The Role of Checkpoint Inhibitors in the Treatment of Head and Neck Cancer

This year, the National Institutes of Health estimates that approximately 60,000 Americans will be diagnosed with head and neck cancer. Although survival rates have increased over the last 30 years, the five-year relative survival rate for oral and oropharyngeal cancers is still only approximately 60% percent. Otolaryngologists, surgeons, and medical and radiation oncologists have had little to offer to patients whose disease has progressed despite surgery, chemotherapy, and radiation—until now.

In early August 2016, the U.S. Food and Drug Administration approved pembrolizumab (Keytruda, Merck Sharp and Dohme Corp.) for use in patients with recurrent or metastatic head and neck squamous cell carcinoma that is refractory to platinum-based chemotherapy. The drug received accelerated approval based on early data from the KEYNOTE-012 trial. Trial participants received 200 mg of pembrolizumab IV every three weeks for 24 months, or until disease progression or they reached intolerable toxicity. The overall objective response rate was 16%, with a complete response rate of 5%. The drug elicited response in both HPV-positive and HPV-negative tumors (24% vs. 16%). Eighty-two percent of those who responded to the medication did not have progression of disease for at least six months. Now, some patients are doing well more than two years out from their initial treatments (J Clin Oncol. 2016;34(suppl; abstr 6011)).

The traditional platform for treating head and neck has been a table with three legs, surgery, radiotherapy, and chemotherapy. Immunotherapy, in essence, brings a fourth leg to the table. —David Brizel, MD

Pembrolizumab is a checkpoint inhibitor, a drug that essentially unmasks tumor cells so the immune system can attack and destroy them. Specifically, pembrolizumab is a PD-L1 inhibitor; it inhibits the interaction of PD-L1, a protein on tumor cells and PD-1, a protein on T-cells. Checkpoint inhibitors “turn off the off switch, which has the net effect of turning the immune system back on,” said David Brizel, MD, Leonard Prosnitz Professor of Radiation Oncology at Duke University in Durham, N.C.

The idea of unleashing the immune system against cancer cells is not new. What is new is the hope that these medications are offering hope to patients who would otherwise have no options. Maura Gillison, MD, PhD, professor of medicine and Jeg Coughlin Chair of Cancer Research at The Ohio State University Comprehensive Cancer Center in Columbus, has seen remission following checkpoint inhibitor treatment in some of her patients.

Checkpoint inhibitors “fulfill the promise of the immunotherapy that we’ve had for decades,” said Robert Ferris, MD, PhD, professor of otolaryngology and co-leader of the Cancer Immunology Program University at the Pittsburgh Cancer Institute. “Early clinical trial data suggests that checkpoint inhibitors can provide long-term, durable regression or stability. That durability has been the ‘holy grail’ for many years.”

Another Weapon in the Arsenal

In 2014, the National Cancer Institute’s Head and Neck Steering Committee held a clinical trials planning meeting to discuss the possible role of immunotherapy, including checkpoint inhibitors, in the treatment of head and neck cancer. At the time, checkpoint inhibitors had already shown promise in the treatment of melanoma, renal cell carcinoma, non-small cell lung cancer, urothelial bladder cancer, and recurrent or metastatic squamous cell carcinoma of the head and neck. The group planned priority phase II/III trials to help physicians determine the best ways to integrate immunotherapy into practice.

Since then, researchers have learned that head and neck cancers are particularly good targets for checkpoint inhibitors. Why? Many head and neck cancers are caused by smoking, and the tumors have a high mutational load. “There is some data to suggest that tumors that have frequent mutations in them are more likely to generate tumor-specific neoantigens that T-cells can recognize as foreign in attack. And, there have been studies showing that the higher the number of mutations in the tumor, the more robust the response to checkpoint inhibitors,” Dr. Gillison said.

No one yet knows, though, how to tell which patients will be among the 20% or so who respond to checkpoint inhibitor therapy, and which ones will be among the 80% who do not benefit. “We unfortunately do not have a biomarker to tell us for sure if the patient will respond or not,” said Erminia Massarelli, MD, PhD, associate clinical professor of medical oncology at City of Hope in Duarte, Calif. “High mutational load could possibly predict response to immunotherapy, but it’s not ready as a biomarker. The PD-L1 test is a very weak biomarker, because it is a continually changing response; if a tumor is PD-L1 negative, it doesn’t mean that it cannot be PD-L1 positive at some point.”

