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.
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
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.”
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.
There’s some hope, based on ‘window of opportunity’ trials, that we might be able to give a checkpoint inhibitor and chemotherapy to reduce tumor size. —Jeffrey Myers, MD, PhD
EAGLE and JAVELIN Trials
Enthusiasm to introduce other immunotherapy agents and to move to earlier stages of disease has been tempered by two recent trials. The first trial, EAGLE, tested the potential efficacy of a combination of anticytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, tremelimumab) and anti-PD-L1 blockade (durvalumab, Imfinzi) in R/M HNSCC (Ann Oncol. 2020;31:942-950).
Patients were randomly assigned to receive durvalumab, durvalumab plus tremelimumab, or standard of care (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary endpoints were overall survival (OS) for durvalumab versus standard of care, and OS for durvalumab plus tremelimumab versus standard of care. Secondary endpoints included progression-free survival (PFS), objective response rate, and duration of response. There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus standard of care. However, higher PFS at 12 to 24 months and objective response rates demonstrated clinical activity for durvalumab.
“What we found is that the combination of the PD-L and CTLA-4 antibody had no benefit,” Dr. Ferris noted, “which definitely surprised us. CTLA-4 agents have been shown to improve melanoma, renal, and lung cancers. Interestingly, the control arm [chemotherapy] did far better than the treatment arms. We suspect that the targeting or dosing schedule of the CTLA-4 wasn’t optimal. We’re in the process of analyzing the results of the trial; papers will be presented at the 2020 European Society for Medical Oncology Virtual Congress.”
In the JAVELIN Head and Neck 100 study, 697 treatment-naïve patients with locally advanced HNSCC were randomly assigned to receive avelumab (Bavencio), an anti-PD-L1 agent, added to chemoradiotherapy and compared with standard treatment. Patients were given one dose of avelumab before chemoradiation, and then every three weeks during the trial. This trial was ended early as it was unlikely to meet its endpoint of PFS and objective response rate, according to a press release from the manufacturer.
Results from several of the other Phase III trials in the definitive setting are anticipated soon, including the Keynote-412 trial.
Although the EAGLE and JAVELIN trails failed to meet their primary endpoints, there are a number of trials in progress looking at introducing immunotherapy prior to radiation, chemotherapy, and surgery for patients with oropharyngeal squamous cell carcinoma (OPC), for example.
Window of opportunity surgical trials offer an approach to discover biomarkers and investigate their preoperative therapeutic impact. In 28 patients with stage II or locally recurrent OPC, MD Anderson Cancer Center researchers, led by Renata Ferrarotto, MD, and Neil Gross, MD, compared neoadjuvant durvalumab with durvalumab plus tremelimumab. Patients were given two courses of immunotherapy prior to transoral robotic surgery (TORS). In aggregate, responses were seen in 43% of patients, and 29% had major pathologic response of the primary tumor and no pathologic evidence of metastasis. Although neither baseline CD8+TIL density nor PD-L1 expression level correlated with overall response, there was a trend toward greater CD8+TIL infiltration after immunotherapy in patients who had a pathologic response. (Clin Cancer Res. 2020;26:3211-3219).
“This study is encouraging because it shows that we can stimulate an immune response in patients with OPC,” Dr. Myers said. “The agents were able to block inhibitory tumor T-cell interactions, regardless of whether the patients were HPV positive or negative.”
In the ongoing AZ TORS study at UCLA, led by radiation oncologist Robert Chin, MD, PhD, subjects received five doses of stereotactic radiotherapy with concurrent immunotherapy prior to resection. “We anticipated a significant reduction in toxicity, but the magnitude of tumor response exceeded our expectations,” said Dr. St. John. “Most patients had a complete response at the time of resection and no other subclinical disease.”
In another phase II trial led by Dr. Uppaluri, neoadjuvant pembrolizumab was studied in patients with HPV-unrelated HNSCC (ClinicalTrials.gov Identifier: NCT02296684). Pebrolizumab was given two to three weeks prior to surgical tumor ablation and postoperative chemoradiation. Any pathologic tumor response (pTR) occurred in 44%, of patients, and the one-year relapse rate among high-risk patients was 16.7%, which was lower than historical rates (Clin Cancer Res [published online ahead of print July 14, 2020]). This concept is now being tested in an international Phase III clinical trial (NCT03765918, KEYNOTE 689). Multiple other neoadjuvant approaches are being tested in HNSCC.
Patients with preexisting immunologic diseases and those with organ transplants who are on immunosuppressive therapy aren’t good candidates for immunotherapy because these agents can worsen underlying disease or damage the transplanted organ, Dr. Gourin noted. However, researchers at Johns Hopkins are conducting a new trial for organ transplant patients with skin cancers who are on immunosuppression. “The researchers are looking at whether anti-PD-1 agents can be given with lower doses of antirejection medications and steroids to generate anti-tumor immunity while protecting the allograft,” she said.
With all the ongoing trials, I have great enthusiasm for the up-and-coming therapeutic options for HNSCC patients with novel agents and combinations in immunotherapy and beyond. —Ravindra Uppaluri, MD, PhD
An earlier study of T-VEC (talimogene laherparepvec, Imlygic), an oncolytic virus, was successfully used in a heart transplant patient with recurrent melanoma. After five therapy cycles, “no evidence of graft rejection has been observed and the patient achieved a complete remission of their melanoma,” noted the study authors (J Immunother Cancer. 2017;5:45).
Looking back, Dr. Uppaluri noted that few would have predicted the wide impact that immunotherapy has achieved in 2020. “With all the ongoing trials, I have great enthusiasm for the up-and-coming therapeutic options for HNSCC patients with novel agents and combinations in immunotherapy and beyond.”
Nikki Kean is a freelance medical writer based in New Jersey.