Adjuvant Atezolizumab Plus Bevacizumab Strike Out in HCC

The initial results of the IMbrave050 trial raised hopes that an effective adjuvant regimen for hepatocellular carcinoma (HCC) might finally have arrived. 

Patients with HCC treated with a combination of the immune checkpoint inhibitor atezolizumab and angiogenesis inhibitor bevacizumab after resection or ablation showed a 28% improvement in recurrence-free survival at a medium follow-up of 17.4 months. 

However, longer-term follow-up results from the trial — presented at the 2024 European Society for Medical Oncology (ESMO) Congress— indicate that the recurrence-free survival benefit fell through at a medium follow-up of 35.1 months, dashing hopes for the combination. 

“The important message from today is that [atezolizumab plus bevacizumab] is not recommended in the adjuvant setting,” said lead investigator and presenter Adam Yopp, MD, a gastrointestinal surgical oncologist at the University of Texas Southwestern Medical Center, Dallas. 

In the trial, 668 patients with HCC at high risk for relapse after surgery or thermal ablation were randomized to atezolizumab 1200 mg plus bevacizumab 15 mg/kg every 3 weeks or to active surveillance for 1 year. Patients in the active surveillance group could crossover to the treatment group following a protocol-defined recurrence event. 

The study groups were well-balanced. Most patients were Asian men, and hepatitis B was the most common HCC etiology. Most participants initially had a solitary tumor treated with resection.

After following patients for nearly 3 years, median recurrence-free survival was 33.2 months with treatment versus 36 months with surveillance. The lack of recurrence-free survival benefit at the longer follow-up held in more than a dozen subgroup analyses. 

Meanwhile, overall survival outcomes remain pending with over 80% of patients alive in both arms at 35.1 months. Recurrences are likely caught and treated early in the trial, which may explain the unusually high overall survival rate, Yopp said. 

There were no new safety signals with longer follow-up. Over one third of patients in the atezolizumab/bevacizumab group had a grade 3/4 treatment-related adverse event, and there were two treatment-related deaths. 

Despite the latest results, Yopp noted that atezolizumab/bevacizumab remains first-line standard of care for unresectable HCC based on the IMbrave150 trial. 

The findings are “disappointing” given that most patients with high-risk HCC relapse but were “perhaps not entirely unexpected,” said study discussant Maeve Lowery, MD, a gastrointestinal oncologist and researcher at Trinity College, Dublin, Ireland. “We could see the recurrence-free survival curves coming together around the 2-year mark” in the initial report.

So, although treatment may have delayed recurrence in some patients, it did not prevent it, she said.

Whatever the final overall survival outcomes, Lowery added, the findings will be confounded because the trial allowed crossover from surveillance to active treatment and because recurrences were treated with additional resections or ablations with curative intent when possible. 

“Where do we go from here? We await results…from ongoing studies,” she said, including the EMERALD-2 trial, a study of another PD-L1 blocker — durvalumab — with bevacizumab as adjuvant therapy in high-risk HCC. 

The trial was funded by F. Hoffmann-La Roche, which manufactures atezolizumab and bevacizumab through its Genentech subsidiary. Yopp and Lowery have reported being advisors for Genentech, among other industry ties. 

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape. Alex is also an MIT Knight Science Journalism fellow. Email: [email protected]