Now that pembrolizumab has received FDA approval for use in patients with head and neck squamous cell carcinoma, however, practitioners have an alternative to offer patients with recurrent or metastatic disease. Experts predict that nivolumab (Opdivo, Bristol-Myers Squibb), another PD-L1 checkpoint inhibitor, will be the next to receive FDA approval, based on the results coming out of the CheckMate-141 study. According to lead investigator Dr. Gillison, nivolumab reduced the risk of death by 30% compared with standard therapy. One-year survival was 36% in the nivolumab arm, versus 16.6% in the control arm. Further, the proportion of patients who survived a year on nivolumab was double that of the control arm. “This is the first agent ever to show a survival benefit in platinum-refractory head and neck cancer, in the history of treating this disease,” Dr. Gillison said. “That’s why everybody is so excited.”

Indeed, immunotherapy can now be considered the fourth modality of head and neck cancer treatment, Dr. Brizel said. “The traditional platform for treating head and neck has been a table with three legs, surgery, radiotherapy, and chemotherapy. Immunotherapy, in essence, brings a fourth leg to the table.”

Monitoring Patients on Checkpoint Inhibitors

Checkpoint inhibitors are generally well tolerated. In fact, many patients experience fewer adverse events than they did on standard chemotherapy. The most common side effects include fatigue, mild diarrhea, and skin rash or itching.

More serious side effects include pneumonitis, colitis, and endocrine system dysfunction. “About 9% of patients experience immune-mediated toxicity,” Dr. Gillison said. “Those are the ones that can be particularly life-threatening, particularly pneumonitis and colitis.”

Red flag symptoms include difficulty breathing, hypoxia, cough (with no obvious cause), and an increase of four or more bowel movements per day above the patient’s baseline. If these symptoms occur in a patient on checkpoint inhibitors, immediate attention is needed. “If symptoms are severe enough to be life-threatening, you may have to stop the therapy permanently. Other times, you can hold it and see if symptoms improve. You may also need to give steroids to suppress the immune system and treat the side effect,” said Pavlos Msaouel, MD, PhD, oncology fellow at MD Anderson and co-author (with Dr. Massarelli) of a 2016 article (Cancer J. 2016;22:108-116).

There is some data to suggest that tumors that have frequent mutations in them are more likely to generate tumor-specific neoantigens that T-cells can recognize as foreign in attack. There have been studies showing that the higher the number of mutations in the tumor, the more robust the response to checkpoint inhibitors. —Maura Gillison, MD, PhD

Thyroid dysfunction occurs in approximately 16% of patients, said Dr. Msaouel, so patient thyroid function levels should be monitored during treatment; supplemental thyroid hormone should be given as necessary. Because checkpoint inhibitors can affect the liver as well, liver function tests should be checked. Be alert for hypophysitis; very rarely, the pituitary gland is affected.

Most patients, though, tolerate the medication extremely well. In fact, in the CheckMate-141 study, the patients treated with nivolumab experienced a better quality of life than patients treated with the chemotherapy regimen. They “had sustained physical, emotional, and social functioning, whereas the patients treated with chemotherapy had significant declines,” Dr. Gillison said. “So not only did we see an improvement in survival, but we saw a 60% reduction in moderate to severe toxicity and market stability in quality of life outcomes.”

The Future

Ongoing and upcoming clinical trials hope to answer many unanswered questions, such as when to begin and stop checkpoint inhibition and how to best combine checkpoint inhibitors with chemotherapy, radiation, and other immune-oncology agents. New checkpoint inhibitors are being studied, and researchers are working to better understand the physiology of head and neck tumors, hoping to identify a biomarker that can help physicians determine which patients are likely to benefit from checkpoint inhibition.

Ultimately, it is hoped that checkpoint inhibitors will improve the overall survival rate for head and neck cancers. “What everyone is most excited about is trying to move these agents rapidly into the clinic for treatment of newly diagnosed head and neck cancer,” Dr. Gillison said. “We’re hopeful that the survival benefit we’re seeing in the recurrent metastatic platinum-refractory setting may translate into more cures in the primary setting.”

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Jennifer L.W. Fink is a freelance medical writer based in Wisconsin.