Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial

Summary

Background

Single-agent nivolumab showed durable responses, manageable safety, and promising survival in patients with advanced hepatocellular carcinoma in the phase 1–2 CheckMate 040 study. We aimed to investigate nivolumab monotherapy compared with sorafenib monotherapy in the first-line setting for patients with advanced hepatocellular carcinoma.

Methods

In this randomised, open-label, phase 3 trial done at medical centres across 22 countries and territories in Asia, Australasia, Europe, and North America, patients at least 18 years old with histologically confirmed advanced hepatocellular carcinoma not eligible for, or whose disease had progressed after, surgery or locoregional treatment; with no previous systemic therapy for hepatocellular carcinoma, with Child-Pugh class A and Eastern Cooperative Oncology Group performance status score of 0 or 1, and regardless of viral hepatitis status were randomly assigned (1:1) via an interactive voice response system to receive nivolumab (240 mg intravenously every 2 weeks) or sorafenib (400 mg orally twice daily) until disease progression or unacceptable toxicity. The primary endpoint was overall survival assessed in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT02576509.

Findings

Between Jan 11, 2016, and May 24, 2017, 743 patients were randomly assigned to treatment (nivolumab, n=371; sorafenib, n=372). At the primary analysis, the median follow-up for overall survival was 15·2 months (IQR 5·7–28·0) for the nivolumab group and 13·4 months (5·7–25·9) in the sorafenib group. Median overall survival was 16·4 months (95% CI 13·9–18·4) with nivolumab and 14·7 months (11·9–17·2) with sorafenib (hazard ratio 0·85 [95% CI 0·72–1·02]; p=0·075; minimum follow-up 22·8 months); the protocol-defined significance level of p=0·0419 was not reached. The most common grade 3 or worse treatment-related adverse events were palmar-plantar erythrodysaesthesia (1 [<1%] of 367 patients in the nivolumab group vs 52 [14%] of patients in the sorafenib group), aspartate aminotransferase increase (22 [6%] vs 13 [4%]), and hypertension (0 vs 26 [7%]). Serious treatment-related adverse events were reported in 43 (12%) patients receiving nivolumab and 39 (11%) patients receiving sorafenib. Four deaths in the nivolumab group and one death in the sorafenib group were assessed as treatment related.

Interpretation

First-line nivolumab treatment did not significantly improve overall survival compared with sorafenib, but clinical activity and a favourable safety profile were observed in patients with advanced hepatocellular carcinoma. Thus, nivolumab might be considered a therapeutic option for patients in whom tyrosine kinase inhibitors and antiangiogenic drugs are contraindicated or have substantial risks.

Funding

Bristol Myers Squibb in collaboration with Ono Pharmaceutical.

Introduction

The incidence of hepatocellular carcinoma is rising worldwide.¹ Patients with hepatocellular carcinoma are frequently diagnosed at an advanced stage of disease beyond potentially curative treatments, such as surgical resection, transplantation, or ablation.² Until 2020, the only approved first-line therapies for advanced hepatocellular carcinoma included the multikinase inhibitors sorafenib and lenvatinib, with median overall survival of 12·3 months for sorafenib and 13·6 months for lenvatinib.³ However, treatment with these drugs results in a high proportion of treatment-related toxicities, with treatment-related, treatment-emergent adverse events of grade 3 or worse in 49% of patients treated with sorafenib and 57% of patients treated with lenvatinib,³ although some early dermatological adverse events have been linked to improved outcomes.⁴ Moreover, these toxicities often require dose interruption or reduction.3, 5 Consequently, treatments that can prolong survival in hepatocellular carcinoma with an improved safety and tolerability profile are still needed.

