1. Fuerst, Mark L.

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An additional year of follow-up confirms that atezolizumab plus bevacizumab should remain the standard of care for previously untreated, unresectable hepatocellular carcinoma (HCC).

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The IMbrave150 study was a global, randomized, open-label, Phase III study of 501 patients with unresectable HCC that compared a combination of atezolizumab and bevacizumab with sorafenib. Patients were randomized to receive either atezolizumab 1,200 mg intravenously every 3 weeks plus bevacizumab 15 mg/kg intravenously every 3 weeks (336 patients) or sorafenib 400 mg twice daily (165 patients) until unacceptable toxicity or loss of clinical benefit per investigator.


The primary results from the study were published in the New England Journal of Medicine in May 2020 and have supported the global approval of this regimen (doi: 10.1056/NEJMoa1915745). At the time of the primary analysis, there was a median follow-up of 8.6 months that provided an improvement in overall survival (OS) and progression-free survival (PFS) in favor of the combination. At the time of the primary analysis, the median OS in the atezolizumab plus bevacizumab arm had not been reached.


Research Updates

At the 2021 ASCO Gastrointestinal Cancers Symposium, lead author Richard Finn, MD, Director of the Signal Transduction and Therapeutics Program at the UCLA Jonsson Comprehensive Cancer Center, presented updated data with a median follow-up of 15.6 months (Abstract 267). He also provided survival data from the Chinese cohort, which included 137 patients from Taiwan, Hong Kong, and China from the intent-to-treat population, as well as an additional 57 patients from a China extension cohort. Finn also serves as Professor of Clinical Medicine in the Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA.


"We see the median OS for atezolizumab and bevacizumab is now over 19 months. This is the longest survival seen in a Phase III study of advanced liver cancer. And the safety and tolerability of the combination remains consistent with what we saw in the primary analysis," said Finn.


In the patient disposition at follow-up, the majority of patients in the sorafenib arm have gone off study-one-quarter of patients in the sorafenib arm remain on study versus 40 percent with atezolizumab and bevacizumab; 18 percent in the atezolizumab plus bevacizumab arm remain on treatment versus 3 percent in the sorafenib arm. A majority of patients in both arms have discontinued the study, primarily because of death.


The baseline characteristics did not change from the primary analysis. Eligible patients had one or more measurable untreated lesions per RECIST 1.1 criteria, Child-Pugh class A liver function, and an ECOG performance status of 0 or 1. "The majority of patients came from outside of Asia and had high-risk features, such as an elevated alpha-fetoprotein, macrovascular invasion, or extrahepatic spread," Finn said. The study was well-balanced between both arms.


In the updated data, with an additional 12 months of follow-up, atezolizumab had a median OS of 19.2 months versus 13.4 months with sorafenib. Median PFS did not changed significantly-4.3 months versus 6.9 months, respectively.


"With longer follow-up, we have more responses with atezolizumab and bevacizumab than initially reported," said Finn. With the combination, the ORR was 30 percent, including 8 percent complete responses (CR). With sorafenib, the ORR was 11 percent and less than 1 percent CR.


"This resulted in a disease control rate of 74 percent with the combination versus 55 percent with sorafenib," he said. "Median duration of response with the combination is more than 18 months and 14.9 months with sorafenib. This pattern is similar when using HCC modified RECIST criteria."


More patients on the sorafenib arm have progressed and gone on to additional treatments. In both arms of the study, for patients receiving additional treatments, about one-third of patients have received tyrosine kinase inhibitors. In the sorafenib arm, one-quarter of patients received immunotherapy at progression.


The updated safety data show no new safety signals. All-grade treatment-related adverse effects (TRAEs) occurred in 86 percent of patients in the combination arm as compared to 95 percent of patients in the sorafenib arm. Adverse events leading to withdrawal due to treatment occurred in 22 percent of patients in the combination arm versus 12 percent in the sorafenib arm. Dose interruptions occurred in 59 percent of combination patients and 44 percent of sorafenib patients.


There was some increase in TRAEs, 63 percent grade 3/4, with atezolizumab and bevacizumab versus sorafenib, which likely reflects that patients have been on treatment longer, Finn said.


The baseline characteristics of the China cohort show both arms were very well-balanced. "Unlike the intent-to-treat population, we have a higher percentage of patients with hepatitis B-related liver cancer, as expected. In addition, patients have high-risk features such as elevated AFP, extrahepatic spread, and macrovascular invasion," said Finn.


Survival data for the China cohort show median OS for the combination is 24 months versus 11.4 months for sorafenib. The 18-month OS rates were 56 percent with the combination and 33 percent with sorafenib.


In conclusion, the researchers stated: "IMbrave150 showed consistent clinically meaningful treatment benefit and safety with 12 months of additional follow-up. The combination provides the longest survival seen in a frontline Phase III study in advanced HCC, confirming atezolizumab plus bevacizumab as a standard of care for previously untreated, unresectable HCC."


Mark L. Fuerst is a contributing writer.