Dual vs Single Immune Therapy for Lung Cancer

Overseen By Margaret Thomas, MPH

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Alabama at Birmingham

Must not be taking: Immunosuppressants, Live-virus vaccines

Disqualifiers: Autoimmune diseases, HIV, Hep B, 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: 4

Duration: 9 weeks

24 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if double immune therapy plus chemotherapy is more effective than single immune therapy plus chemotherapy for treating non-small cell lung cancer (NSCLC) without the PD-L1 marker. Researchers will compare the two treatment approaches by examining changes in the cancer's DNA found in the blood. Individuals with stage IV non-small cell lung cancer, without a specific mutation, and who have not received advanced cancer treatment before, might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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

The trial information does not specify if you need to stop taking your current medications. However, if you are on systemic corticosteroids or other immunosuppressive medications, you may need to stop them at least 14 days before joining the trial, unless they are at a low dose.

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

Research shows that pembrolizumab, when combined with chemotherapy, is generally well-tolerated. Studies have found that about 19% of patients with non-small cell lung cancer (NSCLC) survive for five years with this treatment, indicating its relative safety for these patients.

For ipilimumab, research indicates it is also generally well-tolerated when combined with nivolumab and chemotherapy. However, some patients experienced immune-related side effects, such as lung inflammation (pneumonitis), occurring in about 9% of patients. Despite this, the combination has demonstrated promising survival benefits for NSCLC patients.

Both treatments have been used for other conditions, providing some confidence in their safety. However, it is important to consider both the potential benefits and any side effects when deciding to join a clinical trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lung cancer because they explore the potential of combining immune checkpoint inhibitors with chemotherapy in innovative ways. The single-agent treatment involves Pembrolizumab, which blocks the PD-1 pathway, allowing the immune system to better target cancer cells. In contrast, the dual-agent approach combines Nivolumab and Ipilimumab, targeting both PD-1 and CTLA-4 pathways to enhance the immune response even further. Unlike the standard chemotherapy options, these combinations aim to leverage the body's own defenses to fight cancer more effectively, offering hope for improved outcomes in patients with non-small cell lung cancer (NSCLC).

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

This trial will compare single and dual immune therapy approaches for lung cancer. Studies have shown that pembrolizumab, which participants in one arm of this trial will receive, can help people with non-small cell lung cancer (NSCLC) live longer. Specifically, a large study found that about 25% of patients treated with pembrolizumab were still alive after five years, suggesting it may extend life for some patients.

In another arm of this trial, participants will receive a combination of ipilimumab and nivolumab. Research indicates that this combination can help patients live longer than with chemotherapy alone. Some studies even report a five-year survival rate much higher than past rates for NSCLC patients. ^{1 3 4 6 7}

Who Is on the Research Team?

Aakash Desai, MD

Principal Investigator

University of Alabama at Birmingham

Are You a Good Fit for This Trial?

The DISCERN trial is for individuals with a type of lung cancer called NSCLC that lacks the PD-L1 marker. Participants should be suitable for chemotherapy but have not been treated with immune therapy before.

Inclusion Criteria

Provision of signed and dated informed consent form

Participants should have a life expectancy of at least 3 months

My cancer can be measured and has grown in areas previously treated with radiation.

Exclusion Criteria

I do not have HIV, Hep B, or Hep C, or if I do, it is well-controlled and won't interact with my treatments.

I have active issues in my abdomen like diverticulitis or blockages.

Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy within 4 weeks prior to administration of study regimen

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either single or dual immune checkpoint blockade (ICB) with chemotherapy. Single agent ICB involves Pembrolizumab every 3 weeks for 4 cycles, while dual agent ICB involves Nivolumab every 3 weeks and Ipilimumab every 6 weeks for 2 cycles.

9 weeks

4 visits (in-person)

Maintenance Therapy

For non-squamous NSCLC, maintenance therapy includes Pembrolizumab and pemetrexed for single agent ICB, or Nivolumab and Ipilimumab for dual agent ICB, administered every 3 to 6 weeks for up to 2 years.

Up to 24 months

Follow-up

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

24 months

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Pembrolizumab

Trial Overview This study compares two treatments: one combines two types of immune therapy (Ipilimumab and Nivolumab) with chemo, while the other uses just one immune therapy (Pembrolizumab) plus chemo. It monitors changes in cancer DNA in blood after treatment begins.

How Is the Trial Designed?

Group I: single agent immune checkpoint blockade (ICB) + chemotherapy (CT) Experimental Treatment 4 Interventions

200 mg of Pembrolizumab will be administered intravenously (IV) every 3 weeks (Q3W) for 4 cycles. Combination chemotherapy: For squamous NSCLC: Carboplatin (dose according to area under the curve (AUC) 6) + paclitaxel 200 mg/m². For non-squamous NSCLC: Carboplatin (AUC 5) + pemetrexed 500 mg/m². Maintenance Therapy for Non-Squamous NSCLC: Pembrolizumab 200 mg + pemetrexed 500 mg/m² Q3W for up to 2 years.

