What is the safest route to neoadjuvant therapy for liver cancer?
According to a meta-analysis of clinical trials, immune checkpoint inhibitors (ICIs) had a more favorable safety profile for advanced liver cancer than tyrosine kinase inhibitors (TKIs).
In a pooled analysis of 30 studies, ICI had significantly fewer serious adverse events (35% versus 69%) and serious adverse events than those seen with TKIs (24% versus 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 versus 21% TKI), the authors wrote in Open JAMA Networkconcluding that ICIs “might therefore be the most appropriate agent in the neoadjuvant setting”.
“As it stands, neoadjuvant therapy in hepatocellular carcinoma is being explored but not yet well established,” said co-author Chris Griffiths, MD, MBA, of McMaster University. in Hamilton. MedPage today.
Although neoadjuvant therapies for hepatocellular carcinoma (HCC) have been shown to be safe and feasible, “surgeons are concerned that adverse effects of neoadjuvant therapy with these agents may lead to delayed or even canceled surgeries,” Serrano’s group noted. .
Since most cases are inoperable at diagnosis, systemic treatment is recommended for most cases of advanced HCC, which remains the second leading cause of cancer-related death worldwide.
“As HCC therapy evolves to combine medical therapy with ICIs and TKIs and targeted surgical and locoregional therapies, such as ablation and embolization, clinicians need a more comprehensive understanding of how the toxic effects of treatment affect subsequent therapies,” Serrano and colleagues wrote.
In particular, combining the two classes may hold 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 rate of serious adverse events was 36% with the combined use of TKI and ICI, compared to 46% with a TKI alone and 24% with an ICI alone, and the confidence intervals overlapped. with the two single-class comparison groups.
“The study authors are to be commended for analyzing the side effects of these trials involving nearly 13,000 patients,” said Bassam Estfan, MD, of the Cleveland Clinic in Ohio. “This aligns with the clinical experience we see in our patients.”
“The landscape for systemic treatment of advanced hepatocellular carcinoma has changed dramatically over the past 5 years with more options available for first- and second-line management of advanced disease,” said Estfan, who did not participate. to this study. “Although this study cannot assess the safety of systemic therapy before surgery (whether operable at baseline or after response), it does offer data to suggest that some therapies, particularly ICI, may be well tolerated before surgery with relatively low hepatic morbidity.”
For this study, Serrano and colleagues reviewed data from 30 trials involving 12,921 patients with advanced HCC that were conducted from 2008 to 2022. The trials assessed TKIs, PD-1/L1-directed ICIs, or CTLA -4, 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-arm phase II trials were included. Of these trials, 25 involved TKI treatment and nine involved ICI. Only two trials included participants with resectable HCC, while the others included patients who were not eligible for surgery.
Overall, the trials included 9142 patients on TKI, 1290 on ICI, 604 on both, and 2084 patients on placebo.
The average age was 62 years and 84% were men. Almost all participants had Childs A cirrhosis, while 82% had an average liver cancer HCC stage from the Barcelona clinic of 3. More than half had extrahepatic disease (61%) and 28% had macrovascular invasion.
Compared to sorafenib (Nexavar), the other TKIs had a similar risk of liver toxic effects (RR 1.06, 95% CI 0.92-1.24) and a higher risk of serious adverse events in the overall (RR 1.24, 95% CI 1.07-1.44).
ICIs also had similar rates of liver toxic effects compared to sorafenib (RR 1.10, 95% CI 0.86-1.40), but no higher risk of serious adverse events than TKIs ( RR 1.19, 95% CI 0.95-1.50).
The authors acknowledged the limitations of the data, including variations in reporting of adverse events between studies and the fact that not all reported hepatotoxic effects. The inclusion criteria also varied from study to study. “Pretrial treatment heterogeneity is the single most important confounder that is not well captured in this study,” they wrote.
Serrano disclosed no conflict of interest.
The co-authors reported relationships with AstraZeneca, Eisai, Ipsen, and Roche.