Summary
IMJUDO® + IMFINZI® is the first therapy to demonstrate unprecedented 4-year OS data in 1L advanced or unresectable HCC, with 1 in 4 patients still alive2
OVERALL SURVIVAL RATE AT 4 YEARS (secondary endpoint)2
25.2% 4-YEAR OS
with IMJUDO® + IMFINZI®
15.1% 4-YEAR OS
with sorafenib
Grade 3 or 4 treatment-related adverse events3
25.8%
Grade 3-4 TRAEs
IMJUDO® + IMFINZI®
36.9%
Grade 3-4 TRAEs
Sorafenib
Overall Survival (primary endpoint): IMJUDO® + IMFINZI®achieved a statistically significant 22% reduction in risk of death vs sorafenib
(HR=0.78 [95% CI, 0.67-0.92]; P=0.0037)2
SINGLE PRIMING DOSE INNOVATION OF IMJUDO® FOR IO-IO THERAPY1
Until disease progression or unacceptable toxicity
* Patients with a body weight of <30 kg must receive weight-based dosing equivalent to 4 mg/kg of IMJUDO®, until body weight is >30 kg.1
# 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 kg.4
CI=confidence interval; HCC=hepatocellular carcinoma; HR=hazard ratio; IO=immuno-oncology; L=line of treatment; OS=overall survival; TRAEs=treatment-related adverse events.
Unmet need
There remains a significant unmet need in 1L advanced or unresectable HCC, despite advances in treatment3
HCC is the 3rd-leading cause of cancer-related death globally5
3-YEAR
Overall
survival
~22%
of patients with unresectable HCC
are alive at 3 years6
Patients with unresectable HCC need therapies that can extend survival
while limiting treatment-related toxicity7
HCC is a heterogeneous disease associated with:
Complex patient factors
CONCOMITANT Liver Disease8
Cardiovascular Health9
Bleeding Risk10
Various Disease Etiologies8
HCV
HBV
Nonviral*
Additional first-line treatment options are needed to address the complex
heterogeneous nature of advanced or unresectable HCC
* Including chronic alcohol consumption, diabetes and obesity-related steatohepatitis.8
HBV=hepatitis B virus; HCC=hepatocellular carcinoma; HCV=hepatitis C virus; L=Line of treatment.
Mechanism of Action
Chronic inflammation and immunosuppression provide a strong rationale for an IO-IO treatment strategy in HCC11,12
Single Tremelimumab Regular Interval Durvalumab (STRIDE) enhances antitumour T-cell activation and function at multiple stages of the immune response, maximising antitumour immunity13
Single priming dose anti-CTLA-4 therapy has been shown to induce T-cell activation and expansion without the need for additional doses16
Dual immunotherapy of anti-PD(L)-1 + anti-CTLA-4 has demonstrated long-term OS benefit in various tumours including melanoma and mNSCLC17,18
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 HCC3
The HIMALAYA study evaluated STRIDE for statistical superiority of overall survival vs sorafenib3
STUDY DESIGN: OPEN LABEL, MULTICENTRE, GLOBAL, PHASE III STUDY3
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
Primary endpoint: Overall survival for STRIDE was evaluated for statistical superiority vs sorafenib3
Select secondary endpoints:§ OS rates at 18, 24 and 36 months, PFS, ORR, DoR, safety, PROs and antidrug antibodies3
Key exclusion criteria:†,3
- 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 study3
* 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.3
# 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.3 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 v1.1.3
† 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.3
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 arms3
BASELINE DEMOGRAPHICS AND DISEASE CHARACTERISTICS (Intent-to-treat population)3
Adapted from Abou-Alfa GK, et al. NEJM Evid. 2022.3
- * Includes Brazil, Canada, France, Germany, Italy, Japan, Russia, Spain, Ukraine and the United States.3
- # No active viral hepatitis identified.3
- § The ECOG PS scale ranges from 0 to 5 with higher numbers corresponding to greater disability.3
- † 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 15.3
- ‡ None of the above.3
- ¶ The BCLC staging classification system includes stages 0 (very early), A (early), B (intermediate), C (advanced), and D (end stage).3
- || 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%).3
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
IMJUDO® + IMFINZI® is the first therapy to demonstrate unprecedented 25% OS rate at 4 years in 1L advanced or unresectable HCC, with 1 in 4 patients still alive2
22%
reduction in the risk of death with IMJUDO® + IMFINZI® vs sorafenib2
overall survival in THE INTENT-TO-TREAT POPULATION (updated analysis)*,2
Median duration of follow-up: 49.12 months (range, 46.95–50.17) for IMJUDO® + IMFINZI® and 47.31 months (range, 45.08–49.51) for sorafenib.2
Adapted from Sangro B et al. 2023.2
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 sorafenib2
* OS HRs and 95% CIs were calculated using a Cox proportional hazards model adjusting for treatment, aetiology, ECOG PS and MVI. The 36-month OS rate had a nominal 2-sided p-value of 0.0006. Updated analysis data cut-off: 23 January 2023.2
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
IMJUDO® + IMFINZI® demonstrated numerically lower rates of Grade 3 or 4 treatment-related adverse events vs sorafenib3
TREATMENT-RELATED ADVERSE EVENTS REPORTED IN ≥10% (ANY GRADE) OR GRADE 3 OR 4 REPORTED IN ≥2% OF PATIENTS IN SAFETY ANALYSIS SET3
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).3
Adapted from Abou-Alfa GK, et al. NEJM Evid. 2022.3
Grade 3 or 4 treatment-related adverse events3
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 sorafenib3
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
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 kg4
IO=immuno-oncology; IV=intravenous, uHCC= unresectable hepatocellular carcinoma.
References
- IMJUDO® [Information for Healthcare Professionals for medicinal products for human use] www.swissmedicinfo.ch.
- 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).
- Abou-Alfa GK, Lau G, Kudo M, et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 2022;1(8) (including Supplementary Appendix and Protocol). doi:10.1056/EVIDoa2100070.
- IMFINZI® [Information for Healthcare Professionals for medicinal products for human use] www.swissmedicinfo.ch.
- Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249.
- Straś W,Gotlib J, Małkowski P, et al. Overall survival in patients with hepatocellular carcinoma treated with sorafenib: a Polish experience. Med Sci Monit. 2021;27:e931856.
- Fulgenzi CA, D’Alessio A, Airoldi C, et al. Comparative efficacy of novel combination strategies for unresectable hepatocellular carcinoma: a network metanalysis of phase III trials. Eur J Cancer. 2022;174:57-67.
- Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7(1):6. doi:10.1038/s41572-020-00240-3.
- Zhang X, El-Serag HB, Thrift AP. Predictors of five‑year survival among patients with hepatocellular carcinoma in the United States: an analysis of SEER‑Medicare. Cancer Causes Control. 2021;32(4):317-325.
- Liu X, Lu Y, Qin S. Atezolizumab and bevacizumab for hepatocellular carcinoma: mechanism, pharmacokinetics and future treatment strategies. Future Oncol. 2021;17(17):2243-2256.
- Llovet JM, Castet F, Heikenwalder M, et al. Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol. 2022;19(3):151-172.
- Refolo MG, Messa C, Guerra V, et al. Inflammatory mechanisms of HCC development. Cancers (Basel). 2020;12(3):641.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- Sangro B, Galle PR, Kelley RK, et al. Patient-reported outcomes from the Phase 3 HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. Poster presented at: 2022 ASCO Annual Meeting; 3–7 June 2022; Chicago, Illinois, USA.
Professionals can request the mentioned references from AstraZeneca AG.