Combination regimens are increasingly defining the frontline treatment landscape for hepatocellular carcinoma (HCC), offering the potential for more personalized and effective strategies. Recent data from key trials, including HIMALAYA, LEAP-012, EMERALD-1, and IMbrave050, alongside real-world evidence from the STELLAR study, are shaping clinical practice and future research directions. The focus is shifting towards combination therapies that leverage the benefits of immunotherapy, targeted agents, and locoregional treatments.
HIMALAYA Trial: Long-Term Survival with STRIDE Regimen
The HIMALAYA trial, a landmark study in unresectable HCC, evaluated the STRIDE regimen (single dose of tremelimumab plus durvalumab) against sorafenib. The 5-year overall survival (OS) update presented at the 2024 ESMO Congress demonstrated a significant advantage for the STRIDE regimen. Patients treated with STRIDE (n = 393) achieved a median OS of 16.43 months (95% CI, 14.16-19.58) compared to 13.77 months (95% CI, 12.25-16.13) for sorafenib (HR, 0.76; 95% CI, 0.65-0.89; 2-sided P = .0008). Notably, the OS rates at 60 months were 19.6% for STRIDE versus 9.4% for sorafenib, marking the longest follow-up in phase 3 studies for unresectable HCC treatments.
LEAP-012: Adding Lenvatinib and Pembrolizumab to TACE
The LEAP-012 trial investigated the combination of lenvatinib, pembrolizumab, and transarterial chemoembolization (TACE) in patients with intermediate-stage HCC. Data presented at the 2024 ESMO Congress showed that the triplet combination (n = 237) significantly improved median progression-free survival (PFS) to 14.6 months (95% CI, 12.6-16.7) compared to 10.0 months (95% CI, 8.1-12.2) with TACE alone (HR, 0.66; 95% CI, 0.51-0.84; P = .0002). The addition of lenvatinib and pembrolizumab also led to an OS benefit (HR, 0.80; 95% CI, 0.57-1.11; P = .0867).
EMERALD-1: TACE Plus Durvalumab and Bevacizumab
The EMERALD-1 study evaluated TACE in combination with durvalumab, with or without bevacizumab, in patients with unresectable HCC eligible for embolization. The study met its primary endpoint, demonstrating that patients who received TACE with durvalumab and bevacizumab (n = 204) achieved a median PFS of 15.0 months (95% CI, 11.1-18.9) compared to 8.2 months (95% CI, 6.9-11.1) among patients treated with TACE alone (HR, 0.77; 95% CI, 0.61-0.98; log-rank P = .032).
IMbrave050: Atezolizumab and Bevacizumab as Adjuvant Therapy
IMbrave050 examined the combination of atezolizumab and bevacizumab versus active surveillance in patients with resected or ablated high-risk HCC. Updated findings presented at the 2024 ESMO Congress indicated that the initial recurrence-free survival (RFS) benefit observed with atezolizumab plus bevacizumab did not persist with longer follow-up. At a median follow-up of 35.1 months, the median RFS in the investigational arm (n = 334) was 33.2 months (24.3-NE) versus 36.0 months (95% CI, 22.7-NE) in the active surveillance arm (n = 334; HR, 0.90; 95% CI, 0.72-1.12).
Real-World Evidence: STELLAR Trial
The real-world STELLAR trial provided insights into the safety and effectiveness of lenvatinib and sorafenib in patients with advanced or unresectable HCC. The study found that lenvatinib offered a median OS of 16.3 months (95% CI, 11.8-NE) compared to 13.6 months (95% CI, 8.4-NE) in the sorafenib group. The safety profiles were consistent with previous clinical trials, supporting the use of TKIs for patients ineligible for or failing immunotherapy.
Nivolumab and Ipilimumab: Awaiting Approval
Based on the CheckMate 9DW trial, the FDA is considering nivolumab plus ipilimumab as a frontline treatment for unresectable HCC, with a decision expected by April 21, 2025. The trial demonstrated a median OS of 23.7 months (95% CI, 18.8-29.4) in the combination arm versus 20.6 months (95% CI, 17.5-22.5) in the lenvatinib/sorafenib arm (HR, 0.79; 95% CI, 0.65-0.96; P = .018).
