Noninferiority Trial Establishes Chemoradiotherapy Regimen as ‘First Standard of Care for HPV-Positive Oral Cancer’

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A noninferiority phase III trial, previously reported in The Lancet, has established the standard of care in human papillomavirus (HPV)-related oral cancer, according to Andy M. Trotti, MD, a radiation oncologist at Moffitt Cancer Center in Tampa, Florida. Data from the NRG Oncology RTOG 1016 trial showed that radiotherapy plus cetuximab was associated with poorer overall survival when compared with chemoradiotherapy with cisplatin in HPV-positive cancer of the oropharynx.1

Andy M. Trotti, MD

Andy M. Trotti, MD

Patients with HPV-related oropharyngeal cancer have a high survival rate (85%) and local control when treated with radiotherapy plus cisplatin, but the investigators initially hypothesized that substituting cisplatin with cetuximab might reduce short- and long-term toxicities, with comparable (noninferior) 5-year overall survival.

“Noninferiority of cetuximab was not demonstrated, so this was a negative trial, but it showed that accelerated intensity-modulated radiation therapy (IMRT)—70 Gy over 6 weeks with 2 cycles of high-dose cisplatin—is the standard of comparison for future trials,” said Dr. Trotti, who presented a clinical trial update at the 2019 Winship Cancer Institute of Emory University Updates in Management American Association for Cancer Research (AACR) and American Head and Neck Society (AHNS) Head and Neck Cancer Conference in Austin, Texas.2

Trial Schema

In the NRG Oncology RTOG 1016 trial, 805 patients with histologically confirmed HPV16-positive tumors were stratified by T stage (T1–T2 vs T3–T4), N stage (N0–N2a vs N2b–N3), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1), and smoking history (≤ 10 pack-years vs > 10 pack-years). Then they were randomly assigned to treatment in a 1:1 fashion.


  • Noninferiority of cetuximab was not demonstrated in the NRG Oncology RTOG 1016 trial, establishing the standard of care in human papillomavirus (HPV)-positive oropharyngeal cancer as intensity-modulated radiation therapy plus high-dose cisplatin.
  • Cisplatin was associated with better overall survival, progression-free survival, and locoregional failure when compared with cetuximab.
  • Measuring acute toxicity with the T-score method showed significantly higher toxicity in the cisplatin arm.

All patients received accelerated IMRT at 70 Gy over 6 weeks, in combination with either 2 cycles of high-dose cisplatin (100 mg/m2) given on days 1 and 22 of radiotherapy (n = 406) or cetuximab given at a loading dose of 400 mg/m2 5 to 7 days before radiotherapy, followed by 250 mg/m2 weekly for 7 doses (n = 399). The primary endpoint was overall survival.

According to Dr. Trotti, the patient population was typical: 90% male and a high performance status, about one-third smokers, and minimal T4 disease but very high rates of advanced nodal disease (90%).

“This study enrolled about twice as quickly as we predicted,” he added. “We thought it would take 6 or 7 years, but it actually took half that: in 3.5 years, we enrolled 987 patients.”

Noninferiority of Cetuximab Not Demonstrated

The estimated 5-year overall survival was significantly worse with cetuximab than with cisplatin: 78% vs 85% (P = .02). The progression-free survival was also significantly worse with cetuximab, at 67% vs 78% at 5 years (P < .001).

Furthermore, locoregional failure was significantly lower with cisplatin than with cetuximab (10% vs 17%; P < .001). And there was a trend toward less distant metastasis in the cisplatin arm, although this did not reach significance.

Moderate to High Toxicity Observed

“Outcomes were very good in this population, so it will be hard to do better, but patients did experience moderate to high toxicity,” said Dr. Trotti.

“Accelerated intensity-modulated radiation therapy—70 Gy over 6 weeks with 2 cycles of high-dose cisplatin—is the standard of comparison for future trials [in HPV-positive oropharyngeal cancer].”
— Andy M. Trotti, MD

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The investigators measured toxicity in several ways. With the standard “worst grade” method of measuring acute moderate to severe toxicity, each patient contributes one high-grade event to the bottom line. This method showed no significant difference between the arms. However, measuring acute toxicity burden by combining all grade 3 or 4 acute events (T score), showed a significant 40% increased acute toxicity in the cisplatin arm (P < .001).

“Using the T-score method, cisplatin was definitely more toxic than cetuximab,” commented Dr. Trotti. “This gives a truer representation of cisplatin toxicities.”

Late moderate to severe toxicities were similar in the two arms. There appeared to be no long-term impact on swallowing observed with either drug.

According to Dr. Trotti, future directions will focus on modulating the dose of cisplatin or the total dose of radiotherapy in this patient population. Data from multiple ancillary studies will also be analyzed (ie, biomarkers, tobacco, quality of life, cost-utility). ■

DISCLOSURE: Dr. Trotti reported no conflicts of interest.


1. Gillison ML, Trotti AM, Harris J, et al: Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): A randomised, multicenter, non-inferiority trial. Lancet 393:40-50, 2019.

2. Trotti AM: Radiotherapy plus cetuximab or cisplatin in human papilloma-virus positive oropharyngeal cancer (NRG 1016): A randomized multicenter non-inferiority trial. 2019 AACR-AHNS Head and Neck Cancer Conference. Plenary Session 5. Presented April 30, 2019.