Radiation + Immunotherapy for Non-Small Cell Lung Cancer

Overseen By John Villano, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: John L. Villano, MD, PhD

Must be taking: Immune checkpoint inhibitors

Disqualifiers: Active infection, Uncontrolled illness, 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: Unknown

Duration: 2 weeks

76 Participants Needed

Trial Summary

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have had chemotherapy or radiation within 21 days before starting the trial treatment.

What data supports the effectiveness of the treatment combining radiation and immunotherapy for non-small cell lung cancer?

Research shows that combining pembrolizumab (an immunotherapy drug) with radiotherapy can enhance the body's immune response against tumors in non-small cell lung cancer. Additionally, pembrolizumab has been FDA-approved for improving survival in patients with metastatic non-small cell lung cancer, indicating its effectiveness in treating this condition. ^{1 2 3 4 5}

Is the combination of radiation and immunotherapy safe for treating non-small cell lung cancer?

Pembrolizumab, an immunotherapy drug, has been used in various cancer treatments and is generally considered less toxic than traditional chemotherapy. However, it can cause side effects like pneumonitis (lung inflammation), which occurs in 1%-5% of patients. Common side effects include fatigue, cough, nausea, and rash, but the benefits often outweigh these risks in serious conditions. ^{1 5 6 7 8}

How is the treatment of radiation combined with Atezolizumab, Nivolumab, and Pembrolizumab unique for non-small cell lung cancer?

This treatment is unique because it combines radiation with immunotherapy drugs (Atezolizumab, Nivolumab, and Pembrolizumab) to potentially enhance the body's immune response against cancer, which is different from standard treatments that typically involve chemotherapy and radiation without immunotherapy. ^{2 3 9 10 11}

What is the purpose of this trial?

This study proposes to treat metastatic non-small cell lung cancer (NSCLC) and head/neck squamous cell cancer (HNSCC) patients who are already initiating an immune checkpoint inhibitor (such as Nivolumab, Atezolizumab or Pembrolizumab) for disease treatment as per FDA approved guidelines. In these patients we will deliver a short-course radiation to a single systemic (non-CNS) site within 14 days of receiving the first dose of immune checkpoint inhibitors. This sequence allows radiation to release tumor antigens from immune inaccessible areas such as necrotic tumor or low perfusion to provide a robust anti-tumor immune response with immune checkpoint inhibitors. The primary objective is to assess six-month progression free survival (PFS) compared to historical control.

Research Team

John Villano, MD, PhD

Principal Investigator

University of Kentucky

Eligibility Criteria

Adults with advanced non-small cell lung cancer or head/neck squamous cell carcinoma, who can have radiation therapy and are starting immune checkpoint inhibitors. They must not be pregnant, agree to use contraception, and have no major surgery within 14 days before the trial. No other cancers unless cured over 3 years ago.

Inclusion Criteria

AST and ALT if no hepatic metastasis ≤ 2.5 times x ULN

My liver enzymes are not more than 5 times the normal limit.

Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

I have been treated with immune checkpoint inhibitors before.

I do not have a serious infection worse than a moderate level.

I haven't had major surgery or significant injury in the last 14 days, or minor non-brain surgery in the last 3 days.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive immune checkpoint inhibitors and radiation therapy within 14 days of the first dose

2 weeks

Multiple visits for radiation and immune therapy administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

Regular follow-up visits to assess progression-free survival

Treatment Details

Interventions

• Atezolizumab
• Nivolumab
• Pembrolizumab
• Radiation Therapy

Trial Overview The study tests if a short course of radiation at a single site enhances the effect of FDA-approved immune checkpoint inhibitors like Nivolumab in patients with metastatic lung or head/neck cancer by improving six-month progression free survival rates.

Participant Groups

Group I: Immune Checkpoint Inhibitor + Radiation Experimental Treatment 2 Interventions

Immune checkpoint inhibitor (Nivolumab OR Pembrolizumab OR Atezolizumab) PLUS Radiation Therapy (Stereotactic Body Radiation Therapy OR fractionated radiation therapy)

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

John L. Villano, MD, PhD

Lead Sponsor

Trials

3

Recruited

90+

Findings from Research

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a study of 98 patients with advanced non-small-cell lung cancer (NSCLC), those who had previously received radiotherapy experienced significantly longer progression-free survival (4.4 months) and overall survival (10.7 months) when treated with pembrolizumab compared to those without prior radiotherapy.

