Neoadjuvant Cemiplimab Elicits Complete Pathological Responses in HCC

Significant tumor necrosis was observed in 20% of patients with resectable hepatocellular carcinoma (HCC) who received neoadjuvant treatment with cemiplimab-rwlc (Libtayo), according to data from an open-label, multicohort phase 2a study (NCT03916627) that was virtually presented during the AACR Annual Meeting 2021.

Significant tumor necrosis, defined as greater than 70% necrosis of the resected tumor, was reported in 4 of 20 patients following treatment with neoadjuvant cemiplimab, meeting the primary end point of the study. Additionally, 15% of patients (n = 3/20) achieved complete tumor necrosis of 100%, while 35% of patients (n = 7/20) had tumor necrosis of at least 50%.

“The pathological response data support larger trials to identify optimal clinical end points that correlate with improvement in survival, and to establish the utility and safety of perioperative PD-1 in patients with resectable HCC,” lead study author Thomas Urban Marron, MD, PhD, the assistant director of immunotherapy and early phase trials at The Tisch Cancer Institute, and an assistant professor of medicine, Hematology and Medical Oncology, at the Icahn School of Medicine at Mount Sinai, said in an oral presentation on the data.

For patients with early-stage HCC, the recommended first-line treatment is surgery. Although negative margins are often observed at the time of resection, most of the tumors recur. It is hypothesized that disease recurrence is a result of micrometastases that persist after surgery. Neoadjuvant therapy could potentially improve outcomes for patients with HCC, although there is no standard recommended treatment in this setting.

Cemiplimab is an IgG4 monoclonal anti–PD-1 agent that has been FDA approved for select patients with advanced cutaneous squamous cell carcinoma, as well as select patients with advanced or metastatic basal cell carcinoma, and in patients with non–small cell lung cancer (NSCLC) who have a PD-L1 expression of 50% or higher. In the phase 2a study, investigators sought to examine the clinical activity of the agent in patients with resectable HCC.

To be eligible for enrollment, patients had to be at least 18 years of age, have an ECOG performance status of 0 or 1, and acceptable organ function. Those who had received prior cancer treatment within 6 months before entering the study or who had undergone major surgery within 14 days of starting neoadjuvant treatment were excluded. Additionally, those with metastatic disease for whom surgery would not be curative, who had ongoing or active infection that required antibiotics, active autoimmune disease that required systemic treatment in the past year, or who had undergone an organ transplant, were not eligible.

Patients with HCC who were candidates for surgical resection were treated with neoadjuvant cemiplimab intravenously at a dose of 350 mg every 3 weeks (Q3W) for 2 cycles prior to surgery. Following the procedure, patients were treated with the same dosing regimen for an additional 8 cycles.

“Before treatment, patients underwent 3D MRI imaging and core needle biopsies of their tumor,” Marron noted. “Blood was collected throughout the perioperative period, and patients underwent repeat 3D MRI imaging immediately before surgical resection.”

The primary end point of the study was significant tumor necrosis, based on pathological analysis of gross tumor resection at the time of surgery. Secondary end points included delay of surgery, disease-free survival, overall response rate per modified RECIST v1.1 criteria, overall survival, adverse effects, and change in lymphocyte infiltration.

Among the 21 patients enrolled to the study, the median age was 68 years (range, 45-82), and 85.7% were male. Additionally, 52.4% were of Asian descent and 85.7% had an ECOG performance status of 0. Patients received a median duration of 6 weeks (range, 5.3-6.7) of neoadjuvant treatment. One patient was found to have metastatic disease upon surgery and resection was aborted.

Additionally, pathological assessments of change in necrosis and tumor-infiltrating CD8 T cell density from baseline were conducted in both pretreatment biopsies and resected tumor samples following neoadjuvant treatment. Resected tumor samples were processed for tumor DNA, multiplex ion beam imaging, immunohistochemistry (IHC) assays, mutational analysis, and single-cell biomarker analysis.

Initial pathological assessments demonstrated a potential association between immune cell infiltration and tumor necrosis. Multiplex IHC and single-cell tissue and blood analysis are ongoing.

In terms of safety, 90.5% of patients (n = 19/20) experienced at least 1 treatment-emergent adverse effect (TEAE) of any grade, while 28.6% (n = 6) reported an effect that was grade 3 or higher in severity.

The most common TEAEs of any grade comprised increased aspartate aminotransferase (28.6%; n = 6), increased alanine aminotransferase (14.3%; n = 3), increased blood creatine phosphokinase (14.3%; n = 3), constipation (14.3%; n = 3), and fatigue (14.3%; n = 3), while the most frequent grade 3 or higher TEAEs included elevated blood creatine phosphokinase (9.5%; n = 2), increased aspartate aminotransferase (4.8%; n = 1), and hypoalbuminemia (4.8%; n = 1).

Additionally, 1 patient experienced grade 3 pneumonitis while receiving neoadjuvant treatment with cemiplimab, which resulted in a surgery delay of 2 weeks per the protocol-defined surgical window. Once the TEAE was resolved, the patient underwent surgery.

Reference

Marron T, Gunasekaran G, Tabrizian P, et al. Neoadjuvant cemiplimab demonstrates complete pathological responses in hepatocellular carcinoma. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT182.