Immunotherapy + Local Consolidation Therapy for Lung Cancer

Recruiting at 5 trial locations

Overseen By Mehmet Altan, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunotherapy, Chemotherapy

Disqualifiers: Autoimmune disease, Active infection, 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: 12

Duration: 2 years

400 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase III trial studies how well nivolumab and ipilimumab works with or without local consolidation therapy in treating patients with stage IV non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Local consolidation therapy, such as surgery or radiation therapy, may improve survival outcomes in patients with non-small cell lung cancer. It is not yet known whether giving nivolumab and ipilimumab with local consolidation therapy works better than nivolumab and ipilimumab alone in treating patients with stage IV non-small cell lung cancer.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have had any approved anti-cancer therapy, including chemotherapy or hormonal therapy, within 3 weeks before starting the study treatment, except for hormone-replacement therapy or oral contraceptives.

What data supports the effectiveness of the drugs Ipilimumab and Nivolumab in treating lung cancer?

Research shows that the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) provides long-term benefits for patients with advanced non-small cell lung cancer, offering better outcomes than traditional chemotherapy. Additionally, nivolumab alone has been shown to improve survival rates in patients with advanced lung cancer who have already undergone chemotherapy. ^{1 2 3 4 5}

Is the combination of immunotherapy drugs like Nivolumab and Ipilimumab safe for lung cancer patients?

The combination of Nivolumab and Ipilimumab has been studied for safety in lung cancer patients, showing that while it can be effective, it often comes with increased risks of side effects, including immune-related reactions. These side effects can be serious, such as pneumonitis (lung inflammation), which was found to occur more frequently than previously reported. ^{6 7 8 9 10}

How is the treatment with Ipilimumab and Nivolumab for lung cancer different from other treatments?

This treatment combines two immunotherapy drugs, Ipilimumab and Nivolumab, which work by boosting the immune system to attack cancer cells, offering a novel approach compared to traditional chemotherapy and radiation. Unlike standard treatments, this combination targets specific immune checkpoints, potentially providing benefits for patients with advanced lung cancer who have limited options. ^{2 3 11 12 13}

Research Team

John V. Heymach, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for adults with stage IV non-small cell lung cancer. Eligible participants must have measurable disease, adequate organ function, and no prior immunotherapy for metastatic NSCLC. Women of childbearing potential must test negative for pregnancy and use contraception, as should men if their partners are of childbearing potential. Patients with treated brain metastases may qualify if stable.

Inclusion Criteria

My lung cancer does not have common EGFR or ALK mutations, or if it does, there's no standard treatment for them.

My lung cancer is confirmed and not small cell or carcinoid type.

I am a man, sexually active with a woman capable of bearing children, and will use effective contraception.

Exclusion Criteria

I do not have an active autoimmune disease, except for allowed conditions like vitiligo or type I diabetes.

Things like family, emotions, where you live, or other social factors may make it hard for you to follow the study plan and schedule.

I haven't taken steroids for pneumonitis in the last 60 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive nivolumab and ipilimumab intravenously over specified intervals for up to 2 courses

12 weeks

3 visits (in-person)

Local Consolidation Therapy (LCT)

Patients receive LCT consisting of surgery and/or radiation 14 days after completion of Induction Phase

2-4 weeks

Treatment

Patients receive nivolumab and ipilimumab every 6 weeks for 2 years

2 years

Every 6 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Every 3 months (in-person)

Treatment Details

Interventions

• Ipilimumab
• Local Consolidation Therapy
• Nivolumab
• Therapeutic Conventional Surgery

Trial Overview The study is testing the effectiveness of nivolumab and ipilimumab (immunotherapy drugs) with or without local consolidation therapy (surgery or radiation) in treating advanced lung cancer. The goal is to see if adding local treatments to immunotherapy improves outcomes compared to immunotherapy alone.

Participant Groups

Group I: Arm B (ipilimumab, nivolumab, LCT) Experimental Treatment 6 Interventions

INDUCTION PHASE: Patients receive nivolumab IV over 90 minutes on days 1, 15, and 29, and ipilimumab IV over 60 minutes on day 1. Treatment repeats every 6 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients receive LCT consisting of surgery and/or radiation 14 days after completion of Induction Phase. Patients then receive nivolumab and ipilimumab as in arm A beginning within 4 weeks after LCT. Courses repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

Group II: Arm A (ipilimumab, nivolumab) Experimental Treatment 3 Interventions

INDUCTION PHASE: Patients receive nivolumab IV over 90 minutes on days 1, 15, and 29, and ipilimumab IV over 60 minutes on day 1. Treatment repeats every 6 weeks for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients receive nivolumab IV over 60 minutes on days 1, 15, and 29 and ipilimumab IV over 90 minutes on day 1. Courses repeat every 6 weeks for 2 years in the absence of disease progression or unacceptable toxicity.

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?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

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 101 patients with locally advanced non-small cell lung cancer, 83 started durvalumab as consolidation therapy after chemoradiotherapy, while 18 did not, primarily due to higher baseline lactate dehydrogenase levels and worse performance status.

Factors such as pre-treatment diabetes, reduced hemoglobin, and lung diffusion capacity were linked to a higher risk of not receiving durvalumab, indicating that addressing these issues could help more patients complete their treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Factors associated with failure to start consolidation durvalumab after definitive chemoradiation for locally advanced NSCLC. Langberg, CW., Horndalsveen, H., Helland, Å., et al.[2023]

Immune checkpoint inhibitors targeting PD-1/PD-L1 have shown significant survival benefits in patients with metastatic non-small cell lung cancer, particularly when used as consolidation therapy after chemoradiotherapy in locally advanced cases, as demonstrated in the PACIFIC trial.

