Nivolumab + Ipilimumab for Liver Cancer

(CheckMate 9DW Trial)

Not currently recruiting at 460 trial locations

Overseen By BMS Study Connect Contact Center http://www.bmsstudyconnect.com/

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Bristol-Myers Squibb

Disqualifiers: Fibrolamellar HCC, Liver transplant, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: Unknown

Duration: 12 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining two drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), helps people with advanced liver cancer live longer compared to the usual treatments, sorafenib or lenvatinib. It focuses on individuals who have not yet received any systemic treatment for their liver cancer. Suitable candidates have advanced liver cancer confirmed by a doctor and have not undergone systemic therapy. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that using nivolumab and ipilimumab together yields mixed safety results for people with liver cancer. In some studies, only a small percentage of participants (0.6%) experienced serious side effects, such as heart inflammation (myocarditis) and lung inflammation (pneumonitis). This indicates that while the treatment can be effective, it also carries some risks.

The FDA has approved this drug combination for certain liver cancers, confirming it has undergone testing for safety and effectiveness. Overall, the treatment has extended patients' lives, but potential side effects should be considered. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of Nivolumab and Ipilimumab for liver cancer because these drugs work together to harness the body's immune system against cancer cells. Unlike the standard treatments like Sorafenib and Lenvatinib, which primarily target cancer cell growth, Nivolumab and Ipilimumab are immune checkpoint inhibitors. They block proteins that prevent the immune system from attacking cancer, potentially leading to a more robust and sustained immune response. This innovative approach could offer new hope for patients by targeting the disease in a way that standard therapies do not.

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

Research has shown that using nivolumab and ipilimumab together, which participants in this trial may receive, may help treat advanced liver cancer. Studies indicate that more patients experienced tumor shrinkage or disappearance with this combination than with standard treatments like sorafenib or lenvatinib, which are part of another treatment arm in this trial. Specifically, patients lived an average of 23.7 months with the nivolumab and ipilimumab treatment, compared to 20.6 months with the other drugs. These results suggest that nivolumab plus ipilimumab could be a more effective option for those fighting advanced liver cancer, also known as hepatocellular carcinoma (HCC). ^{5 6 7 8 9}

Who Is on the Research Team?

Bristol-Myers Squibb

Principal Investigator

Bristol-Myers Squibb

Are You a Good Fit for This Trial?

This trial is for adults with advanced liver cancer (HCC) who haven't had systemic therapy before. They need to have a certain level of physical fitness (ECOG 0 or 1), and their liver must be functioning fairly well (Child-Pugh score 5 or 6). People with specific HCC subtypes, prior liver transplants, recent serious brain complications, or severe hepatic encephalopathy can't join.

Inclusion Criteria

My condition is advanced liver cancer.

My liver cancer diagnosis was confirmed through a tissue sample.

My liver function is slightly impaired.

Exclusion Criteria

I have had severe liver-related brain issues in the last year.

My liver cancer is of a specific rare type.

There are other requirements that need to be met which are described in the study's guidelines.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either nivolumab plus ipilimumab or standard of care (sorafenib or lenvatinib) as first-line treatment for advanced hepatocellular carcinoma

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Lenvatinib
• Nivolumab
• Sorafenib

Trial Overview The study is testing the effectiveness of combining two immunotherapy drugs, Nivolumab and Ipilimumab, against standard treatments Sorafenib or Lenvatinib in improving survival rates for patients. Participants are randomly assigned to receive either the combination treatment or one of the standard care options.

How Is the Trial Designed?

Group I: Nivolumab + Ipilimumab Experimental Treatment 2 Interventions

Group II: Sorafenib/lenvatinib Active Control 2 Interventions

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Bristol-Myers Squibb

Lead Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

Nivolumab combined with ipilimumab significantly improves overall survival in adult patients with intermediate/poor-risk advanced renal cell carcinoma compared to sunitinib, with a hazard ratio of 0.63, indicating a 37% reduction in the risk of death.

