activity in patients (pts) with advanced or metastatic urothelial carcinoma (mUC) bearing FGFR3 alterations. In a study by Pal et al.1 67 cisplatin-ineligible mUC patients with FGFR3 mutations were treated with BGJ398 orally at 125 mg/day on 3 weeks on, 1 week off schedule until unacceptable toxicity or progression. Among 67 patients treated, an overall response rate of 25.4% was observed and an additional 38.8% of patients had disease stabilization, translating to a disease control rate of 64.2%.

However, as the data noting the distinct biologic characteristics of upper tract UC (UTUC) and urothelial carcinoma of the bladder (UCB) has been increasing, the authors of this study sought to determine if infigratinib had varying activity in UTUC patients and UC patients. To that effect, they assessed the same 67 eligible pts with mUC with activating FGFR3 mutations/fusions and prior platinum-based chemotherapy – and the mUC could be either UTUC or UC in origin. As mentioned above, pts received infigratinib 125 mg orally daily (3 wks on/1 wk off).

The primary outcome was overall response rate (ORR), which included complete response and partial response (CR+PR), and disease control rate (DCR), which was overall response rate and patients with stable disease (SD). These were characterized in UCB and UTUC pts separately.

In addition, comprehensive genomic profiling was performed on FFPE tissues in a CLIA-certified lab (Foundation Medicine; Cambridge, MA). Blood was collected for cell-free (cf)DNA analysis using a 600-gene panel on an Illumina HiSeq 2500 sequencer.

67 pts were enrolled. The full demographics are noted below:

ASCO2019 UCB UTUC

The majority (70.1%) had received ≥2 prior antineoplastic therapies.

Interestingly, looking at the FGFR3 alterations in UTUC (n=8) and UCB (n=59), there are many more alterations in UCB. This may just be due to the number of patients included.

As noted previously, for the entire cohort, ORR was 25.4% and DCR was 64.2%. Separated by source histology, in the 8 pts with UTUC, 1 CR and 3 PRs were observed (ORR 50%); the remainder had the best response of SD, so the DCR was 100%. UTUC pts were predominantly 2nd line (62.5%), with only 2 (25%) showing response to previous treatment. In contrast, in the 59 pts with UCB, 13 PRs were observed (ORR 22%), and 22 pts had a best response of SD, for a DCR of 59.3%. These results are all summarized below:

ASCO2019 UCB UTUC efficacy

As for translation to PFS and OS, these KM curves are seen below, broken down for the entire cohort, UTUC and UCB:

ASCO2019 UCB UTUC KM

Safety profiles were similar in both cohorts.

Notable differences in genomic alterations between cohorts included a higher frequency of FGFR3-TACC3 fusions (12.5% vs 5.8%) and FGFR3 R248C mutations (50% vs 11.5%) and a lower frequency of FGFR3 S249C mutations (25% vs 59.6%) in UTUC vs UCB.

Consistent with previous reports, UTUC pts had a differential frequency of alterations in HRAS, CDKN2B and ARID1A.2 Sufficient cfDNA yield was obtained in UTUC and UCB pts. Their main findings are as follows:

  • FGFR3 alterations were concordant in 30/38 (79%) of patients with both tumor tissue and cfDNA at screening.
  • A more complex genomic profile with an increased mutational tumor burden was observed in the cfDNA of UCB than in patients with UTUC:
ASCO2019 UCB cfDNA

  • Across the majority of genes, the variant allele frequency was higher in UCB than in UTUC
  • The higher VAF in cfDNA observed in UCB suggests UCB patients may have higher disease burden or different mechanisms of metastases compared to UTUC
  • Median VAF for FGFR3 mutations was higher in tumor tissue and cfDNA in UCB than in UTUC
Based on this retrospective analysis of their original data, the authors note differences in cumulative genomic profile between UCB and UTUC in this FGFR3-restricted experience, underscoring the distinct biology of these diseases. It would appear that the results with infigratinib in UTUC support a planned phase III adjuvant study predominantly in this population.

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

Written by: Thenappan Chandrasekar, MD, Clinical Instructor, Thomas Jefferson University, @tchandra_uromd, @JEFFUrology at the 2019 ASCO Annual Meeting #ASCO19, May 31- June 4, 2019, Chicago, IL USA

References:
  1. Pal SK, Rosenberg JE, et al. Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations. Cancer Discov. 2018 Jul;8(7):812-821. doi: 10.1158/2159-8290.CD-18-0229. Epub 2018 May 30.
  2. Sfakianos JP, Cha EK, et al. Genomic Characterization of Upper Tract Urothelial Carcinoma. Eur Urol. 2015 Dec;68(6):970-7. doi: 10.1016/j.eururo.2015.07.039. Epub 2015 Aug 14.
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