Head and Neck Cancer Immunotherapy in Locally Advanced Disease: Clinical Trial Updates

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Programmed cell death protein 1 (PD-1) inhibitors are approved for the second-line treatment of head and neck cancer and likely will be soon in the first-line treatment of locally advanced disease. According to Robert L. Ferris, MD, PhD, developments in immunotherapy for this population should be driven by studies in those with locally advanced disease. Studying these patients to identify biomarkers of response, rather than focusing on patients with metastatic disease, could potentially drive personalized immunotherapy.

At the 2019 American Association for Cancer Research (AACR) and American Head and Neck Society (AHNS) Head and Neck Cancer Conference in Austin, Texas, Dr. Ferris discussed trials aimed at finding a place for immunotherapy in locally advanced disease.1

The Current Landscape

Locally advanced head and neck cancer is dominated by two subsets—human papillomavirus (HPV)-associated disease and smoking-associated cancers. The role of immunotherapy differs depending on the clinical features of these diseases.

“HPV-positive and -negative diseases are changing, so the shift in etiology as well as in prevalence mandates that we perform prospective clinical trials,” said Dr. Ferris, Director of the University of Pittsburgh Medical Center Hillman Cancer Center. “A control group in any study is crucial because the disease is changing, the outcome is changing, and so, our comparison to the current standard disease will vary.”

As we talk about where immunotherapy fits [in locally advanced head and neck cancer], we should not discard the fact that cetuximab could remain a good partner for immunotherapy.
— Robert L. Ferris, MD, PhD

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According to Dr. Ferris, the current therapeutic options for locally advanced disease tend to be institution-driven, rather than data-driven, but concurrent chemoradiotherapy with cisplatin is the nonsurgical regimen of choice. “As we talk about where immunotherapy fits, we should not discard the fact that cetuximab could remain a good partner for immunotherapy,” he noted. “We may see data emerge in the locally advanced setting that bring cetuximab back into consideration.”

Other standard treatment options include cetuximab plus radiation, radiation alone, surgery followed by adjuvant radiation or chemoradiation, and induction therapy followed by concurrent chemoradiation. But immunotherapy may have an emerging role in locally advanced disease, particularly in those for whom surgery would be disfiguring. Immunotherapy could also potentially replace current therapy or serve as de-intensification among low-risk patients with HPV-positive tumors.2

According to Dr. Ferris, part of the reason immunotherapy is appealing as a treatment option in these patients is because of the viral etiology of head and neck cancer. The question now is whether that viral status can be harnessed for locally advanced treatment.

De-intensification Strategies

Eastern Cooperative Oncology Group (ECOG) 1308 was the first de-intensification trial for HPV-positive cancers. The study showed that patients with good prognoses (never-smokers with low or intermediate tumor burden) could safely get by with less radiation.3


  • Held April 29–30, 2019, in Austin, Texas
  • Theme: Optimizing Survival and Quality of Life Through Basic, Clinical, and Translational Research

The phase II ECOG 3311 trial in HPV-positive patients explored transoral robotic/laser surgery as a potential modality for de-intensification, but 30% of patients in the trial ended up receiving all three modalities: surgery, radiation, and chemotherapy.4 According to Dr. Ferris, this begs the question: can immunotherapy help with this clinical problem?

In response, he and his colleagues designed a trial ( identifier NCT03715946) that is now up and running at the University of Pittsburgh, with the hope of involving other centers. The trial enrolled 135 patients with gross extracapsular spread and five or more metastatic nodes. Instead of weekly cisplatin plus radiotherapy at 66 Gy, patients received a regimen of 50 Gy over 4 weeks (accelerated at 6 fractions per week) with nivolumab every 2 weeks, followed by 6 months of adjuvant nivolumab. “The ECOG 3311 trial may give us a hint as to whether this strategy will improve over the standard of care,” he said.

Immunotherapy for Intensification

The Radiation Therapy Oncology Group (RTOG) 3504 trial demonstrated the safety and early efficacy of introducing immunotherapy—in this case nivolumab—to chemoradiotherapy with cetuximab or cisplatin for patients with intermediate-risk and high-risk locoregionally advanced squamous cell head and neck cancer.5 For surgically dissected patients, the standard of care for high-risk individuals with positive margins and extracapsular spread is concurrent chemoradiation with weekly cisplatin, but a phase I trial demonstrated the safety of adding the anti–PD-1 antibody atezolizumab to this treatment regimen.

“The hope now is to integrate this as an arm into the high-risk RTOG 1216 population,” said Dr. Ferris. “This regimen would be tested with a concurrent control group, asking: can we take these patients who have a very poor postoperative outcome and receive an intensive regimen, and add something that appears to be as safe as an intensification regimen?”

