This retrospective correlative analysis of specimens from the EXTREME trial provided very useful information. As background, EXTREME was a phase 3 randomized trial that compared six cycles of platinum-based doublet chemotherapy with the same chemotherapy plus the EGFR-directed antibody cetuximab during and following chemotherapy. The trial confirmed earlier data that cetuximab enhanced response in this setting. It also demonstrated a significant improvement in PFS and OS for the addition of cetuximab. Cetuximab also is known to improve local control and OS when it is added to definitive radiation.

Both the EXTREME trial and the definitive study were done at a time when HPV-associated head and neck cancers were becoming more prevalent, but before it had become routine to ascertain HPV status, or to study HPV-associated and non-associated cancers in different trials. Thus, an important unanswered question was whether the benefit from the use of cetuximab would be confined to one or the other of these diseases.

Previously, the issue had been addressed in the context of the SPECTRUM trial by Stoehlmacher-Williams and colleagues (Stoehlmacher-Williams J. Abstract #5504. Presented at: the American Society of Clinical Oncology Annual Meeting; June 1-5, 2012; Chicago.) SPECTRUM was a study similar in design to EXTREME, but it tested an alternate EGFR-directed antibody, panitumumab. In the correlative analysis, p16 status was determined by immunohistochemistry, and tumors with greater than 10% staining for p16 were deemed HPV-associated. The hazard ratio (HR) for benefit from panitumumab was 0.76 for p16-negative cases, and 1.0 for p16-positive cases, suggesting that panitumumab activity is greatest in HPV-negative cancers.

There were some reservations about the Stoehlmacher-Williams data related to the relatively high proportion of HPV-associated cases for an international trial in metastatic disease, the use of the 10% p16 cut-point — which differs from a 70% positive cut-point used in the largest chemoradiation studies — and the fact that panitumumab has not demonstrated a survival advantage in any line of therapy in head and neck cancers.

It should be borne in mind that, although panitumumab has high affinity for EGFR, it may have less optimal distribution characteristics in tumor than cetuximab and, as an IgG2 antibody, will be less effective in recruiting immune effector cells in many patients. Thus, data from the EXTREME trial — a positive study done with a validated therapy — are of great interest.

Psyrri and colleagues accessed tissue from an impressive 86% of patients on EXTREME and conducted p16 testing with the Ventana histology kit, using the more conventional 70% positive cells cutpoint. As expected, p16-positive metastatic disease was much less frequent here than in the SPECTRUM data, providing confidence in the p16 methodology. The HR for OS benefit from cetuximab was 0.63 for HPV-associated cases and 0.82 for HPV-nonassociated cases. In both instances the 95% confidence intervals cross 1; however, these subset analyses were not planned for and, as a result, are underpowered.

At present, there is no reason to withhold cetuximab from patients with HPV-associated cancer. Although the question has not been looked at in specimens from the definitive radiation trial, the current RTOG trial R1016 randomized patients with p16-positive cancer to cisplatin/radiation or cetuximab/radiation and should provide a conclusive answer to this question in patients with locally advanced disease.