Immunotherapy + Chemotherapy for Non-Small Cell Lung Cancer

(G360-IIT Trial)

Recruiting at 3 trial locations

Overseen By Suzanne Kosky

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Hackensack Meridian Health

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: EGFR, ALK, ROS1, MET, RET, 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

Compensation: Varies

Number of Visits: 3

Duration: 5 weeks

108 Participants Needed

Trial Summary

What is the purpose of this trial?

This clinical trial plans to assess to what extent the on-treatment circulating tumor DNA (ctDNA) can predict the subset of patients with NSCLC who will respond to immunotherapy treatment only and which patients will need both immunotherapy and chemotherapy modalities for their treatment regimen.

Will I have to stop taking my current medications?

The trial protocol 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 adjust your dosage as per the trial's requirements.

What data supports the effectiveness of the drug combination of immunotherapy and chemotherapy for non-small cell 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 (NSCLC), improving survival rates compared to chemotherapy alone. Additionally, nivolumab has been shown to significantly prolong survival in patients with advanced NSCLC who have previously received chemotherapy. ^{1 2 3 4 5}

Is the combination of immunotherapy and chemotherapy safe for treating non-small cell lung cancer?

The combination of immunotherapy (like ipilimumab) and chemotherapy (such as paclitaxel and carboplatin) has been studied for safety in treating non-small cell lung cancer. While it can improve outcomes, it may also lead to more severe side effects compared to chemotherapy alone, including higher rates of serious treatment-related adverse events and some treatment-related deaths. ^{6 7 8 9 10}

How is the drug combination of Carboplatin, Ipilimumab, and Nivolumab unique for treating non-small cell lung cancer?

This drug combination is unique because it combines chemotherapy (Carboplatin) with two immunotherapy drugs (Ipilimumab and Nivolumab) that work by enhancing the body's immune response against cancer cells. This approach has shown durable and long-term efficacy in patients with advanced non-small cell lung cancer, offering a chemotherapy-sparing option compared to traditional treatments. ^{1 6 11 12 13}

Research Team

Martin E Gutierrez

Principal Investigator

Hackensack Meridian Health

Eligibility Criteria

Adults over 18 with newly diagnosed, untreated Stage IV NSCLC and positive PD-L1 expression. They must have proper liver function, no severe heart conditions or autoimmune diseases, not be pregnant or breastfeeding, agree to use contraception, and have no other cancers unless in remission for 2+ years.

Inclusion Criteria

I have a tumor that can be measured and hasn't been treated with radiation.

You are willing to have multiple blood tests to check for specific genetic material as needed for the study.

Willing to use highly effective contraceptive measures if child-bearing potential or if the patient's sexual partner is a woman of childbearing potential

Exclusion Criteria

I have moderate numbness or pain in my hands or feet.

I haven't taken high-dose steroids or other immune-weakening drugs in the last 2 weeks.

I have lung disease that could affect my treatment's safety monitoring.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nivolumab 360 mg intravenously every 3 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks. At five weeks, ctDNA response evaluation is conducted.

5 weeks

1 visit (in-person) every 3 weeks

Response Evaluation

ctDNA response evaluation with Guardant360 Response assay at 6 weeks post-randomization and at the time of progression.

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment with interval imaging every 12 weeks until disease progression.

36 months

1 visit (in-person) every 12 weeks

Treatment Details

Interventions

• Carboplatin
• Ipilimumab
• Nivolumab
• Paclitaxel
• Pemetrexed

Trial Overview The trial is testing if ctDNA levels can predict who will benefit from immunotherapy alone (Nivolumab/Ipilimumab) versus those needing both immunotherapy and chemotherapy (Carboplatin/Paclitaxel/Pemetrexed). Participants are selected based on their ctDNA profile.

Participant Groups

Group I: Arm B Experimental Treatment 2 Interventions

Arm B - control arm (Immunotherapy only) Nivolumab 360 mg/kg every 3 weeks Ipilimumab 1 mg/kg every 6 weeks

Group II: Arm A Active Control 5 Interventions

Arm A - Intervention arm (Immunotherapy and Chemotherapy) Nivolumab 360 mg/kg every 3 weeks Ipilimumab 1 mg/kg every 6 weeks Platinum- doublet Chemotherapy (Histology-based) 4 cycles depending on the investigator's discretion. Carboplatin dosed at AUC 5, and either Paclitaxel 175 mg/m2 for squamous or Pemetrexed 500 mg/m2 for non-squamous

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

Approved in United States as Paraplatin for:

• Ovarian cancer
• Testicular cancer
• Lung cancer
• Head and neck cancer
• Brain cancer

Approved in European Union as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer

Approved in Canada as Carboplatin for:

• Ovarian cancer
• Small cell lung cancer
• Testicular cancer

Who Is Running the Clinical Trial?

