Phase II Trial Finds Neoadjuvant Immunotherapy Feasible in Oral Cavity Cancer

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The results of a phase II study suggest that a short course of immunotherapy prior to surgery for oral cavity cancer may trigger tumor regression, possibly providing long-term benefits for patients. According to data presented at the 2020 Multidisciplinary Head and Neck Cancers Symposium,1 a 3-week neoadjuvant course of the programmed cell death protein 1 (PD-1) inhibitor nivolumab with or without the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor ipilimumab showed promising tumor responses in patients with resectable oral cavity squamous cell carcinoma, with no delays in surgery observed.

Although the study was not powered to directly compare nivolumab with nivolumab/ipilimumab, researchers reported high rates of volumetric and pathologic response with near-complete and complete responses observed, mostly in the combination arm.

Jonathan Schoenfeld, MD, MPH

Jonathan Schoenfeld, MD, MPH

“We were very encouraged by the high response rates and the impressive pathologic responses in both arms, but especially with the nivolumab/ipilimumab combination,” said Jonathan Schoenfeld, MD, MPH, Senior Physician at Dana-Farber Cancer Institute and Brigham and Women’s Hospital and Associate Professor of Radiation Oncology at Harvard Medical School, Boston. “I think the real question is ‘does this translate into a significant progression-free or overall survival advantage?’ That is worthy of further study.”

As Dr. Schoenfeld reported, patients with locally advanced oral cavity squamous cell carcinoma have high rates of relapse and death despite the standard of surgery, which is often followed by adjuvant radiation therapy with or without chemotherapy. Because patients in the neoadjuvant setting are generally untreated and their immune systems have not been affected by prior treatments such as chemotherapy, he explained, there is significant potential for immunotherapy.

“There is an intact tumor that can potentially allow for generation of an antitumor immune response in contrast to other settings,” said Dr. Schoenfeld, who noted that these patients tend to have a lower burden of disease as compared to patients with metastatic disease. “Treatment in the neoadjuvant setting could lead to a durable benefit due to the persistence of this antitumor immune response, even after immunotherapy is stopped.”

In addition, said Dr. Schoenfeld, PD-1 inhibitors have demonstrated a survival advantage in patients with advanced and metastatic oral cavity squamous cell carcinomas. Mechanistic synergy between PD-1 and CTLA-4 immune checkpoint inhibition has been supported both in preclinical models and in other malignancies such as melanoma.

Study Methodology

For this phase II study, Dr. Schoenfeld and colleagues enrolled patients with squamous cell carcinoma of the oral cavity that were clinically at least T2 and/or node-positive. The investigators randomly assigned patients to treatment with two cycles (weeks 1, 3) of nivolumab (3 mg/kg) or nivolumab plus ipilimumab (nivolumab at 3 mg/kg, ipilimumab at 1 mg/kg with the first cycle). Surgery was performed 3 to 7 days after the second cycle.

The study’s primary endpoints were safety; tolerability; and volumetric response, defined as any clinical, radiologic, or pathologic decrease in bidirectional measurements, with the prespecified goal of achieving a 15% response rate in either arm. Secondary endpoints included objective response per Response Evaluation Criteria in Solid Tumors, v1.1, clinical-to-pathologic downstaging, pathologic response of primary tumor (determined by a head and neck pathologist blinded to treatment), and disease-free survival.

Significant Pathologic Response Observed

As Dr. Schoenfeld reported, of the 30 patients treated, investigators excluded 1 patient subsequently found to be ineligible due to metastases at baseline. The most common primary tumor site was the oral tongue (n = 16). Baseline clinical staging included 58% of patients (n = 17) with node-positive disease and 62% with stage IVA disease.


  • In a phase II study, patients receiving nivolumab or nivolumab plus ipilimumab demonstrated promising rates of clinical-to-pathologic downstaging and pathologic response, including complete responses.
  • Although the study was not powered to assess progression-free or overall survival in comparison to historic controls, 86% of patients are alive and disease-free, with a median follow-up of 14 months.

Although there were no delays to surgery, six patients failed to receive the full two-cycle dose, and one patient with T4 disease was shifted to definitive chemoradiation therapy despite evidence of radiologic tumor shrinkage. However, investigators were “encouraged” by the toxicity data seen with this short course of neoadjuvant treatment, said Dr. Schoenfeld. He noted that severe-immune related toxicities, including grade 3 pneumonitis and grade 3 colitis, were generally reversible with treatment and did not interfere with surgery.

Regarding response to immunotherapy, Dr. Schoenfeld reported significant rates of volumetric response, including 50% with nivolumab and 53% with nivolumab plus ipilimumab. The investigators also observed significant pathologic responses. The results showed that 15% of patients treated with nivolumab monotherapy and 33% of patients treated with dual immunotherapy had a pathologic response greater than 50%. Moreover, 20% of patients who received dual inhibitors and 8% of patients who received nivolumab monotherapy had a pathologic response greater than 90%.

The study was not powered to assess progression-free or overall survival in comparison to historic controls, said Dr. Schoenfeld. However, he noted, with median follow-up of 14 months, 86% of patients are alive and disease-free. 

DISCLOSURE: Dr. Schoenfeld disclosed financial relationships with ACI Clinical, AstraZeneca, Bristol-Myers Squibb, Catenion, Debiopharm, Immunitas, LEK, Merck, Nanobiotix, Regeneron, and Tilos.


1. Schoenfeld JD, Hanna GJ, Jo V, et al: Neoadjuvant nivolumab +/- ipilimumab in patients with oral cavity cancer. 2020 Multidisciplinary Head and Neck Cancers Symposium. Abstract 1. Presented February 27, 2020.


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