Thomas Marron, MD, Ph.D., Director of the Early Phase Trials Unit, Associate Professor of Medicine at Icahn School of Medicine at Mount Sinai. In this video, he speaks about Neoadjuvant cemiplimab for resectable hepatocellular carcinoma: a single-arm, open-label, phase 2 trial.
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Overview:
Background Early-stage hepatocellular carcinoma is routinely surgically resected; nevertheless, most tumors return after surgery, and no perioperative intervention has been found to improve survival. Neoadjuvant immunotherapy has generated pathological responses in a variety of tumor types and may reduce the likelihood of hepatocellular carcinoma recurrence after surgery. The goal of this study was to see how well neoadjuvant cemiplimab (an anti-PD-1) worked in patients with resectable hepatocellular carcinoma.
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Patients with resectable hepatocellular carcinoma (stage Ib, II, or IIIb) were enrolled in this single-arm, open-label phase 2 trial and received two cycles of neoadjuvant cemiplimab 350 mg intravenously every 3 weeks followed by surgical resection. Patients required to be at least 18 years old, have confirmed resectable hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0 or 1, and have adequate liver function to be considered. Patients were excluded if they had metastatic disease, if the surgery was not likely to be curative, if they had another malignancy that required active treatment, or if they needed systemic steroid medication or any other immunosuppressive therapy. Patients were given an additional eight cycles of cemiplimab 350 mg intravenously every three weeks after resection as adjuvant therapy. On histological evaluation, substantial tumor necrosis (defined as >70 percent necrosis of the resected tumor) was the primary outcome. The proportion of patients who had an overall response, the change in CD8+ T-cell density, and adverse events were all secondary goals.
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All patients who received at least one dose of cemiplimab and underwent surgical resection were evaluated for tumour necrosis and response; safety and other objectives were assessed in the intention-to-treat group. Biopsies were taken prior to treatment and blood was taken during treatment. This study has been registered with
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The trial is registered at ClinicalTrials.gov (NCT03916627, Cohort B) and is still underway.
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Observations:
Twenty-one patients were enrolled between August 5, 2019 and November 25, 2020. All of the patients were given neoadjuvant cemiplimab, and 20 of them had their tumors successfully removed. Four (20%) of the 20 patients with removed tumors demonstrated substantial tumor necrosis. Three (15%) of the 20 patients experienced a partial response, while the rest of the patients had stable disease. During the neoadjuvant treatment period, 20 patients (95%) experienced a treatment-emergent adverse event of any severity. Elevated aspartate aminotransferase (in four patients), increased blood creatine phosphokinase (in three), diarrhea (in three), and exhaustion were the most common adverse events of any grade (in three). Increased blood creatine phosphokinase (in two individuals) and hypoalbuminemia were among the grade 3 adverse events experienced by seven patients (in one). There were no events in grades 4 or 5 that were witnessed. Pneumonitis struck one of the patients, causing a two-week delay in surgery.
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Analysis:
To our knowledge, this is the largest clinical trial of a neoadjuvant anti-PD-1 monotherapy in hepatocellular carcinoma described to date. The pathological responses to cemiplimab found in this cohort support the establishment of larger studies to determine the best treatment duration and definitively confirm the clinical benefit of preoperative PD-1 inhibition in hepatocellular cancer patients.