Hackensack Meridian Health

Lead Sponsor

Trials

141

Recruited

42,900+

MedSIR

Collaborator

Trials

52

Recruited

24,300+

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]

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]

Nivolumab, used as a first-line treatment for non-small cell lung cancer, shows promise in improving patient survival rates.

Combining nivolumab with platinum-doublet chemotherapy did not enhance survival benefits and may increase toxicity, indicating a need for careful consideration when using these treatments together.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab May Work as First-Line NSCLC Therapy. [2018]

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]

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 a study of 956 patients with advanced squamous non-small-cell lung cancer (NSCLC), the addition of ipilimumab to standard chemotherapy did not significantly improve overall survival compared to chemotherapy alone, with median survival times of 13.4 months versus 12.4 months, respectively.

The combination of ipilimumab and chemotherapy was associated with higher rates of severe treatment-related adverse events, including 51% experiencing grade 3 or 4 events, compared to 35% with chemotherapy plus placebo, indicating a need for careful consideration of safety in treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. Govindan, R., Szczesna, A., Ahn, MJ., et al.[2022]

Combining anti-PD-1 or anti-PD-L1 immunotherapy with platinum-based chemotherapy significantly improves outcomes for patients with advanced non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), based on a systematic review of 9 randomized studies.

While immune-mediated adverse events (AEs) and infusion reactions were more common with the combination therapy, there were no unexpected toxicities, indicating that the treatment is generally safe and manageable with appropriate monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer. Hoffner, B., Leighl, NB., Davies, M.[2020]

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 study of 184 patients with non-small cell lung cancer treated with immune checkpoint inhibitors, 26.6% developed immune-related adverse events (IRAEs), with certain factors like statin use and previous corticosteroid therapy increasing the risk of IRAEs.

Interestingly, patients who experienced IRAEs had significantly better progression-free survival (41 weeks vs. 9 weeks) and overall survival (89 weeks vs. 28 weeks), suggesting that the occurrence of IRAEs may be linked to improved treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. Serino, M., Freitas, C., Martins, M., et al.[2022]

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]

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 phase I study involving 15 Japanese patients with advanced non-small-cell lung cancer (NSCLC), the recommended dose of ipilimumab in combination with paclitaxel and carboplatin was determined to be 10 mg/kg, showing a manageable safety profile.

The study found that the most common adverse events were related to blood cell counts and immune responses, with three patients in each dose cohort achieving a partial response, indicating potential efficacy of the treatment combination.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. Horinouchi, H., Yamamoto, N., Fujiwara, Y., et al.[2022]

In a phase 3 clinical trial involving 252 patients with advanced squamous non-small cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab did not significantly improve overall survival compared to nivolumab alone, with median survival times of 10 months and 11 months respectively.

While the combination treatment showed a slightly better progression-free survival (IA-PFS) of 3.8 months compared to 2.9 months for nivolumab alone, the difference was not statistically significant, and both treatments had similar response rates and adverse event profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial. Gettinger, SN., Redman, MW., Bazhenova, L., et al.[2022]

References

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

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

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

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

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

Nivolumab May Work as First-Line NSCLC Therapy. [2018]

4. Switzerland pubmed.ncbi.nlm.nih.gov

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

5. Switzerland 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. [2023]

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

Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer. [2022]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer. [2020]

8. 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]

9. Spain pubmed.ncbi.nlm.nih.gov

Predictors of immune-related adverse events and outcomes in patients with NSCLC treated with immune-checkpoint inhibitors. [2022]

10. England pubmed.ncbi.nlm.nih.gov

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

11. England pubmed.ncbi.nlm.nih.gov

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

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

Phase I study of ipilimumab in phased combination with paclitaxel and carboplatin in Japanese patients with non-small-cell lung cancer. [2022]

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

Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer: The Lung-MAP S1400I Phase 3 Randomized Clinical Trial. [2022]