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Selective FGFR Inhibitor Shows Promise in Gastric and Breast Cancers

Lisa Miller
Published Online:11:33 PM, Fri June 3, 2016

Nicholas Turner, MD, PhD

Gastric cancers with high-level clonal FGFR2 gene amplification responded to AZD4547, a selective FGFR inhibitor, in a phase II open label trial of previously treated, advanced FGFR amplified cancer. Yet tumors with multiple FGFR1 genes, low level or subclonal amplification of FGFR2 did not respond similarly to the drug.

High-level FGFR2 amplification was found, during the course of the study, to initiate an oncogene addiction phenotype whereby the tumors become addicted to FGFR signaling. The reason for the addiction was investigated to better predict which patients may respond to targeted therapies in FGFR amplified cancers in the future.  

“Our data provide a mechanistic understanding of the distinct pattern of oncogene addiction seen in highly-amplified cancers and demonstrate the importance of clonality in predicting response to targeted therapy,” wrote study authors.

In the study, advanced gastroesophageal cancer patients were screened for FGFR2 gene amplification, which is present in about 8% of gastroesophageal cancers. Nine FGFR2-positive patients were found, and of these, 3 patients (33%) had a confirmed partial response (PR) to AZD4547. The median progression-free survival (PFS) for responding patients was 6.6 months.

Responses were associated with higher copy number FGFR2 amplification in homogeneously amplified tumors. Two of the responding patients had clonal homogeneously amplified tumors. Each of the nonresponding patients had tumors with subclonal heterogeneous amplification with the presence of non-amplified tumor cells, including one patient who had a high-level amplified tumor with heterogeneous amplification that did not produce a response to AZD4547. 

Patients with FGFR1 amplification in estrogen receptor (ER)–positive breast cancer were also tested in the study. High-level amplification was more prevalent in FGFR2 amplified cancers. Only 1 of 8 FGFR1-positive breast cancer patients (12.5%) had a PR, and tumor reduction registered in the FGFR2 amplified cancers alone.

High-level FGFR2 amplified cancers showed high sensitivity to FGFR inhibitors due to reliance on the PI3 kinase signaling. Amplified FGFR2 activates PI3 kinase indirectly through transactivation of RAS and the concurrent binding of p85 to the receptor tyrosine kinases (RTKs) ERBB3 and IGF1R/IRS1, leading to PI3 kinase signaling becoming reliant upon FGFR signaling.

The study authors noted that the PIK3CA mutation does not occur in FGFR2 amplified gastric cancers. This was proven by analysis of the Cancer Genome Atlas (TCGA) data, which showed the dependence of PI3 kinase pathway activation on FGFR2 amplification.

Alternatively, other FGFR driven cell lines did not show the same reliance on the PI3K pathway. In low-level FGFR1 amplified cell lines PI3 kinase and mTOR signaling was not blocked by FGFR inhibition, as with high-level FGFR2 amplification. Signaling in these FGFR1 tumors was limited to MAPK signaling.

By exploiting the tumor addiction to FGFR signaling, therapies can be created to target the FGFR2 cancer gene. Patients with this gene must first be identified.

The study authors wrote that high-level clonal FGFR2 amplification may be detected in patients through circulating tumor DNA (ctDNA) screening, which would simplify the identification of patients that show sensitivity to FGFR inhibitors and would benefit from these kinds of treatments.

"We were able to design a blood test to screen for patients who were most likely to benefit from an FGFR2 inhibitor, helping us to target drug therapy at those patients who were most likely to benefit,” said study co-leader Nicholas Turner, MD, PhD, of the Institute of Cancer Research in London, in statement.

Emma Smith, PhD, science information manager for Cancer Research UK, which supported the study, wrote in a statement, “Developing ways to identify people who are most likely to benefit from drugs targeting particular genetic faults is vital to help ensure each patient gets the most effective treatment. The next steps will be larger clinical trials to see if testing for this genetic abnormality can spot people whose stomach cancer will respond well to this treatment.”
Reference: Pearson A, Smyth E, Babina IS, et al. High-level clonal FGFR amplification and response to FGFR inhibition in a translational clinical trial. [Published online May 13, 2016.] Cancer Discov. doi: 10.1158/2159-8290.CD-15-1246.

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