Pembrolizumab + SRS for Brain Metastases from Breast Cancer

Recruiting at 2 trial locations

Overseen By Fabiana Gregucci, M.D.

Age: 18+

Sex: Female

Trial Phase: Phase 1 & 2

Sponsor: Weill Medical College of Cornell University

Must not be taking: Steroids, Immunosuppressants, Live vaccines

Disqualifiers: Autoimmune, Immunodeficiency, Active infection, 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: 7

Duration: Variable (until progression or toxicity)

41 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of pembrolizumab, a drug that helps the immune system fight cancer, and stereotactic radiosurgery (SRS), a precise form of radiation therapy, to treat brain metastases in people with breast cancer. The researchers aim to determine if this combination can effectively target and treat multiple brain tumors. People with metastatic breast cancer who have at least two untreated brain tumors might be suitable candidates. As a Phase 1, Phase 2 trial, this research focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group. Participants have the opportunity to contribute to groundbreaking advancements in cancer treatment.

Will I have to stop taking my current medications?

The trial requires a two-week washout period (time without taking certain medications) from your last systemic treatment before starting the study. However, you can continue using hormonal therapy or anti-Her2 neu therapy if your brain metastases are progressing during these treatments.

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

Research has shown that SRS, a type of precise radiation treatment, is generally safe for treating brain tumors in breast cancer patients. It effectively controls tumor growth with few side effects. Studies highlight its safety and effectiveness, particularly for those in good health.

Pembrolizumab, a drug already approved by the FDA for certain cancers, is safe for use in people. It aids the immune system in fighting cancer cells. While pembrolizumab can cause side effects, they are usually manageable and well-documented from its other approved uses.

In summary, both SRS and pembrolizumab have demonstrated a good safety record in various studies. They are generally well-tolerated, but patients should still discuss potential side effects with their healthcare provider. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for brain metastases from breast cancer?

Researchers are excited about Pembrolizumab with SRS for treating brain metastases from breast cancer because it offers a unique combination approach. Unlike traditional treatments, which often rely on surgery or whole-brain radiation, this method uses pembrolizumab, an immunotherapy drug, in tandem with stereotactic radiosurgery (SRS). Pembrolizumab works by enhancing the body's immune response to target and destroy cancer cells, while SRS provides precise, high-dose radiation to the tumor. This dual approach not only aims to improve the targeting of cancer cells but also potentially reduces the side effects associated with more invasive or widespread treatments.

What evidence suggests that pembrolizumab and SRS could be effective for brain metastases from breast cancer?

This trial will evaluate the combination of stereotactic radiosurgery (SRS) and pembrolizumab for treating brain metastases from breast cancer. Studies have shown that SRS effectively treats cancer that has spread to the brain, particularly in patients with certain types of breast cancer. SRS controls tumor growth and can relieve symptoms. Research suggests that combining SRS with pembrolizumab, a drug that boosts the immune system, might enhance effectiveness. Pembrolizumab helps the body recognize and fight cancer cells more effectively. Although more information is needed, early findings suggest this combination could be promising for treating brain metastases from breast cancer. ^{1 3 4 6 7}

Who Is on the Research Team?

Silvia Formenti

Principal Investigator

Weill Cornell Medicine - New York Presbyterian Hospital

Are You a Good Fit for This Trial?

This trial is for adults over 18 with metastatic breast cancer and at least two untreated brain metastases visible on MRI. Participants must have good performance status, adequate organ function, and agree to use contraception. Exclusions include recent radiation therapy or immunosuppressive treatment, active infections, other cancers within the past 3 years, severe allergies to pembrolizumab components, certain viral infections like Hepatitis B/C or HIV.

Inclusion Criteria

My MRI shows 2-10 brain lesions, each at least 5mm, identified within the last two weeks.

I have had SRS before, but the areas we're looking to treat now haven't been treated with SRS.

I had a partial tumor removal, and any remaining tumor is smaller than 4cm. I can continue hormone or anti-HER2 therapy if my brain cancer worsens.

Exclusion Criteria

I have an active connective tissue disorder like lupus or scleroderma needing treatment for flares.

