Panitumumab plus chemotherapy improved PFS in metastatic SCCHN

This is a randomized trial of cisplatin/5-fluorouracil chemotherapy with or without the fully human anti-EGFR monoclonal antibody panitumumab. The study was negative for its primary endpoint of OS. Given that an older trial undertaken with similar chemotherapy with or without the chimeric anti-EGFR antibody cetuximab (Erbitux, Eli Lilly) was positive for a benefit in OS, the question is whether the different outcome here results from issues with the study population or the trial design, or whether the two drugs are actually different enough that one impacts survival and the other doesn’t.

This was a large trial with greater power than the EXTREME trial, which established a survival benefit for cetuximab; however, it was conducted in 26 countries, with 239 of the patients enrolled in Eastern Europe. Notably, not only was survival on the control arm shorter for the patients from Eastern Europe than for patients from other geographic regions, the addition of panitumumab appeared somewhat deleterious in these patients, and the overall hazard ratio would have been more favorable had they not been included.

The population also differs from prior trials in the lower objective response but longer OS in the control arm. The authors report an HPV association in the patients enrolled in this trial, and conclude that panitumumab may have been more beneficial for the patients without HPV association; however, this conclusion should be treated cautiously. Firstly, the methodology chosen to assess HPV association was non-standard, in that only 10% of cells were required to display strong p16 staining to be considered associated, whereas a cutpoint of 70% has been used in most studies. Perhaps because of this less specific cutpoint, a higher rate of p16 positive cases were reported in non-oropharynx subsites, where the significance of p16 staining and its correlation to gold standards which measure HPV DNA or RNA, is less clear.

The results reported here contrast with those reported by Psyrri and colleagues (Psyrri A. Abstract #1018O. Presented at: European Society for Medical Oncology Congress; Sept. 28-Oct. 2, 2012; Vienna), in which a high proportion of cancers from the EXTREME trial were subjected to p16 staining, using a conventional cutpoint of 70%. In this study, p16 positive cancers had longer survival on the chemotherapy control arm, apparently mirroring in metastatic/recurrent disease patients the favorable natural history of these cancers as reported by Ang, O’Sullivan, Fakhry and others in the locally advanced setting. Further, the benefit of cetuximab was seen in both p16-positive and p16-negative cases.  Thus, further study is needed before accepting the SPECTRUM trial as evidence that panitumumab — or indeed EGFR inhibition in general — is not appropriate for p16-positive head and neck cancers.

Although the failure of this trial to demonstrate an advantage for panitumumab may have resulted from the inclusion of patients with a more favorable natural history, difference in patterns of care between Eastern Europe and other geographic regions, or undocumented differences in post-progression therapy, it is also the case that panitumumab and cetuximab are not identical drugs. Each is clearly active in squamous cell cancer of the head and neck, they have comparable single-agent response rates, and each can be safely combined with chemotherapy.

Panitumumab has higher binding affinity for the EGFR, and intuitively one would expect this to result in more potent inhibition of EGFR signaling. However, as Adams and others have shown, large molecules such as antibodies may encounter a binding site barrier that is enhanced by higher binding affinity. That is, if the binding affinity is quite high, antibody will bind heavily to tumor cells in close proximity to the blood vessel, with relatively poor distribution into the tumor. Further, high affinity binding may result in a higher proportion of antibody being sequestered by EGFR expressed in normal tissues such as skin. Additionally, panitumumab utilizes an IgG2 backbone, which is less active in induction of ADCC. Thus, the addition of cetuximab to platinoid/5-fluorouracil chemotherapy remains the standard of care for first-line treatment of metastatic/recurrent disease off protocol, despite recognition that panitumumab is active in some patients. HPV association and p16 staining should not be used to direct utilization of EGFR inhibition with the current state of the evidence.