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

L. P. Stabile, A. M. Egloff, M. K. Gibson, W. E. Gooding, J. Ohr, P. Zhou, N. J. Rothenberger, L. Wang, J. L. Geiger, J. T. Flaherty, J. R. Grandis, J. E. Bauman

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)38-45
Number of pages8
JournalOral Oncology
Volume69
DOIs
StatePublished - Jun 1 2017
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Oral Surgery
  • Oncology
  • Cancer Research

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