In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. TPS4144-TPS4144
Abstract:
TPS4144 Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in 〉 90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH 〉 2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.tps4144
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
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