Neoadjuvant Cabozantinib/Nivolumab Leads to Improved Resection Rates in HCC


The combination of cabozantinib and nivolumab as a neoadjuvant regimen led to encouraging margin-negative resection and major pathological response rates in patients with hepatocellular carcinoma, according to results of a single-arm, phase 1b study that were published in Nature Cancer.

Won Jin Ho, MD

Won Jin Ho, MD

The combination of cabozantinib (Cabometyx) and nivolumab (Opdivo) as a neoadjuvant regimen led to encouraging margin-negative resection and major pathological response rates in patients with hepatocellular carcinoma (HCC), according to results of a single-arm, phase 1b study (NCT03299946) that were published in Nature Cancer.1

Specifically, findings showed that 12 of the 15 patients enrolled (80%), underwent successful margin-negative resection; the major pathological response rate was 42% (n = 5/12).

“The patients who are enrolled in this study are typically just thought of as incurable in the current conventional sense, so the fact that we saw these responses was really exciting, because this suggests this strategy could be adopted for very challenging incurable diseases,” said lead study author Won Jin Ho, MD, an assistant professor of oncology at Johns Hopkins University School of Medicine.2

While curative hepatic resection is optimal for patients with HCC, most patients are ineligible for surgery and those who do undergo resection often experience disease recurrence. Previously, the neoadjuvant setting has been a challenging setting with lack of effective agents, the authors noted in the publication.

Prior data of nivolumab plus ipilimumab (Yervoy) and cabozantinib (n = 35), and nivolumab plus cabozantinib (n = 36) alone, as seen in the phase 1/2 CheckMate-040 trial (NCT01658878), also demonstrated clinical signs of efficacy in patients with advanced HCC, providing the rationale for the PD-1/VEGF inhibitor combination in an earlier setting.3 Data showed that with nivolumab/cabozantinib, the investigator-assessed objective response rate was 17%; the disease control rate was 81%. The median progression-free survival and overall survival was 5.5 months and not reached, respectively.

In the single-arm, phase 1b study, investigators tested the feasibility of neoadjuvant cabozantinib plus nivolumab in 15 patients with HCC, including those outside of traditional resection criteria. All patients were recruited from Johns Hopkins Medicine’s Kimmel Cancer Center’s Liver and Biliary Cancer Multidisciplinary Clinic from April 2018 to September 2019. Resection was not recommended for all 15 patients’ disease due to the presence of high-risk tumor features. Six patients (40%) had multinodular disease, 4 (27%) had portal vein invasion, 9 (60%) had infiltrative disease, and 6 patients (40%) had tumor diameters larger than 10 cm. All patients were ineligible for liver transplantation, and most were given palliative locoregional treatment or lenvatinib (Lenvima) or sorafenib (Nexavar).

Cabozantinib was administered alone for 2 weeks before nivolumab treatment was initiated; the total treatment duration was 8 weeks. No patients had treatment-related adverse events (AEs) that prevented them from going to surgery within 60 days of the planned surgical evaluation date (95% CI, 0.0-0.19). One patient died during study treatment due to biliary sepsis, which was not related to the combination.

All-grade TRAEs occurred in 93.3% (n = 14) of patients, the most common of which were nausea, vomiting, and fatigue. Two patients experienced grade 3 or higher TRAEs, which included myasthenia gravis and autoimmune hepatitis and were both related to nivolumab. These improved to grade 1 or lower with immunosuppression.

TRAEs related to transient dose interruptions with cabozantinib occurred in 6 patients (40%), 2 of which (13%) required dose reductions. Grade 1/2 gastrointestinal-related toxicities were the most common cause of dose interruptions/reductions with cabozantinib. Nivolumab dosing was held in 2 patients (13%) because of grade 3/4 immune-related TRAEs.

Neoadjuvant treatment did not lead to any discernible adverse events during the perioperative period following surgery in any patients; no perioperative deaths occurred. One patient underwent extended left hepatectomy and portal vein thrombectomy who developed elevated liver enzymes, ascites, hypotension and lactemia, resulting in a prolonged postoperative hospital course. The patient did experience resolution.

Additional findings showed that the 5 patients who underwent resection experienced significant tumor shrinkage have remained disease free for more than 230 days. In the 4 patients who did not have a significant tumor response, they experienced disease progression between 56 and 155 days.

Seven patients had elevated alpha-fetoprotein (AFP) at study baseline, all of whom experienced a decline in AFP of at least 30% over the course of therapy.

Furthermore, in-depth biospecimen profiling following combination treatment showcased effector T-cell enrichment; tertiary lymphoid structures, CD138+ plasma cells, and a distinct spatial arrangement of B cells in responders vs nonresponders were also observed. These data demonstrate B-cell contribution to antitumor immunity in HCC, the authors concluded.

“We had a hunch that there were patients who were currently incurable that we could get to a surgery who would do well, and sure enough, there was a group of patients who participated in this study who are alive today without tumor who would not have been offered surgery before,” said senior study author Mark Yarchoan, MD, assistant professor of oncology at the Johns Hopkins University School of Medicine.“We wanted to use a combination that reflected the standard of care, and this combination reflected where we feel the field is going in terms of using 2 drugs together to try to maximize the therapeutic effects.”

In January 2021, cabozantinib and nivolumab were granted FDA approval for the frontline treatment of patients with advanced renal cell carcinoma.


  1. Ho WJ, Zhu Q, Durham J, et al. Neoadjuvant cabozantinib and nivolumab convert locally advanced hepatocellular carcinoma into resectable disease with enhanced antitumor immunity. Nat Cancer. Published online July 29, 2021. doi:10.1038/s43018-021-00234-4
  2. Drug Combination Gets Advanced Liver Cancer Patients to Surgery. News release. Johns Hopkins Medicine. July 29, 2021. Accessed August 25, 2021.
  3. Yau T, Zagonel V, Santoro A, et al. Nivolumab (NIVO) + ipilimumab (IPI) + cabozantinib (CABO) combination therapy in patients (pts) with advanced hepatocellular carcinoma (aHCC): results from CheckMate 040. J Clin Oncol. 2020;38(4):478. doi:10.1200/JCO.2020.38.4_suppl.478
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