Immunotherapy in Low-Risk Disease

In low-risk disease, de-intensification is aimed at reducing the radiation dose, eliminating or reducing the morbidity of surgery, and potentially replacing systemic therapy. According to Dr. Ferris, immunotherapy is poised to assume a place in all of these scenarios.

The HN-005 trial (a follow-up to HN-002) was designed to compare radiation at 60 Gy with cisplatin to 60 Gy with anti–PD-1, or 60 Gy of radiation alone. “We’re beginning to see that anti–PD-1 might be a gentler systemic therapy since some of these patients still may develop distant disease,” he noted. “And we’re not overwhelmingly convinced that cisplatin is the drug of choice to reduce distant disease, so perhaps immunotherapy could help in that regard.”

When Should Immunotherapy Be Introduced?

A phase II trial is exploring whether a PD-1 inhibitor should be a sequential or concurrent add-on to chemoradiotherapy.6 In week 2 of radiation, patients in the trial receive on-treatment tumor biopsy so that biomarkers can be -compared during concurrent chemoradiation with or without a PD-1 inhibitor.

Traditionally, we drive therapy advances for locally advanced disease with positive recurrent metastatic disease. I’d like to suggest that we use locally advanced disease itself to guide this therapy with a neoadjuvant approach….
— Robert L. Ferris, MD, PhD

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Another phase II trial demonstrated that combined therapy with nivolumab and ISA 101—a synthetic long-peptide HPV-16 vaccine—results in promising efficacy in HPV-positive patients.

In the CheckMate 358 trial, objective tumor shrinkage was seen in about half of patients after two preoperative doses of neoadjuvant nivolumab, demonstrating the activity of anti–PD-1 in the preoperative setting.7 “So perhaps we could actually use this to change surgery, if not to improve survival,” he said. “But also, can we use the posttreatment specimen to guide and personalize the appropriate regimen?”

Where Do We Go Now?

It has been established that immune checkpoint therapy, specifically PD-1 pathway blockade, improves survival in patients with metastatic squamous cell carcinoma of the head and neck. But when it comes to integrating immunotherapy into locally advanced disease, according to Dr. Ferris, certain questions remain: Does immunotherapy enhance survival as an add-on to intensify treatment? Can immunotherapy be used to replace chemotherapy or reduce radiotherapy or surgery? And how and when can combinations be tested more rapidly?

“Traditionally, we drive therapy advances for locally advanced disease with positive recurrent metastatic disease,” he said. “I’d like to suggest that we use locally advanced disease itself to guide this therapy with a neoadjuvant approach, and not simply target each of these molecules with large phase II and phase III trials with too many combinations, where sequencing is complicated.” 

DISCLOSURE: Dr. Ferris is a consultant/advisor for Bristol-Myers Squibb, Lilly, Pfizer, Amgen, EMD Serono, Tesaro, PPD, Bain Capital Life Sciences, GlaxoSmithKline, Iovance Biotherapeutics, Numab Therapeutics, Oncorus, Ono Pharmaceutical, Regeneron, and TTMS; and has received research funding from Bristol-Myers Squibb, VentiRx, AstraZeneca/MedImmune, Merck, and Tesaro.


1. Ferris R: Integrating head and neck cancer immunotherapy into locally advanced treatment. 2019 AACR-AHNS Head and Neck Cancer Conference. Presented April 30, 2019.

2. Ang KK, Harris J, Wheeler R, et al: Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363:24-35, 2010.

3. Marur S, Li S, Cmelak AJ, et al: E1308: Phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx—ECOG-ACRIN Cancer Research Group. J Clin Oncol 35:490-497, 2017.

4. Li S, Ferris R, Holsinger FC, et al: E3311 trial of transoral surgery for oropharynx cancer: Implementation of a novel surgeon credentialing and quality assurance process. 2016 ASCO Annual Meeting. Abstract 6054. Presented June 4, 2016.

5. Ferris R, Gillison M, Harris J: Safety evaluation of nivolumab concomitant with cetuximab-radiotherapy for intermediate and high-risk local-regionally advanced head and neck squamous cell carcinoma: RTOG 3504. 2018 ASCO Annual Meeting. Abstract 6010. Presented June 1, 2018.

6. Jie HB, Srivastava RM, Argiris A, et al: Increased PD-1+ and TIM-3+ TILs during cetuximab therapy inversely correlate with response in head and neck cancer patients. Cancer Immunol Res 5:408-416, 2017

7. Ferris RL, Goncalves A, Baxi SS, et al: LBA46. An open-label, multicohort, phase 1/2 study in patients with virus-associated cancers (CheckMate 358): Safety and efficacy of neoadjuvant nivolumab in squamous cell carcinoma of the head and neck. Ann Oncol 28(suppl 5):v605-v649, 2017.