Group II: dual agent immune checkpoint blockade (ICB) + chemotherapy (CT) Experimental Treatment 5 Interventions

Drug 1: 360 mg of Nivolumab will be administered intravenously (IV) every 3 weeks (Q3W). Drug 2: 1 mg/kg of Ipilimumab will be administered intravenously (IV) every 6 weeks (Q6W) for 2 cycles. Combination Chemotherapy: For squamous NSCLC: Carboplatin (AUC 6) + paclitaxel 200 mg/m². For non-squamous NSCLC: Carboplatin (AUC 5) + pemetrexed 500 mg/m². Maintenance Therapy for Non-Squamous NSCLC: Nivolumab 360 mg Q3W + Ipilimumab 1mg/kg Q6W for up to 2 years.

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?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Immunotherapy is becoming a key part of first-line treatment for non-small cell lung cancer (NSCLC), with various phase 3 studies showing the effectiveness of drugs targeting PD-1, PD-L1, and CTLA-4, often in combination with chemotherapy.

Patients with high PD-L1 expression (≥ 50%) can be treated with single-agent Pembrolizumab or Atezolizumab, while those with lower expression have multiple treatment options, including combinations of immunotherapy and chemotherapy, highlighting the tailored approach based on tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First line Immunotherapy for Non-Small Cell Lung Cancer. Nasser, NJ., Gorenberg, M., Agbarya, A.[2020]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab, a monoclonal antibody targeting PD-1, showed significant efficacy in treating a 79-year-old patient with advanced squamous cell lung cancer, leading to a complete response after just 3 cycles of treatment.

However, the patient developed acute myelomonocytic leukemia after starting pembrolizumab, highlighting a potential safety concern that warrants further investigation into the drug's effects on blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. Kim, HB., Park, SG., Hong, R., et al.[2020]

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]

In the JAVELIN Lung 100 trial involving 1214 patients with advanced NSCLC, avelumab showed longer median progression-free survival (PFS) compared to platinum-based chemotherapy (8.4 months vs. 5.6 months), indicating its potential efficacy as a first-line treatment.

Although avelumab demonstrated longer median overall survival (OS) compared to chemotherapy (20.1 months vs. 14.9 months), the differences were not statistically significant, suggesting that while avelumab may be beneficial, it did not meet the primary objective of the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Avelumab Versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients With High-Expression Programmed Death-Ligand 1-Positive Metastatic NSCLC: Primary Analysis From the Phase 3 JAVELIN Lung 100 Trial. Reck, M., Barlesi, F., Yang, JC., et al.[2023]

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]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In patients with non-small cell lung cancer (NSCLC), platinum-based chemotherapy significantly increased the presence of NSCLC-specific antibodies and various immune markers in the blood, indicating an immune response to the treatment.

Immune checkpoint inhibitors (ICIs) like Nivolumab and Pembrolizumab also altered the immune profile, enhancing certain T-cell and B-cell markers, which suggests that both chemotherapy and ICIs can modify the immune landscape in advanced NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-cell mass cytometric analysis of peripheral immunity and multiplex plasma marker profiling of non-small cell lung cancer patients receiving PD-1 targeting immune checkpoint inhibitors in comparison with platinum-based chemotherapy. Neuperger, P., Szalontai, K., Gémes, N., et al.[2023]

In the KEYNOTE-024 study involving 305 patients with untreated advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival (OS) compared to platinum-based chemotherapy, with a median OS of 30.0 months versus 14.2 months for chemotherapy.

Pembrolizumab also had a better safety profile, with fewer treatment-related severe adverse events (31.2% for pembrolizumab vs. 53.3% for chemotherapy), indicating it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

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]

In a study of 72 treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) and high PD-L1 expression, pembrolizumab showed an objective response rate of 45.8%, with even higher rates of 70.0% in patients with pre-existing interstitial lung disease (ILD).

Patients with ILD had similar overall survival rates compared to those without ILD, suggesting that pembrolizumab can be safely administered to NSCLC patients with ILD without compromising their prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab. Yamaguchi, O., Kaira, K., Shinomiya, S., et al.[2021]

Citations

1. opdivohcp.com opdivohcp.com/efficacy/nsclc/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy ... In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9937094/

Five-Year Survival Outcomes With Nivolumab Plus Ipilimumab ... Patients with metastatic non–small-cell lung cancer (mNSCLC) have historically had a 5-year survival rate of only 7%, but more recently, immune check point ...

3. nejm.org nejm.org/doi/full/10.1056/NEJMoa1910231

Nivolumab plus Ipilimumab in Advanced Non–Small-Cell ... First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC.

4. ejcancer.com ejcancer.com/article/S0959-8049(24)00952-3/fulltext

Five-year outcomes with first-line nivolumab plus ... This 5-year update supports the long-term, durable OS benefit and improved 5-year survivorship with nivolumab plus ipilimumab with chemotherapy ...

5. jto.org jto.org/article/S1556-0864(24)02355-4/fulltext

Long-Term Survival Outcomes With First-Line Nivolumab ... In patients with squamous NSCLC, median OS was 16.2 versus 8.2 months with nivolumab plus ipilimumab with or without chemotherapy versus ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.01503

Five-Year Survival Outcomes With Nivolumab Plus ... Patients with metastatic non–small-cell lung cancer (mNSCLC) have historically had a poor prognosis, with a 5-year survival rate of 7%.

7. esmoopen.com esmoopen.com/article/S2059-7029(25)00992-5/fulltext

final, 6-year outcomes from CheckMate 9LA The 6-year DOR rate was 19% with nivolumab plus ipilimumab with chemotherapy; all patients in the chemotherapy arm were censored or stopped ...