Adjuvant Atezolizumab/Bevacizumab Shows Recurrence-Free Survival Benefit Over Active Surveillance in HCC

Pierce Chow, MBBS, MMed, FRCS, FAMS, PhD

Following curative-intent resection or ablation, patients with a high risk of hepatocellular carcinoma (HCC) recurrence experienced a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) with adjuvant atezolizumab (Tecentriq) and bevacizumab (Avastin) compared with active surveillance, according to data from the prespecified interim analysis of the phase 3 IMbrave050 trial (NCT04102098).¹

Findings, which were presented at the 2023 AACR Annual Meeting, showed that with a median follow-up of 17.4 months, the median independent review facility (IRF)–assessed RFS was not yet evaluable (NE) with the doublet (n = 334; 95% CI, 22.1-not reached [NR]) or with active surveillance (n = 334; 95% CI, 21.4-NE) but the hazard ratio (HR) was 0.72, in favor of the regimen (95% CI, 0.56-0.93; P = .012).

The 12-month IRF-RFS event-free rates reported in the investigative and surveillance arms were 78% (95% CI, 73%-82%) and 65% (95% CI, 60%-71%), respectively.

“At the prespecified interim analysis, adjuvant atezolizumab plus bevacizumab met its primary end point…,” lead study author Pierce Chow, MBBS, MMed, FRCS, FAMS, PhD, of National Cancer Centre Singapore, Singapore, and Duke-NUS Medical School Singapore, in Singapore, said in a press briefing during the meeting. “Atezolizumab plus bevacizumab may be a practice-changing adjuvant treatment option for patients with high-risk HCC that may change the clinical indications for surgical resection.

Although the risk of postoperative recurrence is high for patients with HCC who have undergone curative-intent resection or ablation, no current standard exists in the adjuvant setting, according to Chow.

He added that at 5 years, a 63% recurrence rate has been observed in this population. For those with high-risk features like having large tumor size, poor tumor differentiation, several tumors, or vascular invasion, this rate is known to be even higher. Disease recurrence is known to peak about 1 to 2 years following surgery or approximately 4 to 5 years after the procedure.²

Atezolizumab plus bevacizumab was established as the standard regimen for patients with advanced, unresectable HCC following data from the phase 3 IMbrave150 study (NCT03434379).³ Updated data showed that at a median follow-up of 15.6 months (range, 0-28.6), the doublet significantly improved progression-free survival (HR, 0.65; 95% CI, 0.52-0.81), overall survival (HR, 0.66; 95% CI, 0.52-0.85), and objective response rate (difference, 18%; 95% CI, 11%-26%) compared with sorafenib (Nexavar) when administered in the frontline setting.⁴

IMbrave050 investigators enrolled patients with a confirmed first diagnosis of HCC who had undergone curative-intent resection or ablation, were free of disease, had Child-Pugh class A disease, and an ECOG performance status of 0 or 1.

To be eligible for enrollment, patients were required to meet the following criteria for high risk of disease recurrence:

• Resection and up to 3 tumors with the largest tumor greater than 5 cm irrespective of vascular invasion or poor tumor differentiation defined as grade 3 or 4;
• Resection and 4 or more tumors with the largest tumor being up to 5 cm regardless of vascular invasion or poor tumor differentiation;
• Resection and up to 3 tumors with the largest tumor up to 5 cm with vascular invasion and/or poor differentiation;
• Ablation and 1 tumor greater than 2 cm but not greater than 5 cm
• Ablation and several tumors but no greater than 4 tumors, all up to 5 cm

Patients could not have extrahepatic disease or minor macrovascular invasion except for Vp1/Vp2.

Study participants were randomly assigned 1:1 to receive atezolizumab at 1200 mg once every 3 weeks plus bevacizumab at 15 mg/kg once every 3 weeks or active surveillance. Treatment continued until disease recurrence or intolerable toxicity.

Notably, patients in the active surveillance arm were permitted to cross over to receive the combination regimen directly after they experienced IRF-confirmed recurrence or after they underwent a second resection or ablation.

Key stratification factors included region (Asia-Pacific excluding Japan vs rest of world), as well as high-risk features and procedures (ablation; resection, 1 risk feature, adjuvant TACE [yes vs no]; resection; 2 or more risk features, adjuvant TACE [yes vs no]).

Beyond IRF-assessed RFS serving as the primary end point of the trial, key secondary end points comprised investigator-assessed RFS, time to disease recurrence per IRF assessment, and overall survival (OS).

