Nivolumab + Ipilimumab for Lung Cancer

(ATLAS Trial)

Overseen By Adrian Sacher, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University Health Network, Toronto

Must not be taking: Immunosuppressants, others

Disqualifiers: Autoimmune disorders, HIV, Hepatitis, 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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

5 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this research study is to look at how effective two drugs, nivolumab and ipilimumab, are for people with non-small lung cancer that has metastasized (has spread to other parts of the body) and to see what effects these drugs have on these tumors.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have received any anticancer therapy within 21 days or palliative radiotherapy within 14 days before starting the study treatment. Also, you should not be using immunosuppressive medication within 14 days before the first dose.

What data supports the effectiveness of the drug combination of Nivolumab and Ipilimumab for lung cancer?

Research shows that the combination of Nivolumab (Opdivo) and Ipilimumab (Yervoy) is effective in treating advanced non-small cell lung cancer (NSCLC), leading to longer survival compared to chemotherapy. Studies indicate that this drug combination provides durable and long-term benefits, especially in patients with specific tumor characteristics. ^{1 2 3 4 5}

Is the combination of Nivolumab and Ipilimumab safe for humans?

The combination of Nivolumab and Ipilimumab has been shown to have a manageable safety profile in patients with advanced non-small cell lung cancer, but it is associated with an increased risk of immune-related side effects. These side effects are specific to the drugs and can occur when they are used together, so careful monitoring and management are important. ^{1 3 6 7 8}

How is the drug combination of Nivolumab and Ipilimumab unique for treating lung cancer?

The combination of Nivolumab and Ipilimumab is unique because it uses two immune checkpoint inhibitors to enhance the body's immune response against cancer cells, offering a chemotherapy-free option for advanced non-small cell lung cancer (NSCLC) and showing long-term survival benefits compared to traditional chemotherapy. ^{1 4 5 9 10}

Research Team

Adrian G. Sacher

Principal Investigator

Princess Margaret Cancer Centre

Eligibility Criteria

Adults with metastatic non-small cell lung cancer, weighing at least 35 kg and expected to live more than 12 weeks. They must not have had prior treatments for this diagnosis or certain other cancers in the last two years, no major organ transplants, active infections like HIV or hepatitis, and no recent heart issues. Participants need functioning organs/marrow and cannot be on immunosuppressants.

Inclusion Criteria

I have not had any treatment for my current lung cancer diagnosis.

My lung cancer has returned or spread to other parts.

My lung cancer can be of any type.

Exclusion Criteria

I am not incarcerated and can consent and follow study procedures.

I haven't taken immunosuppressive drugs in the last 14 days, with some exceptions.

I've had to stop IV drug treatments more than once due to bad reactions.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab every 3 weeks and ipilimumab every 6 weeks, with cfDNA testing to guide potential chemotherapy intensification

12 weeks

4 visits (in-person) for nivolumab, 2 visits (in-person) for ipilimumab

Follow-up

Participants are monitored for safety and effectiveness after treatment, including progression-free survival and overall survival

4 years

Treatment Details

Interventions

• cfDNA blood test
• Ipilimumab, Nivolumab
• Platinum-based Chemotherapy

Trial Overview The trial is testing the effectiveness of nivolumab and ipilimumab drugs on metastatic non-small cell lung cancer. It also examines how a cfDNA blood test can help track tumor changes during treatment. Patients will not have received previous surgery, radiation, or chemotherapy for their current cancer diagnosis.

Participant Groups

Group I: Non-Small cell Lung Cancer Experimental Treatment 4 Interventions

Nivolumab, intravenously (given by vein), once every 3 weeks Ipilimumab, intravenously (given by vein), once every 6 weeks Participants will have blood samples taken for cell free deoxyribonucleic acid (cfDNA) testing. If there is an increasing or stable tumor cfDNA, platinum-doublet chemotherapy will be given.

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

Approved in United States as Yervoy for:

• Melanoma
• Colorectal cancer
• Renal cell carcinoma
• Hepatocellular carcinoma
• Non-small cell lung cancer

Approved in United States as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma
• Gastric cancer
• Gastroesophageal junction cancer

Approved in European Union as Yervoy for:

• Melanoma

Approved in European Union as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Esophageal squamous cell carcinoma

Approved in Canada as Yervoy for:

• Melanoma

Approved in Canada as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma

Approved in Japan as Yervoy for:

• Melanoma

Approved in Japan as Opdivo for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Classical Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma

Who Is Running the Clinical Trial?

