AUA 2022: Interim Results From a Phase 1B Clinical Trial Evaluating Tolerability and Activity of FGFR Inhibition in Localized Upper Tract Urothelial Carcinoma

( In a podium presentation in the Late-Breaking Abstracts session at the 2022 American Urologic Association Annual Meeting held in New Orleans and virtually, Dr. Matin presented the results of a phase Ib trial assessing the tolerability and activity of FGFR inhibition in patients with localized upper tract urothelial carcinoma (UTUC). FGFR alterations are common in UTUC, with a prevalence of 54-74% depending on the study cohort. In the metastatic setting, the potent oral FGFR1-3 inhibitor Infigratinib has demonstrated clinical activity with a response rate of 25%, and even higher response rate (50%) among those with metastatic UTUC. There is further an unmet need for treatment options in UTUC which are kidney sparing. Thus, the authors performed a biomarker-informed preoperative study of infigratinib in patients with localized UTUC.

The authors enrolled patients with low-grade, or localized cisplatin-ineligible high-grade UTUC, undergoing either ureteroscopic (URS) management or nephroureterectomy/ureterectomy (NU/U) into this preoperative phase 1b trial (NCT04228042).

Further eligibility criteria included a glomerular filtration rate (GFR) of 30 or greater, sufficient biopsy tissue for mutational analysis, and a tumor map of all residual tumors after endoscopic biopsy and any ablation. Following enrollment, patients were treated with once-daily infigratinib 125 mg (21 days of 28-day cycle) for 2 cycles. A second tumor map based on URS or NU/U was completed after cycle 2. The authors assessed tolerability through ongoing monitoring and predefined stopping boundaries. The primary endpoint was tolerability, with a key secondary endpoint of objective response based on tumor mapping. The authors planned to enroll a total of 20 patients. Targeted sequencing was performed using a NovaSeq 6000 solid tumor panel covering 610 somatic alterations including 33 fusions.

Between May 2021 and Feb 2022, 12 patients consented and 11 were enrolled of the 20 planned to be enrolled. Of 11 evaluable patients, 9 have completed the planned two cycles of therapy, and 2 required stopping, one for fatigue and one for liver injury.

A response with tumor reduction was seen in 5 of 7 (44%) biomarker-positive patients with a tumor reduction ranging from 25-83%. All four biomarker negative patients did not have responses. Clinically, this meant that 2 patients were converted from planned nephroureterectomy to endoscopic management.

Further, most non-responders had a prior history of bladder cancer and 1 had FGFR3-TACC3 fusion.

Dr. Matin presented two cases highlighting profound tumor responses that may be seen with this treatment approach.

Thus, Dr. Matin concluded that this phase Ib trial demonstrates that infigratinib shows substantial activity in patients with localized UTUC that have FGFR3 mutations, consistent with previous data in the metastatic setting. This study is continuing enrollment with plans for a phase 2 expansion evaluating additional cycles. Additionally, he noted that this approach may be particularly promising as it is an oral compound that may be well accepted by urologists.

Presented by: Surena F. Matin, MD, Professor, Department of Urology, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas

Written by: Christopher J.D. Wallis, University of Toronto, Twitter: @WallisCJD during the 2022 American Urological Association (AUA) Annual Meeting, New Orleans, LA, Fri, May 13 – Mon, May 16, 2022.

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