Treatment with 70 Gy radiation plus cisplatin (the NRG/RTOG 1016 regimen) remains the standard of care for patients with nonsmoking p16-positive oropharyngeal cancer, based on interim futility results of the NRG-HN005 trial presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract LBA03).
The NRG-HN005 trial was designed to test the standard NRG/RTOG 1016 regimen against two deintensified radiation regimens with either cisplatin or nivolumab. However, interim futility analyses showed more progression-free survival (PFS) events in the experimental groups, and the trial was suspended.
“The NRG/RTOG 1016 regimen showed an astounding, impressive result demonstrating a 98% PFS rate through two, even three years,” said Sue S. Yom, MD, PhD, principal investigator of the trial and the Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor in Head and Neck Cancer Radiation Oncology at the University of California, San Francisco. “This is higher than any previous national head and neck trial and emphasizes that patients in this population are cured at exceedingly high rates with traditional chemoradiation approaches.”
The phase 2/3 study included patients with p16-positive oropharyngeal squamous cell carcinoma. Patients had to have 10 or fewer pack-year history of smoking. The investigators randomly assigned patients 1:1:1 to 70 Gy in six weeks, using six fractions per week plus two cycles of cisplatin (group 1; control); 60 Gy in six weeks, using five fractions per week plus two cycles of cisplatin (group 2); or 60 Gy in five weeks, using six fractions per week plus six cycles of nivolumab (group 3). The primary endpoint was PFS noninferiority.
Dr. Yom explained that a preplanned analysis would be triggered for futility when 11 events were reported between a combination of the control group and one of the experimental groups. The phase 3 trial would proceed either if one of the experimental groups did not trigger a futility analysis or at the end of phase 2.
The first futility analysis occurred at a median follow-up of 1.1 years, with nine of the 11 required PFS events occurring in group 2 and two in group 1. The estimated hazard ratio (HR) was 4.34, exceeding the preset boundary of noninferiority of HR <2.4. Group 2 was removed from the protocol, and randomization continued for groups 1 and 3.
The second futility analysis was triggered, at a median of 1.7 years of follow-up, after 11 PFS events occurred, with nine of the 11 required events occurring in group 3. The estimated HR was 4.51, again exceeding the preset boundary of noninferiority. Dr. Yom said that accrual would have stopped at this point, but phase 2 accrual was already complete.
At a median follow-up of 2.2 years, the 2-year PFS was 98.1% in group 1 compared with 88.6% in group 2 and 90.3% in group 3. The 2-year locoregional failure rate was 0% in group 1, 6.5% in group 2, and 5.0% in group 3. The 2-year overall survival estimates are 99.0% in group 1, 98.0% in group 2, and 96.1% in group 3.
“These results set a new benchmark for PFS expectations in this population,” Dr. Yom said. “Deintensification studies going forward must evolve to be more selective and more effective if they are going to be competitive in a more challenging population.”
Commenting on these results during a press conference, Danielle N. Margalit, MD, MPH, of Dana Farber Cancer Institute in Boston, Massachusetts, and vice chair of ASTRO oropharyngeal cancer guideline update, said that this trial is important not because it changes practice, but because it “informs practice tremendously”.
“What that means for patients is that 70 Gy radiation and concurrent cisplatin really remains the standard of care,” Dr. Margalit said. “This regimen has the largest body of scientific evidence and the highest cure rate among all the regimens tested so far for HPV-associated oropharynx cancer in this favorable population.”
This study was supported by the National Cancer Institute and Bristol Myers Squibb.
Dr. Yom reported relationships with EMD Serono, Nanobiotix, Bristol Myers Squibb, Merck, UpToDate, Springer, and Elsevier
Dr. Margalit reports no conflicts of interest.