Late-Breaking Research Supports Standard Cisplatin in HPV+ Oropharyngeal Cancer

Hisham Mehanna, MD

Cisplatin plus radiotherapy improved overall survival (OS) compared with cetuximab (Erbitux) plus radiotherapy in patients with HPV-positive oropharyngeal cancer, according to late-breaking results from the De-ESCALaTE HPV trial presented at the 2018 ESMO Congress.¹Results from this trial support the use of chemoradiotherapy as the standard of care for treatment in this patient population.

“Many patients have been receiving cetuximab with radiotherapy on the assumption that it was as effective as chemotherapy with radiotherapy and caused less side effects, but there has been no head-to-head comparison of the 2 treatments,” said lead investigator Hisham Mehanna, MD. “The surprise of the study was in the survival. What we found was significantly worse survival with cetuximab. The number needed to treat to cause harm was 12.”

During the 2-year study, there were 10 recurrences and 6 deaths in patients randomized to cisplatin compared with 29 recurrences and 20 deaths in those assigned to cetuximab. Patients in the cisplatin arm had a significantly superior 2-year OS rate than those on cetuximab (97.5% vs. 89.4%; HR, 4.99; 95% CI, 1.70-14.67;P= .001).

The difference in OS was driven by a difference in locoregional control and distant control. Patients assigned to cetuximab were 3 times more likely to recur in 2 years compared with cisplatin, with recurrence rates of 16.1% versus 6.0%, respectively (HR, 3.39; 95% CI, 1.61-7.19;P= .0007).

The incidence of oropharyngeal squamous cell carcinoma has been rising rapidly in Western countries with a doubling in the UK from 1996 to 2006, and another doubling from 2005 to 2010, an increase that has been attributed to HPV.

Patients with HPV-positive oropharyngeal cancer tend to be younger than those with HPV-negative cancer and thus will have to endure the lifelong side effects of chemotherapy for perhaps decades, explained Mehanna, chair, Head and Neck Surgery, Institute of Cancer and Genomic Sciences, University of Birmingham, UK.

“Younger patients respond well to treatment but the corollary to that, of course, is that they live for 3 or 4 decades after treatment,” he said at a press briefing. “And the treatment has significant toxicity, so they have to withstand the treatment effects.”

Cetuximab, an EGFR inhibitor, has therefore been proposed for treatment de-escalation to reduce the toxicity of standard cisplatin treatment. Data from a 2006 study showed that cetuximab with radiotherapy reduced the risk of locoregional progression or death without an increase in toxicity compared with radiotherapy alone in patients with locoregionally advanced head and neck cancer.²

The aim of De-ESCALaTE was to compare cetuximab with standard cisplatin for survival and toxicity when combined with radiotherapy in HPV-positive low-risk oropharyngeal cancer. A total of 334 patients were enrolled at 32 centers in the UK, Ireland, and the Netherlands. Patients were randomly assigned to radiotherapy and either cisplatin or cetuximab. Eighty percent of patients were male and the average age was 57 years.

There was no difference in mean global health status or swallowing scores between the 2 groups. The mean number of overall adverse events (AEs) per patients was not different between the cisplatin and cetuximab arms (5.37 vs 5.45 events per patient, respectively. The incidence of acute or late severe (grade ≥3) AEs per patient (4.81 vs 4.82) or all grade acute and late toxicity (29.15 vs 30.05 events per patient) was similar between the cisplatin and cetuximab groups, respectively. Significantly more serious AEs (162 vs 95) were reported in the cisplatin arm compared with the cetuximab arm.

The study “showed that toxicity is the same with chemoradiation and cetuximab, even though there are more serious adverse events with chemoradiation,” said Jean-Pascal Machiels, MD, from the Department of Oncology, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium. “Clearly, we have a signal that chemoradiation has more activity in this setting. It should remain the standard of care.” The results cannot be extrapolated to HPV-negative disease, he added.

In a statement issued by ESMO, Branislav Bystricky, MED, head, Medical and Radiation Oncology Department, University Hospital Trenčín, Slovakia, said that the results from De-ESCALaTE are in agreement with interim findings of the US National Cancer Institute’s RTOG 1016 trial, which is scheduled to report this month.

“We now have two studies showing that these patients should not be given cetuximab,” he said. “Future research should examine whether genotyping for the KRAS-variant can select a group of patients that will benefit from cetuximab treatment with radiotherapy.”

Mehanna said that the findings from De-ESCALaTE emphasize the importance of conducting head-to-head controlled clinical trials before switching from a standard of care. He added that patients with HPV-positive oropharyngeal cancer deemed unable to tolerate chemotherapy may receive cetuximab.

References:

1. Mehanna H, Kong A, Hartley A, et al. Cetuximab versus cisplatin in patients with HPV-positive, low risk oropharyngeal cancer, receiving radical radiotherapy. Presented at: ESMO 2018; October19-23; Munich, Germany. LBA9_PR.
2. Bonner JA, Harrari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.N Engl J Med. 2006;354:567-78.