Radiation + Pembrolizumab for Advanced Breast Cancer

Overseen By Elizabeth Riley, MD

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: University of Louisville

Must be taking: Taxane, CDK 4/6 inhibitors

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Active autoimmune, HIV, Hepatitis, 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

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

Compensation: Varies

Number of Visits: 3

Duration: 1-5 weeks

15 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a phase 2, open-label, single-arm trial designed to evaluate the efficacy and safety of stereotactic body radiation therapy (SBRT) in combination with pembrolizumab following disease progression after two prior lines of standard therapy in unresectable metastatic stage IV breast cancer

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop taking your current medications. However, it mentions that concurrent endocrine therapy or trastuzumab therapy is allowed if clinically indicated, and concurrent bone-modifying agents are allowed for patients with bone metastases.

What data supports the effectiveness of the treatment combining radiation and pembrolizumab for advanced breast cancer?

Research shows that combining radiation with pembrolizumab can enhance the body's immune response against tumors, as radiation can change the tumor environment to make it more responsive to immunotherapy. Studies in various cancers, including breast cancer, have reported that this combination can improve tumor response and potentially increase survival rates. ^{1 2 3 4 5}

Is the combination of radiation therapy and pembrolizumab safe for humans?

The combination of stereotactic body radiotherapy (SBRT) and pembrolizumab has been studied for safety in patients with advanced solid tumors, showing some dose-limiting toxicities in a small percentage of patients. Pembrolizumab alone has been associated with common side effects like fatigue, cough, and nausea, as well as immune-related reactions such as lung inflammation and thyroid issues. ^{3 5 6 7 8}

How is the treatment of radiation plus pembrolizumab unique for advanced breast cancer?

This treatment combines pembrolizumab, an immune system-boosting drug, with radiation therapy to potentially enhance the body's ability to fight cancer. Pembrolizumab works by blocking a protein that stops the immune system from attacking cancer cells, and when combined with radiation, it may improve the overall response to treatment. ^{1 5 9 10 11}

Research Team

Elizabeth Riley, MD

Principal Investigator

UL Health Brown Cancer Center Deputy Director, Health Affairs

Eligibility Criteria

This trial is for women over 18 with stage IV breast cancer that's spread and can't be removed by surgery. They must have tried two previous treatments, including a taxane and specific therapies based on their cancer type. Good organ function and no active brain metastases or immune diseases are required. Women must not be pregnant, breastfeeding, or planning pregnancy soon.

Inclusion Criteria

I am a woman who can have children and have a recent negative pregnancy test.

I have fully recovered from any major surgery before joining the trial.

Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures.

Exclusion Criteria

I do not have an autoimmune disease that could get worse with pembrolizumab treatment.

I am not willing to use birth control during the study and for 4 months after.

I am not pregnant, breastfeeding, nor planning to become pregnant soon.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive stereotactic body radiation therapy (SBRT) in combination with pembrolizumab

1-5 weeks

Pembrolizumab administered every 3 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Palliative Radiation
• Pembrolizumab

Trial Overview The study tests combining stereotactic body radiation therapy (SBRT) with pembrolizumab in patients whose disease progressed after standard treatments. It's an open-label phase 2 trial where all participants receive the same experimental treatment to assess its effectiveness and safety.

Participant Groups

Group I: Palliative Radiation in Combination with Pembrolizumab Experimental Treatment 1 Intervention

Stereotactic radiation therapy will be delivered using either linac-based SBRT using 10x flattening filter-free (FFF) photons or Cyberknife Pencil Beam Technology utilizing 6X photons. Treatment will be delivered in 1-5 fractions. Fractionation and total dose (1500 - 3000 cGy) will depend on the site of disease, previous radiation treatment, and patient symptomatology. Pembrolizumab is supplied as pembrolizumab 100 mg/4 mL vials (25 mg/mL) solution for intravenous infusion. Pembrolizumab at a dose of 200 mg will be administered intravenously every 3 weeks (± 3 days).

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?

