Evolocumab + Immunotherapy for Lung Cancer

(TOP2101 Trial)

Overseen By Anne M Peters, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Scott Antonia

Must not be taking: PCSK9 inhibitors, Steroids

Disqualifiers: Active TB, Hepatitis B/C, HIV, 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: Unknown

Duration: 4 weeks

38 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a research study to find out the safety and tolerability of combining the drug evolucumab with standard immunotherapy in people with advanced lung cancer (a type called non-small cell lung cancer). Nivolumab (Opdivo™) and ipilimumab (Yervoy™) are immunotherapy-type drugs which are approved for the treatment of advanced lung cancer that has expression of PD-L1 greater than or equal to 1%. Evolucumab is being combined with nivolumab and ipilimumab to see if it will improve the anti-tumor capabilities of the immunotherapy. Adding evolocumab to the combination of nivolumab and ipilimumab has not been tested in people before and is considered investigational.

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 be on certain therapies like systemic steroids or other immunosuppressive treatments within 7 days before starting the trial. It's best to discuss your specific medications with the trial team.

What data supports the effectiveness of the drug combination Evolocumab, Repatha, Ipilimumab, Yervoy, Nivolumab, Opdivo 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), improving survival compared to chemotherapy. This combination has shown durable and long-term benefits, especially in patients with certain tumor characteristics. ^{1 2 3 4 5}

Is the combination of Evolocumab and immunotherapy safe for humans?

The combination of nivolumab and ipilimumab, which are types of immunotherapy, has been studied in patients with lung cancer and generally shows a manageable safety profile. Some side effects are related to the immune system, like inflammation of the pituitary gland, intestines, and thyroid, but these can often be managed with medication. ^{3 5 6 7 8}

What makes the drug combination of Evolocumab, Ipilimumab, and Nivolumab unique for lung cancer treatment?

The combination of Ipilimumab and Nivolumab is unique because it uses two immune checkpoint inhibitors to enhance the body's immune response against lung cancer, offering a chemotherapy-free option for patients with advanced non-small cell lung cancer (NSCLC). This approach has shown durable and long-term efficacy compared to traditional chemotherapy. ^{1 3 9 10 11}

Research Team

Scott Antonia, MD

Principal Investigator

Duke University

Eligibility Criteria

This trial is for adults over 18 with advanced non-small cell lung cancer (NSCLC) who haven't had chemotherapy, radiation, or biologic therapy for their current metastatic condition. They should have a performance status indicating they can carry out daily activities with little to no assistance and must not have other active cancers or serious autoimmune diseases.

Inclusion Criteria

I do not have an autoimmune disease that prevents me from taking nivolumab.

Signed written informed consent including HIPAA according to institutional guidelines.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

You don't have a place where the doctor can take a small sample of tissue for testing before starting treatment.

I have a history of active tuberculosis.

My brain metastases are treated and controlled without high dose steroids.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive ipilimumab 1 mg/kg IV every 6 weeks and nivolumab 240 mg IV every 2 weeks, with or without evolocumab 140 mg SC every 2 weeks

4 weeks

Bi-weekly visits for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Treatment Details

Interventions

• Evolocumab
• Ipilimumab
• Nivolumab

Trial Overview The study tests the combination of Evolocumab with standard immunotherapy drugs Nivolumab and Ipilimumab in treatment-naïve patients. It aims to determine if this new mix can enhance the immune system's ability to fight lung tumors more effectively than existing treatments.

Participant Groups

Group I: ipilimumab/nivolumab/evolucumab Experimental Treatment 3 Interventions

Subjects receive ipilimumab 1 mg/kg IV every 6 weeks and nivolumab 240 mg IV every 2 weeks plus evolocumab 140 mg SC every 2 weeks

Group II: Ipilimumab/nivolumab Active Control 2 Interventions

Subjects receive ipilimumab 1 mg/kg IV every 6 weeks and nivolumab 240 mg IV every 2 weeks.

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?

Scott Antonia

Lead Sponsor

Trials

1

Recruited

40+

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 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 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]

Ipilimumab, a monoclonal antibody that enhances immune response against tumors, has shown promising results in treating non-small cell lung cancer (NSCLC) when combined with chemotherapy, leading to improved progression-free survival compared to chemotherapy alone.

The main side effects of ipilimumab are immune-related, such as hypophysitis and enterocolitis, but these can be managed with high-dose glucocorticoids and may even correlate with better tumor responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab: its potential in non-small cell lung cancer. Tomasini, P., Khobta, N., Greillier, L., et al.[2021]

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]

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, a PD-1 inhibitor, has shown significant efficacy and a favorable safety profile in treating non-small cell lung cancer (NSCLC), indicating its potential as a key immunotherapy option.

Despite its benefits, there are still important questions regarding patient selection, optimal treatment timing, management of side effects, and overcoming immunoresistance that need to be addressed for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focus on Nivolumab in NSCLC. Cortinovis, DL., Canova, S., Abbate, M., et al.[2021]

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 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]

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]

References

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

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

2. 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]

3. 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]

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

High TMB Predicts Immunotherapy Benefit. [2019]

5. England pubmed.ncbi.nlm.nih.gov

Ipilimumab: its potential in non-small cell lung cancer. [2021]

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. England pubmed.ncbi.nlm.nih.gov

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

8. Switzerland pubmed.ncbi.nlm.nih.gov

Focus on Nivolumab in NSCLC. [2021]

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

First line Immunotherapy for Non-Small Cell Lung Cancer. [2020]

10. 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]

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

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