Targeted Radiation + Drug Therapy for Lung Cancer

Recruiting at 8 trial locations

Overseen By Daniel Gomez, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Memorial Sloan Kettering Cancer Center

Must be taking: Anti-PD-(L)1, Platinum chemotherapy

Must not be taking: Chronic steroids, Immune modulators

Disqualifiers: Active Hepatitis B, Hepatitis C, Immunosuppression, Autoimmune disease, 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

Compensation: Varies

Number of Visits: Unknown

Duration: Varies based on individual treatment plans

68 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to see whether adding liver stereotactic ablative radiotherapy/L-SABR to standard drug therapy is better than standard drug therapy alone for people with metastatic non-small cell lung cancer/NSCLC.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive drugs or have active autoimmune disease, you may not be eligible to participate.

What data supports the effectiveness of the drug therapy for lung cancer?

Research shows that combining PD-L1 inhibitors with chemotherapy is more effective for advanced non-small cell lung cancer (NSCLC) than using PD-L1 inhibitors alone. Additionally, combining PD-1 inhibitors with chemoradiotherapy improves survival rates for stage III NSCLC. ^{1 2 3 4 5}

Is the combination of targeted radiation and drug therapy for lung cancer safe?

The combination of PD-1/PD-L1 inhibitors with chemotherapy has been studied for lung cancer, showing that while it can improve outcomes, it also comes with potential side effects that need careful management. Common side effects include immune-related reactions and other adverse events, but these can often be managed effectively with proper medical guidance. ^{6 7 8 9 10}

How is the treatment of targeted radiation combined with drug therapy for lung cancer different from other treatments?

This treatment is unique because it combines targeted radiation with immunotherapy drugs that block PD-1/PD-L1, enhancing the body's immune response against cancer cells. This combination has shown to be more effective than using either treatment alone, as radiation can increase the expression of PD-L1 on tumor cells, making them more susceptible to the immunotherapy. ^{2 11 12 13 14}

Research Team

Paul B. Romesser

Principal Investigator

Memorial Sloan Kettering Cancer Center

Eligibility Criteria

This trial is for adults over 18 with stage IV NSCLC without certain genetic mutations, who have liver metastases and are starting standard immunotherapy +/- chemotherapy. They must have a decent performance status and normal liver function tests. People with active hepatitis, prior liver radiation, pregnancy/breastfeeding, ineffective contraception use or significant immunosuppression can't join.

Inclusion Criteria

I am over 18 years old.

I am starting standard immunotherapy with or without chemotherapy soon.

I have newly diagnosed lung cancer that has spread to my liver.

Exclusion Criteria

Patients who are pregnant or breastfeeding.

I am on long-term steroids or drugs for immune conditions.

I am not using any form of birth control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard drug therapy, with the experimental group also undergoing liver stereotactic ablative radiotherapy (L-SABR)

Varies based on individual treatment plans

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 4 years

Treatment Details

Interventions

• Anti-PD-(L)1 based immunotherapy
• L-SABR
• Platinum based chemotherapy

Trial Overview The study is testing if adding targeted radiation therapy (L-SABR) to the usual drug treatments (anti-PD-(L)1 based immunotherapy and platinum-based chemotherapy) provides better outcomes for patients with metastatic NSCLC that has spread to the liver.

Participant Groups

Group I: L-SABR Arm Experimental Treatment 3 Interventions

Participants randomized to the experimental arm will continue with standard of care treatment but will also undergo radiation simulation for L-SABR/Liver Stereotactic Ablative Radiation Therapy.

Group II: Control Arm Active Control 2 Interventions

Participants randomized to the control arm will be treated according to the standard of care.

