Sequential pembrolizumab may be optimal timing with chemoradiotherapy in head/neck cancer
CHICAGO — A sequential schedule of fixed-dose pembrolizumab with chemoradiotherapy conferred numerically higher PFS rates vs. concurrent timing of the drug among patients with locally advanced head and neck cancer, study results showed.
Researchers initiated the randomized phase 2 study among patients with intermediate- or high-risk, previously untreated disease to identify the preferred fixed-dose pembrolizumab (Keytruda, Merck) regimen for future testing.
“Sequential pembrolizumab may be the preferred regimen to compare in future trials,” David Anthony Clump II, MD, PhD, assistant professor of radiation oncology at UPMC and University of Pittsburgh Cancer Institute, said during a presentation of the results at ASCO Annual Meeting.
Background and methods
“Over the last 10 years, a significant amount of work has gone into integration of checkpoint inhibitors into the management of patients with head and neck cancer,” Clump said. He mentioned the CheckMate141 trial of the PD-1 inhibitor nivolumab (Opdivo, Bristol Myers Squibb) and KEYNOTE-148 trial of pembrolizumab plus platinum-containing therapy. Both trials showed improved OS among patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
However, the optimal timing of anti-PD-1 therapy in combination with chemoradiotherapy for locally advanced head and neck cancer has not been determined.
The addition of concurrent avelumab (Bavencio; EMD Serono, Pfizer), a PD-L1 inhibitor, to chemoradiotherapy showed no benefit in the JAVELIN-100 trial.
The randomized, phase 2 study included 80 patients with intermediate-risk, HPV-positive oropharyngeal cancer (more than 10 smoking pack-years or T4 or N3 disease) or HPV-negative, previously untreated locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx or oral cavity (PD-L1 unselected). Researchers randomly assigned patients between May 2016 and May 2021 to chemoradiotherapy (40 mg/m2 cisplatin weekly plus 70 Gy radiation therapy in 35 fractions) plus either concurrent (n = 41) or sequential (n = 39) pembrolizumab, dosed at 200 mg every 3 weeks for a total of eight doses. They stratified randomization according to HPV status and nodal stage.
About 62% of patients in each treatment group had HPV-positive disease.
Patients received pembrolizumab starting 1 week before chemoradiotherapy in the concurrent group and starting 2 weeks after in the sequential group.
Evaluation of the schedules plus chemoradiotherapy in order to recommend a regimen for subsequent testing served as the primary objective.
Median follow-up was 30.3 months.
Key findings
Each treatment schedule met predefined composite endpoints of dose-limiting toxicity rate of 20% or lower, 1-year local failure rate of less than 60% and 1-year PFS of 60% or higher.
Sequential pembrolizumab conferred numerically higher PFS rates vs. concurrent pembrolizumab at 1 year (89% vs. 82%), 2 years (89% vs. 78%) and 3 years (84% vs. 74%), as well as higher OS rates (1-year, 95% vs. 82%; 2-year, 95% vs. 78%; 3-year, 90% vs. 74%). Median PFS and OS had not been reached in either group.
Grade 3 adverse events occurred more often in the concurrent vs. sequential pembrolizumab group (95.1% vs. 87.2%). Two grade 5 events occurred in the sequential group vs. three in the concurrent group.
Implications
Researchers are currently examining single-cell RNA sequencing data with a goal of delineating intrinsic mechanisms related to the outcomes observed and the importance of the sequencing of therapies, Clump said.
“We’re hopeful that our correlative data, whether it’s PD-L1 status .... or that of circulating tumor biomarkers, may provide guidance and optimization of sequence of care,” he said.
Perspective
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With this study and the JAVELIN-100 trial, we have additional results demonstrating that the addition of a concurrent checkpoint inhibitor does not enhance chemoradiotherapy.
For those patients who have surgery as definitive therapy, adjuvant checkpoint inhibition is also under study by industry and in investigator-initiated trials.
Dr. Clump and colleagues from University of Pittsburgh present a well-designed, investigator-initiated phase 2 trial that compares both approaches. The design is internally valid with the outcome of sequential being better than concurrent. Sequential will be studied in the subsequent phase 3 study.
Perspective
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The failure of the JAVELIN trial leaves a major unmet need in bringing immunotherapy into the upfront treatment of potentially curable patients with HNSCC. By improving treatment in these patients, we can actually cure more patients. This randomized phase 2 trial provides encouraging data showing sequential checkpoint inhibitor therapy seems more promising than concurrent — warranting study in a definitive trial.
Harvard Medical School
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Clump DA, et al. Abstract 6007. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.