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

I have an immune system disorder or have been on high-dose steroids or other immune-weakening medicines recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo stereotactic radiosurgery (SRS) to one of the brain lesions

1 week

1 visit (in-person)

Treatment

Pembrolizumab infusion given every 3 weeks until disease progression or unacceptable toxicity

Variable (until progression or toxicity)

Every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Routine imaging every 3 months

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Stereotactic Radiosurgery (SRS)

Trial Overview

The study tests pembrolizumab given intravenously every three weeks in combination with stereotactic radiosurgery (SRS) targeting one brain lesion. The goal is to assess the effectiveness of this combined approach in controlling brain metastases from breast cancer.

How Is the Trial Designed?

Group I: Pembrolizumab and SRS Experimental Treatment 1 Intervention

Pembrolizumab infusion will be given on Day 4 (+/-1) after SRS treatment at the standard dose of 200mg IV over 30 minutes and repeated every 3 weeks until disease progression or unacceptable toxicity.

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?

Weill Medical College of Cornell University

Lead Sponsor

Trials

1,103

Recruited

1,157,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a study of 21 melanoma patients with brain metastases treated with concurrent pembrolizumab and radiation therapy, the treatment was found to be safe, with no severe toxicities reported, although one patient experienced Grade 3 side effects.

The use of stereotactic radiosurgery (SRS) alongside pembrolizumab resulted in a high response rate, with 70% of patients showing complete or partial responses at the first follow-up MRI, which is significantly better than response rates seen with SRS combined with other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. Anderson, ES., Postow, MA., Wolchok, JD., et al.[2022]

Pembrolizumab, an anti-PD-1 antibody, has shown effective control of non-small cell lung cancer (NSCLC) with brain metastases in two reported cases, leading to long progression-free survival and high quality of life for the patients.

The treatment was well-tolerated, with no serious or grade 3-4 adverse events reported, suggesting that systemic immunotherapy may be a viable option for patients with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for non-small cell lung cancer with central nervous system metastases: A two-case report. Di, M., Zhang, L.[2023]

In a phase 2 trial involving 42 patients with untreated brain metastases from non-small-cell lung cancer (NSCLC), pembrolizumab showed a 29.7% response rate in patients with PD-L1 expression of at least 1%, indicating its efficacy in treating brain metastases.

The treatment was generally safe, with serious adverse events occurring in 14% of patients, but no treatment-related deaths were reported, suggesting that pembrolizumab can be a viable option for selected patients with CNS involvement.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. Goldberg, SB., Schalper, KA., Gettinger, SN., et al.[2021]

Pembrolizumab, an anti-PD-1 antibody, has shown a rapid and sustained response in a patient with symptomatic brain metastases from melanoma, achieving complete remission for over a year without the need for additional radiotherapy.

This case suggests that pembrolizumab may be effective for treating brain metastases in melanoma patients, highlighting the importance of conducting further clinical studies to explore its potential in this specific patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition. Lüttmann, N., Grätz, V., Haase, O., et al.[2018]

In a phase II clinical trial involving 23 melanoma patients with untreated brain metastases, pembrolizumab demonstrated a 26% response rate in brain metastases, indicating its potential efficacy in this challenging patient population.

The treatment was associated with acceptable toxicity, as 65% of patients experienced neurologic adverse events, mostly mild (grade 1 or 2), and nearly half of the patients (48%) were alive at 24 months, suggesting durable responses and a need for careful management of brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Kluger, HM., Chiang, V., Mahajan, A., et al.[2020]

In a phase 2 trial involving 36 patients with untreated brain metastases from melanoma or non-small-cell lung cancer (NSCLC), pembrolizumab demonstrated activity, achieving a brain metastasis response in 22% of melanoma patients and 33% of NSCLC patients, with responses being durable for most.

The treatment had an acceptable safety profile, with serious adverse events occurring in a small percentage of patients, indicating that systemic immunotherapy could be a viable option for those with untreated or progressive brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for patients with melanoma or non-small-cell lung cancer and untreated brain metastases: early analysis of a non-randomised, open-label, phase 2 trial. Goldberg, SB., Gettinger, SN., Mahajan, A., et al.[2022]

In a study of 30 patients with non-small cell lung cancer (NSCLC) and asymptomatic brain metastases (BMs), upfront treatment with pembrolizumab showed promising efficacy, with one complete and four partial responses observed.

