FGFR dysregulation is oncogenic driver across tumour types. We examined the efficacy of AZD4547, a potent orally available selective inhibitor of FGFR 1, 2 & 3 receptor tyrosine kinases, in FGFR1/2 amplified cancers. Herein we report results from an FGFR2 amplified GC cohort.
Phase II Simon 2 stage design (3 independent cohorts) for previously treated patients (pts) with FGFR1 (HER2 negative breast/NSCLC) or FGFR2 (GC) amplified (ratio >= 2.0) tumors. All pts were treated with AZD4547 80 mg twice daily. FGFR1/2 amplification was assessed centrally using FISH. Primary endpoint is centrally reviewed confirmed response rate (RR), with the study concluding efficacy if ≥3/17 patients in a cohort had a confirmed response. PET-CT was performed at baseline, D14 and 8 wks, biopsy at baseline and D14 and optionally on progression. Biomarkers included FGFR copy number variation in tumor and plasma, gene expression using NanoString, and MIRAX digital FISH imaging.
Of 135 GC pts with screening results, FGFR2 amplification was detected in 9% (n = 12), high level (FGFR2 ratio >5.0) was present in 5% (n = 7). Confirmed RR was 33% (3/9) in FGFR2 amplified GC, meeting the primary endpoint for this cohort. Median duration of response was 5.7 months, with one pt on study for > 10 months. Common toxicities (all pts) included fatigue (72%), constipation (50%) mucositis, skin and eye changes (44% each). All 3 GC responders had a PET response on D14 PET. Using digital droplet PCR (ddPCR) elevated FGFR2 copy number was detected in free plasma DNA of all responding pts. NanoString analysis revealed the presence of truncated C3 FGFR2 isoform in all responders; these pts also demonstrated high level homogenous FGFR2 amplification on MIRAX digital FISH imaging.
AZD4547 demonstrated promising activity in pts with homogenously FGFR2 amplified GC. The presence of the truncated C3 FGFR2 isoform in tumour tissue and FGFR2 copy number gain in plasma DNA may identify patients more likely to derive benefit from AZD4547 therapy.
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N. Turner: consulting: Servier research funding (Institution) - Astra Zeneca
I. Chau: honoraria - Taiho Pharmaceutical consulting or advisory role - Bristol-Myers Squibb; Gilead Sciences; Merck Serono; Sanofi Research Funding - Merck Serono (Inst); Novartis (Inst); Roche Pharma AG (Inst); Sanofi (Inst). D. Watkins: consulting or advisory Role – Sanofi. E. Kilgour, N.R. Smith, C. Rooney: employment - AstraZeneca Stock and other ownership interests – AstraZeneca. A. Thomas: honoraria - Eli Lilly and Company; Roche Pharma AG. S. Popat: research funding - Boehringer Ingelheim (Inst). D. Cunningham: research funding - Amgen; AstraZeneca; Bayer; Celgene; MedImmune; Merck Serono; Merrimack; Novartis; Roche Pharma AG; Sanofi (Inst); Sanofi (all Inst). All other authors have declared no conflicts of interest.
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