Drug Combo Improves Recurrence-Free Survival After HCC Resection

Neil Osterweil

April 18, 2023

ORLANDO, Florida — Patients with hepatocellular carcinoma (HCC) who undergo surgery or thermal ablation with curative intent are at high risk for recurrence, but currently, no adjuvant therapy standard of care exists for these patients.

New findings signal a promising option for these patients. The combination of the immune checkpoint inhibitor atezolizumab (Tecentriq) and the angiogenesis inhibitor bevacizumab (Avastin) was associated with a significant improvement in recurrence-free survival compared with active surveillance and represents the first option to show efficacy in the adjuvant setting following surgical resection of HCCs for patients at high risk for recurrence.

The recurrence-free survival benefit corresponded to a 28% reduced risk of recurrence or death among patients who received the combination therapy in comparison with active surveillance. However, the overall survival data remain immature.

The data come from an interim analysis of the IMbrave050 trial, which was presented this week at the American Association for Cancer Research (AACR) Annual Meeting 2023.

"Atezolizumab plus bevacizumab may be a practice-changing adjuvant treatment options for patients with high-risk HCC," said lead investigator Pierce Chow, FRCS(E), PhD, from the National Cancer Center Singapore and Singapore General Hospital, who presented the results in an oral abstract session. The combination "may also change clinical indications for surgical resection" because clinicians may be more likely to consider resection for patients at extremely high risk for recurrence if the risk of recurrence can be reduced with this combination, Chow explained.

In the previous IMbrave150 trial, the combination of atezolizumab and bevacizumab significantly improved outcomes for patients with high-risk and non–high-risk unresectable HCC compared with the standard-of-care sorafenib (Nexavar).

In that trial, the median overall survival in the intention-to-treat population was 19.2 months for patients who received atezolizumab-bevacizumab, vs 13.4 months for patients who received sorafenib (P = .0009).

The combination was also associated with improvements in progression-free survival and objective response rates compared with sorafenib.

On the basis of these results, the IMbrave050 investigators explored whether the same benefits would occur for patients with resectable disease who were considered to be at high risk for recurrence owing to tumor size, vascular invasion, or poor tumor differentiation. The trial compared the combination for 334 patients with active surveillance, also for 334 patients, in the adjuvant setting.

Patients were considered good candidates for thermal ablation if they had a single tumor greater than 2 cm but not larger than 5 cm in its longest dimension, or if they had four or fewer tumors, all of which were no larger than 5 cm. For all other patients, surgical resection was recommended.

The median age of the patients was 60. For about half of patients in each arm, the expression level of programmed cell death–ligand-1 (PD-L1) was 1% or higher.

After a median follow-up of 17.4 months, the 12-month recurrence-free survival rate, as assessed by independent review, was 78% for patients in the treatment arm, compared with 65% for patients who were assigned to active surveillance (hazard ratio [HR], 0.72; P = .012). This finding was generally consistent across clinical subgroups, including groups based on age, sex, race/ethnicity, performance status, PD-L1 expression, number of high-risk features, Barcelona Clinic Liver Cancer stage, cancer etiology, procedure type, microvascular invasion, or tumor numbers and size.

Of 133 patients on active surveillance who experienced a protocol-defined recurrence event, 81 (61%) crossed over to the atezolizumab/bevacizumab arm.

The overall survival benefit of the combination therapy was less clear. Chow called the overall survival data "highly immature" at the time of data cutoff.

Overall, 47 patients died — seven more in the combination arm (27 vs 20). More specifically, 17 patients in the combination arm and 16 on active surveillance died from progressive disease; six patients in the treatment arm vs 1 on surveillance died from adverse events. The remaining deaths were attributed to "other" causes. Two deaths in the combination arm were considered treatment related, one from esophageal varices hemorrhage, and the other from ischemic stroke.

Chow noted that the number of deaths attributed to HCC recurrence was similar between the groups. There were three COVID-19–related deaths within 1 year of randomization, all in the combination arm.

As for adverse events, the safety of the combination was largely consistent with that reported in the IMbrave150 trial. Nearly all patients experienced at least one adverse event. Treatment-related grade 3 or 4 adverse events occurred in 34.9% of patients in the combination group, and serious treatment-related events occurred in 13.3%.

The most common adverse events of any grade were proteinuria, hypertension, decreased platelet count, increases in liver enzyme level, hypothyroidism, arthralgia, pruritus, rash, increase in serum bilirubin level, and fever.

Invited discussant Stephen L. Chan, MD, from the Chinese University of Hong Kong, said the study was "definitely" relevant to clinicians and addresses "a very important unmet need."

Chan noted that he thinks this combination will "likely" be practice changing, given the improvement in recurrence-free survival, but "certainly we need more data to guide us in patient selection."

The study was funded by F. Hoffman-La Roche. Chow has consulting for and has received honoraria and grant/research support from Roche and others. Chan has received honoraria from Roche and consulting fees and grant/research support from others.

American Association for Cancer Research (AACR) Annual Meeting 2023: Abstract CT003. Presented April 16, 2023.

Neil Osterweil, an award-winning medical journalist, is a long-standing and frequent contributor to Medscape.

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