What is the comparative efficacy and toxicity of Toriplaimab, Atezolizumab (atezolizumab) and Durvalumab (durvalumab) in the treatment of hepatocellular carcinoma?

Comparative Efficacy and Toxicity of Toriplaimab, Atezolizumab, and Durvalumab in Hepatocellular Carcinoma

Atezolizumab plus bevacizumab remains the first-choice standard of care for advanced HCC, while durvalumab plus tremelimumab represents an effective alternative with potentially reduced bleeding risk; toriplaimab plus bevacizumab shows promising efficacy but lacks regulatory approval outside Asia and has not been extensively tested in non-hepatitis B populations. 1

First-Line Treatment Hierarchy

Atezolizumab-Based Therapy (Preferred Standard)

Atezolizumab 1200 mg IV plus bevacizumab 15 mg/kg IV every 3 weeks is the established first-choice standard based on superior efficacy demonstrated in the IMbrave150 trial. 1, 2

• Efficacy: Overall survival HR 0.58 (95% CI 0.42-0.79; p<0.001) versus sorafenib, with ORR of 29.8% 1, 2
• Critical safety requirement: Upper GI endoscopy within 6 months to evaluate and treat esophageal varices before initiating bevacizumab due to bleeding risk 1, 3, 2
• Absolute contraindications: Active autoimmune disease, history of solid organ transplantation, untreated high-risk varices 3, 2
• Common toxicities: Grade 3-4 adverse events in approximately 50% of patients, with bleeding events being the primary concern requiring variceal management 1

Durvalumab-Based Therapy (Effective Alternative)

Durvalumab plus tremelimumab (STRIDE regimen: tremelimumab single dose plus durvalumab every 4 weeks) is an effective alternative first-line combination with a key advantage of reduced variceal bleeding risk compared to atezolizumab-bevacizumab. 1

• Efficacy: Median OS 16.43 months versus 13.77 months with sorafenib (HR 0.78,96.02% CI 0.65-0.93; p=0.0035) 1
• Response rates: ORR 20.1% versus 5.1% with sorafenib 1
• Delayed benefit: Kaplan-Meier curves showed delayed separation, with HR improving after 9 months (0.70 vs 0.87 before 9 months) 1
• Toxicity profile: Grade 3-4 adverse events in 50.5% (similar to atezolizumab-bevacizumab), but critically, does not require prior variceal management 1, 2
• Immune-related toxicity: IrAEs requiring high-dose glucocorticoids occurred in 20.1% versus 9.5% with durvalumab monotherapy 1
• Regulatory status: Not approved by NICE but represents high-quality evidence alternative 1

Toriplaimab-Based Therapy (Limited Evidence)

Toriplaimab (toripalimab) 240 mg plus bevacizumab 15 mg/kg every 3 weeks shows promising efficacy in phase II data but has significant limitations for widespread recommendation. 4

• Efficacy data: ORR 31.5% by RECIST v1.1 (95% CI 19.5-45.6) and 46.3% by mRECIST in a single-arm phase II trial 4
• Survival outcomes: Median PFS 8.5-9.8 months; median OS not reached with 12-month OS rate of 77.3% and 24-month OS rate of 63.5% 4
• Critical limitations:
  • No phase III randomized controlled trial data comparing to standard of care 1
  • Not extensively tested in non-hepatitis B populations outside Asia 1
  • Not approved by NICE or FDA 1
  • Single-arm study design limits comparative conclusions 4

Toxicity Comparison

Atezolizumab Plus Bevacizumab Toxicity Profile

• Grade ≥3 adverse events: 50-65% in real-world studies 5, 6
• Bleeding risk: 10% bleeding events grade ≥3, including 2% fatal outcomes in post-progression setting 5
• Most common toxicities: Proteinuria (59.3%), hypertension (38.9%), elevated liver enzymes 6, 4
• Treatment discontinuation: Bevacizumab frequently discontinued due to proteinuria and fluid retention 7
• Hepatic function: Albumin-bilirubin and Child-Pugh scores do not significantly worsen within 6 weeks of treatment initiation 6

