Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer

Abstract

BACKGROUND. EGFR and Src family kinases are upregulated in head and neck squamous cell carcinoma (HNSCC). EGFR interacts with Src to activate STAT3 signaling, and dual EGFR-Src targeting is synergistic in HNSCC preclinical models. pSrc overexpression predicted resistance to the EGFR inhibitor, erlotinib, in a prior window trial. We conducted a 4-arm window trial to identify biomarkers associated with response to EGFR and/or Src inhibition. METHODS. Patients with operable stage II-IVa HNSCC were randomized to 7-21 days of neoadjuvant erlotinib, the Src inhibitor dasatinib, the combination of both, or placebo. Paired tumor specimens were collected before and after treatment. Pharmacodynamic expression of EGFR and Src pathway components was evaluated by IHC of tissue microarrays and reverse-phase protein array of tissue lysates. Candidate biomarkers were assessed for correlation with change in tumor size. RESULTS. From April 2009 to December 2012, 58 patients were randomized and 55 were treated. There was a significant decrease in tumor size in both erlotinib arms (P = 0.0014); however, no effect was seen with dasatinib alone (P = 0.24). High baseline pMAPK expression was associated with response to erlotinib (P = 0.03). High baseline pSTAT3 was associated with resistance to dasatinib (P = 0.099). CONCLUSIONS. Brief exposure to erlotinib significantly decreased tumor size in operable HNSCC, with no additive effect from dasatinib. Baseline pMAPK expression warrants further study as a response biomarker for anti-EGFR therapy. Basal expression of pSTAT3 may be independent of Src, explain therapeutic resistance, and preclude development of dasatinib in biomarker-unselected cohorts. TRIAL REGISTRATION. NCT00779389. FUNDING. National Cancer Institute, American Cancer Society, Pennsylvania Department of Health, V Foundation for Cancer Research, Bristol-Myers Squibb, and Astellas Pharma.

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1. CONSORT diagram.

Patient enrollment, allocation, and biospecimen analysis are specified according to treatment arm.

Figure 2. Response by treatment arm.

(A) Waterfall plot for individual patient responses, as measured by percentage change in RECIST-measurable index lesions, presented by treatment arm. Each box represents one of the 41 patients with CT scan data both before and after treatment. (B) Box-and-whisker plots showing the distribution of percentage change in tumor size for each of the 4 treatment arms. Boxes show the interquartile range, with the median shown as a dark horizontal line; whiskers extend to 1.5 times the interquartile range. Percentage change in RECIST-measurable index lesions was compared among groups by 2-way ANOVA. Erlotinib was associated with reduction in tumor size (P = 0.0006). Tests for main effect (P = 0.29) and interaction (P = 0.49) confirmed no significant favorable or detrimental effect from dasatinib. C, combination; D, dasatinib; E, erlotinib; P, placebo.

Figure 3. Baseline IHC biomarkers of response or resistance.

(A) Among erlotinib-treated patients, baseline pMAPK was inversely associated with response. An analysis of covariance found the presence of interaction between baseline pMAPK and erlotinib exposure (P = 0.0232). Separate slope estimates were calculated: the slope for patients not exposed to erlotinib was positive (0.25, P = 0.092), whereas the slope for the erlotinib group was negative (–0.169, P = 0.099), suggesting that greater baseline pMAPK protein levels enhanced erlotinib antitumor response. (B) Among dasatinib-treated patients, baseline pSTAT3 was associated with resistance. An analysis of covariance suggests moderate interaction between baseline pStat3 and dasatinib exposure (P = 0.0875). Separate slope estimates were calculated: the slope for the no dasatinib group was not different from 0 (P = 0.7334), whereas the slope for the dasatinib group was positive (P = 0.0235), suggesting that greater baseline pStat3 protein levels contributed to dasatinib resistance.