Trial of Single-Agent or Combination Vofatamab Demonstrates Safety, Activity in Metastatic Urothelial Cancer

Andrea Necchi, MD

Andrea Necchi, MD

Vofatamab when given as a monotherapy or in combination with docetaxel was well tolerated and had no long-term safety issues in 55 patients with metastatic urothelial cancer (mUC) who had failed platinum-based chemotherapy, according to the results of a phase II expansion study (NCT02401542).¹Findings were presented during the 2019 American Urologic Association annual meeting in Chicago, Illinois.

Historically, patients with mUC who have failed platinum-based chemotherapy have a poor prognosis. It is estimated that 20% of patients with mUC harborFGFR3mutations or fusions. Vofatamab, a fully human monoclonal antibody, prevents FGFR3 activation via 2 mechanisms—by blocking ligand activation of the receptor and preventing mutation/fusion signaling.

The phase Ib portion of the study investigated 19 patients with mUC who were treated with vofatamab combined with docetaxel.²This served as the lead-in for the current phase II expansion study.

In the current study, several hundred patients were screened forFGFR3mutations/fusions. Mutations or fusions were identified in 20%, and these patients were then assigned by the investigators to the combination arm (n = 21) or the monotherapy arm (n = 21), said lead investigator Andrea Necchi, MD.

Patient eligibility criteria were similar to salvage studies and included patients with mUC who failed ≥1 line of prior chemotherapy plus a checkpoint inhibitor with measurable disease and Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients in the combination arm were taxane naïve and those in the monotherapy arm had prior taxane use. Primary endpoints were safety and objective response rate (ORR).

There were 19 men (90%) in the combination arm and 16 men (76%) in the monotherapy arm and the median age was 64 years and 70 years, respectively. Fifty-two percent (n = 11) of patients in the combination arm and 43% (n = 9) in the monotherapy arm had visceral metastases. Twenty-four percent (n = 5) and 19% (n = 4) of patients had liver metastases, respectively.

The median number of prior lines of therapy was 2 (range, 1-4) and 3 (range, 1-7) for the combination and monotherapy arms, respectively. Prior use of checkpoint inhibitors was identical for both arms (n = 11, 52%).

“Importantly, the median time from most recent line of therapy was very small, which was 1.3 months in the combination arm and 1.6 months in the monotherapy arm,” Necchi said, a medical director in the Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

The most commonFGFR3genetic alteration was the S294C mutation, which was identified in 52% of patients in the combination arm and 36% in the monotherapy arm, followed by theFGFR3-TACC3fusion with 24% in the combination arm and 27% in the single-agent arm.

In the combination arm, the median number of vofatamab doses was 4 (range, 1-19) and the median number of vofatamab dosed was 6 (range, 3-16) in the monotherapy arm. In the combination arm, 33% (n = 7) of patients received ≥6 cycles (4+ months) and 43% of patients (n = 9) in the monotherapy arm received ≥6 cycles. Two patients in the combination arm continued receiving vofatamab after discontinuing docetaxel. Progressive disease was the most common reason for ending treatment with 5 patients in the combination arm and 13 in the monotherapy arm discontinuing. 

In general, the agent was well tolerated; only 2 patients discontinued treatment due to adverse events. Across both treatment arms, the majority of patients described themselves as having good or better quality of life after 3 cycles (57%), which was maintained for 6 cycles (55%), as measured by the Patient-Reported Outcomes Measurement Information System Global Physical Health (PROMIS GPH) T-Score.

The most common grade 1/2 treatment-emergent adverse events (TEAEs) associated with vofatamab were asthenia (21%), diarrhea (21%), decreased appetite (12%), and rash (12%). Four cases (19%) of grade ≥3 anemia were observed in the combination arm and 2 cases (10%) in the monotherapy arm. Overall, the most common TEAEs of any grade—decreased appetite, diarrhea, and pyrexia—were reported in 29% (n = 12) of all patients. 

“Importantly, there were no cases of hyperphosphatemia, or ocular or nail toxicity observed, which are commonly seen with FGFR3 inhibitors,” Necchi said. One patient reported grade 2 skin toxicity, however.

“Efficacy results are preliminary, with a median follow-up time of 2.6 months in the combination arm and 5.1 months in the single-agent arm,” Necchi said. Similarly, the time to response is short, reported respectively as 3.5 months and 4 months. As a result, the ORR could not be reported in both arms and the progression-free survival was only reported for the monotherapy arm at 4 months. “The disease control rate at 6 months, which is a good indicator in the second-line setting, is promising, indicating a rate of 27% in the combination arm and 21% in the single-agent arm,” he said.

As a next step, the use of vofatamab in combination with pembrolizumab (Keytruda) is undergoing evaluation in the FIERCE-22 phase Ib/II trial (NCT03123055) involving patients with metastatic bladder cancer who have progressed on at least 1 platinum-based chemotherapy and who are anti—PD-1/L1 naïve.

References:

1. Necchi A, Castellano D, Pang ST, et al. FIERCE-21: Phase 2 study of vofatmab (B-701), a selective inhibitor of FGFR3, as salvage therapy in metastatic urothelial carcinoma (mUCC). Presented at: 2019 AUA Annual Meeting; May 3-6, 2019; Chicago, IL. Abstract PD47-08. www.eventscribe.com/2019/AUA2019/fsPopup.asp?Mode=presInfo&PresentationID=535245.
2. Bellmunt J, Picus J, Kohli M, et al. FIERCE-21: Phase 1b/2 study of docetaxel + b-701, a selective inhibitor of FGFR3, in relapsed or refractory (R/R) metastatic urothelial carcinoma (mUCC). J Clin Oncol; 2018;36(suppl_15):4534. doi: 10.1200/JCO.2018.36.15_suppl.4534.