Atezolizumab Plus Bevacizumab Extends Survival in Frontline HCC

Levi Garraway, MD, PhD

The frontline combination of atezolizumab (Tecentriq) and bevacizumab (Avastin) reduced the risk of disease progression or death by 42% compared with sorafenib (Nexavar) in patients with unresectable hepatocellular carcinoma (HCC), according to topline results from the phase III IMbrave150 trial presented at the 2019 ESMO Asia Congress.¹

The median OS was not yet reached in the combination arm compared with 13.2 months (95% CI, 10.4—not estimable) in the sorafenib arm (HR, 0.58; 95% CI, 0.42-0.79; P = .0006). The median progression-free survival (PFS) was 6.8 months (95% CI, 5.7-8.3) versus 4.3 months (95% CI, 4.0-5.6), respectively (HR, 0.59; 95% CI, 0.47-0.76; P <.0001).

“For the first time in a decade, we are seeing a treatment that has improved overall survival for people with unresectable hepatocellular carcinoma compared with the current standard of care,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development of Genentech (Roche), the developer of atezolizumab and bevacizumab, stated in a press release. “Tecentriq in combination with Avastin could transform the treatment of this aggressive disease, and we are working closely with global health authorities in the hope of bringing this treatment option to patients as soon as possible.”

In the international, multicenter, open-label, phase III IMbrave150 study, 501 patients with unresectable HCC who did not receive prior systemic therapy were randomized 2:1 to receive atezolizumab combined with bevacizumab, or sorafenib alone. Atezolizumab was administered intravenously (IV) at 1200 mg on day 1 of each 21-day cycle; IV bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. Oral sorafenib was administered at 400 mg twice daily, on days 1 to 21 of each 21-day cycle. Treatment in both arms was given until unacceptable toxicity or loss of clinical benefit as determined by the investigator.

To be eligible for enrollment, patients had to have locally advanced or metastatic and/or unresectable HCC, had received no prior systemic therapy, had ≥1 measurable lesion, an ECOG performance status of 0 or 1, adequate hematologic and end-organ function, and have Child-Pugh class A disease.

Those with a history of leptomeningeal disease; active or history of autoimmune disease or immune deficiency; history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography scan; active tuberculosis, history of cancer other than HCC within 5 years prior to screening; known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC; and a history of hepatic encephalopathy were some of the exclusion criteria.

The coprimary endpoints were OS and PFS by an independent review facility (IRF) per RECIST v1.1 criteria. Secondary endpoints included overall response rate (ORR), time to progression, and duration of response as measured by RECIST v1.1 (investigator-assessed and IRF) and HCC mRECIST (IRF), patient-reported outcomes, safety, and pharmacokinetics.

Regarding safety, grade 3/4 adverse events (AEs) occurred in 57% and 55% of the combination and control arms, respectively. The mortality rate was 5% versus 6%, respectively.

In July 2018, the FDA granted a breakthrough therapy designation to the combination of atezolizumab and bevacizumab as a first-line treatment for patients with advanced or metastatic HCC, based on results from a phase Ib trial (NCT02715531).

Previously reported data from the phase Ib trial showed that at a median follow-up of 10.3 months, results from independent reviewers determined that atezolizumab/bevacizumab elicited an ORR of 65% (n = 15) among the 23 evaluable patients.² Additionally, the responses were observed across patient subgroups defined by etiology, geography, baseline AFP levels, and extrahepatic spread.

The 65% ORR comprised a complete response rate of 4% (n = 1) and a partial response rate of 61% (n = 14). Additionally, 7 (30%) patients had stable disease and 1 (4%) patient had progressive disease. A disease control rate of ≥6 months was reported for 16 (70%) patients.

References

1. Genentech presents pivotal data demonstrating Tecentriq in combination with Avastin improves overall survival in people with the most common form of liver cancer [news release]. South San Francisco, CA: Genentech. Posted November 22, 2019. bit.ly/35rZfGc. Accessed November 22, 2019.
2. Stein S, Pishvaian MJ, Lee MS, et al. Safety and clinical activity of 1L atezolizumab + bevacizumab in a phase Ib study in hepatocellular carcinoma (HCC).&#8239; J Clin Oncol. 2018;36(suppl 15; abstr 4074). doi: 10.1200/JCO.2018.36.15_suppl.4074.