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Phase II study of AZD4547 in FGFR amplified tumours: gastroesophageal cancer (GC) cohort clinical and translational results

Date

20 Dec 2015

Session

Gastrointestinal tumours 2

Presenters

Elizabeth Smyth

Citation

Annals of Oncology (2015) 26 (suppl_9): 42-70. 10.1093/annonc/mdv523

Authors

E.C. Smyth1, N. Turner2, A. Pearson3, C. Peckitt1, I. Chau1, D. Watkins1, E. Kilgour4, N.R. Smith4, A. Gillbanks1, S. Chua5, G. Brown6, R. Cutts3, C. Rooney4, N. Tarazona Llavero3, A. Thomas7, S. Popat8, D. Cunningham1

Author affiliations

  • 1 Gastrointestinal Oncology, Royal Marsden Hospital NHS Foundation Trust, SW3 6JJ - London/GB
  • 2 Breast Oncology, Royal Marsden Hospital NHS Foundation Trust, London/GB
  • 3 Institute Of Cancer Research, Institute of Cancer Research ICR, London/GB
  • 4 Innovative Medicines, Astra Zeneca, Cheshire/GB
  • 5 Nuclear Medicine, Royal Marsden Hospital NHS Foundation Trust, SW3 6JJ - London/GB
  • 6 Radiology, Royal Marsden Hospital NHS Foundation Trust, SW3 6JJ - London/GB
  • 7 Gastrointestinal Oncology, University Hospitals of Leicester NHS Trust Leicester Royal Infirmary, Leicester/GB
  • 8 Department Of Medicine, Royal Marsden Hospital NHS Foundation Trust, SW3 6JJ - London/GB
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Aim/Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

NCT01795768

Disclosure

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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