Pathologic complete responses were seen in 29% of patients with resectable hepatocellular carcinoma treated with a perioperative immunotherapy regimen in the first interim analysis of a phase II trial, reported Yehia I. Abugabal, MD, in his presentation at the 2019 ILCA Annual Conference.
Yehia I. Abugabal, MD
Pathologic complete responses (pCRs) were seen in 29% of patients with resectable hepatocellular carcinoma (HCC) treated with a perioperative immunotherapy regimen in the first interim analysis of a phase II trial, reported Yehia I. Abugabal, MD, in his presentation at the 2019 ILCA Annual Conference. The randomized, open-label study evaluated nivolumab (Opdivo) alone versus nivolumab plus ipilimumab (Yervoy) in patients with resectable HCC.
“While surgical resection is associated with a very high recurrence rate, we currently do not have any effective neoadjuvant or adjuvant therapy despite the fact that hepatocellular carcinoma is a very immunogenic tumor. In fact, low intratumoral CD8 T cells and ratio Teff:Treg cells [effector T cells:regulatory T cells] has been shown repeatedly to be related to a high incidence of recurrence and low survival after hepatocellular carcinoma resection,” said Abugabal, of The University of Texas MD Anderson Cancer Center in Houston. “Recently, PD-1 antagonists have shown significant activity in hepatocellular carcinoma and have been granted conditional approval.”
The study design was a randomized 1:1 trial of patients with resectable HCC, determined by surgeons as good candidates for either conservative hepatic resection or liver resection with curative intent. Thirty patients were expected to be enrolled and randomized between arms A and B. The primary endpoints were safety and tolerability, and the secondary endpoints included overall response rate and time until recurrence. Additional exploratory objectives focused on immunological/biomarker changes in the tumor tissue and peripheral blood.
Arm A received neoadjuvant nivolumab alone at 240 mg intravenously (IV) every 2 weeks for three doses. Surgery took place at the 6-week mark, followed by adjuvant nivolumab starting at week 10 at 240 mg IV every 2 weeks until recurrence or up to 2 years. Surveillance, including imaging, blood samples, insulin-like growth factor-1 score, and magnetic resonance elastography, occurred every 12 weeks.
Arm B followed the same surgical timeline, but with a neoadjuvant combination therapy of nivolumab 240 mg IV plus ipilimumab 1 mg/kg IV every 2 weeks for 3 doses. Adjuvant chemotherapy included nivolumab alone at 240 mg IV every 2 weeks plus ipilimumab 1 mg/kg IV every 6 weeks for up to 2 years or until recurrence, with surveillance completed every 12 weeks.
Four patients achieved a pCR, with a 50/50 split between the 2 study arms. One patient in each arm who achieved pCR had hepatitis C virus (HCV), one patient in the nivolumab-alone arm had hepatitis B virus (HBV), and one patient in the combination arm did not have hepatitis.
Two patients in arm A experienced grade 3 or higher treatment-related adverse events (TRAEs) post-operatively, including possible lipase and amylase increases. In arm B, 2 patients experienced grade 3 or higher events prior to surgery, of possible increases in ALT/AST, and one patient had a grade 3 TRAE post-operatively of definite colitis.
Treatment was deemed safe and surgical resection was not delayed. Only 1 patient did not undergo planned resection due to reasons that were unrelated to the study treatment.
Blood sampling and tumor sampling also took place prior to treatment as well as prior to surgery. “Imaging showed that prior to surgery the tumor looked very vascular, typical of HCC. At the time of surgery, there was no enhancement in the tumor,” said Abugabal.
“Further analysis identified very specific highly cytotoxic tumors in CD8 T cells,” he said. “These are a reflection of the activity of cytotoxic T cells.”
Pathological complete response was associated with a significant increase in 2 specific clusters of CD8 T cell and in the Teff/Treg ratio after therapy.
Two more patients have since been enrolled in the study, Abugabal noted.
“After validation, the study may contribute to a paradigm shift in the perioperative treatment of resectable HCC,” he concluded.
Kaseb AO, Duda DG, Tran Cao HS, et al. Randomized, open-label, perioperative phase II study evaluating nivolumab alone versus nivolumab plus ipilimumab in patients with resectable HCC. Presented at: 2019 ILCA Annual Conference; September 20-22, 2019; Chicago, IL. Abstract O-02.