Combination Therapy for Non-Small Cell Lung Cancer

Overseen By BrUOG

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brown University

Disqualifiers: Thoracic radiation, 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: 3

Duration: 7-9 weeks

25 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with certain types of non-small cell lung cancer (NSCLC) that can be surgically removed. The study tests a mix of two drugs, ipilimumab (Yervoy) and nivolumab (Opdivo), both immunotherapy drugs, along with stereotactic body radiotherapy (SBRT), a type of focused radiation therapy, to assess their combined effectiveness before surgery. Researchers aim to determine if this approach can effectively shrink tumors and identify its side effects. Suitable candidates have been diagnosed with stage IB - III non-small cell lung cancer that is operable and have not received previous chest radiation. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking cancer treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor to get personalized advice.

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

Research has shown that combining the drugs ipilimumab and nivolumab with stereotactic body radiation therapy (SBRT) has been studied before. These studies found that this combination is generally well-tolerated. Specifically, past research involving patients with non-small cell lung cancer reported no major safety issues. Some side effects, such as tiredness and skin reactions, occurred but were mostly mild to moderate.

The safety of this combination remains under study, but early results suggest it is manageable for patients. As this trial is in an early phase, researchers are closely monitoring participants to ensure their safety. Prospective participants should discuss potential risks and benefits with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this combination treatment for non-small cell lung cancer because it brings together immunotherapy and advanced radiotherapy techniques. Unlike traditional chemotherapy, which attacks cancer cells directly, Ipilimumab and Nivolumab are immunotherapy drugs that help your immune system recognize and fight cancer cells more effectively. Additionally, Stereotactic Body Radiotherapy (SBRT) delivers highly precise radiation doses in just a few sessions, potentially reducing side effects and making treatment faster. This combination has the potential to enhance the body's natural defenses while efficiently targeting tumors, offering hope for improved outcomes compared to existing treatments.

What evidence suggests that this combination therapy might be an effective treatment for non-small cell lung cancer?

This trial will evaluate the combination of ipilimumab, nivolumab, and stereotactic body radiation therapy (SBRT) for treating non-small cell lung cancer (NSCLC). Studies have shown that using ipilimumab and nivolumab with SBRT can effectively treat NSCLC. Research indicates that this combination can significantly improve patient outcomes, including longer survival rates. This treatment has shown promise in shrinking tumors and enhancing the immune system's ability to fight cancer. A key benefit is its ability to target cancer cells while sparing healthy tissue. Initial findings suggest this approach can lead to major reductions in cancer cells found in surgical tissue. Overall, evidence supports the potential effectiveness of this combination therapy for NSCLC. ^{1 2 3 4 6}

Who Is on the Research Team?

Christopher G Azzoli, MD

Principal Investigator

Brown University

Thomas A DiPetrillo, MD

Principal Investigator

Brown University

Are You a Good Fit for This Trial?

This trial is for adults over 18 with operable stage IB-IIIB non-small cell lung cancer (NSCLC) who can undergo surgery. They must have good organ function, be able to tolerate lung resection, and not be pregnant or nursing. Participants need an ECOG Performance Status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory.

Inclusion Criteria

I am postmenopausal or not pregnant if premenopausal.

Nonpregnant and non-nursing

My lung cancer diagnosis was confirmed through a lab test.

Exclusion Criteria

I have never had radiation therapy to the chest area.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pre-operative ipilimumab, nivolumab, and low-dose stereotactic body radiation therapy (SBRT) concurrently

7-9 weeks

3 visits (in-person) for infusions

Surgery

Participants undergo surgery to evaluate pathologic response

1 week

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Regular follow-up visits

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• Nivolumab
• Stereotactic Body Radiotherapy

Trial Overview The study tests a combination of pre-operative treatments: ipilimumab + nivolumab immunotherapies with low-dose stereotactic body radiation therapy (SBRT). It aims to see how well the cancer responds before surgery. The main goal is to measure the pathologic response after treatment.

