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FGFR1–3 Inhibitor AZD4547 in Refractory Tumors Harboring FGFR Activating Mutations and Fusions


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As reported in the Journal of Clinical Oncology by Chae et al, findings in a cohort of the phase II NCI-MATCH trial (EAY131, Subprotocol W) indicated that the oral inhibitor of fibroblast growth factor receptor 1, 2, and 3 (FGFR1–3), AZD4547, produced a small number of responses in patients with a wide range of refractory solid tumors harboring FGFR1–3 point mutations or fusions, with no responses observed in those with FGFR1–2 amplification.  

NCI-MATCH is a national histology-agnostic, signal-finding, molecular profile–driven trial enrolling patients with refractory cancers, lymphomas, or myelomas.

Study Details

In the trial, 48 eligible patients with tumors harboring predefined actionable aberrations in FGFR1–3 received AZD4547 at 80 mg twice daily continuously in 28-day cycles until disease progression or intolerance. The most common primary tumors were breast cancer (33.3% of patients), urothelial cancer (12.5%), and cervical cancer (10.4%).

Overall, 20 patients had FGFR1–2 amplification, 19 had FGFR2–3 single-nucleotide variants, and 9 had FGFR1 or FGFR3 fusions. The primary endpoint was an overall response rate of ≥ 16% on Response Evaluation Criteria in Solid Tumors among all 48 patients.

Responses

Of the 48 patients, 7 (14.6%) were not evaluable for response. Confirmed partial response was observed in 4 of 48 (8%; 90% confidence interval [CI] = 3%–18%), including 2 (10.5%) of 19 with FGFR1–3 point mutations (FGFR2 Y376C, FGFR3 A393E) and 2 (22.2%) of 9 with FGFR3-TACC3 fusions. Stable disease was observed in 18 patients (37.5%), and progressive disease was seen in 19 (39.6%). The median duration of response was 7.9 months.

KEY POINTS

  • An objective response was observed in 4 of 48 patients.
  • Responses were observed in 2 of 19 patients with FGFR1-3 point mutations and 2 of 9 with FGFR fusions.

After median follow-up of 9.2 months, median progression-free survival was 3.4 months, with a 6-month rate of 15%. Progression-free survival at 6 months was 0% among patients harboring FGFR amplifications, 6% among those with point mutations, and 56% among those with FGFR fusions.

Adverse Events

Grade ≥ 3 adverse events considered at least possibly related to treatment were mucositis in three patients; palmar-plantar erythrodysesthesia in two; elevated transaminases in two; elevated alkaline phosphatase in two; and diarrhea, dizziness, peripheral sensory neuropathy, and syncope in one each. Ocular toxicity was observed in two patients. In total, adverse events led to discontinuation of treatment in 12 patients (24.5%).

The investigators concluded, “Preliminary signals of activity appeared to be limited to cancers harboring FGFR activating mutations and fusions, although AZD4547 did not meet the primary endpoint. Different FGFR somatic alterations may confer different levels of signaling potency and/or oncogene dependence.”

Christos Vaklavas, MD, of Huntsman Cancer Institute, University of Utah, Salt Lake City, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Cancer Institute. For full disclosures of the study authors, visit ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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