Dr El-Khoueiry on Immune Suppression in Advanced HCC After Checkpoint Inhibitors

Anthony B. El-Khoueiry, MD, associate director, clinical research, University of Southern California (USC) Norris Comprehensive Cancer Center, associate professor, clinical medicine, the Keck School of Medicine of USC, discusses findings from an exploratory biomarker analysis conducted as part of the phase 2 trial (NCT04696055) that evaluated the combination of regorafenib (Stivarga) and pembrolizumab (Keytruda) in patients with advanced hepatocellular carcinoma (HCC) who experienced disease progression following one prior immune checkpoint inhibitor–containing regimen.

The biomarker analysis aimed to compare tumor microenvironment characteristics between tumor samples from patients with advanced HCC treated with regorafenib plus pembrolizumab in the post–immune checkpoint inhibitor study (n=23) vs those in a phase 1b study (NCT03347292) who were treated with the combination in the first line and were naive to an immune checkpoint inhibitor (n = 17). The findings revealed distinct differences in the immune landscape of these two patient populations, El-Khoueiry says.

In patients whose disease had progressed on prior immunotherapy, El-Khoueiry explains that there was a notable increase in T-cell exhaustion and a higher prevalence of regulatory T cells within the tumor microenvironment. These features indicate a more immunosuppressive environment, which may contribute to the diminished effectiveness of subsequent immunotherapy in these patients, he says.

El-Khoueiry notes that these observations have significant implications for future therapeutic strategies and clinical trials in advanced HCC. The increased T-cell exhaustion and presence of regulatory T-cell lymphocytes suggest that the tumor microenvironment becomes more resistant to immune-based therapies following initial checkpoint inhibition, he explains. This highlights the need for novel approaches that can re-invigorate the immune response or target the immunosuppressive elements within the tumor microenvironment, El-Khoueiry adds.

These findings should inform the design of future studies and the rationale to incorporate new targets aimed at modulating the immune microenvironment to overcome resistance and improve therapeutic outcomes, El-Khoueiry continues. Understanding these biomarkers could lead to more effective treatment strategies for patients with advanced HCC who have limited options following progression on immune checkpoint inhibitors, El-Khoueiry concludes.