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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial compares two treatments for liver cancer, specifically hepatocellular carcinoma (HCC), to determine which is more effective and safe. One group will receive the medicines atezolizumab and bevacizumab, while the other will undergo a procedure targeting the liver directly, known as TACE or TARE. The trial is suitable for individuals diagnosed with HCC that has not spread outside the liver and who are not eligible for surgery or liver transplants. Participants should not have received recent cancer treatments and must be able to manage daily activities. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings in liver cancer treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using atezolizumab and bevacizumab together is generally safe for people with liver cancer that cannot be removed by surgery. These drugs can help patients live longer and slow the cancer's growth. Common side effects include fatigue, high blood pressure, and liver issues, but these are usually manageable.

For treatments like transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), research indicates they can be effective and are often well-tolerated. However, they might cause side effects such as pain, fever, or nausea. These treatments target liver tumors directly, which can help reduce side effects in other parts of the body.

Overall, both types of treatments have shown promising safety results in studies, but it is important to consider potential side effects and discuss them with a healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for liver cancer because they offer innovative approaches compared to the standard care options like sorafenib or lenvatinib, which primarily target cancer cell growth and blood supply. Atezolizumab and bevacizumab are unique because they combine an immune checkpoint inhibitor with a VEGF inhibitor, enhancing the body's immune response while also cutting off the tumor's blood supply. Meanwhile, locoregional therapies like TACE and TARE directly deliver chemotherapy or radiation to the tumor site, potentially minimizing systemic side effects and targeting the cancer more precisely. By exploring these different mechanisms, researchers hope to improve treatment effectiveness and patient outcomes in liver cancer.

What evidence suggests that this trial's treatments could be effective for liver cancer?

In this trial, participants will receive either systemic therapy or locoregional therapy for liver cancer. Research has shown that combining atezolizumab with bevacizumab, which participants in Arm A may receive, holds promise for treating liver cancer, specifically hepatocellular carcinoma (HCC). Studies have found that this combination helps patients live longer and delays disease progression more effectively than treatments like sorafenib. Meanwhile, participants in Arm B will undergo locoregional therapy with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE). TARE often results in better response rates and disease control for some patients, while TACE has been successful in the early and middle stages of HCC, offering significant improvements. Both treatments have benefits, but the best option may depend on individual patient factors. ^{2 3 4 6 7}

Who Is on the Research Team?

David Hsieh, MD

Principal Investigator

UT Southwestern Medical Center

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40677696/

Systematic review and meta-analysis of real-world evidence Pooled 6- and 12-month OS was 82% (95% CI: 76-86%; I 2 = 80%) and 65% (95% CI: 60-70%; I 2 = 66%). Median OS of patients with CP-A liver ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S2589555925001089

Efficacy of atezolizumab plus bevacizumab for ... This study provides real-world evidence supporting the long-term efficacy of atezolizumab plus bevacizumab (A+B) for unresectable hepatocellular carcinoma.

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1915745

Atezolizumab plus Bevacizumab in Unresectable ... In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival ...

4. tecentriq.com tecentriq.com/hcc/results/how-tecentriq-may-help.html

How TECENTRIQ + Avastin ® (bevacizumab) May Help TECENTRIQ + Avastin was more effective in treating HCC than sorafenib. More patients LIVED LONGER and HAD A LOWER CHANCE of tumors growing or spreading ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.24.00645

Clinical Outcomes and Histologic Findings of Patients With ... Durable partial response (PR) and durable stable disease (SD) are often seen in patients with hepatocellular carcinoma (HCC) receiving atezolizumab plus ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38756146/

Safety and Efficacy of Atezolizumab/Bevacizumab in Patients ... We compared the safety and efficacy of atezolizumab/becavizumab treatment in patients with unresectable HCC and various degrees of liver dysfunction.

7. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-025-14400-9

Safety and efficacy of atezolizumab/bevacizumab in ... We conclude that the combination of atezolizumab and bevacizumab is a safe and effective option for patients with unresectable hepatocellular carcinoma ...