Pembrolizumab for Triple Negative Breast Cancer

(Pembro/IORT Trial)

Recruiting at 2 trial locations

Overseen By Eileen P. Connolly

Age: 18+

Sex: Female

Trial Phase: Phase 1

Sponsor: Eileen Connolly

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Metastatic disease, Active infection, Autoimmune, 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: 1

Duration: 3 months

15 Participants Needed

Trial Summary

What is the purpose of this trial?

Assess response to pembrolizumab in both primary tumor, normal breast stroma, circulating lymphocytes and serum exosomes in treatment naive triple negative breast cancer (TNBC) patients. Assess for change in tumor-infiltrating lymphocytes (TILS) both stromal (sTILS) and intraepithelial (iTILS) in newly diagnosed early stage TNBC patients treated with two doses of MK-3475 prior to lumpectomy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are on chronic systemic steroid therapy or immunosuppressive therapy, you may need to stop these before starting the trial.

What data supports the effectiveness of the drug pembrolizumab for treating triple-negative breast cancer?

Research shows that pembrolizumab, when used alone or with chemotherapy, has been effective in treating triple-negative breast cancer by improving survival rates and reducing tumor size. Studies like KEYNOTE-086 and KEYNOTE-355 have demonstrated its antitumor activity and manageable safety profile in patients with this type of cancer. ^{1 2 3 4 5}

Is pembrolizumab safe for treating triple-negative breast cancer?

Pembrolizumab, also known as KEYTRUDA, has been shown to have manageable safety in treating triple-negative breast cancer, but it can cause immune-related side effects in some patients. In studies, about 44% of patients experienced these side effects, which are generally considered manageable. ^{2 3 5 6 7}

How is the drug pembrolizumab unique for treating triple-negative breast cancer?

Pembrolizumab is unique because it is an immunotherapy drug that helps the immune system fight cancer by targeting a protein called PD-1, and it is used in combination with chemotherapy to improve treatment outcomes for triple-negative breast cancer, especially in patients with PD-L1 positive tumors. ^{2 3 5 8 9}

Research Team

Eileen Connolly, MD

Principal Investigator

Assistant Professor Of Radiation Oncology

Eligibility Criteria

This trial is for women over 21 with early-stage triple negative breast cancer (TNBC) that's ≤3cm and hasn't spread. They must have good organ function, no prior cancer treatments in the last 6 months, not be pregnant or breastfeeding, and agree to use contraception. Excluded are those with larger tumors, active infections or autoimmune diseases requiring recent treatment, certain other cancers within 5 years, psychiatric/substance issues affecting participation, previous immunotherapy or live vaccines recently.

Inclusion Criteria

I am willing to use birth control during and for 4 months after the study.

Be willing and able to provide written informed consent/assent for the trial

I am 21 years old or older.

Exclusion Criteria

My cancer has spread to other parts of my body.

I have had a stem cell transplant from a donor.

You currently have active Hepatitis B or C.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive two doses of MK-3475 (Pembrolizumab) prior to lumpectomy and intraoperative radiation therapy (IORT)

3 months

1-2 visits for Pembrolizumab administration, 1 visit for IORT

Follow-up

Participants are monitored for changes in tumor-infiltrating lymphocytes (TILs) and other immune markers after treatment

4 weeks

Treatment Details

Interventions

• Intraoperative radiation therapy (IORT)
• Pembrolizumab

Trial Overview The study tests Pembrolizumab's effects on TNBC before surgery by measuring changes in tumor-infiltrating lymphocytes. Participants receive two doses of Pembrolizumab followed by a lumpectomy where Intraoperative radiation therapy (IORT) is also applied. The goal is to see how the drug alters the tumor environment and immune response.

Participant Groups

Group I: Single Arm open label Experimental Treatment 2 Interventions

Participants receive 'Merck 3475 Pembrolizumab' by vein one to two times before Intraoperative radiation therapy (IORT). The Intrabeam® Photon Radiosurgery System is a miniature electron beam-driven X-ray source which provides a point source of low energy X-rays (50 kV maximum) at the tip of a 3.2 mm diameter tube. The radiation source can be inserted into the area of interest immediately after excision of the tumor and switched on for 20-35 minutes to provide intraoperative radiotherapy accurately targeted to the tissues that are at the highest risk of local recurrence. The dosimetric characteristics and early clinical applications of this device have been well studied and this is the device which was utilized in the international TARGIT trial.

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?

Eileen Connolly

Lead Sponsor

Trials

1

Recruited

20+

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 the KEYNOTE-522 study involving 1174 patients, the addition of pembrolizumab to neoadjuvant chemotherapy significantly improved pathologic complete response (pCR) rates, with 58.7% achieving pCR compared to 40.0% in the placebo group, regardless of PD-L1 status.

Event-free survival (EFS) was also enhanced, with a 36-month EFS rate of 91.2% for the pembrolizumab group versus 77.2% for the placebo group, indicating that this treatment combination could be a new standard of care for early triple-negative breast cancer in Asian populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. Takahashi, M., Cortés, J., Dent, R., et al.[2023]

In a phase 3 trial involving 847 patients with untreated metastatic triple-negative breast cancer, the addition of pembrolizumab to chemotherapy significantly improved progression-free survival, especially in patients with a PD-L1 combined positive score (CPS) of 10 or more, with a median survival of 9.7 months compared to 5.6 months for placebo.

