Osimertinib + Ipilimumab for Lung Cancer

(Osi+Ipi Trial)

Overseen By Susan Sharry

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Utah

Must be taking: Osimertinib

Must not be taking: Immunosuppressants

Disqualifiers: Autoimmune disease, Cardiac disease, others

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with metastatic non-small cell lung cancer (NSCLC). It combines two drugs, osimertinib (a daily pill) and ipilimumab (an IV infusion every three weeks), to assess their combined effectiveness. Suitable candidates for this trial are those who have been on a stable dose of osimertinib for at least four weeks without cancer progression. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research has shown that osimertinib is usually well-tolerated for treating advanced non-small cell lung cancer. In studies, fewer than 10% of patients experienced side effects such as hair loss and nosebleeds. However, some reported more serious issues like lung disease. Conversely, ipilimumab, when combined with other treatments, can cause immune-related side effects. These can be severe, particularly in patients who have recently undergone similar treatments. This trial is in an early stage, so researchers are still gathering information on the safety of combining these two drugs for participants. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining Osimertinib and Ipilimumab for lung cancer because this duo could offer a fresh approach to treatment. Unlike traditional treatments like chemotherapy, which broadly attack rapidly dividing cells, Osimertinib specifically targets a mutation in the EGFR gene found in some lung cancers. Adding Ipilimumab, an immune checkpoint inhibitor, may enhance the immune system's ability to fight cancer by unleashing T-cells. This combination aims to not only directly target cancer cells but also boost the body's natural defenses, potentially leading to more effective and lasting results.

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

Research has shown that osimertinib works well for certain lung cancers. Studies found that patients with specific genetic markers (EGFR mutations) who took osimertinib had an 88% chance of living for 5 years, which is higher than those who did not take it. In this trial, all participants will receive osimertinib. Meanwhile, ipilimumab, when used with another treatment, has also shown promising results. In advanced lung cancer, the 2-year survival rate with ipilimumab combinations was 40.4%, which is better than typical chemotherapy results. Participants in this trial will also receive ipilimumab alongside osimertinib. These treatments have shown good potential in helping lung cancer patients live longer. ^{6 7 8 9 10}

Who Is on the Research Team?

Matthew Gumbleton, MD

Principal Investigator

Huntsman Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

Citations

1.

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 ...

2.

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, ...

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa1910231

Nivolumab plus Ipilimumab in Advanced Non–Small-Cell ...

The 2-year overall survival rates were 40.4% for nivolumab plus ipilimumab and 23.0% for chemotherapy. Figure 2. Overall Survival in Patients with a Tumor PD-L1 ...

4.

ejcancer.com

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

Five-year outcomes with first-line nivolumab plus ...

Patients who discontinued nivolumab plus ipilimumab with chemotherapy due to treatment-related adverse events had a 5-year OS rate of 37%. Five- ...

5.

sciencedirect.com

sciencedirect.com/science/article/pii/S1525730425000099

Comparative Effectiveness of Nivolumab and Ipilimumab ...

This study aims to assess the real-world outcomes of nivolumab plus ipilimumab combined with chemotherapy in mNSCLC patients with < 1% PD-L1 expression and to ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11900531/

Real-World Data on Osimertinib-Associated Cardiac Toxicity

Lung cancer leads the global statistics for cancer-related deaths, surpassing the combined mortality rates of breast, prostate, colorectal, and ...

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC7360149/

Severe immune-related adverse events are common with ...

PD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L)1 blockade.

8.

tagrissohcp.com

tagrissohcp.com/metastatic/flaura/safety-side-effects.html

Safety Profile of TAGRISSO® (osimertinib) for Metastatic ...

Clinically relevant adverse reactions in FLAURA in <10% of patients receiving TAGRISSO were alopecia (7%), epistaxis (6%), interstitial lung disease (3.9%), ...

9.

lungcancerstoday.com

lungcancerstoday.com/post/study-provides-safety-data-from-laura-trial-of-osimertinib-in-egfr-mutated-nsclc

Safety Data From LAURA Trial of Osimertinib in EGFR- ...

Osimertinib demonstrated a manageable safety profile for the treatment of stage III epidermal growth factor (EGFR)-mutated advanced non-small cell lung cancer ...

10.

sciencedirect.com

sciencedirect.com/science/article/pii/S1040842824000386

The study of primary and acquired resistance to first-line ...

Osimertinib is currently the common first-line therapy in EGFR-mutated non-small cell lung cancer patients. •. Understanding primary and acquired resistance ...