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Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET.

List of Supplemental Materials: Supplemental Table 1. Criteria for Unresectable Disease Supplemental Table 2. Modified RECIST Criteria for Head and Neck Cancer. Supplemental Table 3. Summary of Serum Analyte Levels. Supplemental Figure 1. Study Schematic Supplemental Figure 2. Time to locoregional failure for all eligible and treated patients (a) and by tumor HPV status (b). Log rank test comparing time to failure for HPV+ versus HPV- p value provided. Supplemental Figure 3. Representative tissue cores with high or low expression levels of XPF or ERCC1 as assessed by AQUA. Tumors were stained for cytokeratin (CK) to create a tumor mask and with DAPI to define the nuclear compartment. Supplemental Figure 4. Representative tumor IHC molecular correlates ERCC1, XPF and MET.

Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m2) followed by 250 mg/m2/week and cisplatin 75 mg/m2 q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%–61%]. Two-year overall survival (OS) was 66% (95% CI, 53%–77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. Clin Cancer Res; 20(19); 5041–51. ©2014 AACR.