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Summary

5 reasons to prescribe

IMJUDO® + IMFINZI® — The only IO regimen with 5-year OS data in 1L uHCC3

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Statistically superior OS in a diverse patient population
(ITT primary analysis)1

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Unprecedented 5-year OS data in a Phase III study
(exploratory analysis)3†

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Dual-IO approach combines a priming, single-dose of IMJUDO® with IMFINZI®, followed by monthly (Q4W) IMFINZI® monotherapy1

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Fewer discontinuations due to TRAEs than sorafenib (8.2% vs 11%; primary analysis)2

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No EGD required
to initiate therapy in the HIMALAYA study2

† Estimates of OS rates calculated using Kaplan-Meier technique. OS data maturity across the IMJUDO®+ IMFINZI® and sorafenib arms was 79% and 85%, respectively. Data cutoff: March 1, 2024.3

1L=first line; EGD=esophagogastroduodenoscopy; IO=immuno-oncology; ITT=intent-to-treat; OS=overall survival; Q4W=every 4 weeks; TRAE=treatment-related adverse event; uHCC=unresectable hepatocellular carcinoma.

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Treatment Goals

The heterogeneity of HCC reflects a diverse patient population2

Treatment decisions informed by this diversity may help more patients reach their goals

Treatment goals in uHCC include:

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Extend survival

+
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Maintain liver function
and quality of life

Key considerations when evaluating
1L treatment options

Bleeding risk
factors4

Patient situations and priorities5

COMORBIDITIES6

Explore the underlying factors that can inform treatment selection

1L=first line; HCC=hepatocellular carcinoma; uHCC=unresectable hepatocellular carcinoma.

Mechanism of Action

Chronic inflammation and immunosuppression provide a strong rationale for an IO-IO treatment strategy in HCC22,23

Single Tremelimumab Regular Interval Durvalumab (STRIDE) enhances antitumour T-cell activation and function at multiple stages of the immune response, maximising antitumour immunity24

Mechanism of Action infography
Mechanism of Action infography

Single priming dose anti-CTLA-4 therapy has been shown to induce T-cell activation and expansion without the need for additional doses28

Dual immunotherapy of anti-PD(L)-1 + anti-CTLA-4 has demonstrated long-term OS benefit in various tumours including melanoma and mNSCLC29,30

CD28=cluster of differentiation 28; CD80/86=cluster of differentiation 80/86; CTLA-4=cytotoxic T-lymphocyte associated protein 4; HCC=hepatocellular carcinoma; IO=immuno-oncology; mNSCLC=metastatic non-small cell lung cancer; OS=overall survival; PD-1=programmed cell death protein 1; PD-L1=programmed death-ligand 1.

Study design

HIMALAYA evaluated innovative single priming dose IMJUDO® + IMFINZI®, (an infusion regimen termed STRIDE), followed by IMFINZI® Q4W vs sorafenib in patients with unresectable HCC2

The HIMALAYA study evaluated STRIDE for statistical superiority of overall survival vs sorafenib2

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STUDY DESIGN: OPEN LABEL, MULTICENTRE, GLOBAL, PHASE III STUDY2

Inclusion criteria:

  • Adults (­≥18 years) with confirmed unresectable hepatocellular carcinoma, BCLC Stage C or B (not eligible for locoregional therapy), CP-A score, and ECOG PS 0-1
  • No prior systemic treatment for HCC
  • ≥1 target lesion per RECIST v1.1

Stratification factors

  • Macrovascular invasion (MVI), etiology of liver disease (hepatitis B or C virus or other/non viral) and ECOG PS 0 or 1
Stride IMFINZI Sorafenib

Primary endpoint: Overall survival for STRIDE was evaluated for statistical superiority vs sorafenib2

Select secondary endpoints:§ OS rates at 18, 24 and 36 months, PFS, ORR, DoR, safety, PROs and antidrug antibodies2

Key exclusion criteria:†,2

  • Clinically meaningful ascites or hepatic encephalopathy‡
  • Portal vein thrombosis
  • Active or prior GI variceal bleed, history of upper GI bleeding, ulcers or oesophageal varices with bleeding within 12 months; adequate endoscopic therapy according to institutional standards is required for patients with history of oesophageal variceal bleeding or assessed as high risk for oesophageal variceal by the treating investigator
  • Active or prior documented autoimmune or inflammatory disorders
  • Patients with oesophageal varices were included except those with active or prior documented GI bleeding within 12 months prior to study entry
  • HBV and HCV coinfection

