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Investigational compound targets FGFR pathway
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CHICAGO — A novel selective inhibitor of the FGFR pathway yielded a 33% response rate in a small cohort of patients with gastroesophageal cancer, according to findings presented at the ASCO Annual Meeting.
Elizabeth Catherine Smyth, MD, clinical research fellow in the gastrointestinal and lymphoma department at The Royal Marsden in London, and colleagues investigated AZD4547 (AstraZeneca) — a selective inhibitor of FGFR 1, 2 and 3 receptor tyrosine kinases — in patients with FGFR1/2-amplified cancers.
“The FGFR signaling pathway plays a key role in oncogenesis,” Smyth said during the presentation. “The nature and frequency of FGFR pathway abnormalities varies frequently between tumor types. The focus of this study is on FGFR-amplified tumors.”
Smyth and colleagues screened 285 patients with advanced cancer and identified FGFR1 amplification in 18% (n = 20 of 111) of patients with HER-2–negative breast cancer and 9.5% (n = 4 of 42) of patients with non–small cell lung cancer, as well as FGFR2 amplification in 7.6% (n = 10 of 132) of patients with gastroesophageal cancer.
Patients received 80 mg AZD4547 orally twice a day. Patients were treated initially on an intermittent-, and following a protocol amendment, a continuous-dosing schedule.
The objective response rate in each tumor group served as the primary endpoint.
Eighteen patients have been treated to date. Three of nine patients with gastric cancer and one of eight patients with breast cancer have responded to treatment. PET imaging on day 14 demonstrated response in all three of the gastroesophageal cancer responders.
“The responses were profound and durable,” Smyth said. “Median duration of response for responding patients with gastroesophageal cancer was approximately 6 months, with one patient treated for 10 months.”
Results of an exploratory analysis indicated that phosphatase was consistently elevated above baseline, but that changes in phosphates were not associated with response. Also, there was no difference in phosphate response in patients treated intermittently or continuously.
In another correlative analysis, Smyth and colleagues found that the FGFR2 copy number was elevated in the free-plasma DNA of the three responders in the gastroesophageal cancer group.
Regarding tolerability, Smyth said that the toxicities were in line with other studies. Fatigue occurred in more than 70% of the cohort. Patients also experienced mucositis, nausea, nail changes and hyperphosphatemia.
“The hyperphosphatemia was low grade and manageable,” Smyth said.
“AZD4547 resulted in high activity, with a one-third response rate in FGFR2-amplified gastroesophageal cancer and a 12.5% response rate in FGFR1-amplified breast cancer,” she added. – by Rob Volansky
For more information:
Smyth EC, et al. Abstract 2508. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: Smyth reports no relevant financial disclosures. Please see the abstract for a list of all other researchers’ relevant financial disclosures.