Cetuximab benefits patients with oropharyngeal cancer, regardless of HPV, p16 status

Barbara A. Burtness , MD

Bonner and colleagues conducted a pivotal trial evaluation the addition of cetuximab (Erbitux, Lilly) to radiation from April 1999 to March 2002 a time when the incidence of HPVassociated oropharynx cancer was already rising, but before p16 or HPV testing was routinely used to establish this association and prospectively identify treatment-sensitive patients. The addition of cetuximab significantly improved outcomes relative to radiation alone, and the good results in the radiation-alone arm were attributed to a higher-than-usual proportion of intermediate-risk patients. This reflects patient selection decisions that arose because the control arm of this trial was radiation alone at a time when cisplatin with radiation was an increasingly accepted standard for definitive treatment of locally advanced disease.

As the proportion of HPVassociated cancers increased steadily in the years following the initial publication of the Bonner trial, and as our understanding of the increased radiosensitivity of HPVassociated oropharynx cancers grew, the question arose whether it was the inclusion of patients with HPVinitiated tumors into the trial that led to the favorable performance of the control arm. An additional question was whether such patients would be more or less likely to benefit from the addition of cetuximab.

A reliable biomarker for cetuximab sensitivity or resistance has yet to be established epidermal growth factor receptor gene amplification has not been predictive, very high EGFR protein content may relate inversely to response and, recently, loss of PTEN expression has been proposed as a predictor of resistance. HPVassociated cancers which overall have a lower mutational burden, lower EGFR content and are less likely to have lost PTEN expression might be predicted to be cetuximab sensitive. Individual exceptional responders, and the findings of a correlative analysis of the EXTREME trial support this possibility.

On the other hand, the absence of EGFR mutations in HPVassociated cancers and the results of the SPECTRUM trial have been used to argue that cetuximab does not have a role in HPVassociated cancers.

The SPECTRUM data merit scrutiny. This was a trial that evaluated the addition of panitumumab (Vectibix, Amgen) to chemotherapy. Although the survivals in the panitumumab arm were numerically superior, these differences were not statistically significant and, indeed, panitumumab has not yielded a survival benefit in any line of therapy in head and neck cancer despite a number of large trials. Correlative analysis in this trial was performed with p16 staining as a surrogate for HPV association on a large subset of tissues from all subsites, although p16 is a well-established surrogate only in oropharynx cancers.

Further concern regarding these data arises because an unconventionally low cutoff for p16positivity was chosen. Perhaps because of the cutoff point, unusually large proportions of p16positive cancers were seen outside the oropharynx, with the proportion of p16positive larynx (32%) and oral cavity (29.5%) cancers actually exceeding the proportion of p16positive oropharynx cancers. Thus, further data have been badly needed from trials in which the EGFRdirected antibody under study is active, and in which the methodology for assigning HPV association is rigorous.

Rosenthal and colleagues have now reported the results of p16 testing on specimens from the Bonner trial to examine whether cetuximab is beneficial to patients with HPVinitiated disease who are being treated with radiation. Appropriately, the p16 analysis is confined to patients with oropharynx cancer, which is the site of the overwhelming majority of HPVinitiated head and neck cancers, and the cancer for which the improved treatment sensitivity with cisplatin and radiation is best proven. These investigators used the consensus p16 cutoff point of staining in 70% or more tumor cells. The results were not unexpected for the years of study accrual, with 41% of the patients with p16assessable oropharynx cancers staining positively for p16.

A further internal control of the quality of these data is the finding that in the radiation-alone arm, patients with p16positive disease had significantly better locoregional control and survival than those with p16negative disease. Patients with p16positive oropharynx cancer who received cetuximab with radiation had a 3-year survival of 87.8%, compared with 72.3% for those receiving radiation alone (HR = 0.38). The 3-year survival for p16negative patients was 41.9% with cetuximab and radiation, and 33.5%, with radiation alone (HR = 0.93). The researchers point out that this suggests a pronounced treatment effect only in patients with p16positive disease, but at the sample size available for study, no significant interaction between treatment group and p16 status was shown (P = .085).

The data from this report are compelling as they come from a well-conducted positive trial, and as the correlative assays were performed appropriately and yielded the predicted distribution of HPVassociated cancers. A large randomized trial of radiation with either cisplatin or cetuximab (R1016) has been completed in HPVassociated oropharynx cancer and will likely provide further confirmation that cetuximab is an active radiosensitizer in HPVinitiated oropharynx cancer, and is likely to provide greater nuance with regard to optimal patient selection based on stage, comorbidities, tobacco exposure and radiation center.

For patients with HPVassociated oropharynx cancer, small T stage and tobacco use greater than 10 pack-years, a current generation of trials focuses on maintaining the high cure rates achieved for this population with chemoradiation, while attempting to minimize acute or chronic toxicity.

One strategy pursued in NRG HN002 is the omission of chemotherapy. The finding that 28% of HPVassociated patients had died at 3 years when treated with radiation alone highlights the importance of patient selection and careful prospective study as we move toward treatment deintensification.

In the meantime, Rosenthal and colleagues have conclusively demonstrated that cetuximab with radiation is an appropriate standard for p16positive oropharyngeal cancer.

References:

Bonner JA, et al. N Engl J Med. 2006;doi:10.1056/NEJMoa053422.

Vermorken JB, et al. Ann Oncol. 2014;doi:10.1093/annonc/mdu003.

Vermorken JB, et al. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70181-5.