ASCO GU 2019: Fierce-21: Phase II Study of Vofatamab, a Selective Inhibitor of FGFR3, as Salvage Therapy in Metastatic Urothelial Carcinoma

San Francisco, CA (UroToday.com)  Dr. Necchi presented the Fierce-21 phase 2 study of vofatamab, a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma. Patients with metastatic urothelial carcinoma who have failed platinum-based chemotherapy have a poor prognosis. Approximately 20% of these patients harbor fibroblast growth factor receptor 3 (FGFR3) mutations or fusions. FGFR3 alterations have been shown preclinically to be oncogenic drivers of bladder cancer. FGFR3 inhibitors are revolutionizing the clinical management of metastatic urothelial carcinoma in biomarker-selected and potentially poor immunoncology responding patients.  

Vofatamab (B-701) is a fully human monoclonal antibody against FGFR3 that blocks activation of the wildtype and genetically activated receptor. In normal signaling Vofatamab binds to the receptor and shuts down the signaling, it also prevents mutant/fusion signaling. 

FIERCE-21 is a phase 1b/2 study designed to evaluate vofatamab monotherapy or in combination with docetaxel. The trial design is shown in figure 1. In this phase 2 trial, the cohort was limited to patients with FGFR3 mutations. For this trial, the inclusion criteria included metastatic urothelial carcinoma patients with failure in first line prior to chemotherapy and prior checkpoint inhibitor therapy, with measurable disease and ECOG <=1. The efficacy was assessed by the investigators (RECIST 1.1), and the primary endpoints included safety and activity. The basic demographic data and clinical data are shown in table 1 and 2, respectively. 

Figure 1 – Trial design:
Fierce 21 Phase II study of vofatamab B 701 a selective inhibitor of FGFR3 as salvage therapy in metastatic urothelial carcinoma picture 1

Table 1 – Demographic data:
Fierce 21 Phase II study of vofatamab B 701 a selective inhibitor of FGFR3 as salvage therapy in metastatic urothelial carcinoma table 1

Table 2 – Clinical data: 
Fierce 21 Phase II study of vofatamab B 701 a selective inhibitor of FGFR3 as salvage therapy in metastatic urothelial carcinoma table 2

The median follow-up time was 2.6 months and 5.1 months in the combination and monotherapy arms, respectively. Time to response was 3.5 months in the combination arm compared to 4 months in the monotherapy arm. The median progression-free survival was not reached in the combination arm, and it was four months in the monotherapy arm. The duration of study treatment in both arms is shown in figure 2. 

Figure 2 – Duration of study treatment: 
Fierce 21 Phase II study of vofatamab B 701 a selective inhibitor of FGFR3 as salvage therapy in metastatic urothelial carcinoma figure 2

The most common adverse events, occurring in more than 20% of patients in the combination arm included decreased appetite (29%),  diarrhea (29%), pyrexia (29%), asthenia (21%), anemia (21%), dyspnea (21%), and fatigue (21%). 

In conclusion, Vofatamab was shown to be well-tolerated and had no long-term safety issues, allowing patients to receive long term treatment. The combination with docetaxel was also manageable and well-tolerated, with no signal of added toxicity. Vofatamab monotherapy in heavily pretreated patients showed single-agent activity. There was a substantial proportion of patients benefitting long term from both monotherapy and combination with docetaxel. Combination activity was promising, and other combinations are being explored clinically with vofatamab. Dr. Necchi concluded his talk, stating that a phase 2 study of Vofatamab in combination with a checkpoint inhibitor is currently ongoing. 

Presented by:  Andrea Necchi, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA
email news signup