Patients did not require an EGD to screen for gastro-oesophageal varices to be eligible for the HIMALAYA study2

* Total patient count is reflective of an additional arm of therapy: The IMJUDO® 75 + IMFINZI® arm (n=153) was closed following a pre-planned analysis of a Phase II study. Patients randomised to this arm could continue treatment following arm closure. Results from this arm are not reported in this material and this dosing regimen is not approved for use.2
# The HIMALAYA study had an additional arm of therapy that evaluated IMFINZI® monotherapy for noninferior overall survival vs sorafenib. Results from this arm are not reported here.2 IMFINZI® monotherapy is currently not approved by Swissmedic for the treatment of advanced or unresectable HCC.
§ PFS, ORR and DoR were investigator assessed according to RECIST v1.1.2
† For full eligibility criteria, refer to Sections 3.1 and 3.2 of the HIMALAYA protocol, available at evidence.nejm.org.
‡ Ascites requiring nonpharmacologic intervention within 6 months, hepatic encephalopathy within 12 months.2

BCLC=Barcelona Clinic Liver Cancer; BID=twice a day; CP-A=Child-Pugh Class A; DoR=duration of response; ECOG=Eastern Cooperative Oncology Group; EGD=esophagogastroduodenoscopy; GI=gastrointestinal; HBV=hepatitis B virus;HCC=hepatocellular carcinoma; HCV=hepatitis C virus, MVI=macrovascular invasion; ORR=objective response rate;- OS=overall survival; PFS=progression-free survival; PROs=patient-reported outcomes; PS=performance status; Q4W=once every 4 weeks; R=randomized; RECIST=Response Evaluation Criteria in Solid Tumors.

Patient demographics and disease characteristics were generally balanced between treatment arms2

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BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS (Intent-to-treat population)2

baseline demographic table information

Adapted from Abou-Alfa GK, et al. NEJM Evid. 2022.2

  • * Includes Brazil, Canada, France, Germany, Italy, Japan, Russia, Spain, Ukraine and the United States.2
  • # No active viral hepatitis identified.2
  • § The ECOG PS scale ranges from 0 to 5 with higher numbers corresponding to greater disability.2
  • † The Child-Pugh classification of liver disease severity is determined by the degree of ascites, serum concentrations of bilirubin and albumin, prothrombin time, and degree of encephalopathy and classified as follows: class A (well-compensated disease), score of 5 to 6; class B (significant functional compromise), score of 7 to 9; and class C (decompensated disease), score of 10 to 15.2
  • ‡ None of the above.2
  • ¶ The BCLC staging classification system includes stages 0 (very early), A (early), B (intermediate), C (advanced), and D (end stage).2
  • || Baseline PD-L1 results were not available for patients who were randomized but not treated. PD-L1 expression level was based on the tumour and immune cell positivity score method as PD-L1 positive (≥1%) or negative (<1%).2

AFP=alpha-fetoprotein; BCLC= Barcelona Clinic Liver Cancer; ECOG=Eastern Cooperative Oncology Group; HBV=hepatitis B virus; HCV=hepatitis C virus; PD-L1=programmed death-ligand 1; PS=performance status.

Results

  • OS
  • OS by disease control
  • OS subgroups
  • ORR
  • Median DoR / Median TTR

    • IMJUDO® + IMFINZI® is the first therapy to demonstrate unprecedented 19.6% OS rate at 5 years in 1L advanced or unresectable HCC, with 1 in 5 patients still alive3

    24%

    reduction in the risk of death with IMJUDO IMJUDO® + IMFINZI® vs sorafenib3

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    overall survival in THE INTENT-TO-TREAT POPULATION (updated analysis)*,3

    Median duration of follow-up: 62.49 months (range, 59.47–64.79) for IMJUDO® + IMFINZI® and 59.86 months (range, 58.32–61.54) for sorafenib.3

    Adapted from Rimassa L, et al. ESMO congress, 2024.3

    Median OS was 16.4 months (95% CI: 14.2–19.6) with IMJUDO® + IMFINZI® vs. 13.8 (95% CI: 12.3–16.1) with sorafenib3

    * OS HRs and 95% CIs were calculated using a Cox proportional hazards model adjusting for treatment, aetiology, ECOG PS and MVI. Updated analysis data cut-off: 01 March 2024.3

    CI=confidence interval; ECOG=Eastern Cooperative Oncology Group; HCC=hepatocellular carcinoma; HR=hazard ratio; L=line of treatment; MVI=macrovascular invasion; OS=overall survival; PS=performance status.

