Atezolizumab with or without bevacizumab in unresectable hepatocellular carcinoma (GO30140): an open-label, multicentre, phase 1b study

Summary

Background

Dual blockade of PD-L1 and VEGF has enhanced anticancer immunity through multiple mechanisms and augmented antitumour activity in multiple malignancies. We aimed to assess the efficacy and safety of atezolizumab (anti-PD-L1) alone and combined with bevacizumab (anti-VEGF) in patients with unresectable hepatocellular carcinoma.

Methods

GO30140 is an open-label, multicentre, multiarm, phase 1b study that enrolled patients at 26 academic centres and community oncology practices in seven countries worldwide. The study included five cohorts, and the two hepatocellular carcinoma cohorts, groups A and F, are described here. Inclusion criteria for these two groups included age 18 years and older; histologically, cytologically, or clinically (per American Association for the Study of Liver Diseases criteria) confirmed unresectable hepatocellular carcinoma that was not amenable to curative treatment; no previous systemic treatment; and Eastern Cooperative Oncology Group performance status of 0 or 1. In group A, all patients received atezolizumab (1200 mg) and bevacizumab (15 mg/kg) intravenously every 3 weeks. In group F, patients were randomly assigned (1:1) to receive intravenous atezolizumab (1200 mg) plus intravenous bevacizumab (15 mg/kg) every 3 weeks or atezolizumab alone by interactive voice-web response system using permuted block randomisation (block size of two) and stratification factors of geographical region; macrovascular invasion, extrahepatic spread, or both; and baseline α-fetoprotein concentration. Primary endpoints were confirmed objective response rate in all patients who received the combination treatment for group A and progression-free survival in the intention-to-treat population in group F, both assessed by an independent review facility according to Response Evaluation Criteria in Solid Tumors version 1.1. In both groups, safety was assessed in all patients who received at least one dose of any study treatment. This study is registered with ClinicalTrials.gov, NCT02715531, and is closed to enrolment.

Findings

In group A, 104 patients were enrolled between July 20, 2016, and July 31, 2018, and received atezolizumab plus bevacizumab. With a median follow-up of 12·4 months (IQR 8·0–16·2), 37 (36%; 95% CI 26–46) of 104 patients had a confirmed objective response. The most common grade 3–4 treatment-related adverse events were hypertension (13 [13%]) and proteinuria (seven [7%]). Treatment-related serious adverse events occurred in 25 (24%) patients and treatment-related deaths in three (3%) patients (abnormal hepatic function, hepatic cirrhosis, and pneumonitis). In group F, 119 patients were enrolled and randomly assigned (60 to atezolizumab plus bevacizumab; 59 to atezolizumab monotherapy) between May 18, 2018, and March 7, 2019. With a median follow-up of 6·6 months (IQR 5·5–8·5) for the atezolizumab plus bevacizumab group and 6·7 months (4·2–8·2) for the atezolizumab monotherapy group, median progression-free survival was 5·6 months (95% CI 3·6–7·4) versus 3·4 months (1·9–5·2; hazard ratio 0·55; 80% CI 0·40–0·74; p=0·011). The most common grade 3–4 treatment-related adverse events in group F were hypertension (in three [5%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group) and proteinuria (in two [3%] patients in the atezolizumab plus bevacizumab group; none in the atezolizumab monotherapy group). Treatment-related serious adverse events occurred in seven (12%) patients in the atezolizumab plus bevacizumab group and two (3%) patients in the atezolizumab monotherapy group. There were no treatment-related deaths.

Interpretation

Our study shows longer progression-free survival with a combination of atezolizumab plus bevacizumab than with atezolizumab alone in patients with unresectable hepatocellular carcinoma not previously treated with systemic therapy. Therefore, atezolizumab plus bevacizumab might become a promising treatment option for these patients. This combination is being compared with standard-of-care sorafenib in a phase 3 trial.

Funding

F Hoffmann-La Roche/Genentech.

Introduction

Primary liver cancer is the sixth most common tumour worldwide and has the fourth highest cancer-related mortality (mortality-to-incidence ratio 0·93).1, 2 Hepatocellular carcinoma accounts for 90% of liver cancers worldwide, and approximately 80% of patients first present with unresectable disease because of the late appearance of symptoms.³ Patients with unresectable hepatocellular carcinoma have a poor prognosis, with rapid progression and short overall survival.