Anti-PD-(L)1 based immunotherapy is already approved in United States, European Union, China for the following indications:

Approved in United States as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United States as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma

Approved in United States as Atezolizumab (Tecentriq) for:

• Urothelial carcinoma
• Non-small cell lung cancer
• Triple-negative breast cancer
• Hepatocellular carcinoma

Approved in United States as Avelumab (Bavencio) for:

• Merkel cell carcinoma
• Urothelial carcinoma
• Renal cell carcinoma

Approved in United States as Durvalumab (Imfinzi) for:

• Urothelial carcinoma
• Non-small cell lung cancer
• Biliary tract cancer

Approved in European Union as Pembrolizumab (Keytruda) for:

• Melanoma
• Non-small cell lung cancer
• Head and neck squamous cell carcinoma
• Urothelial carcinoma
• Colorectal cancer
• Hepatocellular carcinoma
• Renal cell carcinoma

Approved in European Union as Nivolumab (Opdivo) for:

• Melanoma
• Non-small cell lung cancer
• Renal cell carcinoma
• Hodgkin lymphoma
• Squamous cell carcinoma of the head and neck
• Urothelial carcinoma
• Colorectal cancer

Approved in European Union as Atezolizumab (Tecentriq) for:

• Urothelial carcinoma
• Non-small cell lung cancer
• Triple-negative breast cancer

Approved in European Union as Avelumab (Bavencio) for:

• Merkel cell carcinoma
• Urothelial carcinoma
• Renal cell carcinoma

Approved in European Union as Durvalumab (Imfinzi) for:

• Urothelial carcinoma
• Non-small cell lung cancer

Approved in China as Camrelizumab (SHR-1210) for:

• Hodgkin lymphoma
• Non-small cell lung cancer

Approved in China as Sintilimab (IBI308) for:

• Non-small cell lung cancer

Who Is Running the Clinical Trial?

Memorial Sloan Kettering Cancer Center

Lead Sponsor

Trials

1,998

Recruited

602,000+

Findings from Research

Combining chemotherapy with a PD-(L)1 inhibitor for first-line treatment of advanced non-small cell lung cancer (NSCLC) significantly reduces the rates of severe immune-related adverse events (irAEs), such as pneumonitis and endocrine reactions, compared to using the PD-(L)1 inhibitor alone.

The overall rate of irAEs was lower with the combination treatment (7.1% for grade 3 or higher) compared to the PD-(L)1 inhibitor alone (10.6%), suggesting that this combination not only enhances treatment efficacy but also improves safety by minimizing serious side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune-related adverse events of a PD-L1 inhibitor plus chemotherapy versus a PD-L1 inhibitor alone in first-line treatment for advanced non-small cell lung cancer: A meta-analysis of randomized control trials. Wang, M., Liang, H., Wang, W., et al.[2021]

The combination of PD-1 inhibition with chemoradiotherapy for stage III non-small cell lung cancer (NSCLC) was found to be safe and tolerable, with no dose-limiting toxic effects observed in a study of 21 patients over a median follow-up of 16 months.

Patients receiving at least one dose of pembrolizumab showed a promising median progression-free survival (PFS) of 18.7 months, with 69.7% of patients remaining progression-free at 12 months, indicating potential efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial. Jabbour, SK., Berman, AT., Decker, RH., et al.[2021]

In a study of 44 advanced non-small cell lung cancer (NSCLC) patients, high levels of the cytokine IL-8 were found to be significantly associated with poor prognosis in those treated with hypofractionated radiotherapy (HFRT) combined with PD-1 blockade.

IL-8 was shown to impair immune memory function by increasing apoptosis in certain T cell subsets, suggesting it could serve as a valuable biomarker for evaluating treatment efficacy in advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade. Kang, P., Liu, D., Li, L., et al.[2023]

In a study of 321 metastatic non-small cell lung cancer (NSCLC) patients, those receiving PD-1/PD-L1 inhibitors combined with radiotherapy had a median overall survival of 22.8 months, compared to 16.6 months for those who did not receive radiotherapy, indicating a significant survival benefit from the combination treatment.

