Immune Therapies Emerging in Disease-Specific Treatment of HPV-Positive Head and Neck Cancer

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Patients with human papillomavirus (HPV)-related head and neck cancer stand to benefit greatly from immunotherapy, according to Nabil F. Saba, MD, FACP, Director, Head and Neck Medical Oncology Program, Winship Cancer Institute of Emory University, Atlanta. He added, immunotherapy will likely play a role in de-escalation regimens and could possibly be added to the standard-of-care backbone of cisplatin and radiation therapy for the intermediate risk group of HPV related head and neck cancer.

Nabil F. Saba, MD, FACP

Nabil F. Saba, MD, FACP

“Both HPV related disease and its treatment are rapidly evolving fields, in addition to the fact that immunotherapy applications are rapidly evolving as well,” said Dr. Saba at the 2019 Winship Cancer Institute of Emory University Updates in the Management of Head and Neck Cancer Symposium.1 “We know that the potential of immunotherapy in HPV-related cancer is quite significant, but the question is how to better define the role of immunotherapy, and in what setting? How do we harness the immune system to fight this virally driven cancer?”

Dr. Saba maintains that the answer to that question lies in more research—particularly clinical trials that target HPV-positive disease specifically, rather than focusing on both HPV-positive and HPV-negative cancers.

Current State of Immunotherapy in HPV-Related Disease

Currently, there are no immunotherapy regimens approved specifically for HPV-positive disease, no immunotherapy indications specific to HPV within de-intensification approaches, and no indications in the intermediate-risk HPV group within the backbone of platinum-based chemotherapy and radiation (which remains the standard of care for treating HPV-related disease). The programmed cell death protein 1 (PD-1) inhibitors pembrolizumab and nivolumab are approved in recurrent or metastatic disease that has failed to respond to platinum therapy, regardless of HPV status.

Even though the current standard of care in immunotherapy does not differ according to HPV status, this approach will likely change with future trials, according to Dr. Saba. Two clinical trials in particular focusing on immunotherapy in HPV-positive head and neck cancer should be on the oncologists’ radar, he noted.

Disease-Specific Trials Underway

The Eastern Cooperative Oncology Group (ECOG) 3161 trial will enroll patients with locally advanced, intermediate-risk HPV-positive oropharyngeal cancer ( identifier NCT03811015). According to Dr. Saba, this trial is unique in that it builds on the backbone of the current standard of care and adds immunotherapy in the maintenance phase. Patients in the trial will be randomly assigned to either cisplatin and intensity-modulated radiation therapy followed by nivolumab or cisplatin and radiation followed by observation.

“You have here a healthier patient population who may not need as much treatment intensity beyond cisplatin and radiation as the HPV-negative population,” said Dr. Saba. “So, it makes perfect sense to use a maintenance immunotherapy approach for that group of patients, rather than a concurrent approach or intensification.”

The phase II/III NRG-HN005 trial will explore whether the use of immunotherapy can allow for safe de-intensification of therapy in the early-stage, HPV-positive population (NCT03952585). As there are currently no biomarkers for identifying those patients whose therapy can be de-intensified safely, de-intensification can be risky, even in early-stage disease, noted Dr. Saba. In this trial, de-intensified radiation therapy with nivolumab will be compared head to head with standard-of-care cisplatin and radiation.

“I think HN005 is set to answer some important questions in terms of whether the use of nivolumab with lower-dose radiation is safe for the HPV-positive, low-risk population,” Dr. Saba stated. “But the backbone always comes back to cisplatin and radiation; anything that claims to be aimed at improving care for HPV-positive patients has to be compared with that backbone.”

Treading Lightly: De-escalation in HPV-Related Disease

De-intensification in HPV-related cancer is now being adopted “widely but haphazardly,” and these efforts are occurring simultaneously with the development of immunotherapy. Despite some encouraging results in de-escalation, there are still many unanswered questions, warned Dr. Saba.

“De-intensification needs to be done carefully.”
— Nabil F. Saba, MD, FACP

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Not all patients with HPV-positive tumors are candidates for de-escalation, as some tumors behave aggressively, and distant metastases remain a predominant concern in HPV-related head and neck cancer. He emphasized the potential dangers inherent in de-intensification and wide misinterpretation of the AJCC 8th edition that resulted in a large group of patients with stage IV disease (by AJCC 7) moving to stage I by AJCC8. Just because these patients have a better outcome than historical patients does not per se justify de-intensification as their improved outcome is based on the standard intensive therapy they received. He stressed the importance of de-intensifying treatment within the confines of a clinical trial setting whenever possible.

“I want to impress upon you that de-intensification needs to be done carefully,” he said, citing a recently reported phase III trial in which HPV-positive patients randomly assigned to radiation plus cisplatin had better 5-year outcomes than those who received radiotherapy plus cetuximab.2 “These results were a wakeup call as they showed that, even for patients who receive full-dose radiation therapy, the outcome seems to be affected by changing the systemic agent.”

According to Dr. Saba, potential immunotherapeutic combinations in head and neck cancer will depend on multiple factors, not just HPV status. However, in HPV-related cancer, the ultimate focus should be on identifying “the targeted therapeutic best married with immunotherapy that will ultimately lead to making a difference in this particular setting,” he concluded. ■

DISCLOSURE: Dr. Saba is a consultant and has received compensation from Pfizer, Merck, BMS, Lilly, Vaccinex, Kura, Celldex Therapeutics, and Aduro; and has received funding from BMS, Exelixis, Novartis, and the National Institutes of Health.


1. Saba N: Immuno-oncology applications in HPV-related OPSCC. 2019 Winship Cancer Institute of Emory University Updates in the Management of Head and Neck Cancer Symposium. Presented April 27, 2019.

2. 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, multicentre, non-inferiority trial. Lancet 393:40-50, 2019.