The safety profile was acceptable, with similar rates of severe pulmonary toxicity between patients who had and had not received thoracic radiotherapy, suggesting that combining radiotherapy with pembrolizumab may be a beneficial treatment strategy for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. Shaverdian, N., Lisberg, AE., Bornazyan, K., et al.[2022]

In a pooled analysis of 148 patients with metastatic non-small-cell lung cancer, adding radiotherapy to pembrolizumab significantly improved the best out-of-field response rate (41.7% vs 19.7%) and best disease control rate (65.3% vs 43.4%), indicating enhanced efficacy of the combination treatment.

Patients receiving the combination therapy also experienced longer median progression-free survival (9.0 months vs 4.4 months) and overall survival (19.2 months vs 8.7 months) compared to those receiving pembrolizumab alone, with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. Theelen, WSME., Chen, D., Verma, V., et al.[2021]

In a phase I study involving 20 patients with early-stage non-small cell lung cancer, the combination of stereotactic ablative radiotherapy (SABR) and the immune-checkpoint inhibitor atezolizumab was well tolerated, with the maximum tolerated dose established at 1200 mg.

Early efficacy signals were observed, with 17% of patients showing responses after two cycles of atezolizumab before starting SABR, and specific biomarkers indicating T cell activation were found to be predictive of treatment benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial. Monjazeb, AM., Daly, ME., Luxardi, G., et al.[2023]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

In a trial involving 25 patients with locally advanced non-small-cell lung cancer (LA-NSCLC) and a PD-L1 tumor proportion score of ≥50%, the combination of pembrolizumab and risk-adapted radiotherapy achieved a 1-year progression-free survival rate of 76%, indicating strong efficacy without the use of chemotherapy.

The treatment was well-tolerated, with only 8% of patients experiencing grade 3 adverse events like colitis and esophagitis, and no higher-grade treatment-related adverse events reported, suggesting a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective Personalized Radioimmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial. Ohri, N., Jolly, S., Cooper, BT., et al.[2023]

A case study of a 52-year-old man with HIV and lung adenocarcinoma showed that combining pembrolizumab with stereotactic body radiotherapy led to serious immune-related adverse events, including massive pericardial effusion and interstitial pneumonia.

Despite initial treatment with pembrolizumab and radiotherapy, the patient's condition worsened, highlighting the need for caution and further clinical trials to assess the safety and efficacy of this combination therapy in HIV-infected patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with stereotactic body radiotherapy in a patient with human immunodeficiency virus and advanced non-small cell lung cancer: a case report. Li, D., He, C., Xia, Y., et al.[2018]

In a phase 2 trial involving 90 patients with non-small-cell lung cancer resistant to PD-1/PD-L1 therapy, the combination of PD-L1 (durvalumab) and CTLA-4 (tremelimumab) with radiotherapy did not show improved overall response rates compared to the therapy alone, leading to the trial's early termination due to futility.

The most common serious adverse events were manageable, but one patient in the low-dose radiotherapy group died from respiratory failure potentially related to the treatment, highlighting the need for careful monitoring in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. Schoenfeld, JD., Giobbie-Hurder, A., Ranasinghe, S., et al.[2023]

References

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

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial. [2022]

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

Pembrolizumab with or without radiotherapy for metastatic non-small-cell lung cancer: a pooled analysis of two randomised trials. [2021]

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

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial. [2023]

5. England pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. [2022]

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

7. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

Selective Personalized Radioimmunotherapy for Locally Advanced Non-Small-Cell Lung Cancer Trial. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab combined with stereotactic body radiotherapy in a patient with human immunodeficiency virus and advanced non-small cell lung cancer: a case report. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Durvalumab plus tremelimumab alone or in combination with low-dose or hypofractionated radiotherapy in metastatic non-small-cell lung cancer refractory to previous PD(L)-1 therapy: an open-label, multicentre, randomised, phase 2 trial. [2023]