University Health Network, Toronto

Lead Sponsor

Trials

1,555

Recruited

526,000+

Bristol-Myers Squibb

Industry 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

Findings from Research

In a phase 1 study involving 78 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab as first-line therapy demonstrated a tolerable safety profile with no treatment-related deaths and manageable adverse events, such as increased lipase and pneumonitis.

The treatment showed promising efficacy, with confirmed objective response rates of 47% in the ipilimumab every-12-weeks cohort and 38% in the every-6-weeks cohort, suggesting potential benefits over anti-PD-1 monotherapy and warranting further investigation in larger trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. Hellmann, MD., Rizvi, NA., Goldman, JW., et al.[2022]

The phase III CheckMate-227 trial indicates that the combination of ipilimumab and nivolumab significantly improves progression-free survival in non-small cell lung cancer patients with a high tumor mutation burden, with 43% of patients remaining progression-free after 1 year.

In contrast, only 13% of patients treated with chemotherapy experienced progression-free survival, highlighting the potential efficacy of the checkpoint inhibitor combination over traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High TMB Predicts Immunotherapy Benefit. [2019]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

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 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]

In a study of 1255 patients with metastatic non-small cell lung cancer (NSCLC), first-line treatment with nivolumab plus ipilimumab (NIVO+IPI) showed a high incidence of treatment-related adverse events (TRAEs), with 78% experiencing any-grade TRAEs and 34% experiencing severe (grade 3 or 4) TRAEs, but the treatment was generally well tolerated.

Patients who discontinued NIVO+IPI due to TRAEs still had a favorable long-term survival rate, with a 3-year overall survival of 50%, indicating that stopping treatment because of side effects did not negatively impact their long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. Paz-Ares, LG., Ciuleanu, TE., Pluzanski, A., et al.[2023]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

Monoclonal antibodies like nivolumab and pembrolizumab, which target PD-1, have shown a survival benefit and better tolerability compared to standard second-line chemotherapy in non-small cell lung cancer, as demonstrated in three phase III trials.

Patients receiving PD-1 inhibitors may experience unique immune-related adverse events that require early recognition and a multidisciplinary management approach, highlighting the need for ongoing education among healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. O'Kane, GM., Labbé, C., Doherty, MK., et al.[2018]

The combination of nivolumab and ipilimumab has shown promise as a first-line treatment for previously untreated advanced non-small-cell lung cancer, as demonstrated in the Phase III CheckMate 227 study.

This study is significant because it is the first to evaluate a chemotherapy-sparing approach using dual immune checkpoint inhibition, while also considering tumor mutational burden as a biomarker for selecting suitable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in non-small-cell lung cancer. Reck, M., Borghaei, H., O'Byrne, KJ.[2019]

Nivolumab plus ipilimumab (N+I) and nivolumab plus ipilimumab with chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), but both treatments are not cost-effective compared to chemotherapy alone, with high incremental cost-effectiveness ratios (ICERs) of $239,072 and $838,198 per quality-adjusted life year (QALY) respectively.

The cost-effectiveness analysis showed that N+I had a very low probability (2.6%) of being considered cost-effective at a willingness-to-pay threshold of $150,000 per QALY, indicating that while these treatments may improve survival, they come at a significant financial burden to the healthcare system.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer. Yang, SC., Kunst, N., Gross, CP., et al.[2022]

References

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

Nivolumab plus ipilimumab as first-line treatment for advanced non-small-cell lung cancer (CheckMate 012): results of an open-label, phase 1, multicohort study. [2022]

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

High TMB Predicts Immunotherapy Benefit. [2019]

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

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. [2022]

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

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

5. England 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. [2023]

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

Safety of First-Line Nivolumab Plus Ipilimumab in Patients With Metastatic NSCLC: A Pooled Analysis of CheckMate 227, CheckMate 568, and CheckMate 817. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. [2022]

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

Monitoring and Management of Immune-Related Adverse Events Associated With Programmed Cell Death Protein-1 Axis Inhibitors in Lung Cancer. [2018]

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

Nivolumab plus ipilimumab in non-small-cell lung cancer. [2019]

10. Switzerland pubmed.ncbi.nlm.nih.gov

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer. [2022]