The combination therapy also resulted in a higher disease control rate and similar rates of adverse events compared to patients who only received immunotherapy, suggesting that this approach is both effective and well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer. Zhou, ZC., Chen, KY., Li, N., et al.[2022]

Combining anti-PD-L1 immunotherapy with radiation therapy has shown promising results in increasing progression-free survival (PFS) and overall survival (OS) in patients with advanced melanoma and metastatic non-small cell lung cancer (NSCLC), based on several preclinical studies and two early clinical trials.

Low doses of radiation enhance T-cell activity, which is further boosted by anti-PD-L1 therapy, suggesting that this combination can effectively overcome the immune suppression caused by PD-L1, leading to better tumor control and regression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation Therapy Plus Anti-Programmed Death Ligand 1 Immunotherapy: A Review on Overall Survival. Krcik, EM.[2019]

Immune checkpoint antibodies targeting the PD-1/PD-L1 pathway have shown significant antitumor activity and have been approved for use as single-agent therapies in metastatic malignant melanoma and nonsmall-cell lung cancer.

Understanding the toxicities associated with PD-1/PD-L1 blockade and having effective management strategies is crucial for maximizing both the safety and efficacy of these treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Naidoo, J., Page, DB., Li, BT., et al.[2023]

Combining anti-PD-1 or anti-PD-L1 immunotherapy with platinum-based chemotherapy significantly improves outcomes for patients with advanced non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), based on a systematic review of 9 randomized studies.

While immune-mediated adverse events (AEs) and infusion reactions were more common with the combination therapy, there were no unexpected toxicities, indicating that the treatment is generally safe and manageable with appropriate monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer. Hoffner, B., Leighl, NB., Davies, M.[2020]

This case study presents the first successful treatment of enteritis related to the PD-1 inhibitor tislelizumab using adalimumab in an advanced lung cancer patient, highlighting a potential new management strategy for this adverse reaction.

Adalimumab was administered at a dose of 40mg every two weeks for three doses, effectively alleviating symptoms and allowing the patient to continue their cancer treatment without significant diarrhea, suggesting its efficacy when glucocorticoids are insufficient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tislelizumab-related enteritis successfully treated with adalimumab: A case report. Chen, N., Qian, MJ., Zhang, RH., et al.[2022]

Monoclonal antibodies targeting PD-1/PD-L1 have shown significant efficacy in treating non-small cell lung cancer, especially when used as first-line or second-line therapies, and their combination with other treatments like chemotherapy enhances effectiveness.

Despite their benefits, anti-PD-1/PD-L1 therapies can cause notable adverse effects, making it crucial to understand and manage these toxicities to ensure safe and effective clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Effects of Anti-PD-1/PD-L1 Therapy in Non-small Cell Lung Cancer. Su, C., Wang, H., Liu, Y., et al.[2020]

In a meta-analysis of 18 studies involving 5,649 patients with non-small cell lung cancer, first-line therapy using PD-1/PD-L1 inhibitors showed a significantly higher risk of treatment-related adverse events (trAEs) and immune-related adverse events (irAEs) compared to subsequent therapies, indicating a need for careful monitoring in initial treatments.

Despite the higher incidence of adverse events in first-line therapy, the types of trAEs and irAEs were largely similar across different therapy lines, suggesting that while the severity may differ, the overall spectrum of side effects remains consistent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety of first and subsequent lines of PD-1/PD-L1 inhibitors monotherapy in non-small cell lung cancer patients: a meta-analysis. Yang, Y., Pang, P., Xie, Z., et al.[2022]

Combining radiotherapy with immune checkpoint inhibitors targeting PD-1/PD-L1 significantly improves treatment outcomes for patients with non-small-cell lung cancer (NSCLC), as evidenced by better prognoses in patients who received radiotherapy before anti-PD-1 treatment.

