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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of radiation therapy and the drug pembrolizumab to evaluate its effectiveness for individuals with advanced breast cancer that cannot be surgically removed and has metastasized. Researchers aim to determine if this combination can slow or halt cancer progression after standard treatments have failed. This trial suits individuals who have undergone two different cancer treatments and still have stage IV, inoperable breast cancer. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants an opportunity to contribute to significant advancements in cancer treatment.

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.

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

Previous studies have shown that pembrolizumab has lasting effects in fighting tumors in patients with advanced breast cancer. However, pembrolizumab can cause the immune system to mistakenly attack healthy parts of the body, which can be serious or even life-threatening. These reactions have been reported in various parts of the body, so careful monitoring is essential.

Research indicates that stereotactic body radiation therapy (SBRT) is usually well-tolerated. This type of radiation has been effective in managing pain and slowing cancer growth in bones. In a study with 581 patients with metastatic breast cancer, radiation therapy significantly reduced the risk of death.

Overall, while both treatments offer potential benefits, they also come with risks. It's crucial to discuss these with healthcare providers to understand their implications for individual health situations. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard treatments for advanced breast cancer, which include chemotherapy and hormone therapy, the combination of palliative radiation with pembrolizumab offers a novel approach by harnessing the body's own immune system. Pembrolizumab is an immunotherapy drug that works by blocking the PD-1 pathway, effectively removing the "brakes" on the immune system and allowing it to attack cancer cells more effectively. This treatment is exciting because it not only targets the cancer cells directly through the precision of stereotactic radiation but also enhances the immune response, potentially leading to more effective and longer-lasting results. Researchers are particularly interested in how the synergy between precise radiation and pembrolizumab might improve outcomes for patients with advanced breast cancer.

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

Research has shown that combining pembrolizumab with chemotherapy can extend the lives of people with advanced breast cancer compared to chemotherapy alone. In another study, 32.7% of patients initially scheduled for a mastectomy were able to undergo breast-conserving surgery instead, due to pembrolizumab. In this trial, participants will receive a combination of pembrolizumab and palliative radiation. Previous research found a 30% lower risk of death for those with metastatic breast cancer receiving palliative radiation. Stereotactic body radiation therapy (SBRT) significantly relieved pain and slowed cancer progression. Together, these treatments offer hope for better outcomes in advanced breast cancer. ^{3 4 5 6 7}

Who Is on the Research Team?

Elizabeth Riley, MD

Principal Investigator

UL Health Brown Cancer Center Deputy Director, Health Affairs

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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 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 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 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) 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]

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]

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 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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10800428/

Survival analysis of palliative radiotherapy in patients with ... A prospective study involving 581 metastatic breast cancer patients demonstrated a 30% reduction in the risk of death after receiving RT (14).

2. advancesradonc.com advancesradonc.com/article/S2452-1094(24)00193-3/fulltext

Stereotactic Body Radiation Therapy for Palliative ... In this report, we specifically describe details of localizing and treating a breast cancer acrometastasis with SBRT and compare intensity- ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39549757/

Outcomes After Palliative Radiation Therapy in Patients With ... The 1-year OS and LC rates were 37% and 63%, respectively. Eighty-one percent experienced improvement in symptoms within 3 months after RT, the ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1040842822001998

Stereotactic body radiation therapy versus conventional ... SBRT significantly improved complete pain response rates at 3 months, delayed local progression and increased pain flare rates.

5. practicalradonc.org practicalradonc.org/article/S1879-8500(24)00099-7/fulltext

External Beam Radiation Therapy for Palliation of ... Specifically, an RCT of SBRT using 2400 cGy in 2 fractions reported significantly higher rates of complete pain response at 3 months as compared ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11583694/

Stereotactic Body Radiation Therapy for Palliative ... In this report, we specifically describe details of localizing and treating a breast cancer acrometastasis with SBRT and compare intensity-modulated RT with ...

7. redjournal.org redjournal.org/article/S0360-3016(24)03143-2/fulltext

The Hidden Benefits of Palliative Radiation Therapy Only 2 of 112 trials reported off-protocol radiation therapy utilization rates and no data were reported on the use of SABR therapy. No trials ...