Adjuvant Combo May Change Practice in High-Risk Liver Cancer

ORLANDO — For the first time, adjuvant therapy has improved recurrence-free survival (RFS) after surgery or ablation for hepatocellular carcinoma (HCC), the most common type of liver cancer, according to the randomized IMbrave050 trial presented here.

After a median follow-up of 17.4 months, RFS significantly improved by almost 30% with adjuvant atezolizumab (Tecentriq) and bevacizumab (Avastin) as compared with surgery or ablation alone. The 12-month recurrence rate was 34% without the adjuvant combination and 20% with it.

A preliminary analysis of overall survival (OS) showed no significant difference between treatment groups, although more deaths had occurred in the atezolizumab-bevacizumab arm. The OS data remain immature, so the difference in deaths is not a reason for alarm at this point, reported Pierce Chow, MD, of National Cancer Center of Singapore, at the American Association for Cancer Research meeting.

“Atezolizumab plus bevacizumab may be a practice-changing adjuvant treatment option for patients at high risk of recurrence of HCC and may potentially also change clinical indications for surgical resection,” said Chow.

“As a surgeon I see a lot of patients come back for follow-up of surgical resection who are really demoralized by the fact that there is no treatment for them that can prevent a recurrence,” he added. “Patients after surgical resection have such poor survival at 5 years compared to other early-stage cancers, such as colorectal,” he added. “We’re talking about a 5-year median overall survival of about 60-70% versus 90%. So this is a huge unmet clinical need … I think the impact of the treatment on HCC is really big.”

As the first study to show that adjuvant therapy can prevent recurrence, the findings represent a major therapeutic development for the field of liver cancer, according to Jason Castellanos, MD, of Fox Chase Cancer Center in Philadelphia, who was not involved with the study.

“This study demonstrates significantly decreased recurrence in high-risk patients treated with immunotherapy and targeted therapy at 12 months … and based on these results the study was ended early,” Castellanos told MedPage Today via email. “Perhaps almost as impressive was the excellent safety profile, with patients tolerating this treatment for a median of 11 months.”

“This provides us with an important new tool for those high-risk patients, especially those with larger solitary tumors, to maximize their chances of cure from HCC and will likely be incorporated into the clinical setting rapidly,” according to Castellanos.

Although surgery or ablative therapy for HCC often leads to no evidence of disease, the recurrence rate is high, about 63% at 5 years, even higher in patients with high-risk disease (large tumor, multiple tumors, poor differentiation, and vascular invasion). No standard of care exists for adjuvant therapy, and clinical studies have failed to show a survival benefit with different adjuvant strategies, said Chow.

In patients with unresectable HCC, atezolizumab plus bevacizumab significantly improved progression-free survival, OS, and objective response, leading to FDA approval of the combination as first-line therapy. The clinical performance in unresectable disease led to the phase III IMbrave050 trial to evaluate atezolizumab-bevacizumab in patients at high risk of recurrence after curative-intent surgery or ablation.

Eligible patients had achieved disease-free status after surgery or ablation but remained at high risk of recurrence. Patients with extrahepatic disease or macrovascular invasion were excluded. Investigators randomized patients to atezolizumab-bevacizumab or active surveillance. The primary endpoint was RFS as assessed by independent review.

Data analysis included 668 patients who had a median age of about 60. HCC had a viral origin in almost three-fourths of the cases.

The primary analysis showed that patients who received adjuvant atezolizumab-bevacizumab had better 12-month RFS versus the active surveillance arm (78% vs 65%, HR 0.72, 95% CI 0.56-0.93, P=0.012). Similarly, investigator-assessed RFS yielded a hazard ratio of 0.70 (95% CI 0.54-0.91).

The 12-month independent-review assessed disease recurrence rate was 20% in the atezolizumab-bevacizumab arm, a significant improvement from the 34% among controls (HR 0.67, 95% CI 0.52-0.88, P=0.003).

The adjuvant combination demonstrated beneficial effects despite the fact that 61% of patients on active surveillance crossed over to atezolizumab-bevacizumab, said Chow.

As expected, treatment-emergent adverse events (TEAEs) occurred more often in patients who received adjuvant therapy. The type and severity of events were consistent with the known safety profile of the two drugs, said Chow. Grade 3/4 TEAE rates were 41% with adjuvant treatment and 13.3% with surveillance, while rates of serious TEAEs were 24.1% and 10.3%, respectively.

The 27 deaths in the adjuvant treatment arm included 17 due to progressive disease and six from TEAEs — three COVID-related deaths occurred in this group as well. Twenty deaths occurred in the active surveillance group, including 16 from progressive disease and one due to a TEAE.