Heterogeneity of Treatment Effects of Adding Locoregional Therapies to Atezolizumab Plus Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma (ISMIO-026)

Heterogeneity of Treatment Effects of Adding Locoregional Therapies to Atezolizumab Plus Bevacizumab in Patients With Unresectable Hepatocellular Carcinoma Based on Clinical and Multiregional, Multiphase Contrast-Enhanced CT/MRI Features (ISMIO-026)

uHCC imposes a substantial disease burden in China and the Asia-Pacific region. Atezo+Bev is an important first-line regimen for patients who have not received prior systemic therapy; however, not all patients achieve adequate and durable tumor control. In clinical practice, ablation, radiotherapy, or transarterial therapy is often added to Atezo+Bev to intensify intrahepatic disease control. The indications, timing, efficacy, and risk of liver-function impairment vary across LRTs. Most existing studies report average treatment effects and often use TACE as a fixed backbone, and therefore do not directly identify which patients receiving Atezo+Bev should receive early LRTs.

Using target trial emulation and HTE analysis, this study will integrate baseline clinical variables with pretreatment contrast-enhanced CT/MRI features to estimate the CATE of early LRT initiation and identify patients likely to achieve greater survival benefit.

Study Overview

• Status: Not yet recruiting
• Conditions: Unresectable Hepatocellular Carcinoma

• Study Type: Observational
• Enrollment (Estimated): 2658

Contacts and Locations

• Study Contact: Name: Jian Lu; Phone Number: 13616106021; Email: lujian43307131@126.com

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 213003
      • Zhongda hospital
      • Contact: Jun-Hao Mei; Phone Number: 15052007938; Email: jh_mei240225@126.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adults with uHCC who initiate first-line Atezo+Bev and have received no prior systemic therapy for HCC.

Description

Inclusion Criteria:

• Age ≥18 years on the index date.
• Receipt of at least one dose each of atezolizumab and bevacizumab as part of the same first-line combination regimen, with an interval of ≤28 days between the first administrations of the two drugs.
• At least one intrahepatic lesion amenable to a protocol-specified LRT on the index date, with no absolute contraindication to Atezo+Bev or to all feasible LRTs.
• A clinical, radiologic, or pathologic diagnosis of uHCC on or before the index date; baseline EHS is permitted.
• Survival status or the date last known alive after the index date can be ascertained.
• No systemic therapy for HCC before the regimen initiation date.
• No LRT within 60 days before the index date or between baseline imaging and the index date; earlier prior LRTs are permitted provided that an untreated, measurable intrahepatic lesion remains.
• A technically adequate baseline contrast-enhanced CT/MRI examination and at least one untreated intrahepatic lesion that can be delineated and evaluated.
• Baseline ECOG performance status of 0-2.

Exclusion Criteria:

• Another primary malignancy requiring active systemic treatment on the index date, except for a malignancy that has been cured and has a low risk of recurrence.
• Participation on the index date in an interventional study that could affect treatment allocation or outcome assessment.
• Suitability for immediate curative resection or liver transplantation following multidisciplinary assessment.
• An absolute contraindication to Atezo+Bev or to all feasible LRTs.
• Active autoimmune disease or immunodeficiency requiring systemic immunosuppression or constituting a contraindication to atezolizumab.

Inadequately controlled high-risk esophageal/gastric varices, recent variceal bleeding, an uncorrected bleeding tendency, or clinically significant coagulopathy.

• Inability to determine the index date, primary treatment strategy, OS outcome/censoring date, or absence of a technically adequate baseline contrast-enhanced CT/MRI examination.

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
Training Cohort
Retrospective validation cohort
Prospective validation cohort
Biological validation cohort

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall survival	With OS as the primary outcome, to estimate the overall treatment effect and CATE of initiating LRTs within 60 days after Atezo+Bev initiation versus not initiating LRTs within 60 days; and to integrate baseline clinical variables with multiregional radiomic, dynamic/habitat, and deep representation features from pretreatment contrast-enhanced CT/MRI to develop and validate an HTE decision model.	through study completion, an average of 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Model calibration		through study completion, an average of 1 year
Benefit ranking		through study completion, an average of 1 year
PFS/mPFS	Defined as the time from index date to the first occurrence of disease progression or death from any cause (whichever occurs first), as determined by the investigator according to RECIST v1.1 or mRECIST.	through study completion, an average of 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse event	To describe and compare the spectrum and severity of AEs between the two strategies and within their subgroups, with particular attention to hemorrhage, hypertension, hepatotoxicity, immune-related AEs, and complications associated with each type of LRT.	through study completion, an average of 1 year

Collaborators and Investigators

• Sponsor: Zhongda Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: September 1, 2026
• First Submitted That Met QC Criteria: September 11, 2026
• First Posted (Actual): September 17, 2026

Study Record Updates

• Last Update Posted (Actual): September 17, 2026
• Last Update Submitted That Met QC Criteria: September 11, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: ISMIO-026

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No