Dr Franses on the Feasibility of Co-Inhibiting Angiogenesis and PD-1 Pathways in HCC

Joseph Franses, MD, PhD, assistant professor, medicine, University of Chicago Medicine Comprehensive Cancer Center, debates whether targeting angiogenesis and the PD-1/PD-L1 pathway in hepatocellular carcinoma (HCC) is always a reliable approach.

Results from the phase 3 IMbrave150 trial (NCT03434379) of atezolizumab (Tecentriq) and bevacizumab (Avastin) generated a lot of optimism for the co-inhibition of angiogenesis and immune checkpoints as a general approach to advanced hepatocellular carcinoma (HCC) management, Franses begins. However, the broader application of similar treatment strategies has been met with mixed results in subsequent studies he says. Frances adds that it is important to recognize that not all combination therapies have yielded the same level of success, and the field has encountered several notable setbacks.

For example, combinations such as cabozantinib (Cabometyx) plus atezolizumab and lenvatinib (Lenvima) plus pembrolizumab (Keytruda) have not demonstrated the desired efficacy in this patient population, tempering initial enthusiasm, Franses explains. This highlights the challenges and limitations inherent in combining these therapeutic pathways.

One significant issue is the potential for synergistic toxicity, which can restrict the doses of each drug that can be safely administered, Franses continues. For instance, preclinical data have shown that TKI inhibition can effectively target pathological angiogenesis, but it can also induce toxicity in the liver, he explains. This toxicity was mediated by various immune components, including natural killer cells, and could explain the difficulty in translating these combinations into effective clinical treatments, he details.

The theoretical foundation for combining angiogenesis inhibition with immune checkpoint inhibition is sound, Franses emphasizes, explaining that inhibiting angiogenesis could normalize the tumor microenvironment, making it more susceptible to immune-mediated attack. However, this theoretical synergy has not consistently translated into clinical success. The complexity of the tumor microenvironment, potential for increased toxicity, and variability in patient responses all contribute to the challenges in developing effective combination therapies, Franses concludes.