The safety profile of pembrolizumab-chemotherapy was comparable to placebo-chemotherapy, with similar rates of grade 3-5 treatment-related adverse events (68% vs. 67%), indicating that the combination therapy is both effective and manageable in terms of safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. Cortes, J., Cescon, DW., Rugo, HS., et al.[2021]

In the KEYNOTE-355 trial, patients with previously untreated metastatic triple-negative breast cancer (mTNBC) who received pembrolizumab combined with chemotherapy experienced a significant improvement in quality-adjusted survival, gaining an average of 3.7 months more time without symptoms or treatment toxicity compared to those receiving chemotherapy alone.

The benefits of pembrolizumab plus chemotherapy increased over time, with a 20% relative gain in quality-adjusted survival at a maximum follow-up of 52 months, indicating both efficacy and manageable safety in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1. Huang, M., O'Shaughnessy, J., Haiderali, A., et al.[2023]

In the KEYNOTE-086 study involving 254 patients with metastatic triple-negative breast cancer, several biomarkers such as PD-L1, CD8, stromal tumor-infiltrating lymphocytes (sTILs), tumor mutational burden (TMB), and T-cell-inflamed gene expression profile (TcellinfGEP) were significantly associated with better clinical outcomes when treated with pembrolizumab.

These findings suggest that assessing these biomarkers can help identify which patients are more likely to benefit from pembrolizumab monotherapy, enhancing personalized treatment strategies for metastatic triple-negative breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association Between Biomarkers and Clinical Outcomes of Pembrolizumab Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer: KEYNOTE-086 Exploratory Analysis. Loi, S., Salgado, R., Schmid, P., et al.[2023]

In a phase 3 trial involving 622 patients with metastatic triple-negative breast cancer, pembrolizumab did not significantly improve overall survival compared to standard chemotherapy, with median survival times of 9.9 months for pembrolizumab and 10.8 months for chemotherapy.

Pembrolizumab showed a manageable safety profile, with fewer severe treatment-related adverse events compared to chemotherapy, suggesting it may be safer for some patients despite not demonstrating superior efficacy overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Winer, EP., Lipatov, O., Im, SA., et al.[2021]

In a multicenter retrospective analysis of early triple-negative breast cancer (eTNBC) patients treated with pembrolizumab and chemotherapy, the incidence of immune-related adverse events (irAEs) was found to be 63.9%, with 20% of patients experiencing severe (grade 3 or higher) irAEs.

The study reported a pathological complete response (pCR) rate of 57.1%, with a significant correlation between the occurrence of irAEs and higher pCR rates (72.2% vs. 30.8%), indicating that while irAEs are common, they may be associated with better treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer. Marhold, M., Udovica, S., Halstead, A., et al.[2023]

Pembrolizumab, when combined with chemotherapy, significantly improves pathological complete response (pCR) and event-free survival (EFS) in patients with high-risk, early-stage triple-negative breast cancer, as shown in the KEYNOTE-522 trial with 123 EFS events in the pembrolizumab group compared to 93 in the control group.

Despite 44% of patients experiencing immune-related adverse reactions, the benefits of pembrolizumab, including a 7.5% absolute improvement in pCR rates, support its use as an effective neoadjuvant and adjuvant treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Neoadjuvant and Adjuvant Treatment of Patients with High-Risk Early-Stage Triple-Negative Breast Cancer. Shah, M., Osgood, CL., Amatya, AK., et al.[2023]

In a phase II trial involving 50 patients with early triple-negative breast cancer, 66% achieved a pathological complete response (pCR) after treatment with nab-paclitaxel and pembrolizumab, indicating a promising efficacy of this combination therapy.

The treatment was associated with manageable side effects, with fatigue, peripheral sensory neuropathy, and neutropenia being the most common adverse events, suggesting that this regimen could be a viable alternative to platinum-based chemotherapy for patients who cannot tolerate it.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer - A single-arm phase II trial (NeoImmunoboost, AGO-B-041). Fasching, PA., Hein, A., Kolberg, HC., et al.[2023]

In the phase III KEYNOTE-522 trial, pembrolizumab combined with chemotherapy showed increased effectiveness as a neoadjuvant treatment for triple-negative breast cancer, leading to a higher rate of pathologic complete response compared to chemotherapy alone.

This benefit was observed regardless of the PD-L1 expression levels in patients, suggesting that pembrolizumab may be a broadly effective option for this aggressive cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Pembrolizumab Takes on TNBC. [2020]

References

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

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer: A Secondary Analysis of a Randomized Clinical Trial. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): a randomised, placebo-controlled, double-blind, phase 3 clinical trial. [2021]

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

Q-TWiST analysis of pembrolizumab combined with chemotherapy as first-line treatment of metastatic triple-negative breast cancer that expresses PD-L1. [2023]

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

Association Between Biomarkers and Clinical Outcomes of Pembrolizumab Monotherapy in Patients With Metastatic Triple-Negative Breast Cancer: KEYNOTE-086 Exploratory Analysis. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. [2021]

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

Emergence of immune-related adverse events correlates with pathological complete response in patients receiving pembrolizumab for early triple-negative breast cancer. [2023]

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

FDA Approval Summary: Pembrolizumab for Neoadjuvant and Adjuvant Treatment of Patients with High-Risk Early-Stage Triple-Negative Breast Cancer. [2023]

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

Pembrolizumab in combination with nab-paclitaxel for the treatment of patients with early-stage triple-negative breast cancer - A single-arm phase II trial (NeoImmunoboost, AGO-B-041). [2023]

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

Neoadjuvant Pembrolizumab Takes on TNBC. [2020]