Adjuvant Atezolizumab Plus Bevacizumab Improve RFS in Early-Stage Hepatocellular Carcinoma

Mark Yarchoan, MD

Atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) given as adjuvant treatment following surgery showed improvement in recurrence-free survival (RFS) vs active surveillance in patients with early-stage hepatocellular carcinoma (HCC) who are at a high-risk for recurrence, meeting the primary end point of the phase IMbrave050 study (NCT04102098).¹

“This is the first time that any systemic therapy has demonstrated conclusive benefit for patients with resectable HCC in a phase 3 clinical trial. This heralds a new era where systemic therapy in HCC will be used not only to prolong life in the most advanced patients, but also to increase cure rates," Mark Yarchoan, MD, associate professor of oncology at Johns Hopkins Medicine, told Targeted Oncology™.

IMbrave050 randomized 662 patients in a 1:1 fashion to receive atezolizumab 1200 mg every 3 weeks plus bevacizumab 5 mg/kg every 3 weeks for up to 12 months, or no intervention with active surveillance.

In addition to RFS, the study is exploring overall survival (OS) and RFS as determined by the investigator, and RFS in patients with PD-L1-positive disease as key secondary end points. The OS rate, RFS rate, time to recurrence, percentage of patients with adverse events, serum concentration of atezolizumab, and number of patients with anti-drug antibodies to atezolizumab are also outcomes being assessed in the study.^1,2

At the time of the interim analysis, OS data were immature. The safety profile of the combination was consistent with the know safety profile of each drug individually, and some of the safety events that occurred during the study were a result of the underlying disease. Genentech, developer of atezolizumab and bevacizumab, plans to share the interim analysis results with regulatory authorities and present the full data at an upcoming medical meeting.

“Based on this announcement, adjuvant atezolizumab plus bevacizumab is likely to become a new standard of care for patients with resectable HCC. There are still several unanswered questions. Patients on this study were heterogeneous, and subset analysis may provide information about whether the benefit of adjuvant atezolizumab and bevacizumab are consistent or are limited to the patients with the very highest risk of recurrence. Also, these data will not answer whether both atezolizumab and bevacizumab are needed, or whether the immunotherapy drug (atezolizumab) alone could have provided the same benefit with less toxicity. Several other studies are ongoing, including studies of immunotherapy alone without bevacizumab, which may help to answer this question,” Yarchoan added.

The combination of atezolizumab and bevacizumab is FDA approved for the treatment of adult patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment, based on results from the prior IMbrave150 study (NCT03434379). In IMbrave150, atezolizumab 1200 mg plus bevacizumab 5 mg/kg given on day 1 of each 21-day cycle was compared with the standard of care therapy at the time, sorafenib (Nexavar), administered at 400 mg twice per day on days 1-21 of each 21-day cycle.³

Atezolizumab plus bevacizumab demonstrated statistically significant and clinically meaningful improvements in OS vs sorafenib (HR, 0.58 [95% CI, 0.42-0.79]; P <0.001), and progression-free survival (PFS; HR, 0.59 [95% CI, 0.47-0.76]; P <0.001). In 501 patients followed for a median of 15.6 months, the median OS was 19.2 month with atezolizumab plus bevacizumab vs 13.4 months with sorafenib. The median PFS was 6.8 months with atezolizumab plus bevacizumab vs 4.3 months with sorafenib.

The atezolizumab/bevacizumab arm also had a better confirmed objective response rate (ORR) compared with the sorafenib arm. The confirmed ORR 27.3% (95% CI, 22.5%-32.5%) with the combination vs 11.9 % (95% CI, 7.4%-18.0%) with sorafenib. Moreover, ongoing responses were seen in 86.5% of the atezolizumab plus bevacizumab arm compared with only 68.4% of the sorafenib arm.

Atezolizumab plus bevacizumab is now being explored as an adjuvant treatment because resection and ablation are associated with high rates of recurrence. Using immunotherapy after surgery is hypothesized to be a solution to this problem, according to Yarchoan.

_REFERENCES:

_{1. Genentech’s Tecentriq plus Avastin is the first treatment combination to reduce the risk of cancer returning in people with certain types of early-stage liver cancer in a phase III trial. News release. Genentech. January 18, 2023. Accessed January 19, 2023. https://bit.ly/3QOhA9f}

_{2. A study of atezolizumab plus bevacizumab versus active surveillance as adjuvant therapy in patients with hepatocellular carcinoma at high risk of recurrence after surgical resection or ablation (IMbrave050). ClinicalTrials.gov. Updated November 21, 2022. Accessed January 19, 2023. https://clinicaltrials.gov/ct2/show/NCT04102098}

_{3. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020; 382:1894-1905. doi:10.1056/NEJMoa1915745}