How Is the Trial Designed?

Group I: Protocol Therapy Experimental Treatment 3 Interventions

Ipilimumab: 1mg/kg IV day 1. Nivolumab: 3mg/kg IV days 1, 15, 29. SBRT delivered as 1-2 fractions to the gross primary tumor and nodal disease following day 1 infusion and completed by day 3 (7Gy x 1; 4Gy x 2).

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?

Brown University

Lead Sponsor

Trials

480

Recruited

724,000+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

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 phase II trial involving 106 patients with metastatic cancers, the combination of ipilimumab and stereotactic ablative radiotherapy (SABR) showed promising long-term survival rates, with 5-year overall survival rates of 15%.

Patients receiving SABR targeting lung metastases had significantly better overall survival (18.67 months) and progression-free survival (6.87 months) compared to those with liver metastases, highlighting the importance of tumor location in treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease. He, K., Hong, DS., Tang, C., et al.[2023]

In a randomized phase 2 trial involving 156 participants, combining stereotactic ablative radiotherapy (SABR) with immunotherapy (I-SABR) significantly improved 4-year event-free survival from 53% to 77% for early-stage non-small-cell lung cancer (NSCLC), indicating a promising treatment strategy.

The I-SABR approach had manageable toxicity, with only 15% of participants experiencing grade 3 immunological adverse events related to nivolumab, and no severe adverse events associated with SABR, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial. Chang, JY., Lin, SH., Dong, W., et al.[2023]

The combination of stereotactic ablative radiotherapy (SABR) and immune checkpoint inhibitors (ICIs) shows promising safety and efficacy in treating oligometastatic non-small-cell lung cancer (NSCLC), with recent trials indicating improved progression-free and overall survival.

Ongoing clinical trials are focused on validating the effectiveness and safety of this combined treatment approach, as well as determining the best sequence for administering SABR and ICIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation and immune checkpoint inhibitors in the treatment of oligometastatic non-small-cell lung cancer: a practical review of rationale, recent data, and research questions. Zayed, S., Louie, AV., Breadner, DA., et al.[2023]

Stereotactic ablative radiation therapy (SABR) for lung oligometastases shows promising safety and efficacy, with a 24-month overall survival rate of 74.6% and minimal toxicity, as only one significant adverse event was reported among 77 patients studied over an average follow-up of 22 months.

Colorectal metastases exhibited a notably higher local failure rate compared to other types of tumors, suggesting they may be more resistant to SABR, indicating a need for potential dose escalation strategies for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Colorectal Histology Is Associated With an Increased Risk of Local Failure in Lung Metastases Treated With Stereotactic Ablative Radiation Therapy. Binkley, MS., Trakul, N., Jacobs, LR., et al.[2022]

Stereotactic ablative radiotherapy (SABR) may enhance the immune response in patients with non-small cell lung cancer (NSCLC) when combined with immune checkpoint inhibitors, potentially improving treatment outcomes.

Recent studies, including prospective trials, suggest that this combination therapy could lead to better survival rates compared to traditional palliative radiotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation and immunotherapy combinations in non-small cell lung cancer. Azghadi, S., Daly, ME.[2021]

The combination of stereotactic ablative radiotherapy (SABR) and ipilimumab was found to be safe, with only 2 out of 35 patients experiencing dose-limiting toxicity, and 34% experiencing grade 3 toxicity.

Clinical benefits were observed in 23% of patients, with increased peripheral CD8+ T cells and other immune markers correlating with positive outcomes, particularly after liver irradiation, which enhanced T-cell activation more than lung irradiation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells. Tang, C., Welsh, JW., de Groot, P., et al.[2022]

In a study of 40 patients with central and ultracentral non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR), those with ultracentral tumors experienced worse overall survival (OS) and progression-free survival (PFS) compared to those with central tumors, indicating a need for careful consideration in treatment planning.

