Abstract
Abstract Preclinical data indicate that activation of Src family kinases (SFKs) provides a mechanism for circumventing epidermal growth factor receptor (EGFR) targeting in head and neck squamous cell carcinoma (HNSCC). We performed a Simon two-stage, phase II trial combining dasatinib and cetuximab in patients with recurrent/metastatic HNSCC and analyzed candidate blood and tumor biomarkers for association with response. Significant biomarkers were evaluated in additional cetuximab-treated cohorts to evaluate specificity of association with response. Patients received 150 mg daily dasatinib three days after the loading dose of cetuximab; daily dasatinib and weekly cetuximab were continued until progressive disease (PD). Responses were assessed after 6 weeks and every 12 weeks thereafter until PD. Before and after treatment serum levels of interleukin-6 (IL6), transforming growth factor-alpha (TGF-α), hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF) were measured by ELISA. Phospho-SFK levels were evaluated in pretreatment archived tumor specimens. Cell line models of HNSCC were assessed for in vitro cell viability following cetuximab-dasatinib treatment and the effects of IL6 modulation on treatment response. Fourteen patients were enrolled and treated during the first stage. The median treatment duration was 47 days. Thirteen patients were evaluable for response: 6 had stable disease (SD) and 7 had PD. No partial or complete response was observed; enrollment was halted according to the pre-specified futility rule. Low baseline serum IL6 levels (<17.85 pg/ml) were associated with clinical benefit, including prolonged SD (p = 0.028) and improved survival (p = 0.009) while other analyzed blood and tissue biomarkers showed no association with clinical outcomes. Low serum IL6 was also associated with SD in analyses of IL6 levels in a separate phase I trial of dasatinib-cetuximab (p = 0.013, n = 14), but IL6 levels were not associated with clinical benefit in a third trial of recurrent/metastatic HNSCC patients treated with cetuximab plus bevacizumab. Enhanced in vitro cell death was observed with combined cetuximab-dasatinib compared to treatment with either agent alone; addition of IL6-containing media abrogated the enhanced killing of HNSCC cell lines by combined cetuximab-dasatinib. Clinical benefit from the dasatinib-cetuximab combination was more likely among patients with low baseline serum IL6 levels. Increased baseline IL6 may activate EGFR- and SFK-independent STAT3 signaling, bypassing dual blockade and conferring resistance to the combined treatment regimen. Post hoc comparisons among cetuximab-containing trials for recurrent/metastatic HNSCC point to low serum IL6 as a candidate predictive marker specific for combined cetuximab-dasatinib, and preclinical studies support IL6 as a modifier of cetuximab-dasatinib response. Citation Format: Laura P. Stabile, Ann Marie Egloff, Pei Zhou, William E. Gooding, Jennifer R. Grandis, Julie E. Bauman. Phase II study of dasatinib in combination with cetuximab in recurrent/metastatic head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT119.
Published Version
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