Systemic Therapy vs Locoregional Therapy for Liver Cancer

(LOST-B Trial)

Overseen By Ellen Siglinsky

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Texas Southwestern Medical Center

Must be taking: Antivirals

Must not be taking: Immunotherapy, Immunosuppressants

Disqualifiers: Chemotherapy, Radiotherapy, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 21

Duration: 24 months

204 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you have hepatitis B or C, you must manage these conditions as per local practice during the study. Also, certain medications like systemic immunosuppressive drugs and specific anticoagulants are restricted before starting the trial.

What data supports the effectiveness of the treatment Atezolizumab and bevacizumab combined with transarterial chemoembolization (TACE) for liver cancer?

Research shows that combining TACE with the drugs atezolizumab and bevacizumab can improve outcomes for patients with advanced liver cancer, as these drugs help the immune system fight cancer and block blood supply to tumors. Studies indicate this combination can enhance survival rates and control disease progression in patients with liver cancer. ^{1 2 3 4 5}

Is the combination of atezolizumab and bevacizumab with TACE or TARE safe for liver cancer patients?

The combination of atezolizumab and bevacizumab with transarterial chemoembolization (TACE) has been studied for safety in liver cancer patients, showing it is generally safe, though immune-related side effects can occur. These treatments have been evaluated in clinical trials, and while they are considered safe, monitoring for side effects is important. ^{1 2 3 6 7}

How is the treatment of atezolizumab and bevacizumab with TACE or TARE unique for liver cancer?

This treatment combines systemic therapy (atezolizumab and bevacizumab) with locoregional therapies (TACE or TARE), offering a novel approach by targeting cancer both throughout the body and directly in the liver, which may improve outcomes for patients with advanced liver cancer. ^{2 3 5 8 9}

What is the purpose of this trial?

The purpose of this research study is to compare the effectiveness and safety of two standard of care treatments in people who have been diagnosed with hepatocellular carcinoma (HCC).This research study is being done to compare atezolizumab/bevacizumab to locoregional therapy with either transarterial chemoembolization (TACE) or transarterial radioembolization (TARE).

Research Team

David Hsieh, MD

Principal Investigator

UT Southwestern Medical Center

Eligibility Criteria

This trial is for adults with intermediate-stage hepatocellular carcinoma (HCC) who haven't had previous cancer treatments. They should have liver-localized tumors not suitable for surgery, no extrahepatic disease or vascular invasion, and be in good physical condition (ECOG 0 or 1). Participants must not have certain infections or be on immunosuppressive drugs, and they need to agree to use contraception.

Inclusion Criteria

My liver cancer diagnosis is confirmed by imaging or biopsy.

Negative HIV test at screening

Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

I have high calcium levels in my blood that are causing symptoms.

I have recovered from side effects of previous cancer treatments.

My high blood pressure is not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either atezolizumab and bevacizumab or locoregional therapy with TACE or TARE

24 months

Atezolizumab and bevacizumab every 21 days; TACE every 8 weeks; TARE every 12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 months

Treatment Details

Interventions

• Atezolizumab and bevacizumab
• transarterial chemoembolization (TACE) or transarterial radioembolization (TARE)

Trial Overview The study compares the effectiveness of atezolizumab/bevacizumab versus locoregional therapies like TACE or TARE in treating HCC. It aims to determine which treatment provides better outcomes for patients who meet specific criteria related to their liver cancer stage and overall health.

Participant Groups

Group I: Arm A: Atezolizumab and bevacizumab Experimental Treatment 1 Intervention

Atezolizumab will be administered by IV infusion at a fixed dose of 1200 mg on Day 1 of each 21-day cycle. Bevacizumab will be administered by IV infusion at a dose of 15 mg/kg on Day 1 of each 21-day cycle. Atezolizumab will be administered first followed by bevacizumab, with a minimum of 5 minutes between dosing.

Group II: Arm B: Locoregional therapy with TACE or TARE Active Control 1 Intervention

Patients will undergo locoregional therapy with TACE or TARE per investigator preference. TACE will be administered every 8 +/- 4 weeks; TARE will be administered every 12 +/- 4 weeks. Proportion of patients being treated with TARE will be capped at 50% of cohort at a protocol level. After 50% cap is reached, patients randomized to Arm B will be treated with TACE.

Atezolizumab and bevacizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq and Avastin for:

• Unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment

Approved in European Union as Tecentriq and Avastin for:

• Unresectable locally advanced or metastatic hepatocellular carcinoma (HCC) with no prior systemic treatment

Who Is Running the Clinical Trial?

University of Texas Southwestern Medical Center

Lead Sponsor

Trials

1,102

Recruited

1,077,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Findings from Research

This phase II clinical trial is investigating the combined efficacy and safety of transcatheter arterial chemoembolization (TACE) with atezolizumab and bevacizumab in patients with stage-B hepatocellular carcinoma (HCC), aiming to improve treatment outcomes.

The primary goal of the study is to assess the objective response rate, while secondary endpoints include overall survival and progression-free survival, which will help establish a new treatment approach for patients with unresectable HCC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcatheter arterial chemoembolization plus atezolizumab and bevacizumab for unresectable hepatocellular carcinoma: a single-arm, phase II trial. Wang, K., Yu, HM., Xiang, YJ., et al.[2022]

In a study of 139 patients with advanced hepatocellular carcinoma, the combination of transarterial chemoembolization (TACE) with atezolizumab and bevacizumab (TACE-Atez/Bev) resulted in a significantly higher objective response rate (38.7%) compared to atezolizumab and bevacizumab alone (16.9%).

