HIMALAYA Trial, Tremelimumab plus Durvalumab in Unresectable HCC

Background

Phase III RCT of 1171 patients with unresectable hepatocellular carcinoma and no prior systemic therapy. Child-Pugh A, ECOG 0-1.

Interventions and follow up

Arm A (STRIDE): Tremelimumab 300 mg IV x1 + durvalumab 1500 mg IV Q4W
Arm B: Durvalumab 1500 mg IV Q4W
Arm C: Sorafenib 400 mg PO BID
Primary endpoint: OS for STRIDE vs sorafenib
Key secondary endpoint: OS noninferiority for durvalumab vs sorafenib
mFollow up: 33.2 mo (Arm A) vs 32.6 mo (Arm B) vs 32.2 mo (Arm C)

Results

mOS: 16.43 mo (Arm A) vs 16.56 mo (Arm B) vs 13.77 mo (Arm C); HR 0.78, 96.02% CI 0.65–0.93; P=.0035 for Arm A vs Arm C
OS noninferiority (B vs C): Durvalumab noninferior to sorafenib; HR 0.86, 95.67% CI 0.73–1.03 (noninferiority margin 1.08)
3-yr OS: 30.7% vs 24.7% vs 20.2% (Arm A vs B vs C)
mPFS: Not significantly different among the three groups

Adverse events

Grade 3-4 events (A vs B vs C): 50.5% vs 37.1% vs 52.4%
Discontinuation due to AEs (A vs B vs C): 13.7% vs 8.2% vs 16.8%

Conclusions

The STRIDE regimen (single priming dose of tremelimumab plus regular-interval durvalumab) significantly improved OS versus sorafenib, and durvalumab monotherapy was noninferior to sorafenib, in patients with unresectable HCC.

Key Limitations

Open-label design; sorafenib comparator now dated; predominantly Child-Pugh A; no direct comparison to atezolizumab/bevacizumab; PFS not improved.

Clinical Context

HIMALAYA led to FDA (2022) and EMA approval of tremelimumab + durvalumab (STRIDE) for unresectable HCC, establishing a chemotherapy- and antiangiogenic-free 1L option. Along with atezolizumab/bevacizumab (IMbrave150), STRIDE is an ESMO-endorsed 1L standard, useful when bevacizumab is contraindicated (e.g., varices, bleeding risk).

References