In the United States and European countries, many oncologists are using cetuximab (Erbitux)/radiotherapy instead of cisplatin/radiotherapy in the treatment of human papillomavirus (HPV)-positive oropharyngeal cancer, based on the belief that cetuximab is equally effective with less toxicity than cisplatin. However, late-breaking data presented at the European Society for Medical Oncology (ESMO) 2018 Congress demonstrated that cetuximab actually is associated with similar toxicity and poorer survival compared with cisplatin/radiotherapy, thus supporting the continuation of cisplatin/radiation therapy as the standard of care for platinum-eligible patients with low-risk HPV-associated oropharyngeal cancer.¹

The study was not powered to identify a survival difference. Hence, we were surprised to find a significantly worse overall survival with cetuximab.

— Hisham Mehanna, MD

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“Many patients have been receiving cetuximab based on the assumption that it was as effective as cisplatin with fewer side effects. In a head-to-head comparison of the two treatments, cetuximab had the same toxicity, same quality of life, and swallowing function as well as fewer serious adverse events compared with cisplatin but worse overall survival and worse locoregional and distant tumor control. Cisplatin remains the standard of care when patients are able to receive platinum,” said study author Hisham Mehanna, MD, Chair, Head and Neck Surgery, Institute of Cancer and Genomic Sciences, University of Birmingham, United Kingdom.

“Only when we do appropriately designed phase III trials comparing a treatment with standard of care can we see reliable results. In my view, we should not change clinical practice without head-to-head trials. This is why we need head-to-head trials,” he added.

The incidence of HPV-positive oropharyngeal cancer is rapidly rising in the United States and other Western countries. HPV-positive cancer is associated with younger age, a greater number of sex partners, and a history of oral sex. This type of cancer has a good prognosis with chemoradiotherapy, the current standard of care. Most patients with HPV-positive oropharyngeal cancer are younger and have a good prognosis. With standard cisplatin/radiotherapy, patients can survive for decades, but they are plagued by acute and late toxicity, including dry mouth, difficulty swallowing, and taste disturbances. Thus, de-escalation of therapy is an attractive goal if outcomes are similar to those with the standard of care.

Study Details

The DeESCALATE trial was designed to compare the side effects and survival of two different chemoradiation strategies. The study enrolled 334 patients with low-risk HPV-positive oropharyngeal cancer from 32 centers in the UK, Ireland, and The Netherlands. Patients were randomly assigned 1:1 to receive cetuximab or cisplatin plus radiation therapy (70 Gy in 35 fractions over 7 weeks in both arms). Cisplatin at 100 mg/m² was given on days 1, 22, and 43. Cetuximab was given with a pretreatment loading dose followed by 250 mg/week. The average patient age was 57 years, and 80% were male.

With a minimum follow-up of 24 months, no difference was observed between the treatment arms for severe overall acute and late toxicity (mean number of 5.45 events per patient for cetuximab and 5.37 events per patient for cisplatin), with similar rates of grades 3 to 5 and all-grade toxicities in both arms. Significantly more serious adverse events were observed with cisplatin than with cetuximab (162 vs 95). In both treatment arms, quality of life was similar, as was swallowing function.

Poorer Overall Survival With Cetuximab

Survival was significantly worse with cetuximab, with an 8.1% difference in overall survival favoring cisplatin. Two-year overall survival was 89.4% for cetuximab vs 97.5% for cisplatin (P = .001). Dr. Mehanna said the number needed to cause harm to 1 patient was 12.

“The study was not powered to identify a survival difference. Hence, we were surprised to find a significantly worse overall survival with cetuximab,” Dr. Mehanna noted.

Cancer was more than three times more likely to recur in 2 years with cetuximab (29 recurrences) than with cisplatin (10 recurrences), with recurrence rates of 16.1% vs 6.0%, respectively (P = .0007). There were 20 deaths on the cetuximab arm and 6 deaths on the platinum arm.