Chow noted that the baseline characteristics across the arms were well balanced. The median age was 59.5 years (range, 19-89) and most patients were male (83.1%), Asian (81.6%), from the Asia Pacific region (71.2%), had an ECOG performance status of 0 (78.9%), and Barcelona Clinic Liver Cancer stage A at diagnosis (84.4%). Regarding PD-L1 status in the doublet arm, 54.0% had a status of 1% or higher and 46.0% had a status of less than 1%; these rates were 50.2% and 49.8%, respectively, in the active surveillance arm. Across the arms, 62.3% of patients had hepatitis B and 10.8% had hepatitis C.

Moreover, 87.7% of those in the doublet arm had undergone resection vs 87.4% of those in the active surveillance arm. Most patients had 1 tumor (89.9%) with the longest diameter of the largest tumor at diagnosis being a median of 5.6 cm. A total 11.3% of patients received adjuvant TACE after resection, 60.6% had microvascular invasion present, and 41.9% had poor tumor differentiation. Additionally, 12.5% of patients across the arms underwent ablation. Most patients had 1 tumor (72.3%) with the longest diameter of the largest tumor at diagnosis being a median of 2.6 cm.

Additional data indicated a similar RFS improvement with atezolizumab plus bevacizumab vs active surveillance by investigator assessment (HR, 0.70; 95% CI, 0.54-0.91). Notably, these benefits were observed to be “generally consistent” across the clinical subsets analyzed.

The IRF-assessed disease recurrence rate was 33% lower with atezolizumab plus bevacizumab than with active surveillance (HR, 0.67; 95% CI, 0.52-0.88; P = .003). The 12-month recurrence event rates were 20% (95% CI, 16%-24%) and 34% (95% CI, 29%-40%), respectively.

At the data cutoff date of October 21, 2022, the OS data were noted to be highly immature, with a 7% event-patient ratio (n = 47). As such, the median OS in the in the doublet and surveillance arms were NE (HR, 1.42; 95% CI, 0.80-2.54). “Longer follow-up for OS is needed,” Chong said.

Chow noted that 7 more deaths had occurred in the investigative arm vs the surveillance arm, at 27 and 20, respectively, and there was a similar number of deaths due to disease recurrence. Three deaths were related to COVID-19 and occurred within 1 year of randomization; all were in patients assigned to the doublet arm.

Of the 133 patients who experienced an RFS event during active surveillance, 61% (n = 81) crossed over to receive the combination.

The median duration of treatment was 11.1 months for atezolizumab and 11.0 months for bevacizumab. In the investigative arm, 98.2% of patients experienced at least 1 adverse effect (AE) vs 62.1% of those in the surveillance arm; 88.3% of these effects were treatment related in the doublet arm. Grade 3 or 4 AEs were reported in 41.0% of those who received the doublet (34.9% treatment related) vs 13.3% of those who underwent active surveillance.

Serious AEs occurred in 24.1% of those who received atezolizumab plus bevacizumab vs 10.3% of those who had active surveillance. Treatment-related serious AEs occurred in 13.3% of those who received the doublet. Six patients in the investigative arm experienced a grade 5 toxicity vs 1 patient in the surveillance arm. Only 2 of the grade 5 events were related to treatment and they were in the form of esophageal varices hemorrhage and ischemic stroke.

Moreover, 46.7% of patients in the doublet arm experienced toxicity that required dose interruption of any drug, and 19.0% of patients experienced toxicities that resulted in treatment withdrawal.

“The safety profile of adjuvant atezolizumab plus bevacizumab was generally consistent with that of each agent and with the underlying disease,” Chow concluded.

In the Q&A portion of the presentation, it was noted that patients with HCC tend to fare poorly compared with patients with other solid tumors like colorectal cancer (CRC), breast cancer, and lung cancer. When Dr Chow was prompted to share how he felt the trial addressed the imbalance, he said, “As a surgeon, I see a lot of patients come back for follow-up after surgical resection who are really demoralized by the fact that there is no treatment for them that can prevent recurrence. Patients with HCC [who undergo] surgical resection have such poor survival at 5 years compared with those [who have] other early-stage cancers like CRC; you’re talking about an OS [rate] of 60% to 70% vs 90%. So, this is a huge unmet clinical need for patients with HCC. I think a positive adjuvant therapy trial really offers these patients hope for better survival, and better cancer-free survival. I think the impact on the treatment of HCC is really big.”

References

1. Chow P, Chen M, Cheng A-L, et al. IMbrave050: phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma at high risk of disease recurrence following resection or ablation. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, Florida. Abstract CT003.
2. Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200-207. doi:10.1016/s0168-8278(02)00360-4
3. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745
4. Cheng A-L, Qin S, Ikeda M, et al. Updated efficacy and safety data from IMbrave150: atezolizumab plus bevacizumab vs sorafenib for unresectable hepatocellular carcinoma. J Hepatol. 2022;76(4):862-873. doi:10.1016/j.jhep.2021.11.030