IL6 is associated with response to dasatinib and cetuximab: Phase II clinical trial with mechanistic correlatives in cetuximab-resistant head and neck cancer. (June 2017)

• Record Type: Journal Article
• Authors: Stabile, L.P.; Egloff, A.M.; Gibson, M.K.; Gooding, W.E.; Ohr, J.; Zhou, P.; Rothenberger, N.J.; Wang, L.; Geiger, J.L.; Flaherty, J.T.; Grandis, J.R.; Bauman, J.E.
• Is Part Of: Oral oncology. Volume 69(2017)
• Page Start: 38
• Page End: 45
• Publication Date: 2017-06
• Subjects: EGFR epidermal growth factor receptor -- SFK Src-family kinase -- HNSCC head and neck squamous cell carcinoma -- IL6 interleukin-6 -- HGF hepatocyte growth factor -- VEGF vascular endothelial growth factor -- IRB institutional review board -- PD progressive disease -- ORR overall response rate -- AE adverse events -- HPV human papilloma virus -- SD stabile disease -- ISH in situ hybridization -- PFS progression-free survival -- OS overall survival; HNSCC -- Dasatinib -- Cetuximab -- Interleukin-6 -- EGFR -- Src-family kinases; Mouth -- Cancer -- Periodicals; Mouth -- Tumors -- Periodicals; Mouth Diseases -- Periodicals; Mouth Neoplasms -- Periodicals; Bouche -- Cancer -- Périodiques; Bouche -- Tumeurs -- Périodiques; Tumeurs -- Périodiques; Electronic journals; 616.9943105
• DOI: 10.1016/j.oraloncology.2017.03.011
• Languages: English
• ISSNs: 1368-8375

Abstract

Highlights: A phase II trial of dasatinib-cetuximab in cetuximab-resistant patients was conducted. Low serum IL6 was associated with clinical benefit and prolonged survival. Preclinical studies also support IL6 as a modulator of dasatinib-cetuximab effects. 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.