Neoadjuvant Cabozantinib/Nivolumab Feasible For Borderline Resectable Patients with HCC

Preliminary data showing the neoadjuvant use of cabozantinib and nivolumab to be feasible for borderline resectable patients with hepatocellular carcinoma that can lead to potentially curative resection.

The combination of neoadjuvant cabozantinib (Cabometyx) and nivolumab (Opdivo) in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC) was found to be a feasible treatment with potential long-term benefits, according to research presented at the American Society of Clinical Oncology (ASCO) 2021 Gastrointestinal Cancers Symposium.1

The neoadjuvant combination therapy of these systemic therapies, which are traditionally used as monotherapy for patients with advanced HCC, met the primary safety and feasibility end point in the phase I study (NCT03299946) that looked at 15 patients with borderline resectable or locally advanced HCC. Twelve patients ultimately underwent successful R0 margin negative surgical resection, with 7 having either no pathological response or a minor pathological response. Five resected patients (41.7%), however, achieved either major or complete pathologic responses after 8 weeks of therapy on the neoadjuvant combination of cabozantinib and nivolumab prior to surgery. At a median follow up of 1 year, 4 out of the 5 patients with pathologic responses did not have disease recurrence.

“All patients with an [Alpha-Fetoprotein] that was elevated at baseline, achieved an AFP drop of 30% or greater over the course of neoadjuvant therapy,” said Mark Yarchoan, MD, in a presentation of these data at the symposium. “Encouragingly, the patients who had major pathologic responses had outstanding disease-free survival, with all of these patients having disease-free survival of greater than 200 days after surgery, whereas patients who did not achieve major pathologic responses had a high rate of disease recurrence quite early on.”

The trial met its primary safety endpoint as no patients experienced a treatment-related adverse effect (TRAE) that prevented them from continuing on to surgery within 60 days of their planned surgical evaluation. One patient declined surgery and 1 tumor could not be resected. One patient died due to biliary sepsis prior to surgical evaluation, but this was unrelated to treatment on the study. Of the 15 patients on the trial treatment, 8 (53.3%) experienced Grade 1/2 fatigue with other common Grade 1/2 AEs including nausea (33.3%), vomiting (20%), anorexia (13.3%0, diarrhea (13.3%), and palmar-plantar erythrodysesthesia syndrome (13.3%). Only 2 patients experienced grade 3/4 AEs, 1 patient had autoimmune hepatitis and 1 patient experienced myasthenia gravis.

The phase I study was an open-label single-arm study where patients received 8 weeks of therapy with oral cabozantinib 40mg daily plus 240mg of nivolumab intravenously every two weeks, followed by restaging of the patients and possible surgical resection depending on their response.2

Patients with locally advanced HCC were defined as borderline resectable by the researchers as having a solitary tumor bigger than 5 centimeters (cm), or unilobar multifocal disease with either 3 tumors or one tumor bigger than 3cm, or bilobar disease, or their tumor was bigger than 3cm with macrovascular invasion. Patients with extrahepatic spread, or with bilateral left and right branch portal vein involvement, were excluded from the trial. Notable tumor features highlighted in the presentation of these data saw that 40% (n=6) of patients had multinodular disease, 27% (4) had portal vein invasion, 60% (9) had infiltrative disease, and 40% (6) of patients had a tumor diameter over 10cm.1

The researchers also profiled the tumors after surgical resection, finding an enrichment of IFNγ+ effector memory, CD4+ and granzyme B+ effector, CD8+ T cells along with tertiary lymphoid aggregates in the pathologic responders.2 Looking at the spatial relationship of the cell types in responders and non-responders alike the researchers found that B cells were spatially distinct in patients that responded to the neoadjuvant treatment. Moreover, their cell “neighbors” were other B cells consistent with aggregated tumor lymphoid aggregates, according to Yarchoan, assistant professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, in the presentation.1

“Not only were there increased T-cells in the tumor microenvironment of responders versus nonresponders, but we were also surprised by the high infiltration of C20 positive B cells that were organized in tertiary lymphoid aggregates,” explained Yarchoan.

To the knowledge of the researchers, the use of cabozantinib plus nivolumab was the first use of a targeted therapy in combination with an immune checkpoint inhibitor in the neoadjuvant setting of patients with HCC who were initially ineligible for curative surgery.


1. Yarchoan M, Zhu Q, Durham J, Gross N, et al. Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC). Presented at: 2021 ASCO Gastrointestinal Cancers Symposium; Jan 15-17 2021; Virtual. Abstract 335. Accessed February 12, 2021.

2. Yarchoan M, Zhu Q, Durham J, Gross N, et al. Feasibility and efficacy of neoadjuvant cabozantinib and nivolumab in patients with borderline resectable or locally advanced hepatocellular carcinoma (HCC). J Clin Onol. 2021;39 (suppl 3):335-335. doi: 10.1200/JCO.2021.39.3_suppl.335