What’s the Safest Path to Neoadjuvant Therapy in Liver Cancer?

What’s the Safest Path to Neoadjuvant Therapy in Liver Cancer?

July 18, 2022 0 By Jennifer Walker

Immune checkpoint inhibitors (ICIs) had a more favorable safety profile for advanced liver cancer than did tyrosine kinase inhibitors (TKIs), according to a clinical trial meta-analysis.

In a pooled analysis of 30 studies, ICIs had significantly fewer serious adverse events (35% vs 69%) and severe adverse events than seen with TKIs (24% vs 46%), reported Pablo E. Serrano, MD, MPH, of the Juravinski Hospital in Hamilton, Ontario, and colleagues.

Liver-related events occurred at a similar rate between the two classes (28% ICI vs 21% TKI), the authors wrote in JAMA Network Open, concluding that ICIs “therefore may be the more appropriate agent in the neoadjuvant setting.”

“As it stands, neoadjuvant therapy in hepatocellular carcinoma is being explored but is not yet well established,” coauthor Chris Griffiths, MD, MBA, of McMaster University in Hamilton, told MedPage Today.

Although neoadjuvant therapies for hepatocellular carcinoma (HCC) have appeared safe and feasible, “surgeons are concerned that adverse effects of neoadjuvant therapy with these agents could lead to delayed or even cancelled surgeries,” Serrano’s group noted.

With most cases inoperable at diagnosis, systemic therapy is recommended for most cases of advanced HCC, which remains the second leading cause of worldwide cancer-related mortality.

“As HCC therapy evolves to combine medical therapy with ICIs and TKIs and targeted surgical and locoregional therapies, such as ablation and embolization, clinicians require a more comprehensive understanding of how treatment toxic effects affect subsequent therapies,” Serrano and colleagues wrote.

In particular, combination of the two classes may offer the most promise for improving objective response rates in the neoadjuvant setting without toxicity that would prevent patients from reaching surgery, the group suggested.

In their analysis, the serious adverse event rate was 36% with combined TKI and ICI use, compared with 46% on TKI alone and 24% on an ICI alone, and confidence intervals overlapped with both of the single-class comparator groups.

For this study, Serrano and colleagues examined data on 30 trials involving 12,921 advanced HCC patients that were conducted from 2008 to 2022. Trials assessed TKIs, PD-1/L1- or CTLA-4-directed ICIs, or their combined use.

After searching the Cochrane central register of controlled trials (CENTRAL), Embase, and Medline databases, 18 phase III randomized controlled trials, 10 phase II randomized controlled trials, and two single-group phase II trials were included. Of those trials, 25 involved a TKI treatment and nine involved an ICI. Only two trials included participants with resectable HCC, while the rest included patients who were ineligible for surgery.

Overall, the trials included 9,142 patients on a TKI, 1,290 on an ICI, 604 on both, and 2,084 patients who received placebo.

Mean age was 62, and 84% were men. Nearly all participants had Childs A cirrhosis, while 82% had a mean Barcelona clinic liver cancer HCC stage of 3. Over half had extrahepatic disease (61%), and 28% had macrovascular invasion.

When compared with sorafenib (Nexavar), other TKIs had similar risk of toxic liver effects (RR 1.06, 95% CI 0.92-1.24) and higher risk of severe adverse events overall (RR 1.24, 95% CI 1.07-1.44).

ICIs also had similar rates of toxic liver effects compared with sorafenib (RR 1.10, 95% CI 0.86-1.40) but no higher risk of severe adverse events than the TKI (RR 1.19, 95% CI 0.95-1.50).

The authors acknowledged limitations to the data, including variations in reporting of adverse events across the studies and that not all reported hepatotoxic effects. Inclusion criteria also varied across studies. “Heterogeneity in pretrial treatment is the most significant confounding factor not well accounted for in this study,” they wrote.

  • author['full_name']

    Zaina Hamza is a staff writer for MedPage Today, covering Gastroenterology and Infectious disease. She is based in Chicago.


Serrano did not disclose any conflicts of interest.

Coauthors reported relationships with AstraZeneca, Eisai, Ipsen, and Roche.