Redefining BCLC B, Intermediate-Stage HCC: Is There a Role for Combination Systemic Therapy?

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide with a rising incidence in the United States. BCLC B intermediate stage HCC, defined as patients with unresectable, liver-limited disease and preserved liver function, encompasses a broad range of patients with variable tumor size, number, and location.

Locoregional therapies (LRTs), including arterially-directed therapies, are the mainstay of treatment, and demonstrate an average survival benefit of approximately 2.5 years. However, the success of these interventions is challenging to characterize given the variability of techniques, patient eligibility, and the number of repeat treatment sessions.

For example, OPTIMIS (NCT01933945) was a real-world observational study of patients with unresectable HCC who underwent transarterial chemoembolization (TACE).¹ Results from the study indicated that at the time of the inclusion visit, 39% of patients (n = 636) who underwent TACE were not eligible for this approach, deviating from practice guidelines. A total of 507 patients became TACE ineligible during the study; of those patients, 9% (n = 47) went on to receive systemic therapies like sorafenib (Nexavar) at the time of ineligibility, suggesting that TACE may be overutilized.

Of note, the study was conducted when sorafenib was the only FDA-approved systemic agent for patients with HCC, and so patients may have been overtreated when the alternative was long-term therapy with a considerable safety profile and limited efficacy. Additionally, although treatment-related mortality from LRT is less than 5%, complications include pancreatitis, cholecystitis, liver failure, and bone marrow suppression, all of which can potentially lead to patients being ineligible for systemic options.²

With recent advances made in systemic therapies, redefining the management of patients with unresectable disease will be essential to improve outcomes. Recently, the combination of the an anti–PD-L1 antibody atezolizumab (Tecentriq) and the anti-VEGF antibody bevacizumab (Avastin) was evaluated in patients with unresectable HCC in the IMbrave150 trial (NCT03434379).³ Thirty-seven percent of patients on the trial had unresectable HCC without extrahepatic spread and 52% previously received local therapies.

The combination resulted in a 12-month overall survival rate of 67.2% (95% CI, 61.3%-73.1%) versus 54.6% with sorafenib (95% CI, 45.2%-64.0%), with an impressive objective response rate of 27.3% (95% CI, 22.5%-32.5%) versus 11.9% (95% CI, 7.4%-18.0%), respectively. The doublet also had a tolerable safety profile compared with sorafenib. Final analyses are pending, but this is the first trial in HCC to show a survival advantage with combination therapy in the first-line setting.

Based on the promising results of IMbrave150 trial, several ongoing trials are examining combination strategies. For example, the phase 3 LEAP-002 trial (NCT03713593) is evaluating lenvatinib (Lenvima) plus pembrolizumab (Keytruda), while the phase 3 HIMALAYA study (NCT03298451) is examining durvalumab (Imfinzi) plus tremelimumab in this population. Additionally, the phase 3 CheckMate-9DW trial (NCT04039607) is assessing nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with advanced disease, while the phase 3 COSMIC-312 trial (NCT03755791) is examining cabozantinib (Cabometyx) plus atezolizumab in these patients. If approved down the line by the FDA, there will be 5 first-line options beyond TKI monotherapy available for the treatment of patients with unresectable and advanced-stage HCC.

The treatment of HCC is evolving, and the effectiveness of combination systemic therapy may be comparable to LRT in patients with intermediate-stage HCC; however, this will need to be further investigated in controlled clinical trials where optimal patient selection can be explored. The IMbrave150 data show promise, and although LRT is considered to be standard practice, combination systemic therapies may be considered in the following scenarios:

• Patients who have a high chance of residual disease post procedure (ie, large or multiple tumors, tumors that are difficult access)
• Patients with a high chance of recurrence (ie, high alpha-fetoprotein, large multifocal bilobar tumors, and vascular invasion)
• Patients who are considered to be refractory to LRT and maintain adequate liver function
• Patients who could be downsized or bridged to surgery

References

1. Peck-Radosavljevic M, Kudo M, Raoul J-L, et al. Outcomes of patients (pts) with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization (TACE): Global OPTIMIS final analysis. J Clin Oncol. 2018;36(suppl 15):4018. doi:10.1200/JCO.2018.36.15_suppl.4018
2. Molinari M, Kachura JR, Dixon E, et al. Transarterial chemoembolism for advanced hepatocellular carcinoma: results from a North American cancer centre. Clin Oncol (R Coll Radiol). 2006;18(6):684-692. doi:10.1016/j.clon.2006.07.012
3. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894-1905. doi:10.1056/NEJMoa1915745