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Cetuximab Failure in HPV+ Head and Neck Cancer

— Inferior survival when paired with radiation therapy

MedpageToday

An attempt to de-escalate treatment of human papillomavirus (HPV)-positive oropharyngeal cancer failed to pass muster in a randomized trial that ended prematurely because of inferior survival with the experimental strategy.

An interim analysis of data showed that patients treated with the combination of cetuximab (Erbitux) and radiation therapy had worse progression-free survival (PFS) and overall survival rates as compared with patients who received conventional treatment with cisplatin and radiotherapy. A statement from the National Cancer Institute, which , provided few details about the results, as the study will be reported in full at the American Society for Radiation Oncology (ASTRO) annual meeting in October.

"The goal of this trial was to find an alternative to cisplatin that would be as effective at controlling the cancer but with fewer side effects," said the co-principal investigator, Andy Trotti, MD, of the Moffitt Cancer Center in Tampa, Florida. "We were surprised by the loss of tumor control with cetuximab."

Serious (grade ≥3) adverse events occurred in a similar proportion of patients in each treatment group. However, the types of toxicity differed between the two regimens, as cisplatin was associated with more renal toxicity, ototoxicity, and bone marrow suppression, whereas rash was the most common adverse effect associated with cetuximab.

The investigators enrolled and randomized 849 patients with HPV-positive, T1-2 N2a-N3 or T3-4 any N oropharyngeal carcinoma with no distant metastases. After a median follow-up of 4.5 years, all patients had completed treatment.

"This is the first randomized clinical trial specifically designed for patients with HPV-positive oropharyngeal cancer, and it establishes cisplatin and radiation as the standard of care," said the other co-principal investigator, Maura Gillison, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston.

Multiple studies have shown that HPV-associated oropharyngeal cancer has a more favorable prognosis compared with HPV-negative oropharyngeal cancer, which is more closely associated with tobacco and alcohol use. The more favorable prognosis for HPV-positive disease sparked considerable interest in strategies to de-escalate or reduce the intensity of treatment to spare patients unnecessary toxicity.

Several strategies of de-escalation have been evaluated in single-arm trials. A of limited-dose intensity modulated radiation therapy and low-dose cisplatin produced "excellent" 2-year outcomes in patients with favorable-risk HPV-positive oropharyngeal carcinoma. involving fewer than 100 patients produced results "worthy of further study" with cisplatin-based induction chemotherapy, followed by radiation therapy and cetuximab.

A study reported showed that adding cetuximab to radiation therapy improved outcomes in patients with head and neck cancer compared with radiation therapy alone. The findings led to speculation that cetuximab might be substituted for cisplatin in patients treated with chemoradiation, said Paul Harari, MD, of the University of Wisconsin in Madison, and another investigator in the randomized trial.

Calling the randomized trial a "powerful study," Harari said the results came as a "mild surprise."

"Many experts predicted the results might show equivalent survival outcomes but differing toxicity profiles," Harari, current president of ASTRO, told ľֱ by email. "Although it will be important to learn more about the comparative toxicities, this study examined favorable HPV-positive patients where we expect high survival rates on the order of 80%, and we certainly don't wish to compromise survival for these patients."

"This study examined just one approach to de-escalate therapy for HPV-positive head and neck cancer patients," he added. "The results indicate we cannot simply substitute cetuximab for cisplatin in HPV-positive H&N patients without risking a compromise in overall survival. Several other de-escalation approaches are under active investigation including radiation dose reduction, radiation volume reduction, chemotherapy dose reduction or elimination, the role of induction chemotherapy, transoral surgery, and others."

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined ľֱ in 2007.

Disclosures

No disclosure/conflict-of-interest information was reported.