    Safety and Quality of Life

  • Adverse Events
  • Hepatic/Haemorrhage TRAEs
  • imARs
  • Patient-reported outcomes

    • IMJUDO® + IMFINZI® demonstrated numerically lower rates of Grade 3 or 4 treatment-related adverse events vs sorafenib2

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    TREATMENT-RELATED ADVERSE EVENTS REPORTED IN ≥10% (ANY GRADE) OR GRADE 3 OR 4 REPORTED IN ≥2% OF PATIENTS IN SAFETY ANALYSIS SET2

    Within the safety analysis set of the HIMALAYA study, the median duration of treatment for IMJUDO® + IMFINZI® (n=388) was 5.5 months (range, 0.4-42.7) and 4.1 months (range, 0.1-38.6) for sorafenib (n=374).2

    Adapted from Abou-Alfa GK, et al. NEJM Evid. 2022.2

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    Grade 3 or 4 treatment-related adverse events2

    25.8%

    Grade 3-4 TRAEs
    IMJUDO® + IMFINZI®

    36.9%

    Grade 3-4 TRAEs
    Sorafenib

    Treatment-related adverse events led to discontinuation in 8.2% of patients treated with IMJUDO® + IMFINZI® and 11% of patients treated with sorafenib2

    ALT=alanine aminotransferase; AST=aspartate aminotransferase, TRAEs=treatment-related adverse events.

    Dosing and administration

    STRIDE: Single priming dose innovation of IMJUDO® for IO-IO therapy1

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    Until disease progression or unacceptable toxicity

    • IMJUDO® and IMFINZI® are each administered as separate 60-minute IV infusions1
    • Administer IMJUDO® prior to IMFINZI® on the same day1
    • Patients with uHCC with a body weight of 30 kg or less must receive weight-based dosing equivalent to IMJUDO® 4 mg/kg and IMFINZI® 20 mg/kg until weight is greater than 30 kg1
    • Patients with a body weight of ≤30 kg must receive weight-based dosing equivalent to 20 mg/kg of IMFINZI® until body weight is >30 kg27

    IO=immuno-oncology; IV=intravenous, uHCC= unresectable hepatocellular carcinoma.