There is emerging evidence that PD-1/PD-L1 inhibitors may also be effective in early-stage lung cancer as neoadjuvant therapy, but further research is needed to clarify their role as adjuvant treatment after surgery and to evaluate the effectiveness of combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibition in Non-metastatic Non-small Cell Lung Cancer: Chance for Cure? Heigener, DF., Reck, M.[2020]

Nivolumab (Opdivo) is the first PD-1 inhibitor approved for advanced-stage squamous cell non-small-cell lung cancer, showing improved overall survival and progression-free survival compared to docetaxel in the Phase III CHECKMATE 017 trial.

Nivolumab demonstrated better safety and tolerability, along with improved patient-reported outcomes, although PD-L1 expression did not predict treatment outcomes, indicating a need for further research on predictive biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. Ang, YL., Lim, JS., Soo, RA.[2020]

Nivolumab (Opdivo) significantly improves overall survival and response rates in previously-treated patients with advanced nonsquamous non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CheckMate 057 trial.

Nivolumab has a manageable adverse event profile and is better tolerated than docetaxel, making it a valuable treatment option for patients who have progressed after chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. Keating, GM.[2018]

In a meta-analysis of 4413 patients from 8 randomized controlled trials, PD-1/PD-L1 inhibitors showed a significantly lower risk of all-grade adverse events (66.20% vs. 86.08%) and high-grade adverse events (14.26% vs. 43.53%) compared to chemotherapy, indicating a better safety profile.

While PD-1/PD-L1 inhibitors are generally safer, they are associated with a unique set of immune-related adverse events (irAEs) that can be severe, such as pneumonitis and thyroid dysfunction, which clinicians need to monitor closely to manage patient quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. Luo, W., Wang, Z., Tian, P., et al.[2021]

In a meta-analysis of 14 studies, PD-1/PD-L1 inhibitors showed a significantly lower risk of treatment-related death compared to control groups, with a risk ratio of 0.37, indicating a safer profile for lung cancer patients.

While PD-1/PD-L1 inhibitors alone had a lower overall rate of adverse events compared to chemotherapy, combining them with chemotherapy increased the risk of adverse events leading to treatment discontinuation (RR = 1.68).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The overall safety evaluation of programmed cell death/programmed cell death ligand 1 (PD-1/PD-L1) treatment for lung cancer patients: An updated systematic review and meta-analysis. Shang, H., Zhang, Z., Feng, A., et al.[2022]

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]

In a study of 205 patients with advanced non-small cell lung cancer (NSCLC) receiving anti-PD-1/PD-L1 therapy, the incidence of checkpoint inhibitor pneumonitis (CIP) was found to be 19%, significantly higher than the 3%-5% reported in clinical trials.

The study identified tumor histologic type as a potential risk factor for developing CIP, with a median onset time of 82 days and severe outcomes associated with higher-grade CIP, highlighting the need for improved monitoring and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. Suresh, K., Voong, KR., Shankar, B., et al.[2019]

In a study involving 576 patients with unresectable stage III non-small cell lung cancer (NSCLC), the PD-L1 inhibitor durvalumab showed a favorable safety profile, with only 22.7% of patients experiencing adverse events, primarily mild esophagitis.

Durvalumab treatment after concurrent chemoradiotherapy (cCRT) resulted in consistent outcomes across both PD-L1 positive and negative patients, indicating its potential as a standard care option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program. Avrillon, V., Daniel, C., Boisselier, P., et al.[2022]

In a phase 3 study of 713 patients with stage III non-small-cell lung cancer, durvalumab significantly improved progression-free survival compared to placebo, with a median of 16.8 months versus 5.6 months, respectively.

Durvalumab also showed a higher response rate (28.4% vs. 16.0%) and longer median time to death or distant metastasis (23.2 months vs. 14.6 months), while safety profiles were similar between durvalumab and placebo groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. Antonia, SJ., Villegas, A., Daniel, D., et al.[2022]

Consolidation immunotherapy after chemoradiation has significantly improved five-year survival rates for patients with unresectable, locally advanced lung cancer, but challenges like disease progression and the need for personalized treatment remain.

New concurrent immunotherapy approaches and novel agents are being explored, showing promising efficacy, but they may also increase the risk of additional side effects, highlighting the need for innovative therapies for patients with specific challenges like PD-L1 negative tumors or intolerable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Locally Advanced Lung Cancer. Oh, S., Botros, GN., Patel, M., et al.[2023]

References

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

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

2. Switzerland pubmed.ncbi.nlm.nih.gov

Factors associated with failure to start consolidation durvalumab after definitive chemoradiation for locally advanced NSCLC. [2023]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Immune Checkpoint Inhibition in Non-metastatic Non-small Cell Lung Cancer: Chance for Cure? [2020]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Profile of nivolumab in the treatment of metastatic squamous non-small-cell lung cancer. [2020]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Nivolumab: A Review in Advanced Nonsquamous Non-Small Cell Lung Cancer. [2018]

6. Germany pubmed.ncbi.nlm.nih.gov

Safety and tolerability of PD-1/PD-L1 inhibitors in the treatment of non-small cell lung cancer: a meta-analysis of randomized controlled trials. [2021]

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

The overall safety evaluation of programmed cell death/programmed cell death ligand 1 (PD-1/PD-L1) treatment for lung cancer patients: An updated systematic review and meta-analysis. [2022]

8. 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]

9. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. [2019]

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

Nationwide Real-Life Safety and Treatment Exposure Data on Durvalumab After Concurrent Chemoradiotherapy in Unresectable Stage III, Locally Advanced, Non-small Cell Lung Cancer: Analysis of Patients Enrolled in the French Early Access Program. [2022]

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

Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. [2022]

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

Locally Advanced Lung Cancer. [2023]