Research in context

Evidence before this study

We searched PubMed on April 22, 2021, using the terms “hepatocellular carcinoma or liver cancer” in the title or abstract and “programmed cell death 1 or PD-1 or programmed cell death ligand 1 or PD-L1” as a text word for articles published in English, with no date limits. No clinical trial publications were found before the start of the CheckMate 459 trial, which investigated PD-1 or PD-L1 inhibitors as monotherapy or in combination with other drugs as first-line systemic therapy for hepatocellular carcinoma. Before the start of this study in 2015, sorafenib was the only approved drug for the treatment of hepatocellular carcinoma. However, sorafenib led to only a modest improvement in overall survival and was associated with a high proportion of treatment-related toxicities, often leading to dose modification. The inflammation and immunosuppression often evident in hepatocellular carcinoma and the scarcity of treatment options for patients with advanced hepatocellular carcinoma provided the rationale for investigating the PD-1 inhibitor nivolumab in this setting. The phase 1–2 CheckMate 040 trial appears to be the first to report the use of a PD-1 inhibitor (in this case nivolumab) in patients with advanced hepatocellular carcinoma, most of whom had received previous sorafenib therapy. The results of CheckMate 040 cohorts 1 and 2 showed that nivolumab monotherapy had a clinical benefit. These findings provided the rationale for investigating nivolumab monotherapy in the first-line setting compared with sorafenib, the standard of care at the time this study was designed.

Added value of this study

To our knowledge, CheckMate 459 is the only completed phase 3 trial currently published that reports the results of a single-agent anti-PD-1 or anti-PD-L1 therapy compared with a single-agent tyrosine kinase inhibitor therapy in the first-line setting for patients with advanced hepatocellular carcinoma. The trial did not meet the prespecified boundary for significance for the primary endpoint of overall survival for nivolumab versus sorafenib. Improvements in response and sustained separation of the overall survival Kaplan-Meier curves suggest a prolonged survival benefit with nivolumab at longer follow-up. Nivolumab had a manageable safety profile and no new safety signals were observed. The proportion of patients with grade 3–4 treatment-related adverse events and any-grade treatment-related adverse events leading to discontinuation was lower with nivolumab than with sorafenib. These results are consistent with earlier findings regarding the clinical activity and safety profile of nivolumab in the second-line setting in patients with advanced hepatocellular carcinoma.

Implications of all the available evidence

Since CheckMate 459 commenced, several trials have investigated PD-1 or PD-L1 inhibitors alone or in combination with other drugs as first-line therapy for advanced hepatocellular carcinoma; atezolizumab plus bevacizumab is currently the standard of care in this setting. On the basis of the results from CheckMate 459, nivolumab monotherapy is included in the NCCN Clinical Practice Guidelines in the USA as a first-line systemic therapy option (useful in particular circumstances) for patients with Child-Pugh score of A or B who are ineligible for anti-angiogenic drugs or tyrosine kinase inhibitors.

Given the sustained inflammation and immunosuppression frequently present in hepatocellular carcinoma, the clinical activity (improvements in response, duration of response, and proportion of patients with decreased tumour load) of PD-1 inhibitors as second-line treatment for hepatocellular carcinoma,6, 7, 8, 9 and scarce clinical evidence in the first-line setting, there is a strong rationale for investigating immuno-oncology monotherapy in this setting. In fact, on the basis of findings from the phase 3 IMbrave150 trial,¹⁰ the combination of atezolizumab and bevacizumab is currently considered the standard of care as first-line therapy for patients with advanced hepatocellular carcinoma. The PD-1 inhibitor nivolumab provided objective response of 14%, disease control of 56%, and median overall survival of 15·1 months in patients with advanced hepatocellular carcinoma whose disease progressed on previous sorafenib therapy in the international phase 1–2 CheckMate 040 study regardless of tumour cause (NCT01658878).⁸ These data suggested a potential clinical benefit of nivolumab monotherapy for treating patients with hepatocellular carcinoma who had previously received sorafenib therapy.

On the basis of these findings, the confirmatory phase 3 CheckMate 459 trial, which we report in this Article, investigated nivolumab monotherapy compared with sorafenib monotherapy in patients with advanced hepatocellular carcinoma in the first-line setting.