In a single-institution phase II trial reported in The Lancet Gastroenterology & Hepatology, Marron et al found that neoadjuvant treatment with the PD-1 inhibitor cemiplimab-rwlc in patients with resectable hepatocellular carcinoma produced a high level of pathologic tumor necrosis at resection in approximately one-third of patients.
In the trial, 21 patients with resectable disease (stage Ib, II, or IIIb) were enrolled at the Icahn School of Medicine between August 2019 and November 2020. Patients received two cycles of neoadjuvant cemiplimab at 350 mg every 3 weeks followed by surgical resection; after resection, patients received an additional eight cycles of adjuvant cemiplimab at 350 mg every 3 weeks. The primary endpoint was significant tumor necrosis on pathologic examination, defined as > 70% necrosis of the resected tumor.
A total of 20 patients underwent successful resection; of these, 4 (20%) had > 70% tumor necrosis, including 3 with 100% necrosis. Tumor necrosis ≥ 50% was observed in seven patients (35%). Radiographic partial response was observed in three patients (15%), with all other patients maintaining stable disease on imaging performed at a median of 24 days (interquartile range = 23–29 days) following initiation of cemiplimab. Outcomes of the ongoing adjuvant phase of cemiplimab treatment were not available at the time of analysis.
Immunohistochemical analysis of post-treatment lesions showed increased density of immune infiltrates and greater numbers of tumor-infiltrating lymphocytes in patients with ≥ 50% necrosis vs those with little/no necrosis. Among eight patients with adequate tumor samples, mass cytometry showed significantly higher CD8-positive T-cell infiltration in the tumor (P = .001) in four with ≥ 50% necrosis (three with 100% necrosis and one with 50% necrosis) vs four with little or no necrosis.
During neoadjuvant treatment, treatment-related adverse events of any grade occurred in six patients (29%), with the most common being fatigue (14%) and infusion-related reactions (10%). Grade 3 treatment-related adverse events (no grade ≥ 4 events observed) occurred in two patients, consisting of maculopapular rash and pneumonitis, the latter of which delayed surgery by 2 weeks.
The investigators concluded, “This report is, to our knowledge, the largest clinical trial of a neoadjuvant anti–PD-1 monotherapy reported to date in hepatocellular carcinoma. The observed pathological responses to cemiplimab in this cohort support the design of larger trials to identify the optimal treatment duration and definitively establish the clinical benefit of preoperative PD-1 blockade in patients with hepatocellular carcinoma.”
Thomas U. Marron, MD, of the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, is the corresponding author for The Lancet Gastroenterology & Hepatology.
Disclosure: The study was funded by Regeneron Pharmaceuticals. For full disclosures of the study authors, visit thelancet.com.