In the study involving 1096 patients, the median overall survival was not reached for the nivolumab + ipilimumab group, while it was 25.95 months for the sunitinib group, highlighting the potential of this combination therapy for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

European Medicines Agency extension of indication to include the combination immunotherapy cancer drug treatment with nivolumab (Opdivo) and ipilimumab (Yervoy) for adults with intermediate/poor-risk advanced renal cell carcinoma. Ali, S., Camarero, J., Hennik, P., et al.[2021]

In a phase 1/2 study involving 148 patients with advanced hepatocellular carcinoma (HCC) previously treated with sorafenib, the combination of nivolumab and ipilimumab showed a promising objective response rate of 32% in one treatment arm, indicating potential efficacy for this patient population.

The treatment regimen was generally manageable in terms of safety, although 94% of patients in one arm experienced treatment-related adverse events, highlighting the need for careful monitoring; notably, this combination therapy received accelerated approval in the US based on these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. Yau, T., Kang, YK., Kim, TY., et al.[2022]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

A meta-analysis of nine randomized controlled trials showed that PD-1 inhibitors significantly increase the risk of developing all-grade hepatic adverse events (AEs) in cancer patients, although high-grade AEs were not significantly affected compared to chemotherapy or everolimus.

The combination of nivolumab and ipilimumab resulted in a notably higher risk of all-grade and high-grade hepatic AEs compared to ipilimumab alone, indicating that while PD-1 inhibitors can be effective, they also carry a risk of liver-related side effects, primarily of lower severity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence and risk of hepatic toxicities with PD-1 inhibitors in cancer patients: a meta-analysis. Zhang, X., Ran, Y., Wang, K., et al.[2018]

In a study of 10 patients with advanced hepatocellular carcinoma (HCC) who had previously failed ICI-based treatments, the combination of ipilimumab and nivolumab showed an overall response rate of 30% and a disease control rate of 40%.

The median progression-free survival was 2.9 months and median overall survival was 7.4 months, indicating that this treatment combination is both effective and tolerable for patients with advanced HCC after prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and nivolumab in advanced hepatocellular carcinoma after failure of prior immune checkpoint inhibitor-based combination therapies: a multicenter retrospective study. Roessler, D., Öcal, O., Philipp, AB., et al.[2023]

In a study of 25 patients with advanced hepatocellular carcinoma (HCC) who had previously progressed on immune checkpoint inhibitors (ICIs), the combination of ipilimumab with nivolumab or pembrolizumab showed a 16% objective response rate, indicating some effectiveness in overcoming prior treatment resistance.

The treatment resulted in a median overall survival of 10.9 months, with 42.4% of patients surviving at least one year, while 52% experienced treatment-related adverse events, suggesting that the combination therapy has a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab and nivolumab/pembrolizumab in advanced hepatocellular carcinoma refractory to prior immune checkpoint inhibitors. Wong, JSL., Kwok, GGW., Tang, V., et al.[2022]

Immune checkpoint inhibitors targeting CTLA-4 and PD-1 have been shown to significantly improve survival rates in patients with advanced cancer, leading to their FDA approval and expanding indications.

While hepatotoxicity is a less common side effect of these therapies, it can vary in incidence and severity based on treatment type and cancer, and may necessitate stopping therapy and using immunosuppressive treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Liver Toxicity with Cancer Checkpoint Inhibitor Therapy. Nadeau, BA., Fecher, LA., Owens, SR., et al.[2019]

A review of 2217 adverse drug reaction reports related to immune checkpoint inhibitors (ICIs) from 2011 to 2018 revealed that these drugs, particularly nivolumab, are associated with a higher frequency of serious immune-related adverse events, including gastrointestinal and respiratory disorders.

Emerging safety signals, such as ischaemic heart disease and cardiac failure, were identified, indicating the need for further investigation into the long-term safety profile of ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety profile of immune checkpoint inhibitors: An analysis of the Italian spontaneous reporting system database. Cutroneo, PM., Isgrò, V., Ientile, V., et al.[2021]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

In a retrospective analysis of 34 advanced HCC patients treated with nivolumab, the treatment was found to be safe, with only 5.9% experiencing grade 3 toxicities, indicating a manageable safety profile.

