The treatment landscape for hepatocellular carcinoma (HCC) continues to evolve, with recent clinical trials providing crucial insights into therapeutic approaches while raising new questions about optimal treatment strategies.
CELESTIAL Trial Establishes Cabozantinib's Role
The phase 3 CELESTIAL trial has significantly impacted HCC treatment, establishing cabozantinib (Cabometyx) as a standard therapy for previously treated patients. The study evaluated cabozantinib at 60 mg daily versus placebo in patients with Child-Pugh class A liver function and ECOG performance status of 0 or 1 who had received up to two prior lines of systemic therapy.
The trial demonstrated meaningful survival benefits, with median overall survival reaching 10.2 months for cabozantinib compared to 8.0 months for placebo. The study population was predominantly Western, with approximately 50% from Europe and 25% each from Asia and North America.
"This was a study done in 2018 when we didn't have immune checkpoint inhibitors as first-line therapy," explains Dr. Gentry King from Fred Hutchinson Cancer Center. "Cabozantinib, with its multi-targeted approach against VEGF, AXL, and MET, was specifically designed to address resistance mechanisms to sorafenib."
COSMIC-312: Mixed Results in First-Line Setting
The subsequent phase 3 COSMIC-312 trial investigated the combination of cabozantinib (40 mg daily) plus atezolizumab versus sorafenib in the first-line setting. Despite meeting its progression-free survival (PFS) endpoint, the trial failed to demonstrate an overall survival benefit, limiting its impact on current standard of care.
The COVID-19 pandemic significantly affected trial enrollment, particularly in China, resulting in a predominantly Western patient population. This demographic shift influenced the trial's representation of disease etiologies, with a higher proportion of hepatitis C and nonviral HCC cases.
Current Challenges and Future Directions
A significant gap exists in evidence-based second-line treatment options following newer first-line standards. "The second-line treatments we have are all post-sorafenib, with no prospective, large studies to inform optimal treatment after current standard-of-care regimens," notes Dr. King.
Emerging Research Initiatives
Several promising research directions are currently being explored:
Novel Immunotherapy Combinations
Researchers are investigating new immune checkpoint inhibitor combinations, including anti-LAG-1 antibodies and TIM-3 inhibitors, building upon existing PD-L1 and CTLA-4 targeted approaches.
Integration of Radiotherapy
The EMERALD-Y90 trial is exploring the combination of immunotherapy with Y90 radioembolization, building on positive findings from the NRG/RTOG 1112 trial that demonstrated radiation therapy's benefits in HCC.
Advanced Cellular Therapies
Encouraging results from cellular therapy studies, particularly from China, have sparked interest in CAR T-cell therapies targeting HCC-specific antigens such as glypican-3 (GPC3). These innovative approaches represent a potentially promising new direction in HCC treatment.
