ASCO 2017: Safety and efficacy of docetaxel + b-701, a selective inhibitor of FGFR3, in subjects with advanced or metastatic urothelial carcinoma

Chicago, IL ( In the past 1 year, five different immune checkpoint inhibitors have been approved by the FDA approved for the treatment of metastatic or advanced urothelial carcinoma (UC): atezolizumab, durvalumab, nivolumab, pembrolizumab and most recently avelumab. However, while the initial enthusiasm for this new class of therapies appears warranted, further long-term studies and confirmatory studies are required. Importantly though, each of these drugs has an objective response rate of approximately 20%, indicating that 80% of patients do not have a strong response. So, while studies on ICI’s should continue, additional treatment options for this patient population are needed.

FGFR3 is a gene mutation that is well-established in urothelial carcinoma (UCC) genomics. It is frequently overexpressed in UCC and 15-20% of patients with advanced disease have FGFR3 gene mutations or fusions. B-701 (formerly R3Mab) is a monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor.

In this abstract, we review the preliminary results of a phase Ib/2 andomized, double-blind, placebo-controlled, multicenter, parallel-group study of B-701+docetaxel vs placebo+docetaxel in the treatment of locally advanced or metastatic UCC patients who have relapsed after or are refractory to standard therapy.

Study design:
The study had a initial lead-in phase with planned inclusion of 20 patients (docetaxel+B-701) [Cohort 1]. Eventually, there will be randomization of 201 patients. As of today, there have been two additional lead-in groups added: docetaxel+B-701 (Cohort 2) and B-701 alone (Cohort 3), specifically in patients who have failed immune checkpoint inhibitors and have documented FGFR3 mutation or FGFR3-TACC3 fusion.

Eligible pts: Stage IV UCC, relapsed/refractory to 1 or 2 prior chemotherapy regimens not including taxanes with ECOG 0-1. Treatment protocol: B-701 at 25 mg/kg every 3 weeks (+ loading dose on Cycle 1 Day 8) and Docetaxol at 75 mg/m2 every 3 weeks. Efficacy will be assessed by RECIST 1.1 criteria. Primary outcomes are progression-free survival (PFS) and safety. Secondary outcomes are overall response rate (ORR), duration of response (DOR), disease control rate (DCR), and overall survival (OS).

As of January 2017, 19 patients had enrolled in the Cohort 1 lead-in phase (median age 66 yrs, ECOG 1 58%, Hgb <10 gm/dL 11%, liver mets 26% and ≥ 2 prior regimens 74%).

Grade ≥3 adverse events that occurred included: decreased neutrophils (21%), neutropenia (5%), decreased WBCs (11%). Two patients underwent docetaxol dose reduction and one patient discontinued treatment due to adverse events (disseminated intravascular coagulation). Eleven deaths occurred while on study: 8 due to disease progression, 2 due to adverse events and 1 unknown.

17 of those patients were evaluable for PFS/ORR. 5 pts had FGFR3 mutations or TACC3-fusion. Initial clinical outcomes identified 1 complete response and 2 partial responders in the 17 patients, while disease control rate (DCR) was 58%, PFS 3.25 months, and median OS 5.68 months. In the FGF3+ cohort, there was 1 complete responder and 1 partial responder, while DCR was 80%, PFS 7.9 months, and median OS not reached.

Overall, based on preliminary lead-in data, the authors are encouraged by early safety and tolerability results of combining B-701 with docetaxol. Obviously, ongoing evaluation is needed to ensure safety and to assess efficacy.

First Author: Joaquim Bellmunt

Co-Authors: Sumanta K. Pal, Joel Picus, Manish Kohli, Yull Edwin Arriaga, Matthew I. Milowsky, Jocelyn Holash, S.E. Hirabayashi, David Albert Ramies, Jesse S. McGreivy

Institution(s): Dana-Farber Cancer Institute, Boston, MA; City of Hope Comprehensive Cancer Center, Duarte, CA; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO; Mayo Clinic, Rochester, MN; The University of Texas Southwestern Medical Center, Dallas, TX; University of North Carolina School of Medicine, Chapel Hill, NC; BioClin Therapeutics, Inc., San Ramon, CA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA