Use of EGFR biomarkers for the treatment of gastric cancer with anti-EGFR agents
Inventors
Yang, Jie • Chen, Yiyou • Li, Henry Qixiang • Cai, Jie
Assignees
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Publication Number
US-10442862-B2
Publication Date
2019-10-15
Expiration Date
Abstract
The present invention relates to methods for treating gastric neoplasias, in particular treating patients who have been previously determined to have an EGFR biomarker. Gastric carcinoma (GC) is one of the most common and deadest cancers with −1 million diagnoses and −0.7 million deaths each year worldwide, with high incidence in Eastern Asia.
Core Innovation
The invention relates to treating gastric neoplasia, particularly gastric adenocarcinoma, by administering an anti-EGFR agent such as cetuximab to a patient. Patient selection is based on detecting an EGFR biomarker in tumor tissue obtained from the patient before treatment, and the patient is expected to be more responsive to cetuximab than patients who do not have the relevant EGFR biomarker.
In one aspect, the EGFR biomarker is an EGFR gene copy number biomarker, including EGFR gene copy number thresholds determined by Affymetrix genome-wide human SNP6.0 array with PICNIC algorithm, realtime quantitative PCR, or fluorescence in situ hybridization (FISH). In another aspect, the EGFR biomarker is an EGFR overexpression biomarker, including EGFR mRNA level measured by Affymetrix HG-U219 GeneChip, relative EGFR gene expression measured by quantitative RT-PCR, or EGFR protein level measured by immunohistochemistry (IHC).
The document further addresses patient stratification in relation to HER2 by describing an optional condition that the patient does not have a HER2 biomarker. Correlation between EGFR status and response is discussed, including findings in GC-ADC HuPrime PDX models where cetuximab responders show EGFR gene amplification and higher EGFR expression, and pharmacodynamic analysis includes pERK reduction after cetuximab. The document also indicates that common resistance oncogene mutations have limited contribution and that EGFR-overexpressing or amplified models do not co-express or amplify HER2, supporting selection without concurrent anti-HER2 therapy.
Claims Coverage
The independent claims cover two alternative patient-selection strategies for treating gastric neoplasia with cetuximab, each anchored to a distinct EGFR biomarker measured in pre-treatment tumor tissue. Across the independent claims, the inventive features include defining EGFR gene copy number thresholds or defining EGFR overexpression thresholds, coupled with an expectation of increased responsiveness compared with patients lacking the biomarker.
Cetuximab treatment guided by EGFR gene copy number biomarker thresholds
Administering an effective amount of cetuximab to treat gastric neoplasia in a patient determined to have an EGFR gene copy number biomarker in tumor tissue obtained before treatment, where the patient is expected to be more responsive than patients not having the EGFR gene copy number biomarker; the EGFR gene copy number biomarker is selected from assay-specific thresholds including at least 7 by Affymetrix genome-wide human SNP6.0 array with PICNIC algorithm, at least 4 by realtime quantitative PCR, or at least 2.8 by fluorescence in situ hybridization (FISH).
Cetuximab treatment guided by EGFR overexpression biomarker thresholds
Administering an effective amount of cetuximab to treat gastric neoplasia in a patient determined to have an EGFR overexpression biomarker in tumor tissue obtained before treatment, where the patient is expected to be more responsive than patients not having the EGFR overexpression biomarker; the EGFR overexpression biomarker is selected from assay-specific thresholds including EGFR mRNA level of at least 5.0 measured by Affymetrix GeneChip HG-U219, a relative EGFR gene expression level of at least 0.5 measured by quantitative RT-PCR, or an EGFR protein level of at least 3 measured by immunohistochemical analysis.
Overall, the claim coverage centers on cetuximab therapy for gastric neoplasia where eligibility and expected responsiveness are defined by pre-treatment EGFR gene copy number or EGFR overexpression, with each biomarker defined using specific assay-based threshold options.
Stated Advantages
The patient is expected to be more responsive to cetuximab compared to patients not having the relevant EGFR biomarker.
Documented Applications
Treating gastric neoplasia, particularly gastric adenocarcinoma, by administering cetuximab selected or stratified based on pre-treatment EGFR gene copy number or EGFR overexpression biomarkers in tumor tissue.
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