Patients receiving pembrolizumab alone or in combination with whole-brain radiotherapy (WBRT) had better median survival rates compared to those treated with stereotactic radiosurgery (SRS), suggesting that pembrolizumab may be a viable first-line treatment option for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Upfront pembrolizumab as an effective treatment start in patients with PD-L1 ≥ 50% non-oncogene addicted non-small cell lung cancer and asymptomatic brain metastases: an exploratory analysis. Metro, G., Gili, A., Signorelli, D., et al.[2021]

A patient with brain metastases experienced mental status changes and MRI findings of lesion enlargement after receiving pembrolizumab, an immunotherapy drug, indicating a potential adverse effect of treatment in the central nervous system.

Histological analysis showed that the observed changes were due to pseudoprogression, characterized by tumor cell clusters and inflammatory responses, highlighting the need for careful monitoring and possible immune suppression in patients undergoing immunotherapy for brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment. Cohen, JV., Alomari, AK., Vortmeyer, AO., et al.[2022]

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 phase 2 trial involving 57 patients with untreated and recurrent brain metastases, pembrolizumab showed an intracranial benefit rate of 42.1%, indicating its potential effectiveness in treating this challenging condition.

The median overall survival for patients receiving pembrolizumab was 8.0 months, with some patients experiencing survival beyond 2 years, although over half of the participants reported grade-3 or higher adverse events, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results. Brastianos, PK., Kim, AE., Giobbie-Hurder, A., et al.[2023]

In a study of 3170 patients with PD-L1-positive non-small-cell lung cancer, pembrolizumab significantly improved overall survival compared to chemotherapy, regardless of whether patients had baseline brain metastases.

Pembrolizumab also resulted in better progression-free survival, higher objective response rates, and fewer treatment-related adverse events compared to chemotherapy, making it a safer and more effective option for patients with advanced or metastatic NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes With Pembrolizumab Monotherapy in Patients With Programmed Death-Ligand 1-Positive NSCLC With Brain Metastases: Pooled Analysis of KEYNOTE-001, 010, 024, and 042. Mansfield, AS., Herbst, RS., de Castro, G., et al.[2022]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11446965/

Stereotactic radiosurgery for brain metastases from human ...

In this multi-center retrospective study, we evaluated the safety and efficacy of SRS for brain metastases from HER2-positive primary breast cancer during an 18 ...

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03449238

Study Details | NCT03449238 | Pembrolizumab And ...

Patients with metastatic breast cancer with at least 2 brain metastases, eligible to receive SRS. Patients will complete radiation therapy within 1 week and ...

3.

ascopubs.org

ascopubs.org/doi/10.1200/OP.23.00794

Breast Cancer Brain Metastasis: A Comprehensive Review

Local therapies, such as surgery and stereotactic radiosurgery, can be used to control tumor growth and relieve symptoms. Whole-brain ...

4.

thejns.org

thejns.org/view/journals/j-neurosurg/138/6/article-p1608.xml

Stereotactic radiosurgery and local control of brain metastases ...

SRS is a safe and efficacious treatment for well-selected patients with triple-negative breast cancer, especially for those with a favorable performance status.

5.

thebreastonline.com

thebreastonline.com/article/S0960-9776(24)00088-2/fulltext

The influence of immunotherapy and prognostic factors

SRS demonstrates favourable outcomes in terms of local control and distant brain metastasis-free survival in TNBC.

6.

centerwatch.com

centerwatch.com/clinical-trials/listings/NCT03449238/pembrolizumab-and-stereotactic-radiosurgery-srs-of-selected-brain-metastases-in-breast-cancer-patients

Pembrolizumab And Stereotactic Radiosurgery (Srs) Of ...

Patients with metastatic breast cancer with at least 2 brain metastases will receive pembrolizumab every 3 weeks.

7.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11506708/

Stereotactic Radiosurgery for Intracranial Breast Metastases

Conclusions: SRS demonstrates promising efficacy and safety in managing intracranial metastases from breast cancer, with a favorable toxicity ...