The Need for Prospective Data in Second-Line HCC and Beyond

Dr Franses on the Need for Prospective Data in Second-Line HCC and Beyond

Joseph Franses, MD, PhD, assistant professor, medicine, University of Chicago Medicine Comprehensive Cancer Center, discusses the need for more prospective research to answer remaining questions and expand options in the second-line setting and beyond for patients with hepatocellular carcinoma (HCC).

Improving treatment options in the second line and beyond for patients whose disease progresses following first-line therapy is a key focus within the treatment landscape, Franses begins. He goes on to note that additional data could help address unanswered questions and guide treatment decision-making in the current first-line setting. A considerable number of patients in this setting remain fit enough to pursue additional treatment options if their disease progresses on first-line therapy, Franses states.

In the absence of new clinical trial data, Franses says that there are some approved regimens that can be utilized off-label, though many were initially studied for first-line settings, Franses says. Determining the appropriate sequence of these treatments is necessary to treat patients effectively, he notes. For example, in the absence of dose-limiting toxicities for immunotherapy, it is common practice to use lenvatinib (Lenvima) following frontline immunotherapy.

Numerous second-line studies are underway, Franses continues. These include approaches that combine alternative dual immunotherapies, such as anti–PD-1 plus anti–TGF-beta pathway inhibitors. Precision medicine strategies are also being explored for novel targets like beta-catenin-driven tumors, which account for approximately one-third of HCC cases, he expands. Additionally, there are efforts to target the c-Myc oncogene, which drives a significant proportion of HCC; however, it is not yet identifiable through genomic markers. Research is ongoing to develop biomarkers for these targets, Franses says.

These second-line and beyond studies are vital in providing the data needed to refine and expand treatment options, he emphasizes. As the field progresses, the insights gained from these trials will likely lead to improved therapeutic strategies, enhancing patient outcomes in advanced stages of disease, Franses concludes.

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Joseph Franses, MD, PhD, discusses the need for more prospective data in the second-line setting and beyond for patients with hepatocellular carcinoma.
 

Dr Franses on Considerations for Second-Line Treatment of HCC

Joseph Franses, MD, PhD, assistant professor of medicine, at the University of Chicago Medicine Comprehensive Cancer Center, discusses the considerations for treatment in patients with unresectable or advanced hepatocellular carcinoma (HCC) whose disease progresses after first-line therapy.

Following disease progression on a first-line regimen, a proportion of patients with advanced HCC remain fit enough to pursue additional treatment options, according to Franses. In the absence of prospective clinical trials providing head-to-head comparisons of potential second-line regimens, clinicians are able to utilize various regimens to tailor subsequent therapies based on the patient's response and tolerance to previous treatment, he continues.

Although combination regimens such as atezolizumab (Tecentriq) plus bevacizumab (Avastin) and tremelimumab-actl (Imjudo) plus durvalumab (Imfinzi) have been approved by the FDA for use in the frontline setting for patients with unresectable HCC, off-label use in the second-line setting could be considered, allowing for the potential sequencing of these options if a dose-limiting toxicity is not observed, Franses says. Lenvatinib (Lenvima) monotherapy is also commonly used to treat HCC in the second-line setting, he adds. The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) also received prior FDA approval for the treatment of unresectable HCC after treatment with sorafenib (Nexavar).

Notably, the National Comprehensive Cancer Network Guidelines also list single-agent cabozantinib (Cabometyx), regorafenib (Stivarga), or sorafenib as treatment options for subsequent lines of therapy following disease progression. Nivolumab plus ipilimumab, as well as single-agent pembrolizumab (Keytruda), are also listed under other recommended regimens.

Although there are some treatment options to consider in the second-line setting for patients with unresectable HCC, more prospective data are needed to assess potential options and better inform decision-making for patients whose disease progresses following first-line therapy, Franses concludes.

Joseph Franses, MD, PhD, discusses treatment considerations for hepatocellular carcinoma that progresses after first-line therapy.

Dr Frances 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.

Joseph Franses, MD, PhD, debates whether targeting angiogenesis and the PD-1/PD-L1 pathway in hepatocellular carcinoma is always a reliable approach.
 

Joseph Franses, MD, PhD

Articles

Dr Franses on the Need for Prospective Data in Second-Line HCC and Beyond

Dr Franses on Considerations for Second-Line Treatment of HCC

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