A phase 3 trial (ClinicalTrials.gov Identifier: NCT03434379) in advanced hepatocellular carcinoma (HCC) has compared a combination of bevacizumab and atezolizumab to the standard of care for this disease, sorafenib. As a result, some experts say they may abandon the use of sorafenib or lenvatinib monotherapy based on the results seen in HCC with the use of the monoclonal antibody duo.
The study, published in the New England Journal of Medicine, showed promising results with bevacizumab plus atezolizumab, with an increase in overall survival (OS) at 12 months, an increase in progression-free survival (PFS), and improved quality-of-life (QoL) measures.1
“Liver cancer is unique in that unlike most cancers, 90% of our patients also have underlying liver disease. The malignancy competes with the underlying liver disease as to what cases the bigger problem,” said Richard Finn, MD, professor of medicine at the David Geffen School of Medicine at UCLA and director of the Signal Transduction and Therapeutics program at the UCLA Jonsson Comprehensive Cancer Center, who led the new study.
In the last couple of years, several new drugs in HCC have been approved by the US Food and Drug Administration (FDA), including lenvatinib, another multiple-kinase inhibitor. PD-1/PD-L1 inhibitors have also been trialed compared with sorafenib — but have had limited success, until this point.
“There is an unmet need for drugs for advanced liver cancer. After sorafenib was approved, we thought we would enter a new age of liver cancer drug development — [but] nothing really succeeded; we had failure after failure. Last year we had a setback with checkpoint inhibitors when a large phase 3 study of nivolumab vs sorafenib was negative. People thought that was going to be a slam dunk,” said Dr Finn.
The study involved over 501 patients with unresectable hepatocellular carcinoma, 336 of whom received the combination and 165 who were treated with sorafenib. The OS at 12 months with the combination treatment was 67.2%, compared with 54.6% for sorafenib, and the PFS was 6.8 months and 4.3 months, respectively.
“The primary endpoint was to prove OS based on a hazard ratio. A 0.58 hazard ratio is a 42% decrease in the risk of death. This hazard ratio is highly significant and there aren’t that many studies even in phase 3 that give this level of benefit,” said Dr Finn, noting that the median OS had not yet been reached in the combination treatment line, but that the study reached its primary endpoints.
According to data from a poster published during the ASCO20 Virtual Scientific Program, 6-month OS for the combination was 84.8%, whereas the 6-month OS for those who were administered sorafenib was 72.2%.2
“The follow-up period is quite short and they need more time for overall survival, but there is a significant difference between the 2 treatments and the Kaplan-Meier survival curve separates really well,” said Kit Wong, MD, assistant professor in the department of medicine in the division of oncology at the University of Washington, Seattle. “We like seeing curves that flatten, because it means those curves are stable and might have a durable response,” said Dr Wong.
Although bevacizumab was originally designed as a purely antiangiogenic medication, some newer evidence has suggested that it may increase the efficacy of immunotherapies via several mechanisms.
“We know that by studying the tumor microenvironment, there are so any pathways that interact with each other and immune pathways. The VEGF [vascular endothelial growth factor] pathway itself has immunosuppressive effects, and inhibiting this pathway can actually alter the vasculature and influence T-cell infiltration,” said Dr Wong, who also mentioned that other suppressive mechanisms include the reduction of tumor-infiltrating macrophages and an increase of interferon-gamma production.
Patients are continuing on treatment in the open-label study and are being followed for death, with longer-term follow-ups planned. On May 29, 2020, the combination treatment was approved by the FDA based on the study results under FDA’s Project Orbis initiative and after an application to the Real-Time Oncology Review pilot program.3
But is the evidence from this trial robust enough at this point to recommend the combination therapy as a first choice for people with advanced liver cancer?