SBRT + Pembrolizumab for Lung Cancer

Overseen By Shaneta Waddy, MHA

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: VA Ann Arbor Healthcare System

Must be taking: Immune checkpoint inhibitors

Must not be taking: Live vaccines, Corticosteroids

Disqualifiers: Cirrhosis, Active malignancy, Autoimmune, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 0.5 years

12 Participants Needed

Trial Summary

What is the purpose of this trial?

Determine the feasibility of liver stereotactic body radiation therapy (SBRT) given in combination with systemic therapy (immune checkpoint inhibitors) in adult patients with metastatic NSCLC with liver metastases.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on corticosteroids at a dose higher than 10 mg of prednisone daily, you may not be eligible to participate.

What data supports the effectiveness of the treatment SBRT + Pembrolizumab for Lung Cancer?

Research shows that pembrolizumab, a drug used in this treatment, has been effective in improving outcomes for patients with advanced non-small cell lung cancer (NSCLC), especially when combined with other therapies like chemotherapy and radiation. Additionally, studies suggest that adding Stereotactic Body Radiotherapy (SBRT) to pembrolizumab may enhance its effectiveness in treating NSCLC. ^{1 2 3 4 5}

Is the combination of SBRT and pembrolizumab safe for treating lung cancer?

Pembrolizumab (also known as Keytruda) has been used safely in humans for various cancers, including lung cancer and melanoma. Common side effects include fatigue, cough, nausea, and rash, while more serious immune-related side effects can include lung inflammation (pneumonitis) and thyroid issues. These side effects are generally considered manageable compared to the benefits in treating life-threatening conditions. ^{2 5 6 7 8}

How is the treatment SBRT + Pembrolizumab unique for lung cancer?

The combination of SBRT (a precise form of radiation therapy) and pembrolizumab (an immunotherapy drug) is unique because it aims to enhance the immune response against lung cancer by reducing tumor markers that can inhibit pembrolizumab's effectiveness, potentially leading to longer progression-free survival. ^{2 3 5 9 10}

Research Team

Michael Green, MD

Principal Investigator

VA Ann Arbor

Eligibility Criteria

Adults with metastatic non-small cell lung cancer (NSCLC) and liver metastases can join this trial. They must have good organ function, be able to take immune checkpoint inhibitors, and not be on high-dose steroids. Pregnant or breastfeeding individuals, those with active autoimmune diseases requiring recent treatment, or significant other illnesses are excluded.

Inclusion Criteria

My lung cancer has spread to my liver.

I am 18 years old or older.

I can care for myself and am up and about more than 50% of my waking hours.

Exclusion Criteria

I have an active TB, Hepatitis B, or Hepatitis C infection.

I have not received a live vaccine in the last 30 days.

I have not had any other cancer besides in situ cancers in the last year.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive liver SBRT in combination with immune checkpoint inhibitors during the first cycle of treatment

0.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Liver SBRT
• Pembrolizumab

Trial Overview The trial is testing the combination of liver stereotactic body radiation therapy (SBRT) with Pembrolizumab, an immune checkpoint inhibitor. It aims to see if this combo is feasible for treating NSCLC patients who also have liver metastases.

Participant Groups

Group I: Arm 1 Experimental Treatment 2 Interventions

This is an open-label, single-arm, single center clinical trial to evaluate the feasibility of liver SBRT (up to 4 metastases) during the first cycle of physician's choice ICI for NSCLC.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

VA Ann Arbor Healthcare System

Lead Sponsor

Trials

19

Recruited

10,300+

LUNGevity Foundation

Collaborator

Trials

8

Recruited

1,600+

Lungevity

Collaborator

Trials

1

Recruited

10+

Findings from Research

In a phase 2 study involving 216 patients with stage III non-small cell lung cancer (NSCLC), the combination of pembrolizumab and concurrent chemoradiation therapy (cCRT) showed a high objective response rate of approximately 70.5% in cohort A and 70.6% in cohort B, indicating strong antitumor activity.

