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Oral Oncol. 2017 Jun;69:38-45. doi: 10.1016/j.oraloncology.2017.03.011. Epub 2017 Apr 9.

IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer.

Author information

1
Departments of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, United States.
2
Departments of Otolaryngology and Molecular & Cell Biology, Boston University, Boston, United States.
3
Department of Medicine, Case Western Reserve University, Cleveland, United States.
4
Departments of Biostatistics, University of Pittsburgh, Pittsburgh, United States.
5
Departments of Medicine, University of Pittsburgh, Pittsburgh, United States.
6
Departments of Otolaryngology, Pittsburgh, United States.
7
Department of Otolaryngology-Head and Neck Surgery, University of California San Francisco, San Francisco, United States.
8
Departments of Medicine, University of Pittsburgh, Pittsburgh, United States. Electronic address: jebauman@email.arizona.edu.

Abstract

OBJECTIVE:

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.

PATIENTS AND METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT01488318.

KEYWORDS:

Cetuximab; Dasatinib; EGFR; HNSCC; Interleukin-6; Src-family kinases

[Indexed for MEDLINE]
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