Abstract
In light of positive efficacy and safety findings from the IMbrave150 trial of atezolizumab plus bevacizumab, this novel combination has become the preferred first-line standard of care for patients with unresectable hepatocellular carcinoma (HCC). Several additional trials are ongoing that combine an immune checkpoint inhibitor with another agent such as a multiple kinase inhibitor or antiangiogenic agent. Therefore, the range of first-line treatment options for unresectable HCC is likely to increase, and healthcare providers need succinct information about the use of such combinations, including their efficacy and key aspects of their safety profiles. Here, we review efficacy and safety data on combination immunotherapies and offer guidance on monitoring and managing adverse events, especially those associated with atezolizumab plus bevacizumab. Because of their underlying liver disease and high likelihood of portal hypertension, patients with unresectable HCC are at particular risk of gastrointestinal bleeding, and this risk may be exacerbated by treatments that include antiangiogenic agents. Healthcare providers also need to be alert to the risks of proteinuria and hypertension, colitis, hepatitis, and reactivation of hepatitis B or C virus infection. They should also be aware of the possibility of rarer but potentially life-threatening adverse events such as pneumonitis and cardiovascular events. Awareness of the risks associated with these therapies and knowledge of adverse event monitoring and management will become increasingly important as the therapeutic range broadens in unresectable HCC.
Highlights
The standard of care for first-line systemic treatment of unresectable hepatocellular carcinoma (HCC) has, since 2007, been sorafenib[1,2] or, since 2018, lenvatinib, each of which is an orally administered multi-kinase inhibitor (MKI).[3]
CI, confidence interval; CTLA4, cytotoxic T-lymphocyte-associated protein 4; DCR, disease control rate; DoR, duration of response; HCC, hepatocellular carcinoma; HR, hazard ratio; ICI, immune checkpoint inhibitor; NA, not assessed or not applicable; NCT, ClinicalTrials.gov; NR, not reached; overall response rate (ORR); objective response rate; OS, overall survival; PD-1, programmed cell-death protein 1; PD-L1, programmed death ligand 1; PFS, progression-free survival; PR, partial response; RCCEP, reactive cutaneous capillary endothelial proliferation; SD, stable disease; T300+D, tremelimumab 300 mg + durvalumab 1,500 mg every 4 weeks for 1 dose followed by durvalumab 1,500 mg every 4 weeks; T75+D, tremelimumab 75 mg + durvalumab 1,500 mg every 4 weeks for 4 doses followed by durvalumab 1,500 mg every 4 weeks
adverse events (AEs), adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CTLA4, cytotoxic T-lymphocyte-associated protein 4; HCC, hepatocellular carcinoma; ICI, immune checkpoint inhibitor; NA, not assessed or not applicable; NCT, ClinicalTrials.gov; NR, not reported; PD, progression of disease; PD-1, programmed cell-death protein 1; PD-L1, programmed death ligand 1; RCCEP, reactive cutaneous capillary endothelial proliferation; T300+D, tremelimumab 300 mg + durvalumab 1,500 mg every 4 weeks for 1 dose followed by durvalumab 1,500 mg every 4 weeks; T75+D, tremelimumab 75 mg + durvalumab 1,500 mg every 4 weeks for 4 doses followed by durvalumab 1,500 mg every 4 weeks
Summary
The standard of care for first-line systemic treatment of unresectable hepatocellular carcinoma (HCC) has, since 2007, been sorafenib[1,2] or, since 2018, lenvatinib, each of which is an orally administered multi-kinase inhibitor (MKI).[3] In 2020, a new option was approved for first-line treatment of unresectable HCC: the combination of atezolizumab, an immune checkpoint inhibitor (ICI) that targets programmed death ligand 1 (PD-L1), with bevacizumab, an antiangiogenic agent that targets vascular endothelial growth factor (VEGF).[4] Thanks to positive safety and efficacy findings from the phase III IMbrave[150] trial, this immunotherapy combination is the preferred first-line standard of care, as recommended in the recently revised guideline from the American Society of Clinical Oncology (ASCO).[4,5] the need remains for more effective treatment of HCC in the first line and beyond. TEAEs with pembrolizumab (KEYNOTE-224 study) were similar; immune-mediated AEs
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