TACE-Atez/Bev also demonstrated improved overall survival (14 months vs. 10 months) and progression-free survival (10 months vs. 6 months) compared to the Atez/Bev group, indicating it may be a more effective treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved clinical outcomes in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus atezolizumab and bevacizumab: a bicentric retrospective study. Cao, F., Shi, C., Zhang, G., et al.[2023]

Atezolizumab combined with bevacizumab is the first approved immunotherapy for first-line treatment of unresectable hepatocellular carcinoma (HCC), showing promising efficacy and tolerability in over 80 countries.

The DEMAND study is the first phase II trial to investigate the safety and efficacy of this combination therapy in patients with intermediate-stage HCC undergoing transarterial chemoembolization (TACE), focusing on 24-month survival rates and other important health outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol. Ben Khaled, N., Seidensticker, M., Ricke, J., et al.[2022]

Transcatheter arterial chemoembolization (TACE) combined with capecitabine and cetuximab significantly reduced tumor markers and improved short-term efficacy in colorectal cancer patients with liver metastasis compared to TACE combined with cetuximab alone, based on a study of 140 patients.

Patients receiving the combination treatment (Capecitabine group) had a median survival time of 18.1 months, which was notably longer than the 14.7 months observed in the control group, indicating a significant survival benefit from the addition of capecitabine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of transcatheter arterial chemoembolization combined with capecitabine and cetuximab in the treatment of colorectal cancer with liver metastasis. Yun, X., Meng, H., Zhou, A., et al.[2021]

In a study of 124 patients with unresectable hepatocellular carcinoma (HCC), treatment with (131)I-lipiodol showed no overall survival difference compared to transarterial chemoembolization (TACE) or transarterial embolization (TAE).

However, patients with portal vein thrombosis (PVT) or advanced disease (Barcelona Clinic Liver Cancer stage D) had significantly better survival outcomes when treated with (131)I-lipiodol, indicating its potential benefit in these specific groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transarterial injection of (131)I-lipiodol, compared with chemoembolization, in the treatment of unresectable hepatocellular cancer. Marelli, L., Shusang, V., Buscombe, JR., et al.[2009]

In a study of 61 patients receiving atezolizumab plus bevacizumab (AB) therapy for unresectable hepatocellular carcinoma, 16% developed immune-related adverse events (irAEs) such as liver injury and hypothyroidism.

Patients with pre-existing autoantibodies were significantly more likely to develop irAEs and achieve a complete response, indicating that baseline autoantibody presence is a risk factor for adverse effects during AB therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma. Takada, H., Yamashita, K., Osawa, L., et al.[2023]

In a multicenter study of 121 patients with advanced hepatocellular carcinoma (HCC) treated with atezolizumab plus bevacizumab (Ate/Bev), the objective response rate was 24% and the disease control rate was 76%, demonstrating real-world efficacy similar to phase III trial results.

The most common severe side effect was an increase in aspartate aminotransferase levels (10.7%), and factors like elevated baseline neutrophil-to-lymphocyte ratio were linked to poorer progression-free and overall survival, indicating the need for careful monitoring in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. Cheon, J., Yoo, C., Hong, JY., et al.[2022]

Transarterial radioembolization (TARE) using Y-90 resin microspheres shows comparable overall survival (15.0 months) to the combination immunotherapy of atezolizumab-bevacizumab (AB) (14.9 months) in patients with advanced unresectable hepatocellular carcinoma (HCC), based on an analysis of 140 TARE patients and 202 AB patients.

While TARE had a median progression-free survival of 4.4 months compared to 6.8 months for AB, the differences in overall response rates (19.8% for TARE vs. 25% for AB) were not statistically significant, suggesting that TARE may be an effective alternative treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of transarterial radioembolization using Y-90 resin microspheres versus atezolizumab-bevacizumab in unresectable hepatocellular carcinoma: A matching-adjusted indirect comparison. Agirrezabal, I., Bouattour, M., Pinato, DJ., et al.[2023]

Transarterial chemoembolization (TACE) is a crucial treatment option for hepatocellular carcinoma (HCC) patients who cannot undergo curative treatments like surgery or transplantation.

Combining TACE with new systemic therapies, such as atezolizumab and bevacizumab, may enhance treatment effectiveness for intermediate-stage HCC by improving immune recognition and response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination therapies plus transarterial chemoembolization in hepatocellular carcinoma: a snapshot of clinical trial progress. Brown, ZJ., Hewitt, DB., Pawlik, TM.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Transcatheter arterial chemoembolization plus atezolizumab and bevacizumab for unresectable hepatocellular carcinoma: a single-arm, phase II trial. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Improved clinical outcomes in advanced hepatocellular carcinoma treated with transarterial chemoembolization plus atezolizumab and bevacizumab: a bicentric retrospective study. [2023]

3. England pubmed.ncbi.nlm.nih.gov

Atezolizumab and bevacizumab with transarterial chemoembolization in hepatocellular carcinoma: the DEMAND trial protocol. [2022]

4. Cyprus pubmed.ncbi.nlm.nih.gov

Efficacy of transcatheter arterial chemoembolization combined with capecitabine and cetuximab in the treatment of colorectal cancer with liver metastasis. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Transarterial injection of (131)I-lipiodol, compared with chemoembolization, in the treatment of unresectable hepatocellular cancer. [2009]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Significance of the autoantibody assay in predicting the development of immune-related adverse events in patients receiving atezolizumab plus bevacizumab combination therapy for unresectable hepatocellular carcinoma. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Efficacy and safety of atezolizumab plus bevacizumab in Korean patients with advanced hepatocellular carcinoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Efficacy of transarterial radioembolization using Y-90 resin microspheres versus atezolizumab-bevacizumab in unresectable hepatocellular carcinoma: A matching-adjusted indirect comparison. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Combination therapies plus transarterial chemoembolization in hepatocellular carcinoma: a snapshot of clinical trial progress. [2022]