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
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October 2020
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.
Ongoing Trials
Neoadjuvant Therapy
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.
Immunocompromised Patients
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.