The treatment was associated with manageable safety, with grade 3 or higher pneumonitis occurring in 8.0% of cohort A and 6.9% of cohort B, suggesting that while there are risks, the benefits of this treatment approach may outweigh them for patients with locally advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. Jabbour, SK., Lee, KH., Frost, N., et al.[2022]

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]

The ESPERa trial is designed to evaluate the efficacy and safety of adding Stereotactic Body Radiotherapy (SBRT) to pembrolizumab-pemetrexed maintenance therapy in advanced non-small cell lung cancer (NSCLC) patients who have shown a response or stability after initial treatment, with the primary goal of improving progression-free survival (PFS).

Preliminary data suggest that combining immunotherapy with radiotherapy is safe and effective, but the systematic integration of these treatments in first-line therapy for NSCLC is still under investigation, highlighting the potential for SBRT to enhance treatment outcomes in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study Design and Rationale for Espera Trial: A Multicentre, Randomized, Phase II Clinical Trial Evaluating the Potential Efficacy of Adding SBRT to Pembrolizumab-Pemetrexed Maintenance in Responsive or Stable Advanced Non-Squamous NSCLC After Chemo-Immunotherapy Induction. Belluomini, L., Dionisi, V., Palmerio, S., et al.[2022]

The KEYNOTE-001 trial demonstrated that pembrolizumab significantly improves clinical outcomes for patients with advanced non-small cell lung cancer, indicating its efficacy as a treatment option.

Patients whose tumors express PD-L1 in at least 50% of cells showed better responses to pembrolizumab, suggesting that PD-L1 expression is a key factor in predicting treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Shows Promise for NSCLC. [2015]

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 (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]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

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]

Stereotactic body radiotherapy (SBRT) is an effective standard treatment for patients with early non-small cell lung cancer (NSCLC) who cannot undergo surgery, as well as for those with oligometastatic NSCLC.

A case study in China demonstrated nearly 5 years of progression-free survival with pembrolizumab monotherapy following SBRT, highlighting the potential for enhanced efficacy of immunotherapy after targeted radiotherapy in metastatic NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A patient with metastatic non-small cell lung cancer who received pembrolizumab monotherapy after stereotactic body radiotherapy had progression-free survival of nearly 5 years: a case report. Ni, J., Yang, L., Zhu, H., et al.[2021]

In a study of 68 patients with advanced solid tumors, the combination of stereotactic body radiotherapy (SBRT) followed by pembrolizumab showed a high one-year treated metastasis control rate of 89.5%, indicating effective tumor response regardless of whether the tumors received complete or partial radiation coverage.

The study found that treated metastasis control (TMC) was significantly associated with improved overall survival, and SBRT altered tumor gene expression by increasing immune-related genes while decreasing those related to cell cycle and DNA repair, suggesting a mechanism for enhanced immune response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. Luke, JJ., Onderdonk, BE., Bhave, SR., et al.[2021]

References

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

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. [2022]

2. 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]

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

Study Design and Rationale for Espera Trial: A Multicentre, Randomized, Phase II Clinical Trial Evaluating the Potential Efficacy of Adding SBRT to Pembrolizumab-Pemetrexed Maintenance in Responsive or Stable Advanced Non-Squamous NSCLC After Chemo-Immunotherapy Induction. [2022]

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

Pembrolizumab Shows Promise for NSCLC. [2015]

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

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

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

8. England pubmed.ncbi.nlm.nih.gov

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

9. China pubmed.ncbi.nlm.nih.gov

A patient with metastatic non-small cell lung cancer who received pembrolizumab monotherapy after stereotactic body radiotherapy had progression-free survival of nearly 5 years: a case report. [2021]

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

Improved Survival Associated with Local Tumor Response Following Multisite Radiotherapy and Pembrolizumab: Secondary Analysis of a Phase I Trial. [2021]