Cisplatin was superior in terms of locoregional recurrence as well as distant recurrence. The rate of locoregional recurrence was 12% with cetuximab vs 3% with cisplatin (P = .003), and the rate of distant metastasis was 9% vs 3%, respectively (P = .009). The rate of second primary cancer was 3% in both arms.

The study enrolled low-risk HPV-positive patients who were nonsmokers or had less than 10 pack-years of smoking. The majority had stage I and II disease, which are associated with better outcomes. About 16% had stage III (T4) HPV p16–

Barbara Burtness, MD

positive disease, which is associated with slightly fewer good outcomes. “When we removed those slightly higher-risk patients [ie, with T4 disease] in a post hoc sensitivity analysis, there was still a difference between cetuximab and cisplatin favoring cisplatin,” Dr. Mehanna said.

“Now that we know which of these two drugs we should be using, we are looking at other therapies. However, we will be cautious about de-escalating therapy, because cisplatin was better in locoregional control and distant metastasis,” Dr. Mehanna said. “We need better results before we change practice.”

Cetuximab is still a reasonable choice for patients who cannot tolerate the standard of care.

U.S. Perspective

“In the United States, there is quite a lot of cetuximab use in the elderly and in platinum-ineligible patients,” said Barbara Burtness, MD, of Yale University School of Medicine and Yale Cancer Center, New Haven, Connecticut. “That practice will continue, but in platinum-eligible patients, platinum plus radiotherapy remains the standard of care, according to these results. A 2-year survival of 89% was observed with cetuximab, so cetuximab remains valuable in appropriate patients.”

Additional Commentary

ESMO expert Jean-Pascal Machiels, MD, PhD, of the Cliniques Universitaires St. Luc, UC Louvain, Brussels, said that this is the first randomized controlled trial in the curative setting in patients with HPV-positive oropharyngeal cancer.

Cisplatin plus radiotherapy should remain the standard of care for low-risk HPV-positive oropharyngeal cancer. We cannot extrapolate these results to HPV-negative cancer.

— Jean-Pascal Machiels, MD, PhD

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“Some patients have a very good prognosis with chemoradiotherapy. A previous study found that cetuximab/radiotherapy was superior to radiotherapy alone. Doctors began using cetuximab on this basis, and we thought cetuximab/radiotherapy could replace chemoradiotherapy. The study clearly demonstrated similar toxicity in both arms. Cisplatin plus radiotherapy should remain the standard of care for low-risk HPV-positive oropharyngeal cancer. We cannot extrapolate these results to HPV-negative cancer,” Dr. Machiels said.

“If you can’t give the standard of care with cisplatin/radiotherapy, then cetuximab/radiotherapy is a reasonable option,” he added. ■

DISCLOSURE: The study was sponsored by the University of Warwick and funded by Cancer Research UK. Dr. Mehanna has stock and other ownership interests with Warwickshire Head and Neck Clinic; is on the speakers bureau of Merck, MSD, and Sanofi Pasteur; has received institutional research funding from GlaxoSmithKline, MSD, Sanofi Pasteur, Silence Therapeutics, GlaxoSmithKline as well as personal research funding from AstraZeneca; and has received travel expenses from Sanofi Pasteur, MSD, and Merck. Dr. Burtness is a consultant/advisor to Merck, MedImmune, Boehringer Ingelheim, Amgen, Debiopharm Group, VentiRx, AstraZeneca, Bristol-Myers Squibb, Alligator Biosciences, Genentech/Roche, and Aduro Biotech. Dr. Machiels is a consultant/advisor to Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Debiopharm Group, Nanobiotix, and Innate Pharma; and has received research funding from Novartis, Sanofi, Bayer, and Janssen.

REFERENCE

1. Mehanna H, Kong A, Hartley A, et al: Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy. ESMO 2018 Congress. Abstract LBA9_PR. Presented October 22, 2018.