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

Trial Summary

What is the purpose of this trial?

Patients with metastatic breast cancer with at least 2 brain metastases will receive pembrolizumab every 3 weeks. Patients will undergo stereotactic radiosurgery (SRS) to one of the brain lesions. 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.

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.

What data supports the effectiveness of the drug pembrolizumab for treating brain metastases from breast cancer?

Research shows that pembrolizumab, a drug that helps the immune system fight cancer, has been effective in treating brain metastases from various cancers, with 42.1% of patients experiencing benefits like tumor shrinkage or stabilization. This suggests it might also help some patients with brain metastases from breast cancer. ^{1 2 3 4 5}

Is the combination of Pembrolizumab and SRS safe for treating brain metastases?

Pembrolizumab, used alone or with radiation therapy like SRS, has shown an acceptable safety profile in treating brain metastases from conditions like melanoma and non-small cell lung cancer, with patients generally not experiencing serious side effects. ^{1 3 6 7 8}

What makes the drug pembrolizumab unique for treating brain metastases from breast cancer?

Pembrolizumab is unique because it is an immunotherapy drug that works by blocking a protein called PD-1, which helps the immune system attack cancer cells, including those in the brain. This approach is novel for brain metastases, as traditional treatments often do not focus on enhancing the immune response. ^{1 2 9 10 11}

Research Team

Silvia Formenti

Principal Investigator

Weill Cornell Medicine - New York Presbyterian Hospital

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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 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]

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]

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 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 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]

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, 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]

References

1. England 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. [2021]

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

Pembrolizumab in brain metastases of diverse histologies: phase 2 trial results. [2023]

3. England pubmed.ncbi.nlm.nih.gov

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

4. United States 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. [2022]

5. Italy 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. [2021]

6. Singapore pubmed.ncbi.nlm.nih.gov

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

7. England 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. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Melanoma brain metastases treated with stereotactic radiosurgery and concurrent pembrolizumab display marked regression; efficacy and safety of combined treatment. [2022]

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

Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment. [2022]

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

Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition. [2018]

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

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. [2020]