What is the role of tremelimumab (tremelimumab) and durvalumab (durvalumab) in the treatment of hepatocellular carcinoma (HCC)?

Tremelimumab and Durvalumab in Hepatocellular Carcinoma

Tremelimumab plus durvalumab (STRIDE regimen) is an FDA-approved, first-line treatment option for unresectable hepatocellular carcinoma that demonstrates superior overall survival compared to sorafenib, with a median OS of 16.43 months versus 13.77 months (HR 0.78, p=0.0035). 1

FDA-Approved Indication and Dosing

The combination received full FDA approval in October 2022 for adult patients with unresectable HCC who have not received prior systemic treatment. 1, 2

Recommended Dosing Regimen (STRIDE)

• Tremelimumab 300 mg as a single, one-time dose on day 1 1
• Durvalumab 1,500 mg every 4 weeks (for patients ≥30 kg body weight) 1, 2
• Tremelimumab is administered prior to durvalumab on the same day 2

This unique dosing strategy uses a single priming dose of tremelimumab (anti-CTLA-4) followed by regular durvalumab (anti-PD-L1) maintenance, distinguishing it from other dual checkpoint inhibitor regimens. 1, 3

Clinical Efficacy Data

Survival Outcomes from HIMALAYA Trial

The phase III HIMALAYA trial (n=1,171) established the efficacy of this combination: 1

• Median OS: 16.43 months (95% CI 14.16-19.58) compared to 13.77 months with sorafenib 1
• Hazard ratio for death: 0.78 (96.02% CI 0.65-0.93; p=0.0035) 1
• Delayed separation of survival curves with greater benefit after 9 months (HR 0.70 vs 0.87 before 9 months) 1

Response Rates

• Objective response rate: 24.0% (95% CI 14.9-35.3) in the STRIDE arm 3
• Disease control rate in first-line setting: 65.8-80.9% in real-world studies 4, 5
• PFS was not significantly different among treatment groups, though DCR favored the combination 1

Real-world data confirm these findings, with ORR of 15.8% and DCR of 53.3% across mixed treatment lines. 5

Quality of Life and Safety Profile

Quality of Life

Median time to deterioration of patient-reported QOL was 7.5 months with tremelimumab/durvalumab versus 5.7 months with sorafenib, representing a clinically meaningful improvement. 1

Adverse Events

The safety profile is manageable but requires vigilance: 1

• Grade 3-4 adverse events: 50.5% (comparable to sorafenib at 52.4%) 1
• Immune-related AEs requiring high-dose glucocorticoids: 20.1% (versus 1.9% with sorafenib) 1
• Most common serious AE: liver injury in real-world practice 5
• Treatment discontinuation due to AEs: 19-23.8% 4, 5

High-Risk Populations for Toxicity

Decision tree analysis identified poor liver function and advanced age as significant predictors of treatment discontinuation due to adverse events. 5 Exercise particular caution in these populations, though the regimen remains an option if liver reserve is adequate.

Treatment Line Considerations

First-Line Therapy

As of 2022, tremelimumab/durvalumab and atezolizumab/bevacizumab are the only two ICI-based combinations with full FDA approval for first-line treatment of unresectable HCC. 1

First-line use demonstrates superior disease control compared to later-line therapy (DCR 65.8-80.9% vs 45.9-50%, p=0.034), though ORR and PFS remain similar. 4, 5 This suggests the regimen should be prioritized in treatment-naïve patients when appropriate.

ICI Rechallenge After Atezolizumab/Bevacizumab

Tremelimumab/durvalumab can be used as ICI rechallenge following atezolizumab/bevacizumab failure, with acceptable safety and efficacy. 6

• ORR: 14.3% and DCR: 47.6% in the rechallenge setting 6
• Critical caveat: All patients with progressive disease as best response to atezolizumab/bevacizumab also experienced PD with tremelimumab/durvalumab 6
• 75% of patients with irAEs on atezolizumab/bevacizumab experienced similar irAEs during rechallenge 6

This suggests that patients with primary progression on first-line ICI therapy are unlikely to benefit from ICI rechallenge and should be considered for alternative systemic therapies.

Transition to Second-Line Therapy

The transition rate from first-line tremelimumab/durvalumab to second-line therapy after progression is remarkably high at 94.7%, indicating that liver reserve is generally preserved, allowing for subsequent treatment options. 4 This contrasts favorably with historical sorafenib data and supports first-line use.

Durvalumab Monotherapy Alternative

Durvalumab monotherapy demonstrated non-inferiority to sorafenib (HR 0.86,95.67% CI 0.73-1.03) in HIMALAYA, though it did not show superiority. 1

Consider durvalumab monotherapy for patients at high risk for complications with dual-ICI therapy, such as those with borderline liver function or significant comorbidities, though evidence of survival benefit over sorafenib or lenvatinib is lacking in phase III studies. 1

Liver Reserve Monitoring

Analysis of albumin-bilirubin (ALBI) scores showed no obvious loss of liver reserve for up to 12 weeks with tremelimumab/durvalumab treatment. 4 This preservation of hepatic function is critical for maintaining treatment options and supports the use of this regimen in appropriately selected patients.

Clinical Practice Algorithm

For treatment-naïve patients with unresectable HCC:

1. Assess liver function and age as primary risk factors for toxicity 5
2. If adequate liver reserve and no contraindications: Use tremelimumab/durvalumab as first-line therapy 1
3. If high risk for dual-ICI toxicity: Consider durvalumab monotherapy or atezolizumab/bevacizumab 1

For patients progressing on atezolizumab/bevacizumab:

1. If best response was stable disease or better: Consider tremelimumab/durvalumab rechallenge 6
2. If best response was progressive disease: Avoid ICI rechallenge; use alternative systemic therapy 6
3. If prior irAEs occurred: Anticipate 75% risk of similar irAEs with rechallenge 6