What’s New in Immunotherapy?

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The use of immunotherapy for the management of head and neck squamous cell carcinomas (HNSCC) is now firmly established in otolaryngology as the fourth pillar of therapy, joining surgery, radiation, and chemotherapy. The questions now being asked in a number of ongoing clinical trials are how to improve response rates, how early immunotherapy can be introduced, and which patients will respond.   

The goal of immunotherapy is to either intensify therapy for high-risk patients with locally advanced, previously untreated tumors (T4 or N3) or to deintensify treatment for lower-risk patients (all other tumors), noted Robert L. Ferris, MD, PhD, director of the University of Pittsburgh Medical Center Hillman Cancer Center.

Immunotherapy’s ability to improve outcomes for patients with recurrent/metastatic (R/M) HNSCC was clearly shown in the CheckMate 141 (Oral Oncol. 2018;81:45-51) and Keynote-040 (ClinicalTrials.gov Identifier: NCT02252042) trials. These trials led to FDA approval of two checkpoint inhibitors that block the function of the programmed death receptor 1 (PD-1) pathway in 2016: nivolumab (Opdivo) and pembrolizumab (Keytruda). In 2019, the results of the Keynote-048 clinical trial led to the approval of pembrolizumab as a first-line therapy for patients with R/M HNSCC (ClinicalTrials.gov Identifier: NCT02358031).

Current regimens have revolutionized the treatment of head and neck cancers, noted Theodoros N. Teknos, MD, the president and scientific director of UH Seidman Cancer Center in Cleveland, Ohio. “I’ve seen remarkable durable responses not only when used as first-line agents, but also as second- and third-line options in my patients.” In many cases, Dr. Teknos noted, “these medications have yielded complete remissions in patients who had previously been treated with multiple courses of cytotoxic chemotherapy; they were basically nonresponsive and out of options.”

The response to immunotherapy seen in the CheckMate 141 and Keynote-048 trials was correlated with the extent of PD-1 ligand expression (PD-L1). For pembrolizumab in first-line R/M HNSCC, the combined positive score (CPS) of immunohistochemical PD-L1 staining is now clinically used to stratify patients, according to Ravindra Uppaluri, MD, PhD, director of head and neck surgical oncology at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute in Boston. The score is based on a composite expression of PD-L1, one of the two ligands for the PD-1 receptor, on tumor cells and infiltrating immune cells.

In the Keynote-048 study, pembrolizumab therapy alone was shown to benefit patients who had a CPS>1 (85%). For those with a CPS<1, pembrolizumab in combination with chemotherapy was shown to be beneficial relative to the standard chemotherapy alone, Dr. Uppaluri said. In a subgroup of patients with high PD-L1 expression, the overall survival difference was a bit more pronounced: 14.9 months for the pembrolizumab arm versus 10.7 months for the cetuximab plus chemotherapy arm (HR, 0.61; 95% CI, 0.45-0.83; P=0.0015).

The benefits of nivolumab were seen in the CheckMate 141 trial. The drug “nearly tripled” OS rates at a minimum of 24 months (16.9%) versus standard therapy (6.0%), Dr. Ferris said. “When you look at these patients, the PD-L1-negative patients had the identical long-term survival rates as PD-L1-positive patients. The response was faster in the positive patients, but if you continue immunotherapy treatment in the PD-L1-negative patients, they’ll have similar results—it just takes a little longer to ‘rev up the engine.’”

“Patients with human papilloma virus [HPV]-positive disease had better responses and survival than those who were HPV negative,” added Christine Gourin, MD, MPH, professor of otolaryngology–head and neck surgery at Johns Hopkins University in Baltimore. Although HPV status remains a strong prognostic factor in HNSCC, available data don’t support using HPV to stratify patients for immunotherapy treatment, Dr. Uppaluri said.