Radiotherapy appears to increase PD-L1 expression on tumor cells, enhancing the effectiveness of PD-L1 blockade, which suggests a synergistic mechanism that could be further explored in ongoing clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non-Small-cell Lung Cancer: A Mini-review. Takamori, S., Toyokawa, G., Takada, K., et al.[2019]

Recent advancements in immunotherapy, particularly immune checkpoint inhibitors, have shown promising results in treating metastatic non-small-cell lung cancer (NSCLC), with some patients experiencing robust and durable responses despite overall response rates being below 20%.

Combining immunotherapy with radiotherapy may enhance treatment efficacy by leveraging the immunomodulatory effects of radiation, although more prospective clinical trials are needed to fully evaluate this strategy in various stages of NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Trials Integrating Immunotherapy and Radiation for Non-Small-Cell Lung Cancer. Daly, ME., Monjazeb, AM., Kelly, K.[2016]

Combining ionizing radiation therapy (RT) with PD-1/PD-L1 inhibitors has shown promise in enhancing the immune response against tumors, making it a compelling treatment strategy for various cancers.

The review discusses both preclinical and clinical data supporting the safety and efficacy of this combination, emphasizing the need for careful clinical trial design to optimize outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. Gong, J., Le, TQ., Massarelli, E., et al.[2023]

In a study using C57BL/6 mice, combining radiotherapy with anti-PD-1 antibody treatment significantly increased pulmonary toxicity, as indicated by higher histological scores for radiation-induced lung injury (RILI).

The research found that the anti-PD-1 treatment enhanced IL-17A production from γδ T cells, leading to increased inflammation and neutrophilic infiltration in the lungs, suggesting that PD-1 plays a role in modulating lung injury during concurrent immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PD-1 restrains IL-17A production from γδ T cells to modulate acute radiation-induced lung injury. Sheng, Y., Chen, K., Jiang, W., et al.[2022]

References

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

Immune-related adverse events of a PD-L1 inhibitor plus chemotherapy versus a PD-L1 inhibitor alone in first-line treatment for advanced non-small cell lung cancer: A meta-analysis of randomized control trials. [2021]

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

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer: A Nonrandomized Controlled Trial. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Interleukin 8 in plasma is an efficacy marker for advanced non-small cell lung cancer treated with hypofractionated radiotherapy and PD-1 blockade. [2023]

4. Singapore pubmed.ncbi.nlm.nih.gov

Real-world utilization of PD-1/PD-L1 inhibitors with palliative radiotherapy in patients with metastatic non-small cell lung cancer. [2022]

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

Radiation Therapy Plus Anti-Programmed Death Ligand 1 Immunotherapy: A Review on Overall Survival. [2019]

6. England pubmed.ncbi.nlm.nih.gov

Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. [2023]

7. Netherlands pubmed.ncbi.nlm.nih.gov

Toxicity management with combination chemotherapy and programmed death 1/programmed death ligand 1 inhibitor therapy in advanced lung cancer. [2020]

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

Tislelizumab-related enteritis successfully treated with adalimumab: A case report. [2022]

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

Adverse Effects of Anti-PD-1/PD-L1 Therapy in Non-small Cell Lung Cancer. [2020]

10. China pubmed.ncbi.nlm.nih.gov

The safety of first and subsequent lines of PD-1/PD-L1 inhibitors monotherapy in non-small cell lung cancer patients: a meta-analysis. [2022]

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

Combination Therapy of Radiotherapy and Anti-PD-1/PD-L1 Treatment in Non-Small-cell Lung Cancer: A Mini-review. [2019]

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

Clinical Trials Integrating Immunotherapy and Radiation for Non-Small-Cell Lung Cancer. [2016]

13. England pubmed.ncbi.nlm.nih.gov

Radiation therapy and PD-1/PD-L1 blockade: the clinical development of an evolving anticancer combination. [2023]

14. China pubmed.ncbi.nlm.nih.gov

PD-1 restrains IL-17A production from γδ T cells to modulate acute radiation-induced lung injury. [2022]