University of Louisville

Lead Sponsor

Trials

353

Recruited

76,400+

James Graham Brown Cancer Center

Collaborator

Trials

44

Recruited

9,200+

Findings from Research

Pembrolizumab, an immunotherapy targeting PD-1, showed limited effectiveness in a patient with metastatic renal cell carcinoma, highlighting that only 20-40% of patients benefit from such treatments due to individual tumor biology and immune checkpoint diversity.

The patient's rapid disease progression during treatment may be linked to a lack of tumor-infiltrating lymphocytes (TILs) and the specific radiation dose and schedule used, which could affect the tumor microenvironment and the potential synergy with pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. Alexander, GS., Palmer, JD., Tuluc, M., et al.[2022]

Radiation therapy not only helps eliminate cancer cells but also modifies the tumor microenvironment, potentially enhancing the body's immune response against tumors.

Combining radiation with immune checkpoint inhibitors has shown promise in early clinical trials for breast cancer, suggesting a synergistic effect that could improve treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in Combining Radiation and Immunotherapy in Breast Cancer. Nguyen, AT., Shiao, SL., McArthur, HL.[2021]

The combination of stereotactic body radiotherapy (SBRT) and pembrolizumab (SBRT+P) is safe for patients with large, advanced solid tumors, with only 7.2% experiencing dose-limiting toxicities in a study involving 97 patients.

Patients who showed a positive response to SBRT+P had significantly better overall survival rates, with a 1-year overall survival of 71% for responders, compared to 0% for nonresponders, highlighting the potential efficacy of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases. Korpics, MC., Onderdonk, BE., Dadey, RE., et al.[2023]

In a study of 98 advanced urothelial cancer patients, those who received radiotherapy to the primary tumor showed a significantly higher objective response rate to pembrolizumab (65% vs 19%) compared to those who did not receive radiotherapy.

Patients who had prior radiotherapy also experienced better overall survival rates (77% vs 50% at 12 months), suggesting that radiotherapy may enhance the effectiveness of pembrolizumab in treating advanced urothelial cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of radiotherapy to the primary tumor on the efficacy of pembrolizumab for patients with advanced urothelial cancer: A preliminary study. Fukushima, H., Kijima, T., Fukuda, S., et al.[2023]

In a study involving 8 patients with hormone receptor-positive metastatic breast cancer, combining pembrolizumab with palliative radiation therapy did not result in any objective responses, leading to the study's closure.

The median progression-free survival was only 1.4 months and overall survival was 2.9 months, indicating limited efficacy of this treatment combination in heavily pre-treated patients, although the treatment was generally safe with only one significant adverse event reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. Barroso-Sousa, R., Krop, IE., Trippa, L., et al.[2021]

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 phase II study involving 18 patients with metastatic colorectal cancer, both low-dose fractionated radiation (LDFRT) and hypofractionated radiation (HFRT) were found to be feasible and safe when combined with PD-L1/CTLA-4 blockade, although 84% of patients experienced treatment-related toxicity.

The best treatment response was stable disease in one patient, and the study did not show significant efficacy in terms of tumor shrinkage outside the radiation field, suggesting that while the combination impacts the immune microenvironment, it may not be effective for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer. Monjazeb, AM., Giobbie-Hurder, A., Lako, A., 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) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Immune biomarkers of treatment failure for a patient on a phase I clinical trial of pembrolizumab plus radiotherapy. [2022]

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

Advances in Combining Radiation and Immunotherapy in Breast Cancer. [2021]

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

Partial tumor irradiation plus pembrolizumab in treating large advanced solid tumor metastases. [2023]

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

Impact of radiotherapy to the primary tumor on the efficacy of pembrolizumab for patients with advanced urothelial cancer: A preliminary study. [2023]

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

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer. [2021]

6. 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]

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

A Randomized Trial of Combined PD-L1 and CTLA-4 Inhibition with Targeted Low-Dose or Hypofractionated Radiation for Patients with Metastatic Colorectal Cancer. [2022]

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

New Approved Use for Keytruda. [2022]

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

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

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

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