In recent years, immunotherapies with checkpoint inhibitors have significantly improved the therapeutic options for numerous tumor diseases. Even if phase III data are still outstanding for the treatment of hepatocellular carcinoma (HCC), there are new data from smaller study cohorts.
In the case of hepatocellular carcinoma (HCC), there are currently no approvals for checkpoint inhibitors in Europe; in the USA, nivolumab, and pembrolizumab are restricted on the basis of phase II data for the treatment of patients after failure of tyrosine kinase inhibitors (see source 1). The exact data from a Phase III study with pembrolizumab as second-line therapy for HCC will be presented soon, but it has already been announced that the study missed its primary endpoint (see source 2). Nevertheless, in individual cases, nivolumab and pembrolizumab are also used outside clinical trials at HCC in this indication as part of compassionate use programs. Data on these patients are evaluated in real-world studies. Two of these studies were presented at the ILC in Vienna.
One of these studies comes from Spain, where 42 patients with HCC were treated with second or third line nivolumab outside clinical trials. Of the 20 patients who received nivolumab in the second line (60% Child-Pugh A; 40% Child-Pugh B), five had to discontinue their first-line treatment with sorafenib due to severe side effects but without radiological progression. In these patients, the median overall survival was 28.8 months (95% CI: 9.4 to not assessable). Patients in the third line had received nivolumab with a single exception due to progression under second-line therapy. In this group, overall survival could not be calculated due to limited follow-up and frequency of events. The median follow-up since the beginning of first-line therapy was 21.3 months.
A total of 25 adverse events were reported in 15 patients, 5 of which were Grade 3-4 events. A Grade 5 event (rejection after liver transplantation) occurred. In 5 patients, corticosteroids were required to control side effects. "These data show that the safety profile of Nivolumab in everyday clinical use is consistent with the phase II results," commented Prof. Dr. Leonardo Gomes da Fonseca, Hospital Clinic Barcelona, advising cautious interpretation of the efficacy data. One has to consider that many patients were switched to nivolumab without progression. All in all, the patterns of progression are markedly heterogeneous (see source 3)
The second study was conducted at Austrian and German centers and included 65 patients (49% Child-Pugh A, 43% Child-Pugh B, 8% Child-Pugh C) who received either nivolumab (n=34) or pembrolizumab (n=31) between 2015 and 2018. Immunotherapies were used in these patients as first to fourth line therapy. Of 45 patients, at least one follow-up imaging was available to evaluate radiological progression. The data show a response rate of 12% and disease control in 49% of patients. Radiological progression occurred in 54% of patients and 55% died during follow-up. Median progression-free survival was 4.6 months (95% CI: 3.0-6.2) and median overall survival was 11 months (95% CI: 8.2-13.8).
The most common adverse events were infections (n=7), rash (n=6), pruritus (n=3), fatigue (n=3), diarrhoea (n=3) and hepatitis (n=3). Child-Pugh-B patients showed a similar safety profile to Child-Pugh A patients but had a shorter overall survival. According to study author Dr. Matthias Pinter of the Medical University of Vienna, these data show that immunotherapy with nivolumab or pembrolizumab is also well tolerated by severely pre-treated and very ill patients and that its efficacy in clinical practice corresponds to the results of phase II (see source 4).
1. Mody K, Abou-Alfa GK: Systemic therapy for advanced hepatocellular carcinoma in an evolving landscape. Curr Treat Options Oncol 2019; 20(2): 3
2. Merck Newsroom. Merck Provides Update on KEYNOTE-240, a Phase 3 Study of KEYTRUDA® (pembrolizumab) in Previously Treated Patients with Advanced Hepatocellular Carcinoma [Press release]. 2019. Available at: https://investors.merck.com/news/press-release-details/2019/Merck-Provides-Update-on-KEYNOTE-240-a-Phase-3-Study-of-KEYTRUDA-pembrolizumab-in-Previously-Treated-Patients-with-Advanced-Hepatocellular-Carcinoma/default.aspx
3. Gomes da Fonseca L et al: A multicentric study on the real-life impact of nivolumab in patients with hepatocellular carcinoma. ILC 2019, PS-137
4. Pinter M et al: PD-1 targeted immunotherapy in advanced hepatocellular carcinoma: Efficacy and safety data from an international multicenter real-world cohort. ILC 2019, PS-138
5. International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL), 13 April 2019, Vienna