The overall survival for patients was relatively short, with a median of 7.5 weeks, and those with Child-Pugh B stage disease had significantly poorer outcomes, suggesting that nivolumab's efficacy may be limited in patients with advanced liver disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and safety of nivolumab in advanced hepatocellular carcinoma: real-life experience from three German centers. Finkelmeier, F., Czauderna, C., Perkhofer, L., et al.[2020]

Combining nivolumab with ipilimumab results in higher response rates in cancer treatment compared to using nivolumab alone, indicating a potentially more effective therapeutic strategy.

This combination therapy may enhance the immune response against cancer, but specific details on the number of subjects or study duration are not provided in the abstract.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Ipilimumab Achieves Responses in dMMR/MSI-H Tumors. [2019]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

In a study of 71 patients with advanced hepatocellular carcinoma, the combination of nivolumab and cabozantinib showed promising antitumor activity, with an objective response rate of 17% for the doublet therapy and 29% for the triplet therapy including ipilimumab.

Both treatment combinations had manageable safety profiles, with 50% of patients in the doublet arm and 74% in the triplet arm experiencing grade 3-4 treatment-related adverse events, but no treatment-related deaths were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Cabozantinib With or Without Ipilimumab for Advanced Hepatocellular Carcinoma: Results From Cohort 6 of the CheckMate 040 Trial. Yau, T., Zagonel, V., Santoro, A., et al.[2023]

Citations

1. opdivohcp.com opdivohcp.com/efficacy/hcc

Efficacy Data for Hepatocellular Carcinoma (HCC) - Opdivo View efficacy data for OPDIVO® (nivolumab) and YERVOY® (ipilimumab) in hepatocellular carcinoma (HCC). Please see Indications and Important Safety ...

2. opdivo.com opdivo.com/advanced-hcc/clinical-trial-results/unresectable-immunotherapy-combination

Clinical trial results for previously untreated advanced liver ... More people given OPDIVO + YERVOY had their tumors shrink or completely disappear compared to targeted therapies lenvatinib or sorafenib ...

3. fda.gov fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-ipilimumab-unresectable-or-metastatic-hepatocellular-carcinoma

FDA approves nivolumab with ipilimumab for unresectable ... Median OS was 23.7 months (95% CI: 18.8, 29.4) in the nivolumab + ipilimumab arm and 20.6 months (95% CI: 17.5, 22.5) in the lenvatinib or ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11493385/

Nivolumab plus Ipilimumab: A Novel First-Line ... Efficacy Outcome. The efficacy of nivolumab plus ipilimumab is summarized in Table 1, with a median overall survival (OS) of 23.7 months, the combination ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0168827825024717

Nivolumab plus ipilimumab for potentially resectable ... The estimated 4-year progression-free survival and overall survival rates were 44% (95% confidence interval [CI], 28–59%) and 60% (95% CI, 42–74 ...

6. opdivohcp.com opdivohcp.com/safety/hcc/opdivo-yervoy

Safety Profile in Hepatocellular Carcinoma (HCC) - Opdivo Fatal adverse reactions occurred in 2 (0.6%) patients who received OPDIVO in combination with ipilimumab; these included myocarditis and pneumonitis (1 each).

7. opdivo.com opdivo.com/advanced-hcc

Advanced Hepatocellular Carcinoma (HCC) Liver Cancer ... OPDIVO® (nivolumab) + YERVOY® (ipilimumab) is an immunotherapy treatment option for adults who have had prior treatment with sorafenib for liver cancer or ...

8. cancernetwork.com cancernetwork.com/view/nivolumab-ipilimumab-yielded-superior-efficacy-and-safety-data-in-uhcc

Nivolumab/Ipilimumab Yielded Superior Efficacy and ... Nivolumab plus ipilimumab generated an ORR of 36% vs 13% from levantinib plus sorafenib in unresectable hepatocellular carcinoma in the CheckMate 9DW study.

9. news.bms.com news.bms.com/news/details/2025/U-S--Food-and-Drug-Administration-Approves-Opdivo-nivolumab-plus-Yervoy-ipilimumab-as-a-First-Line-Treatment-for-Unresectable-or-Metastatic-Hepatocellular-Carcinoma/default.aspx

U.S. Food and Drug Administration Approves Opdivo ... The US Food and Drug Administration (FDA) approved Opdivo (nivolumab) plus Yervoy (ipilimumab) as a first-line treatment for adult patients with unresectable ...