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• W2604177176 abstract "Src family kinase (SFK) activation circumvents epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC); dual SFK-EGFR targeting could overcome cetuximab resistance. We conducted a Simon two-stage, phase II trial of the SFK inhibitor, dasatinib, and cetuximab in biomarker-unselected patients with cetuximab-resistant, recurrent/metastatic HNSCC. Pre- and post-treatment serum levels of interleukin-6 (IL6) were measured by ELISA. HNSCC cell lines were assessed for viability and effects of IL6 modulation following dasatinib-cetuximab treatment. In the first stage, 13 patients were evaluable for response: 7 had progressive and 6 had stable disease (SD). Enrollment was halted for futility, and biomarker analysis initiated. Low serum IL6 levels were associated with SD (raw p = 0.028, adjusted p = 0.14) and improved overall survival (p = 0.010). The IL6 classifier was validated in a separate trial of the same combination, but was unable to segregate survival risk in a clinical trial of cetuximab and bevacizumab suggesting serum IL6 may be specific for the dasatinib-cetuximab combination. Enhanced in vitro HNSCC cell death was observed with dasatinib-cetuximab versus single agent treatment; addition of IL6-containing media abrogated this effect. Clinical benefit and overall survival from the dasatinib-cetuximab combination were improved among patients with low serum IL6. Preclinical studies support IL6 as a modifier of dasatinib-cetuximab response. In the setting of clinical cetuximab resistance, serum IL6 is a candidate predictive marker specific for combined dasatinib-cetuximab. The trial was modified and redesigned as a biomarker-enriched Phase II study enrolling patients with undetectable IL6." @default.
• W2604177176 created "2017-04-14" @default.
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• W2604177176 date "2017-06-01" @default.
• W2604177176 modified "2023-10-11" @default.
• W2604177176 title "IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer" @default.
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• W2604177176 doi "https://doi.org/10.1016/j.oraloncology.2017.03.011" @default.
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