Cabozantinib and SBRT: Two feasible post-IO strategies in HCC

Liver cancer is the fourth most common cause of death globally and the third in Hong Kong, where it accounts for approximately 10 percent of all cancer deaths. [Clin Mol Hepatol 2023;29:355-357; https://www.chp.gov.hk/en/healthtopics/content/25/52.html]

Apart from hepatic resection, transplantation, and locoregional treatment including ablation and transarterial therapy, systemic therapy is an important treatment modality for patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Before 2020, first-line systemic therapy consisted of sorafenib or lenvatinib, but it has been revolutionized by the introduction of ICIs. [Lancet 2017;389:2492-2502; N Engl J Med 2020;382:1894-1905; NEJM Evidence 2022;1] In 2021, the combination of atezolizumab and bevacizumab was approved as first-line treatment for HCC, followed by tremelimumab and durvalumab in 2022.

Second-line systemic treatment has also evolved over the past decade. According to both clinical trial and real-world data, 50–60 percent of patients are receiving second-line treatment. [Lancet Oncol 2022;23:995-1008; Liver Cancer 2021;10:107-114; J Clin Oncol 2022;40:379-379] This proportion is expected to increase due to the improved prognosis and hepatic function of patients.

At present, the majority of clinical data for second-line regimens is based on findings in patients who received sorafenib in the first line, while prospective evidence on second-line options following first-line use of ICIs is lacking. Most guidelines currently recommend second-line use of multi-kinase inhibitors (MKIs) following treatment with ICI-based regimens – mainly on the basis of retrospective real-world data. [J Hepatol 2021;75:960-974; J Clin Oncol 2020;38:4317-4345; Ann Oncol 2021;32:801-805]

2L cabozantinib after ICI – phase II trial in HK & South Korea

Cabozantinib is a multi-targeted MKI of VEGFR, MET and AXL, with efficacy demonstrated in the phase III CELESTIAL study involving patients with unresectable HCC who received prior treatment with sorafenib. [N Engl J Med 2018;379:54-63] Cabozantinib has also been studied in the post-ICI setting in multiple retrospective studies, which reported median progression-free survival (PFS) in the range of 3–4 months and median OS of 7–8 months. [Cancers (Basel) 2022;14:5173; Ther Adv Med Oncol 2022;14:17588359221097934; Cancers (Basel) 2021 May;13:2002]

An investigator-initiated phase II, single-arm, open-label, multicentre, prospective study involving three academic centres in Hong Kong and South Korea, namely the Chinese University of Hong Kong (CUHK), Asan Medical Center in Seoul, and Ulsan University Hospital in Ulsan, South Korea, assessed cabozantinib’s efficacy and safety in 47 patients with HCC who previously received ICI treatment (including, but not limited to, atezolizumab plus bevacizumab, tremelimumab plus durvalumab, and camrelizumab plus rivoceranib). [J Hepatol 2024;81:258-264]

Patients were recruited between October 2020 and May 2022. PFS was the primary endpoint. Cabozantinib was given at 60 mg QD.

At a median follow-up of 11.2 months, median PFS was 4.1 months and the 6-month PFS rate was 32.5 percent. Best radiological response of partial response and stable disease occurred in 6.4 and 76.6 percent of patients, respectively. Median OS was 9.9 months and the 1-year OS rate was 45.3 percent.

According to exploratory analyses, among 27 patients who received cabozantinib in the second-line setting, the median PFS and OS were 4.3 and 14.3 months, respectively. In the remaining 20 patients who received cabozantinib as third-line treatment, median PFS and OS were 4.0 and 6.6 months, respectively.

In general, treatment-related toxicity of cabozantinib was consistent with prior studies. The most common grade 3/4 treatment-related adverse events (TRAEs) were thrombocytopenia (6.4 percent) and hypertension (4.3 percent). Cabozantinib dose reductions had to be implemented in 74.5 percent of patients; 12.8 percent of patients discontinued treatment due to adverse events (AEs).

“This is the first clinical trial in the world to report the use of drug in the treatment of immunotherapy-resistant liver cancer. The study provides invaluable data for reference by clinicians and guidelines on liver cancer treatment,” noted Professor Stephen Chan of the Department of Clinical Oncology at CUHK.

SBRT after intrahepatic progression on IO

As well as investigating use of cabozantinib as second-line treatment, the researchers at CUHK also evaluated use of radiotherapy in liver cancer patients who had developed resistance to immunotherapy.

SBRT has been shown to improve response and PFS in multiple cancer types following oligoprogression on systemic therapy, but has not been assessed in detail in patients with advanced HCC. [Cancers (Basel) 2022;14:115] “To our knowledge, this is the first case series reporting the outcomes of SBRT following intrahepatic progression on immunotherapy in advanced HCC,” said Dr Vanessa Yeung of the Department of Clinical Oncology at CUHK.

The researchers retrospectively reviewed 105 HCC patients who received SBRT to the liver for HCC at Prince of Wales Hospital in Hong Kong between 2016 and 2022, and identified five patients who had received this treatment following intrahepatic progression on immunotherapy. All of the patients were male and had advanced Barcelona Clinic Liver Cancer (BCLC) C disease. Most of them were hepatitis B virus carriers, with sizable tumours and main portal vein tumour thrombosis at the time of SBRT. Four out of five patients progressed on nivolumab-based therapy and one had persistent disease on pembrolizumab-based therapy.

Following SBRT, the median OS in this cohort of patients was 24.5 months and the median PFS was 10.5 months. There were no grade ≥3 toxicities related to SBRT. [J Hepatol 2024;80:e282-e283]

“Despite the small number of patients, these survival outcomes were much better than previously reported for patients with major portal vein thrombosis treated with immunotherapy,” noted the researchers. For instance, in the phase III IMbrave150 study, which evaluated use of atezolizumab plus bevacizumab in HCC patients with main portal vein tumor thrombosis, median OS was 7.9 months. [Gastroenterol Hepatol (N Y) 2021;17:14-15] In addition, in retrospective studies examining patterns of progressions and post-immunotherapy survival, the median OS for patients with intrahepatic growth was 5.3 months, and the median OS for patients treated with second-line tyrosine kinase inhibitors was approximately 10 months. [Liver Int 2023;43:695-707; Eur J Cancer 2023;189:112933]

“[As] animal and human studies indicate a synergy between radiotherapy and immunotherapy, we are currently planning a number of clinical trials to expand the role of radiotherapy in the treatment of liver cancer,” said Dr Landon Chan of the Department of Clinical Oncology at CUHK.