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

Trial Summary

What is the purpose of this trial?

This single-arm phase 2 study will enroll patients with resectable and operable stage IB - III non-small cell lung cancer and treat them with pre-operative ipilimumab + nivolumab plus low-dose stereotactic body radiation therapy (SBRT) delivered concurrently. Only patients who proceed to surgery will be evaluable for the primary endpoint. The primary efficacy outcome measurement will be pathologic response (including Major Pathologic Response (MPR), and Complete Pathologic Response (CPR)). Secondary outcome measures include safety, and exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A two-stage design will stop the study if fewer than 3 of the first 9 evaluable patients do not achieve MPR. An early stopping rule for safety will stop the study if more than 12 patients are enrolled to find the first 9 evaluable patients.

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.

What data supports the effectiveness of the treatment combination of Ipilimumab, Yervoy, Nivolumab, Opdivo, and Stereotactic Body Radiotherapy for non-small cell lung cancer?

Research shows that combining stereotactic ablative radiotherapy (SABR) with immune checkpoint inhibitors (like Ipilimumab and Nivolumab) is safe and effective for treating non-small-cell lung cancer, with promising results in survival rates. This combination treatment is being actively studied for its potential to improve outcomes in patients with this type of cancer. ^{1 2 3 4 5}

Is the combination therapy of Ipilimumab and Stereotactic Ablative Radiotherapy (SABR) safe for humans?

The combination of Ipilimumab and Stereotactic Ablative Radiotherapy (SABR) has been shown to be generally safe in humans, with low toxicity levels reported in studies for metastatic cancers. Some patients experienced mild to moderate side effects, but overall, the treatment has a good safety profile. ^{1 6 7 8 9}

How is the combination treatment of Ipilimumab, Nivolumab, and Stereotactic Body Radiotherapy unique for non-small cell lung cancer?

This treatment is unique because it combines immune checkpoint inhibitors (Ipilimumab and Nivolumab) with high-dose, targeted radiotherapy (Stereotactic Body Radiotherapy) to potentially enhance the immune response against cancer, offering a promising approach for patients with advanced non-small cell lung cancer. ^{1 2 4 10 11}

Research Team

Christopher G Azzoli, MD

Principal Investigator

Brown University

Thomas A DiPetrillo, MD

Principal Investigator

Brown University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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]

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]

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 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]

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]

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]

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]

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]

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]

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Five-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease. [2023]

2. England 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. [2023]

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

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

4. England pubmed.ncbi.nlm.nih.gov

Radiation and immunotherapy combinations in non-small cell lung cancer. [2021]

5. England 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. [2023]

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

Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells. [2022]

7. Switzerland 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. [2020]

8. United States 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. [2023]

9. United States 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. [2022]

10. United States 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. [2022]

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

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