Current standard chemoradiation therapy remains the most effective treatment for selected patients with human papillomavirus (HPV)-positive oropharyngeal cancer, based on the results of the NRG-HN005 trial. Researchers have halted this large, randomized phase II/III trial after patients in the control arm reached an unprecedented 2-year progression-free survival rate of 98%, setting a new benchmark for treatment efficacy in early-stage, HPV-associated oropharyngeal cancer. These data were presented at the 2024 American Society for Radiation Oncology (ASTRO) Annual Meeting.¹

The study, which aimed to deintensify radiation treatments to prevent long-term side effects, found that deintensified approaches involving a lower radiation dose and either chemotherapy or immunotherapy in place of chemotherapy did not perform as well as the more rigorous standard chemoradiation approach.

“Deintensification of chemoradiation treatments for HPV-associated oropharyngeal cancers is of very high interest to patients and researchers, but our study makes clear that these approaches should remain experimental.”

— SUE S. YOM, MD, PhD, FASTRO

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“In cancer treatment, 98% progression-free survival at 2 years is a number you just don’t see,” said principal investigator of the trial Sue S. Yom, MD, PhD, FASTRO, the Irwin Mark Jacobs and Joan Klein Jacobs Distinguished Professor in Head and Neck Cancer Radiation Oncology at the University of California, San Francisco. “It is the highest that has ever been published in the literature for head and neck cancer and, in and of itself, is strong evidence that modern chemoradiation therapy is highly effective for these patients.”

Background

As Dr. Yom explained, HPV-positive oropharyngeal cancer now accounts for at least 70% of oropharyngeal cancer cases in the United States, with incidence rates increasing rapidly in most developed nations. It is the most common HPV-related cancer for men and the second most common for women, following cervical cancer. Patients with HPV-associated oropharyngeal cancers tend to be younger, she noted, with an average age at diagnosis of 55 in the United States, and typically have much better outcomes than those who have throat cancer caused by tobacco or alcohol use.

Radiation therapy is particularly effective for HPV-related tumors because of their radiosensitivity, but many patients experience severe side effects during treatment. Some patients also face long-term side effects from chronic inflammation and tissue damage, which can arise up to 20 years later, including difficulty swallowing or recurring infections of the soft tissues in the mouth and throat.

Study Design

The NRG-HN005 trial enrolled a total of 382 patients with HPV-associated, locoregionally advanced oropharyngeal squamous cell carcinomas. Patients were randomly assigned to one of three treatment arms:

• Control arm: 70 Gy total radiation (mildly accelerated over 6 weeks) combined with two cycles of cisplatin chemotherapy
• De-escalation arm 1: 60 Gy total radiation (over 6 weeks) combined with two cycles of cisplatin
• De-escalation arm 2: 60 Gy total radiation (mildly accelerated over 5 weeks) combined with six cycles of nivolumab immunotherapy in place of chemotherapy.

All patients received intensity-modulated radiation therapy. The study population was predominantly male (90.6%), White (87.5%), and never-smokers (79.4%).

New Benchmark for Progression-Free Survival

With a median follow-up of 2.2 years, the standard arm (70 Gy plus cisplatin) achieved a 2-year progression-free survival rate of 98.1% and a 2-year overall survival rate of 99%. The de-escalation arm 1 (60 Gy plus cisplatin) showed a 2-year progression-free survival rate of 88.6% and a 2-year overall survival rate of 98%, and the de-escalation arm 2 (60 Gy plus nivolumab) yielded a 2-year progression-free survival rate of 90.3% and a 2-year overall survival rate of 96.1%.

The phase II trial was designed to trigger a futility analysis for each experimental arm after a predetermined number of patients experienced disease progression. These tests showed that neither deintensified treatment approach met the threshold for noninferiority compared with the standard treatment, leading to the early closure of the trial.

“Deintensification of chemoradiation treatments for HPV-associated oropharyngeal cancers is of very high interest to patients and researchers, but our study makes clear that these approaches should remain experimental,” said Dr. Yom. “Further work needs to be done to find ways that we can reduce side effects while maintaining these extremely high cure rates.”

Dr. Yom concluded: “At this point, neither of the deintensification options we tested would be appropriate for standard-of-care use, because you would actually be changing some patients’ chance for a cure. As researchers, our focus now should be on identifying which patients may benefit from these newer paradigms and then finding a more personalized therapy that works for each of these different groups of patients.” 

DISCLOSURE: The NRG-HN005 study was supported by funding from the National Cancer Institute and Bristol Myers Squibb. Dr. Yom reported financial relationships with EMD Serono, Nanobiotix, Bristol Myers Squibb, Merck, UpToDate, Springer, and Elsevier.

REFERENCE

1. Yom SS, Harris J, Caudell JJ, et al: Interim futility results of NRG-HN005, a randomized, phase II/III non-inferiority trial for non-smoking p16+ oropharyngeal cancer patients. 2024 ASTRO Annual Meeting. Abstract LBA03. Presented September 30, 2024.

EXPERT POINT OF VIEW

Invited discussant Danielle Margalit, MD, MPH, Associate Professor of Radiation Oncology at Harvard Medical School, and a member of the Head and Neck Oncology Program at the Dana-Farber/Brigham & Women’s Cancer Center, underscored the importance of the results of the NRG-HN005 trial.

“This trial may not change practice but informs it tremendously,” she stated. “For many patients, it means that 70 Gy radiation and concurrent cisplatin really matter in achieving the highest possible cure rate. This regimen now has the largest body of scientific evidence and the highest cure rate among all regimens tested so far for HPV-associated oropharynx cancer in this very favorable population.”

According to Dr. Margalit, the study also demonstrates the limitations of broadly applying deintensification strategies. For patients seeking the optimal cure rate, the combination of 70 Gy and cisplatin remains the standard in this large trial–population setting.

“This outcome is surprising, given the decade of research trying to find a deintensified regimen that doesn’t compromise cure rates,” said Dr. Margalit. “However, it’s reminiscent of previous trials, where attempts to replace cisplatin with supposedly less toxic agents such as cetuximab were unsuccessful.”

Despite these results, Dr. Margalit remains hopeful about decreasing toxicity. She suggested that secondary analyses may reveal segments of the study population that did just as well with lower radiation doses or immunotherapy. Ongoing studies are exploring imaging and blood-based biomarkers to identify patients who may safely receive reduced-dose radiation while maintaining cure rates.

The study also creates a new benchmark for progression-free survival that future studies need to incorporate in their statistical design. Dr. Margalit pointed out that new studies will need to target progression-free survival more in the 95% range, which will be challenging and will require larger patient populations.

On a positive note, Dr. Margalit highlighted that despite 70 Gy and cisplatin remaining the standard, radiation therapy for head and neck cancer has evolved and made significant progress in reducing toxicity. This has been achieved by improvements in radiation techniques that spare more normal tissue and, in some cases, treat unilaterally instead of both sides of the neck.

DISCLOSURE: Dr. Margalit has received in-kind research support from Naveris (provision of study materials).