Research in context

Evidence before this study

We searched PubMed for clinical trials published in English between Sept 25, 2014, and Sept 24, 2019, using the terms “PD-L1” or “PD-1” or “immunotherapy” or “immune checkpoint” or “VEGF” in the title or abstract in combination with “HCC” or “hepatocellular carcinoma” in the title. We identified 24 publications, of which two described studies of PD-1 checkpoint inhibitors, six described drugs targeting angiogenesis, one described a combination of CTLA-4 immune checkpoint inhibitor with ablation, and the remainder described other kinase inhibitors, autologous immunotherapies, and vaccines. Phase 1–2 studies of PD-1 checkpoint inhibitors (nivolumab and pembrolizumab) showed durable objective responses in 15–17% of patients with advanced hepatocellular carcinoma. On the basis of these data, nivolumab and pembrolizumab are indicated as second-line treatment for patients previously treated with sorafenib. However, confirmatory phase 3 studies of these drugs compared with standard of care in first-line or second-line hepatocellular carcinoma did not show their ability to improve survival. The VEGF inhibitor bevacizumab combined with temsirolimus led to favourable response rates and overall survival in a small phase 2 study. In two independent phase 3 studies, second-line treatment with the VEGFR inhibitor ramucirumab did not significantly improve survival over placebo in patients with unselected hepatocellular carcinoma, but a survival benefit was seen in patients with advanced hepatocellular carcinoma who had α-fetoprotein concentrations of 400 ng/mL or more. Other US Food and Drug Administration-approved targeted therapies for first-line hepatocellular carcinoma were approved on the basis of overall survival superiority (sorafenib) or non-inferiority (lenvatinib) versus placebo. However, more efficacious treatments or treatment combinations are still needed to improve clinical responses and survival in patients with advanced hepatocellular carcinoma. Studies in other cancer types have shown that treatment efficacy is improved when checkpoint inhibitors are combined with other drugs, including those inhibiting VEGF, supporting the potential for exploration in hepatocellular carcinoma.

Added value of this study

When combining a PD-L1 inhibitor (atezolizumab) and an anti-VEGF antibody (bevacizumab), no new safety signals or additive toxicity occurred. The combination also resulted in clinically meaningful, durable responses in patients with advanced hepatocellular carcinoma not previously treated with systemic therapy. This phase 1b study also showed that bevacizumab combined with atezolizumab resulted in improved progression-free survival compared with atezolizumab monotherapy.

Implications of all the available evidence

The results of this study suggest that combining atezolizumab with bevacizumab can augment antitumour responses and improve progression-free survival in patients with unresectable hepatocellular carcinoma. To find out how this combination therapy compares with the current standard of care, the phase 3 IMbrave150 study (NCT03434379) is being done to compare atezolizumab and bevacizumab combination therapy with sorafenib in a large study population of patients with systemic treatment-naive unresectable hepatocellular carcinoma.

Angiogenesis and immune evasion are two hallmarks of cancer, including hepatocellular carcinoma.⁴ Most hepatocellular carcinoma tumours are hypervascular, and overexpression of VEGF has been linked to disease development and progression.⁵ In addition to its role in angiogenesis, VEGF exerts an immunomodulatory effect, and anti-VEGF therapies mitigate VEGF-mediated immunosuppression within the tumour and its microenvironment.6, 7, 8

Preliminary studies have also shown that inhibition of the PD-L1–PD-1 immune checkpoint enhances the magnitude and quality of tumour-specific T-cell responses, and might provide clinical benefit to patients with hepatocellular carcinoma.9, 10, 11 However, phase 3 trials have not yet shown superiority of immune checkpoint inhibitor monotherapy over current standard of care.12, 13

Approved first-line treatment options for patients presenting with unresectable hepatocellular carcinoma are limited to systemic therapies with multikinase inhibitors, including sorafenib and lenvatinib, which target angiogenic pathways driven by VEGF.5, 14, 15, 16, 17 FOLFOX4 (fluorouracil, leucovorin, and oxaliplatin) is also approved for advanced hepatocellular carcinoma in China.¹⁸ Despite these treatments, a high unmet medical need remains for patients with advanced hepatocellular carcinoma.16, 19, 20, 21, 22

Modest single-agent activity in hepatocellular carcinoma has been observed with bevacizumab.23, 24 As a monotherapy and in combination with PD-L1 inhibitors, bevacizumab has shown immunomodulatory effects in other tumour types, with promising clinical benefit and a good safety profile.25, 26, 27, 28 Additionally, preclinical evidence indicates that immune checkpoint inhibitors can promote vascular normalisation.²⁹ Therefore, combining atezolizumab and bevacizumab might improve the antitumour immune response to provide improved and more durable clinical benefit in patients with hepatocellular carcinoma.

We aimed to describe the efficacy and safety of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma who had received no previous systemic therapy.