The addition of pembrolizumab (Keytruda) to a chemoradiotherapy regimen yielded complete response rates of 85% in patients with human papillomavirus (HPV)-positive advanced squamous cell carcinoma of the head and neck. These findings from a phase Ib study were presented at the 2018 Society for Immunotherapy of Cancer (SITC) Annual Meeting.¹

Steven Powell, MD

“The data for pembrolizumab plus chemoradiotherapy in HPV-positive patients with head and neck cancer show encouraging response rates and progression-free survival in a predominantly higher-risk population,” said lead investigator Steven Powell, MD, of Sanford Cancer Center, Sioux Falls, South Dakota.

As Dr. Powell explained, radiotherapy and chemotherapy can induce upregulation of programmed cell death ligand 1 (PD-L1) in the tumor’s microenvironment, indicating a mechanism of immune escape and providing a rationale for adding anti–programmed cell death protein 1 (anti–PD-1)/PD-L1 drugs to treatment. Furthermore, some mouse models have shown head and neck cancers to be “cold tumors” that do not respond to checkpoint inhibition alone, but the addition of chemoradiation creates synergy that enhances tumor regression. Such findings led to this phase I study of pembrolizumab plus chemoradiotherapy in advanced head and neck cancer, he said.

Study Regimen

The study enrolled patients with HPV-positive and HPV-negative tumors, with 34 and 23 patients, respectively, evaluable for the interim analysis. All patients were eligible for definitive chemoradiotherapy and were not surgical candidates. The HPV-positive cohort had at least 70% of cells staining positive for P16.

The regimen’s backbone was cisplatin at 40 mg/m² given weekly for 6 planned doses, radiation therapy at 2 Gy once daily for a total of 70 Gy, plus pembrolizumab at 200 mg every 3 weeks for 8 planned doses. Patients first received pembrolizumab 1 week before chemoradiation, and this treatment was followed by 2 doses during chemoradiation and 5 doses afterward. Weekly cisplatin was chosen because it is potentially less myelosuppressive than some other regimens and avoids the need for dexamethasone, which may dampen the immune response. The primary endpoint was overall complete response at day 150.

“Defining the efficacy endpoint of complete response for head and neck cancer is a little bit of a challenge,” Dr. Powell noted. “At the end of treatment, these patients often won’t meet standard [Response Evaluation Criteria in Solid Tumors] criteria for complete response because they still have residual measurable disease.”

The addition of pembrolizumab did not impact the safety of standard chemoradiotherapy. We were able to achieve our full radiation dose and, for the vast majority of patients, our intended chemotherapy dose.

— Steven Powell, MD

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The researchers therefore used three different criteria for labeling complete response: Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, the Hopkins criteria, or surgical response. The Hopkins criteria were adapted to include imaging by positron-emission tomography (PET). If the patient did not demonstrate complete response by imaging (ie, there was residual disease), a complete response could be demonstrated on biopsy and/or salvage resection showing no viable tumor cells.

Dr. Powell presented the findings in the 34 patients with HPV-positive, predominantly oropharyngeal tumors. The majority of patients had stage IV disease (based on the 7th edition of the American Joint Committee on Cancer staging system), but those with distant metastasis were excluded. He noted that the study enrolled a large subset with unresectable T4 lesions and/or bilateral neck disease, as well as many patients with a relatively heavy smoking history. Altogether, approximately 80% of the population had intermediate-risk disease, “which is a higher risk group than your standard HPV-related cancer group,” he indicated.

Findings by Criteria for Response

Based on RECIST version 1.1 criteria alone, the complete response rate to pembrolizumab plus chemoradiotherapy was 62%, with partial responses seen in 11 patients (32%). Two patients (6%) had progressive disease. By the Hopkins criteria, using PET scans alone, 78% of the cohort achieved a complete response.

Of the 11 patients with partial response by RECIST version 1.1, 6 ultimately achieved a negative result on PET (Hopkins criteria) and were then judged to have a complete response. One patient with positive disease by PET imaging underwent a salvage neck dissection, which revealed inflammatory tissue and not residual disease; this patient was judged to have a complete response. As for the two patients with progressive disease by RECIST version 1.1, one had a positive result on PET scan, but the biopsies were negative for malignancy; that patient was deemed to have a complete response. If a posttreatment PET scan raises concerns about disease progression, Dr. Powell recommend biopsy for confirmation.

Ultimately, the final complete response rate based on imaging and surgical biopsy was 85%. Of four partial responders, two had negative biopsies; thus, they were deemed to have complete responses clinically that fell short of meeting the study’s efficacy endpoint, however two patients did not undergo salvage surgery due to no clinical evidence of disease. The two remaining patients had locoregional or residual disease.

To date, one responder to the regimen experienced disease progression and died of his disease. There have been no other cases of disease progression or deaths from cancer during the first year of follow-up. The estimated probability of progression-free survival at 1 year is 97.5%. At this point, the overall survival data mirror the progression-free survival data, Dr. Powell reported.

Tolerability

Two patients discontinued treatment due to immune-related adverse events, both of which resolved. Two patients discontinued the study because of protocol reasons. Most adverse events were in line with previous experience with this regimen. The chemotherapy and radiotherapy regimens were able to be administered as planned, with no major delays in treatment. “The addition of pembrolizumab did not impact the safety of standard chemoradiotherapy,” Dr. Powell added. “We were able to achieve our full radiation dose and, for the vast majority of patients, our intended chemotherapy dose.”

Several phase III studies combining chemoradiotherapy with anti–PD-1/PD-L1 agents are ongoing. “It will be interesting to see how this regimen pans out in higher-risk disease,” he said. ■

DISCLOSURE: Dr. Powell is a consultant for Bristol-Myers Squibb.

REFERENCE

1. Powell SF, Gitau M, Reynolds J, et al: Pembrolizumab in combination with chemoradiotherapy in human papillomavirus-associated head and neck squamous cell carcinoma. 2018 SITC Annual Meeting. Abstract O50. Presented November 10, 2018.