Consistent clinical benefit with atezolizumab-bevacizumab in patients with advanced hepatocellular carcinoma: updated results of IMbrave150

The phase III IMbrave150 trial established the combination of atezolizumab-bevacizumab (atezo-bev) as the first treatment to provide a survival benefit over sorafenib in the first-line treatment of patients with advanced hepatocellular carcinoma (HCC). During ASCO GI 2021, updated results of this trial were presented with 12 months of additional follow-up. The 19.2 months median overall survival (OS) reported for atezo-bev is the longest ever reported in a phase III trial in this setting and confirms this combination as the new standard of care in the frontline treatment of patients with advanced HCC.

Introduction

Advanced HCC is a disease that is notoriously difficult to treat due its intrinsic high chemo-resistance and the constant threat of a decline in liver function rendering further treatment impossible. Prior to 2008, no systemic drug was recommended for patients with advanced HCC, an unparalleled situation in oncology. Finally, in 2008, sorafenib emerged as the first effective systemic treatment for patients with advanced HCC and rapidly became the reference therapy in this setting. Unfortunately, this breakthrough was followed by over a decade of negative clinical studies with a broad range of therapeutic agents failing to demonstrate a survival benefit over sorafenib. Recently, this stream of negative trials came to an end with the publication of the IMbrave150 trial results, showing that the atezo-bev combination was associated with a significantly longer OS and PFS than sorafenib. During ASCO GI 2021, updated results of this trial were presented with an additional 12 months of follow-up.

Longest OS reported to date in untreated advanced HCC

In the IMbrave150 trial, a total of 501 previously untreated advanced or metastatic, unresectable HCC patients were randomly assigned (2:1) to receive either atezo (1500 mg IV q3w) in combination with bev (15 mg/kg q3w) or sorafenib (400 mg BID) until loss of clinical benefit or unacceptable toxicity. At the time of this updated analysis, 18% of atezo-bev and 3% of sorafenib patients were still on study treatment.

In the updated OS analysis, atezo-bev was found to be associated with a median OS of 19.2 months as compared to 13.4 months with sorafenib, resulting in a HR for OS of 0.66 (95%CI: 0.52-0.85; p= 0.0009). At 18 months, this translates into an OS rate of 52% for atezo-bev vs. 40% with sorafenib. With respect to PFS nothing much changed from the primary analysis with a median PFS of 6.9 and 4.3 months for atezo-bev and sorafenib, respectively (HR[95%CI]: 0.65[0.53-0.81]; p= 0.0001). At the 18 months landmark, the proportion of patients who were alive and free of progression was twice as high in the atezo-bev arm compared to the sorafenib arm (24% vs. 12%). With atezo-bev, 30% of patients obtained a response, with a complete response in 8% of patients. In contrast, sorafenib induced a treatment in response in only 11% of patients with only 1 patient having a complete response (<1%). Of the patients enrolled in the atezo-bev arm, 36% received some form of subsequent systemic therapy while this was the case for 52% of patients in the sorafenib arm. Of note, in 26% of patients in the sorafenib arm this subsequent therapy consisted of an immune checkpoint inhibitor. With respect to safety no new signals emerged during the additional 12 months of follow-up.

Conclusions

In conclusion, the median OS for atezo-bev in this updated analysis was reported at more than 19 months, making it the longest OS seen in a phase III study of advanced liver cancer to date. This excellent OS is further supported by an improvement in PFS with a hazard ratio of 0.65, a 30% objective response rate including 8% of complete responses and a tolerable safety profile. As such, these findings confirm atezo-bev as the standard of care for previously untreated, unresectable HCC patients.

Reference

Finn R, Qin S, Ikeda M, et al. IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC). Presented at ASCO Gi 2021; Abstract 267.