In 10 years, we’ll likely have a much better understanding of what combination therapeutics are most efficacious, understand what biomarkers can stratify patients for immunotherapy, and further develop novel approaches, including cellular therapies and innate immune targeting. —Ravindra Uppaluri, MD, PhD
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October 2020
Window of Opportunity Trials
Checkpoint inhibitors have changed the practice of treating HNSCC, but even with the positive results, the response rate is still limited to 15% to 20% of patients. “The bottom line is that there continues to be a high need for improved therapy for patients who have locally advanced as well as recurrent or metastatic head and neck disease,” said Maie St. John, MD, PhD, professor and Thomas C. Calcaterra, MD, Chair in Head and Neck Surgery at the University of California, Los Angeles. “It’s a complex balance of immune cell interactions and cell signaling, and we’re trying to harness that to treat our patients.”
Dr. Gourin agreed. “The real challenge ahead is identifying which patients will respond to immunotherapy,” she said. “If we knew this, we could select patients for immunotherapy over conventional treatment with surgery or standard nonsurgical treatment with radiation or chemoradiation.”
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That’s why clinical trials of immunotherapy are shifting from treating the sickest patients—those with recurrent or metastatic cancers—to treating earlier stages of cancer, Dr. Uppaluri said. Such a strategy would allow clinicians “to deintensify treatment and decrease collateral damage to normal tissues by giving less radiation, particularly for patients with HPV-positive HNSCC tumors that have a very favorable prognosis,” said Jeffrey Myers, MD, PhD, professor and Alando J. Ballantyne Distinguished Chair of Head and Neck Surgery at The University of Texas MD Anderson Cancer Center in Houston. “There’s some hope, based on the exciting results of ‘window of opportunity’ trials, that in the future we might be able to give a combination of a checkpoint inhibitor and chemotherapy to reduce the size of tumors that could then be treated with lower doses of radiation, thereby improving treatment-related sequalae of high-dose radiation.”
Immunotherapy also has brought a sea change to the treatment of patients with advanced cutaneous squamous cell carcinoma (CSCC). Two checkpoint inhibitors are approved by the FDA as first-line systemic therapy for these malignancies: pembrolizumab and cemiplimab (Libtayo, Regeneron). In patients with CSCC, PD-1 blockade with cemiplimab yielded a 49% overall response rate, with a prolonged durable response in the majority of responders, and a 15% incidence of adverse events, “which is a much better [clinical] response than seen with chemotherapy,” said Dr. Gourin (N Engl J Med. 2018;379:341-351).
In addition, the side effect profile appears to be more favorable in patients on immunotherapy compared with patients receiving standard of care: Adverse events occurred in 15% of the immunotherapy patients compared with 35% of patients receiving standard therapy. The results of these trials led to FDA approval of cemiplimab in September 2018 for the treatment of patients with metastatic or locally advanced CSCC.