    References

    1. IMJUDO® [Information for Healthcare Professionals for medicinal products for human use] www.swissmedicinfo.ch.
    2. Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8):EVIDoa2100070 (including Supplementary Appendix and Protocol).
    3. Rimassa L, Chan SL, Sangro B, et al. Five-year overall survival (OS) and OS by tumour response measures from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma (uHCC). Presented at: European Society for Medical Oncology Congress; September 13-17, 2024; Barcelona, Spain.
    4. Duffy A, Wilkerson J, Greten TF. Hemorrhagic events in hepatocellular carcinoma patients treated with antiangiogenic therapies. Hepatology. 2013;57(3):1068-1077.
    5. Hart NH, Nekhlyudov L, Smith TJ, et al. Survivorship care for people affected by advanced or metastatic cancer: MASCC-ASCO standards and practice recommendations. JCO Oncol Pract. 2024;20(9):1160-1172.
    6. Mu XM, Wang W, Jiang YY, Feng J. Patterns of comorbidity in hepatocellular carcinoma: a network perspective. Int J Environ Res Public Health. 2020;17(9):3108.
    7. European Association for the Study of Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. [published correction appears in J Hepatol. 2018;69(5):1207]. J Hepatol. 2018;69(2):406-460.
    8. Thabut D, Kudo M. Treatment of portal hypertension in patients with HCC in the era of Baveno VII. J Hepatol. 2023;78(3):658-662.
    9. Lim J, Kim HI, Kim E, et al. Variceal bleeding is aggravated by portal venous invasion of hepatocellular carcinoma: a matched nested case-control study. BMC Cancer. 2021;21(1):11.
    10. Boregowda U, Umapathy C, Halim N, et al. Update on the management of gastrointestinal varices. World J Gastrointest Pharmacol Ther. 2019;10(1):1-21.
    11. Kovalak M, Lake J, Mattek N, Eisen G, Lieberman D, Zaman A. Endoscopic screening for varices in cirrhotic patients: data from a national endoscopic database. Gastrointest Endosc. 2007;65(1):82-88.
    12. Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases [published correction appears in Hepatology. 2017;66(1):304]. Hepatology. 2017;65(1):310-335.
    13. Albillos A, Zamora J, Martínez J, et al. Stratifying risk in the prevention of recurrent variceal hemorrhage: results of an individual patient meta-analysis. Hepatology. 2017;66(4):1219-1231.
    14. Reig M, Forner A, Rimola J, et al. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. J Hepatol. 2022;76(3):681-693.
    15. Rimassa L, Personeni N, Czauderna C, Foerster F, Galle P. Systemic treatment of HCC in special populations. J Hepatol. 2021;74(4):931-943.
    16. Bonafede MM, Korytowsky B, Singh P, et al. Treatment patterns and economic burden by lines of therapy among patients with advanced hepatocellular carcinoma treated with systemic cancer therapy. J Gastrointest Cancer. 2020;51(1):217-226.
    17. Hester D, Golabi P, Paik J, Younossi I, Mishra A, Younossi ZM. Among Medicare patients with hepatocellular carcinoma, non-alcoholic fatty liver disease is the most common etiology and cause of mortality. J Clin Gastroenterol. 2020;54(5):459-467.
    18. Saitta C, Pollicino T, Raimondo G. Obesity and liver cancer. Ann Hepatol. 2019;18(6):810-815.
    19. Munoz-Martinez S, Iserte G, Sanduzzi-Zamparelli M, Llarch N, Reig M. Current pharmacological treatment of hepatocellular carcinoma. Curr Opin Pharmacol. 2021;60:141-148.
    20. European Society for Medical Oncology. What is Hepatocellular Carcinoma? Lugano, Switzerland; 2020.
    21. European Society for Medical Oncology. A user’s manual for oncology clinicians. Lugano, Switzerland; 2013.
    22. Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151-172.
    23. Refolo MG, Messa C, Guerra V, et al. Inflammatory mechanisms of HCC development. Cancers (Basel). 2020;12(3):641.
    24. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23(35):8968-8977.
    25. Boutros C, Tarhini A, Routier E, et al. Safety profiles of anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 2016;13(8):473-486.
    26. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651-668.
    27. IMFINZI® [Information for Healthcare Professionals for medicinal products for human use] www.swissmedicinfo.ch.
    28. Kelley RK, Sangro B, Harris W, et al. Safety, efficacy, and pharmacodynamics of tremelimumab plus durvalumab for patients with unresectable hepatocellular carcinoma: randomized expansion of a phase I/II study. J Clin Oncol. 2021; 39(27):2991-3001.
    29. Ugurel S, Röhmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: The impact of MAP kinase pathway inhibition and immune checkpoint inhibition - Update 2019. Eur J Cancer. 2020; 130:126-138.
    30. Brahmer JR, Lee JS, Ciuleanu TD, et al. Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab Versus Chemotherapy as First-Line Treatment for Metastatic Non–Small-Cell Lung Cancer in CheckMate 227. J Clin Oncol. 2023; 41(6):1200-1212.
    31. Sangro B, Chan SL, Kelley RK, et al. Four-year overall survival update from the Phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Poster presented at: 2023 ESMO World Congress on Gastrointestinal Cancer; 26 June–1 July 2023; Barcelona, Spain (including supplementary information).
    32. Abou-Alfa GK, Chan SL, Kudo M, et al. Phase 3 randomized, open-label, multicenter study of tremelimumab and durvalumab as first-line therapy in patients with unresectable hepatocellular carcinoma: HIMALAYA. 2022 ASCO Gastrointestinal Cancers Symposium. Presented by Abou-Alfa GK January 21, 2022.
    33. Sangro B, et al. Patient-reported outcomes from the phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. J Clin Oncol. 2024;42(23):2790-2799.

    Professionals can request the mentioned references from AstraZeneca AG.

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