Michael Iglesia, MD, PhD, discusses the potential role of disease etiology in frontline HCC treatment decision-making.

Dr Iglesia on the Potential Role for Disease Etiology in Frontline HCC Treatment Selection

Michael Iglesia, MD, PhD, instructor, John T. Milliken Department of Medicine, Division of Oncology, Washington University School of Medicine, discusses the potential role of disease etiology in frontline hepatocellular carcinoma (HCC) treatment decision-making.

The role of disease etiology in frontline HCC treatment selection has been previously investigated, which the majority of prior research comparing viral vs nonviral causes of liver disease, Iglesia begins. Viral etiology mainly comprises long-term infection with hepatitis B or C virus; nonviral forms of HCC include alcoholic liver disease, autoimmune disease, and metabolic disease. Insights into this topic primarily come from global studies, where viral etiologies are more prevalent compared with the US, where nonviral etiology is more common, Iglesia states.

Immune checkpoint inhibitors are currently a standard-of-care therapy for patients with unresectable HCC in the frontline. However, many of these patients will not achieve a response with these agents, with approximately 20% to 40% of patients experiencing primary resistance to these regimens. Current evidence has implicated nonviral HCC in the development of resistance to checkpoint inhibitors. In contrast, patients who develop HCC due to viral infections may experience additional benefits from treatment with checkpoint inhibition, Iglesia details.

Iglesia states that this preference does not significantly influence his own clinical practice at present; however, it may become a more critical factor in the future. He speculates that future treatment strategies may be stratified based on the underlying etiology of the disease, allowing for more personalized and effective therapeutic approaches.

Although knowledge of the underlying cause of HCC does not currently have a substantial impact on treatment decisions in the frontline setting, ongoing research and clinical trials might soon provide more definitive guidance on tailoring therapies to the specific etiologies of HCC, potentially improving outcomes for different patient populations, Iglesia concludes.

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Michael Iglesia, MD, PhD, discusses the potential role of disease etiology in frontline HCC treatment decision-making.
 

Michael Iglesia, MD, PhD, discusses uncertainties surrounding the selection of second-line treatment approaches in hepatocellular carcinoma.

Dr Iglesia on Unmet Needs in Second-Line Therapy Selection in HCC

Michael Iglesia, MD, PhD, instructor, John T. Milliken Department of Medicine, Division of Oncology, Washington University School of Medicine, discusses unmet needs and uncertainties surrounding second-line therapy considerations in hepatocellular carcinoma (HCC).

There is a need for more robust data to guide treatment decisions in second-line HCC, Iglesia begins. Patients often transition to second-line therapy following progression on initial regimens such as durvalumab (Imfinzi) plus tremelimumab (Imjudo) or bevacizumab (Avastin) plus atezolizumab (Tecentriq), he details. Iglesia shares that in his own practice, he typically favors agents like cabozantinib and other TKIs in the second line, often bypassing sorafenib (Nexavar) and lenvatinib (Lenvima). However, there is a lack of evidence to support one approach over the other, he emphasizes.

Of the limited clinical data available, insights can be derived from trials such as phase 3 CELESTIAL trial (NCT01908426) evaluating cabozantinib (Cabometyx) vs placebo in patients with HCC who were previously exposed to sorafenib, Iglesia states. The trial demonstrated an overall survival benefit with cabozantinib vs placebo. Notably, many patients on the trial had previously received a VEGF-targeting TKI or immune checkpoint inhibitor, Iglesia says. This trial population could be considered comparable to the group of patients who had received what we think of as modern first-line therapy, he adds.

Significant gaps persist in determining optimal second-line treatment following initial checkpoint inhibitor or combination therapies, Iglesia continues. Questions have also risen regarding the use of lenvatinib vs approved agents in the second line following progression on either the phase 3 HIMALAYA (NCT0329845) or IMbrave150 (NCT03434379) regimens, he says. Additionally, some patients who previously received an immune checkpoint inhibitor may benefit more from switching to alternate first-line therapies such as bevacizumab plus atezolizumab, Iglesia states. Addressing these uncertainties requires well-designed trials aimed at elucidating the comparative effectiveness and safety of different treatment sequences in advanced HCC, Iglesia concludes.

Michael Iglesia, MD, PhD, discusses outcomes from the phase 3 COSMIC-312 trial of first-line cabozantinib plus atezolizumab in hepatocellular carcinoma.

Dr Iglesia on the COSMIC-312 Trial of Cabozantinib Plus Atezolizumab in HCC

Michael Iglesia, MD, PhD, instructor, John T. Milliken Department of Medicine, Division of Oncology, Washington University School of Medicine, discusses key efficacy and safety data from the phase 3 COSMIC-312 trial (NCT03755791) of first-line cabozantinib (Cabometyx) plus atezolizumab (Tecentriq) in hepatocellular carcinoma (HCC).

The open-label, randomized COSMIC-312 study compared cabozantinib plus atezolizumab with sorafenib (Nexavar) in the first-line treatment of patients with HCC, Iglesia begins. The primary end points of the study were progression-free survival (PFS) and overall survival (OS) in the intention-to-treat population. At the first interim analysis, the combination of atezolizumab and cabozantinib did not show improvements in median OS, thereby failing to meet the trial's primary end point, Iglesia states. This outcome contrasts with results observed in the phase 3 IMbrave150 trial (NCT03434379), which evaluated the VEGF-targeting agent bevacizumab (Avastin) in combination with atezolizumab in HCC, he adds.

Notably, the addition of cabozantinib to atezolizumab treatment in COSMIC-312 resulted in added toxicities compared with sorafenib, Iglesia states. The rate of grade 3 or worse adverse effects (AEs) was 57%, with 7% of patients experiencing grade 4 AEs and 12% having grade 5 events in the investigational treatment group. Additionally, 60% of patients required dose reductions of at least 1 drug, and approximately 14% discontinued at least 1 drug due to AEs, he details.

The observed safety profile of the COSMIC-312 regimen included expected toxicities of cabozantinib, such as hypertension and diarrhea, along with immune-related AEs associated with atezolizumab, Iglesia continues. This pattern of AEs underscores the need for careful management and monitoring when combining VEGF-targeting TKIs with immune checkpoint inhibitors in the treatment of HCC, he explains.

Although COSMIC-312 did not demonstrate the expected efficacy benefits seen in other trials, the findings contribute valuable insights into the challenges and considerations surrounding the use of combination therapies in advanced HCC, Iglesia emphasizes. The lack of improvement in OS in the COSMIC-312 trial highlights the complexity and variability among VEGF-targeting TKIs when used in immunotherapy combinations, underscoring the challenge of identifying the critical targets or combinations necessary to achieve therapeutic benefit in HCC, he concludes.

Michael Iglesia, MD, PhD

Articles

Dr Iglesia on the Potential Role for Disease Etiology in Frontline HCC Treatment Selection

Dr Iglesia on Unmet Needs in Second-Line Therapy Selection in HCC

Dr Iglesia on the COSMIC-312 Trial of Cabozantinib Plus Atezolizumab in HCC