Osimertinib + Ipilimumab for Lung Cancer

(Osi+Ipi Trial)

Overseen By Susan Sharry

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 4

Duration: 12 weeks

24 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a prospective, open label, interventional trial beginning with a phase 1b safety run-in followed by an expansion cohort.

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 must already be on a stable dose of osimertinib for at least 28 days. Some medications might be prohibited, and a washout period (time without taking certain medications) of at least 5 half-lives may be required before starting the trial.

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

Research shows that Ipilimumab, when combined with other drugs, has shown benefits in treating advanced non-small cell lung cancer (NSCLC). Specifically, Ipilimumab combined with Nivolumab has demonstrated improved survival rates compared to chemotherapy in patients with NSCLC. ^{1 2 3 4 5}

What is known about the safety of Ipilimumab and Osimertinib in humans?

Ipilimumab has been studied in various cancers and is known to cause side effects in most patients, which are usually mild to moderate but can be severe in some cases. Osimertinib, while not specifically mentioned in the provided studies, is generally used in lung cancer treatment and has a known safety profile from other research. ^{1 2 6 7 8}

How is the drug combination of Osimertinib and Ipilimumab unique for lung cancer treatment?

The combination of Osimertinib and Ipilimumab is unique because Osimertinib is a third-generation drug that specifically targets a common mutation (EGFR T790M) in lung cancer patients who have developed resistance to previous treatments, while Ipilimumab is an immune checkpoint inhibitor that helps the immune system attack cancer cells. This combination aims to address both the genetic mutation and enhance the immune response, offering a novel approach compared to standard treatments. ^{9 10 11 12 13}

Research Team

Matthew Gumbleton, MD

Principal Investigator

Huntsman Cancer Institute

Eligibility Criteria

This trial is for adults with metastatic non-small cell lung cancer (NSCLC) that has a specific EGFR mutation. Participants must have an ECOG Performance Status of ≤2, indicating they are ambulatory and capable of self-care. They should not have had prior EGFR targeted therapy or recent radiation, and cannot have uncontrolled brain metastases or autoimmune diseases. Effective contraception is required if there's a risk of conception.

Inclusion Criteria

I am post-menopausal or not pregnant.

My lung cancer is confirmed to be non-small cell and has spread.

My tumor has a specific EGFR mutation.

Exclusion Criteria

I am not on immunosuppressive medication, except for allowed steroids.

You have had a serious allergic reaction to the study drug or any of its ingredients in the past.

I do not have any serious recent illnesses or heart conditions that are not under control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Ipilimumab is administered every 3 weeks for a maximum of 4 doses, in combination with daily osimertinib until treatment discontinuation criteria are met

12 weeks

4 visits (in-person) for ipilimumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment, with survival follow-up for 5 years

5 years

Treatment Details

Interventions

• Ipilimumab
• Osimertinib

Trial Overview The study tests the combination of Osimertinib, a medication targeting certain mutations in NSCLC, with Ipilimumab, an immunotherapy drug. It starts with assessing safety (phase 1b), followed by evaluating how well this combination works in more patients (expansion cohort).

Participant Groups

Group I: Treatment: all patients Experimental Treatment 2 Interventions

Patients entering trial should be on stable dose of osi for ≥4 weeks. Patients will self-administer osi by mouth regardless of food once daily. Doses should be taken at about the same time every day (±6hrs) and recorded on the patient dosing diary. Doses missed outside of the dosing window should not be made up but patients should be instructed to take their next dose at their regularly scheduled time. Ipi will be administered at the assigned dose level every 21 days (±3days) for a max of 4 doses. Ipi must be infused using a volumetric pump over 90min (±10min) through an IV line. Upon completion of the ipilimumab regimen, patients will continue osimertinib daily until disease progression, initiation of new anti-cancer therapy, or death by any cause.

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 Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Findings from Research

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]

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 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]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

In a study of 59 patients with advanced melanoma, combining immune checkpoint inhibitors (ICI) with targeted therapies (TT) was found to be a safe treatment option, with only 12% experiencing severe adverse events.

For patients with BRAF wild-type melanoma, the combination of MEK inhibitors and anti-PD1 showed a high tumor control rate of 83% and a median progression-free survival of 7.1 months, suggesting potential effectiveness that warrants further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study. Huynh, S., Mortier, L., Dutriaux, C., et al.[2020]

Osimertinib is an oral medication specifically designed to target the EGFR T790M mutation in advanced non-small cell lung cancer (NSCLC), which helps overcome resistance to previous EGFR TKI therapies.

It received accelerated approval in the USA in November 2015 for patients with metastatic EGFR T790M mutation-positive NSCLC who have progressed after EGFR TKI treatment, and is currently undergoing further development for broader treatment applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib: First Global Approval. Greig, SL.[2022]

In a study of 47 patients with advanced non-small cell lung cancer (NSCLC) who had EGFR mutations, those who received osimertinib immediately after nivolumab treatment experienced a significantly higher rate of severe liver toxicity (57.1%) compared to those treated with other drugs before osimertinib (5.0%).

The findings suggest that administering osimertinib right after immune checkpoint inhibitors like nivolumab may increase the risk of serious adverse events, particularly hepatotoxicity, highlighting the need for careful treatment sequencing in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe hepatotoxicity due to osimertinib after nivolumab therapy in patients with non-small cell lung cancer harboring EGFR mutation. Yamaguchi, O., Kaira, K., Kawasaki, T., et al.[2022]

Osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, was effective for 2.5 years in a 78-year-old woman with T790M-positive lung cancer, but she eventually experienced disease progression due to the emergence of a new resistance mutation (C797G).

The case highlights the potential of liquid biopsy and next-generation sequencing to monitor clonal evolution and identify novel resistance mechanisms in patients treated with osimertinib, which could inform future treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. DE Carlo, E., Schiappacassi, M., Pelizzari, G., et al.[2022]

In a phase 2 study involving 210 patients with EGFR Thr790Met-positive non-small-cell lung cancer (NSCLC), osimertinib demonstrated significant efficacy, with 70% of patients achieving an objective response, including 3% with complete responses.

Osimertinib was found to have manageable side effects, although serious adverse events occurred in 25% of patients, with interstitial lung disease being the only fatal event possibly related to the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. Goss, G., Tsai, CM., Shepherd, FA., et al.[2022]

Osimertinib (AZD9291) is effective in prolonging survival for non-small cell lung cancer patients with EGFR mutations, but resistance to the drug is a common issue, prompting the need to explore resistance mechanisms.

In this study, AZD9291-resistant NSCLC cell lines were established, revealing significant changes in circular RNA (circRNA) expression profiles, which may contribute to drug resistance and could serve as potential targets for future gene therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. Chen, T., Luo, J., Gu, Y., et al.[2022]

References

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

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

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

Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. [2022]

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

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

4. 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]

5. Switzerland pubmed.ncbi.nlm.nih.gov

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

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

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. [2022]

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

Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study. [2020]

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

Osimertinib: First Global Approval. [2022]

10. Singapore pubmed.ncbi.nlm.nih.gov

Severe hepatotoxicity due to osimertinib after nivolumab therapy in patients with non-small cell lung cancer harboring EGFR mutation. [2022]

11. Greece pubmed.ncbi.nlm.nih.gov

Acquired EGFR C797G Mutation Detected by Liquid Biopsy as Resistance Mechanism After Treatment With Osimertinib: A Case Report. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study. [2022]

13. Singapore pubmed.ncbi.nlm.nih.gov

Comprehensive analysis of circular RNA profiling in AZD9291-resistant non-small cell lung cancer cell lines. [2022]