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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new approach for treating lung cancer that has spread to the liver. It combines a precise radiation therapy called SBRT (Stereotactic Body Radiation Therapy) with the immune therapy pembrolizumab to assess the feasibility of this combination. The researchers aim to determine if these treatments can work well together. This trial may suit individuals with a confirmed diagnosis of non-small cell lung cancer (NSCLC) that has spread to the liver and who qualify for immune therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

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.

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

Research has shown that pembrolizumab is generally safe for treating lung cancer. In studies, it helped about 19% of patients live for five years or more when combined with chemotherapy. Most side effects are manageable, though some may be serious.

Liver SBRT, a type of targeted radiation therapy, is also well-tolerated. Reviews indicate it is safe for treating cancer that has spread to the liver, with few severe side effects. Most people experience only minor issues.

Both treatments appear safe for most patients based on current research. However, individual reactions can differ, so discussing potential risks with a healthcare provider is important. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about the combination of SBRT (Stereotactic Body Radiation Therapy) and pembrolizumab for lung cancer because it offers a potentially powerful two-pronged approach. Unlike standard treatments that might focus on either radiation or immunotherapy alone, this combination leverages the precision of SBRT to directly target and destroy cancer cells, while pembrolizumab, an immune checkpoint inhibitor, boosts the body's immune response to fight the cancer. This dual strategy could enhance treatment effectiveness and lead to better outcomes for patients with advanced non-small cell lung cancer (NSCLC). The potential to target up to four metastases during a single cycle of treatment is another exciting aspect, as it could improve patient convenience and reduce overall treatment time.

What evidence suggests that this trial's treatments could be effective for lung cancer?

Research has shown that pembrolizumab, a drug that aids the immune system in fighting cancer, holds promise in treating non-small cell lung cancer (NSCLC). Studies indicate that about 19% of patients using pembrolizumab with chemotherapy survive for five years, outperforming chemotherapy alone. Real-world evidence also supports pembrolizumab's effectiveness, showing similar survival benefits as observed in clinical trials.

For liver stereotactic body radiation therapy (SBRT), research has found it can effectively control liver cancer and improve long-term survival for patients with liver involvement. Although cancer that spreads to the liver usually has a poor outlook, SBRT has successfully managed this spread. This trial is studying the combination of liver SBRT and pembrolizumab for its potential to help patients with lung cancer that has spread to the liver. ^{2 5 6 7 8}

Who Is on the Research Team?

Michael Green, MD

Principal Investigator

VA Ann Arbor

Are You a Good Fit for This Trial?

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

My doctor has approved me for immune therapy.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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]

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]

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 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]

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 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, 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]

Citations

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Four-year follow-up outcomes after stereotactic body radiation ... This study aimed to assess the clinical outcomes and toxicity of patients with central lung cancer treated with SBRT in our institution.

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Long term outcomes of Stereotactic Body Radiation Therapy ... SBRT confers high local control and long-term survival in a substantial proportion of HCC patients unsuitable for, or refractory to standard local/regional ...

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The Role of Stereotactic Body Radiation Therapy in ... Prognoses is often poor in patients with hepatic involvement, with 1-year OS for patients with liver metastases of 15%, compared to 24% in those with non- ...

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Stereotactic body radiotherapy in lung cancer Abstract. The treatment of early stage non-small cell lung cancer (NSCLC) has improved enormously in the last two decades.

5. tandfonline.com tandfonline.com/doi/full/10.2217/lmt-2018-0013

Stereotactic Body Radiation Therapy in Early-Stage NSCLC This paper will review the historical basis of SBRT; examine landmark trials establishing the framework for the current body of evidence; discuss areas of ...

6. practicalradonc.org practicalradonc.org/article/S1879-8500(24)00272-8/abstract

Stereotactic Body Radiation therapy for Liver Metastases This review supports the growing body of evidence that SBRT is an efficacious and safe treatment option for liver metastases. It underscores the ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5601509/

A systematic review of outcomes following stereotactic ... This systematic review considers the evidence supporting the use of SABR in early-stage NSCLC, reported toxicity rates, the use of SABR in centrally located ...

8. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0360301624000075

Combined Stereotactic Body Radiation Therapy and ... Stereotactic body radiation therapy (SBRT) has been demonstrated to be a safe and effective treatment for liver metastases (LM) with low rates of grade 2+ ...