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. 2016 Apr 20;34(12):1300-8.
doi: 10.1200/JCO.2015.62.5970. Epub 2015 Dec 28.

Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab

David I Rosenthal  1 , Paul M Harari  1 , Jordi Giralt  1 , Diana Bell  1 , David Raben  1 , Joyce Liu  1 , Jeltje Schulten  1 , Kian K Ang  1 , James A Bonner  2
Affiliations

Association of Human Papillomavirus and p16 Status With Outcomes in the IMCL-9815 Phase III Registration Trial for Patients With Locoregionally Advanced Oropharyngeal Squamous Cell Carcinoma of the Head and Neck Treated With Radiotherapy With or Without Cetuximab

David I Rosenthal et al. J Clin Oncol. .

Abstract

Purpose: We conducted a retrospective evaluation of the IMCL-9815 study to examine the association of human papillomavirus (HPV) and p16 protein expression status with outcomes in patients with oropharyngeal carcinoma (OPC) receiving radiotherapy (RT) plus cetuximab or RT alone.

Patients and methods: In the IMCL-9815 study, patients were randomly allocated to receive RT plus weekly cetuximab or RT alone. A subpopulation of patients with p16-evaluable OPC was retrospectively evaluated on the basis of locoregional control (LRC), overall survival (OS), and progression-free survival (PFS). Evaluable samples from patients with p16-positive OPC were also tested for HPV DNA.

Results: Tumor p16 status was evaluable in 182 patients with OPC enrolled in the IMCL-9815 study; 41% were p16 positive. When treated with RT alone or RT plus cetuximab, p16-positive patients had a longer OS than p16-negative patients (hazard ratio, 0.40; 95% CI, 0.21 to 0.74 and hazard ratio, 0.16; 95% CI, 0.07 to 0.36, respectively). The addition of cetuximab to RT increased LRC, OS, and PFS in both patients with p16-positive OPC and those with p16-negative disease. Interaction tests for LRC, OS, and PFS did not demonstrate any significant interaction between p16 status and treatment effect (P = .087, .085, and .253, respectively). Similar trends were observed when patients with p16-positive/HPV-positive OPC (n = 49) and those with p16-positive/HPV-negative OPC (n = 14) were compared.

Conclusion: p16 status was strongly prognostic for patients with OPC. The data suggest that the addition of cetuximab to RT improved clinical outcomes regardless of p16 or HPV status versus RT alone.

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Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

Figures

Fig 1.
Fig 1.
CONSORT diagram. HPV, human papillomavirus; OPC, oropharyngeal carcinoma; RT, radiotherapy.
Fig 2.
Fig 2.
Kaplan-Meier plots of (A) locoregional control (LRC), (B) overall survival (OS), and (C) progression-free survival (PFS) in patients with p16-positive and p16-negative oropharyngeal carcinoma treated with radiotherapy (RT) plus cetuximab or RT alone. Because there was minor overlap of the Kaplan-Meier curves, which may have resulted from small sample size, additional statistical analyses were conducted to ensure there was no strong deviation from the original proportional hazards assumption. Both the log-log survival plots and time-dependent Cox models confirmed this assumption was not violated. p16+, p16 positive; p16−, p16 negative.
Fig 3.
Fig 3.
Kaplan-Meier plots of overall survival (OS) in (A) human papillomavirus (HPV)–positive and (B) HPV-negative disease and of locoregional control (LRC) in (C) HPV-positive and (D) HPV-negative disease in patients with p16-positive, HPV-evaluable oropharyngeal carcinoma treated with radiotherapy (RT) plus cetuximab or RT alone.
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