The incidence of severe treatment-related toxicities (grade ≥3) was higher in the ultracentral group, with 12.5% of patients experiencing significant complications, including severe bronchial obstruction and esophageal perforation, highlighting the potential risks associated with SABR in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term outcomes in patients with central and ultracentral non-small cell lung cancer treated with stereotactic body radiotherapy: single-institution experience. Song, X., Zhao, L., Jiang, N., et al.[2023]

In a phase 1 trial involving 37 treatment-naive patients with stage IV NSCLC, combining concurrent stereotactic body radiotherapy (SBRT) with nivolumab and ipilimumab showed no dose-limiting toxicities, indicating a favorable safety profile for this multimodal treatment approach.

The study reported a median progression-free survival of 5.8 months and demonstrated that concurrent therapy was well tolerated, suggesting that this combination could effectively control metastasis in widely metastatic patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 1 Trial of Concurrent or Sequential Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy in Patients With Stage IV NSCLC Study. Bestvina, CM., Pointer, KB., Karrison, T., et al.[2022]

Stereotactic ablative radiotherapy (SABR) is the standard treatment for early-stage non-small-cell lung cancer that cannot be surgically removed, showing high rates of tumor control but facing challenges with regional and distant tumor failures.

Current research is exploring the use of immune checkpoint inhibitors as a systemic therapy option for patients treated with SABR, aiming to provide effective treatment with fewer side effects compared to traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inoperable Early-Stage Non-Small-Cell Lung Cancer: Stereotactic Ablative Radiotherapy and Rationale for Systemic Therapy. Daly, ME.[2022]

The combination of immune checkpoint inhibitors (ICI) and stereotactic ablative radiotherapy (SABR) in treating non-small-cell lung cancer (NSCLC) shows promising efficacy, with local control rates of 71% and distant/abscopal response rates of 41% based on a review of 18 studies involving 1736 patients.

This combination therapy maintains a good safety profile, with toxicity rates similar to those seen with ICI treatment alone, while also improving progression-free survival (PFS) to an average of 4.6 months and overall survival (OS) to 12.4 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Stereotactic Ablative Radiotherapy Combined with Immune Checkpoint Inhibitors Reboots the Immune Response Assisted by Immunotherapy in Metastatic Lung Cancer: A Systematic Review. Chicas-Sett, R., Morales-Orue, I., Castilla-Martinez, J., et al.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11474930/

Phase I/II study of BMS-986156 with ipilimumab or nivolumab ... Herein we describe the results of the safety and efficacy of BMS-986156+ipilimumab or nivolumab with/without stereotactic ablative radiotherapy ...

2. jto.org jto.org/article/S1556-0864(21)02441-2/fulltext

A Phase 1 Trial of Concurrent or Sequential Ipilimumab ... This randomized phase 1 trial combined nivolumab and ipilimumab with sequential or concurrent multisite SBRT in patients with stage IV NSCLC to ...

3. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301623003255

Safety and Efficacy Results From iSABR, a Phase 1 Study ... We are the first to report prospective data to support an acceptable per protocol toxicity profile with combination lung SABR and durvalumab in medically ...

4. aacrjournals.org aacrjournals.org/clincancerres/article/23/6/1388/80598/Ipilimumab-with-Stereotactic-Ablative-Radiation

Ipilimumab with Stereotactic Ablative Radiation Therapy In conclusion, we demonstrate that combination ipilimumab and high-dose SABR is tolerable and has encouraging clinical benefit outside the radiation field, that ...

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.2017.35.15_suppl.TPS9097

NIVORAD: A randomised phase 2 trial of nivolumab and ... Background: Recent data has demonstrated improvements in overall survival in patients with advanced non-small cell lung cancer (NSCLC) treated ...

6. digitalcommons.wustl.edu digitalcommons.wustl.edu/cgi/viewcontent.cgi?article=9409&context=open_access_pubs

Combining stereotactic body radiation therapy with ... Stereotactic body radiation therapy (SBRT) combines conformal radiation dose-shaping, tumor motion management, and on-board daily imaging to ...