Durvalumab Plus Tremelimumab Toxicity Profile

• Grade 3-4 adverse events: 50.5% (comparable to atezolizumab-bevacizumab) 1
• Key advantage: Hepatic/hemorrhage adverse events similar across all arms, but no requirement for variceal screening/treatment reduces practical bleeding risk 1
• Immune-related toxicity: Higher rate of IrAEs requiring high-dose glucocorticoids (20.1%) compared to durvalumab monotherapy (9.5%) 1
• Quality of life: Median time to deterioration 7.5 months versus 5.7 months with sorafenib 1
• Anti-drug antibodies: Anti-durvalumab ADAs in 2.5-3.1%, anti-tremelimumab ADAs in 11% 1

Toriplaimab Plus Bevacizumab Toxicity Profile

• Grade ≥3 adverse events: 50.0% in phase II trial 4
• Common toxicities: Proteinuria (59.3%), hypertension (38.9%), elevated AST (33.3%), elevated amylase (29.6%), thrombocytopenia (27.8%), hyperbilirubinemia (27.8%) 4
• Similar bevacizumab-related risks: Expected to have same variceal bleeding concerns as atezolizumab-bevacizumab, requiring pre-treatment endoscopy 4

Clinical Decision Algorithm

Step 1: Assess Bleeding Risk and Contraindications

• If patient has portal hypertension: Perform upper GI endoscopy within 6 months 1, 3
  • Untreated or high-risk varices present: Choose durvalumab plus tremelimumab 1, 2
  • Varices adequately treated or absent: Proceed with atezolizumab plus bevacizumab 1, 2
• If history of solid organ transplant or active autoimmune disease: Durvalumab plus tremelimumab contraindicated; consider TKI monotherapy (sorafenib or lenvatinib) 3, 2

Step 2: Consider Patient Preferences and Access

• If patient prefers oral therapy or IV therapy contraindicated: Sorafenib or lenvatinib as alternative first-line 1
• If durvalumab-tremelimumab not available (NICE approval issues): Must use atezolizumab-bevacizumab with appropriate variceal management 1
• Toriplaimab: Should only be considered in clinical trial settings or in Asian populations with hepatitis B-related HCC where regulatory approval exists 1

Step 3: Second-Line Sequencing After Progression

After atezolizumab-bevacizumab progression:

• Preferred approach: Switch to TKI (sorafenib, lenvatinib, or cabozantinib) based on mechanism of action 1, 8
• Lenvatinib shows superior PFS: 6.1 months versus 2.5 months with sorafenib (p=0.004), though OS comparable (16.6 vs 11.2 months) 8
• Alternative if AFP ≥400 ng/mL: Ramucirumab 8 mg/kg IV every 2 weeks 1, 2
• Emerging option: Durvalumab plus tremelimumab may be effective after atezolizumab-bevacizumab failure when bevacizumab cannot be continued 7

After durvalumab-tremelimumab progression:

• Recommended approach: Sorafenib, lenvatinib, regorafenib, cabozantinib, ramucirumab (if AFP ≥400 ng/mL), or atezolizumab-bevacizumab 1

Critical Pitfalls to Avoid

Variceal Bleeding Risk

Never initiate bevacizumab-containing regimens without endoscopic evaluation and treatment of varices in patients with portal hypertension. 1, 3, 2 This is the most common preventable serious adverse event.

Population-Specific Limitations

Do not extrapolate toriplaimab efficacy to non-Asian or non-hepatitis B populations without recognizing the limited evidence base in these groups. 1 The combination has not been extensively tested outside Asia and lacks phase III data.

Child-Pugh Status

All pivotal trials excluded Child-Pugh B8-C patients. 2 Use extreme caution with any immunotherapy combination in patients with deteriorated liver function, as safety and efficacy data are lacking.

Sequential ICI Therapy

While case reports suggest potential benefit of switching from atezolizumab-bevacizumab to durvalumab-tremelimumab when bevacizumab cannot be continued 7, this approach lacks prospective validation and should be considered experimental.

Biomarker Limitations

There are no validated biomarkers to guide treatment selection between atezolizumab-bevacizumab and durvalumab-tremelimumab. 1, 2 Treatment decisions must be based on contraindications, bleeding risk assessment, and toxicity profiles rather than predictive markers.