Pembrolizumab + Radiation for Breast Cancer

Overseen By Cindi Martin

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Stephen Shiao

Must not be taking: Immunosuppressants, Corticosteroids, Live vaccines, others

Disqualifiers: HER2-positive, Inflammatory breast cancer, Metastatic disease, 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

Compensation: Varies

Number of Visits: 2

Duration: 6 weeks

66 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot use chronic immunosuppressants or systemic corticosteroids, and you should not have had certain cancer treatments or live vaccines recently. It's best to discuss your specific medications with the study team.

What data supports the effectiveness of the treatment Pembrolizumab + Radiation for Breast Cancer?

Research suggests that combining radiation with pembrolizumab, a drug that helps the immune system fight cancer, may enhance the body's ability to attack tumors. This combination has shown promise in other cancers, like lung cancer, and early studies in breast cancer are exploring similar benefits. ^{1 2 3 4 5}

Is Pembrolizumab (Keytruda) safe for use in humans?

Pembrolizumab (Keytruda) has been used in various cancer treatments and is generally considered safe, but it can cause side effects like fatigue, cough, and nausea. Rarely, it may lead to immune-related issues like type 1 diabetes. Combining it with radiation appears safe, but caution is advised due to limited data. ^{6 7 8 9 10}

How is the treatment of pembrolizumab plus radiation for breast cancer different from other treatments?

This treatment combines pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells, with radiation therapy, which can enhance the immune response against tumors. This combination aims to improve the effectiveness of treatment by using both the body's immune system and targeted radiation to fight breast cancer, which is different from traditional treatments that may not use this dual approach. ^{1 2 3 11 12}

What is the purpose of this trial?

This study is being done to assess the feasibility of pembrolizumab (study drug) combined with standard radiation to the tumor (tumor boost) before patients undergo standard treatment that can consist of one or more of the following: breast-conserving surgery, radiation to the entire breast/chest wall after surgery, and chemotherapy. Study participants will receive two doses of the study drug intravenously (through the vein) before their planned breast surgery or chemotherapy. The study drug will be administered three weeks apart. At the time of the second dose, radiation to the tumor in the affected breast will be given. This type of radiation treatment is called a "tumor boost", which is a standard part of radiation therapy for breast cancer that may occur either before or after planned breast-conserving surgery. Patients will receive breast surgery or begin chemotherapy approximately six weeks after your first dose of the study drug.

Research Team

Stephen Shiao, MD

Principal Investigator

Cedars-Sinai Medical Center

Eligibility Criteria

This trial is for adults with invasive breast cancer, specifically high-risk ER-positive/HER2-negative or triple-negative types without distant metastases. Participants must have a tumor ≥2 cm, be willing to undergo biopsies and adhere to the study schedule. It excludes those with certain cosmetic breast augmentations, other active cancers within 3 years, inflammatory breast cancer, contraindications to radiation therapy or breast-conserving therapy, known HIV/Hepatitis B/C infections, uncontrolled medical disorders or active autoimmune diseases.

Inclusion Criteria

My cancer has been tested for ER, PR, and HER2.

My cancer may or may not have spread to the lymph nodes.

I am fully active or can carry out light work.

Exclusion Criteria

My breast cancer is HER2-positive based on specific test results.

I have an immune system disorder or am on long-term steroids.

I have another cancer that is getting worse or was treated in the last 3 years.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of pembrolizumab three weeks apart, with radiation therapy (tumor boost) administered at the time of the second dose.

6 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of tumor-infiltrating lymphocytes and adverse events.

8 weeks

Long-term follow-up

Participants are monitored for disease-free survival and immune-related adverse events.

Up to 1 year

Treatment Details

Interventions

• Pembrolizumab
• RT Boost

Trial Overview The trial tests pembrolizumab (an immunotherapy drug) combined with a 'tumor boost' of radiation before standard treatments like surgery or chemotherapy. Patients will receive two doses of pembrolizumab three weeks apart; during the second dose they'll also get radiation. Surgery or chemotherapy starts about six weeks after the first dose.

Participant Groups

Group I: Pembrolizumab with RT Boost Experimental Treatment 2 Interventions

Study drug plus "tumor boost" before standard of care treatment

Who Is Running the Clinical Trial?

Stephen Shiao

Lead Sponsor

Trials

2

Recruited

100+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

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]

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]

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 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]

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, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Combining anti-HER2 monoclonal antibodies like trastuzumab and pertuzumab with radiation therapy appears to be safe, showing no significant increase in toxicity based on the reviewed literature.

However, caution is advised when combining radiation with tyrosine kinase inhibitors (like lapatinib and tucatinib) and certain antibody-drug conjugates, as the safety of these combinations is not well established.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence. Debbi, K., Grellier, N., Loganadane, G., et al.[2023]

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]

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]

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]

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

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

2. 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]

3. 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]

4. 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]

5. 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]

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

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Interaction between Radiation Therapy and Targeted Therapies in HER2-Positive Breast Cancer: Literature Review, Levels of Evidence for Safety and Recommendations for Optimal Treatment Sequence. [2023]

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

New Approved Use for Keytruda. [2022]

10. 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]

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

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

12. 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]