Phase III study of pembrolizumab for high-risk early-stage ER+/HER2– breast cancer

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Dec 2018 → ongoing

Decision date (initial)

2023-11-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-506921-12-00

EudraCT number

2017-004869-27

WHO UTN

U1111-1294-6352

ClinicalTrials.gov

NCT03725059

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy

1. To compare the rate of pCR at the time of surgery, using the definition of ypT0/Tis ypN0 as assessed by the local pathologist, of pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
2. To compare the EFS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies, as determined by the investigator.

Secondary objectives 7

1. To compare the OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies.
2. To compare the rate of pCR at the time of surgery, using the definition of ypT0 ypN0 as assessed by the local pathologist, of pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
3. To compare the rate of pCR at the time of surgery, using the definition of ypT0/Tis as assessed by the local pathologist, of pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies.
4. To compare the rate of pCR at the time of surgery, using 3 definitions (ypT0/Tis ypN0, ypT0 ypN0, and ypT0/Tis) as assessed by the local pathologist, of pembrolizumab versus placebo, both in combination with the protocol-specified neoadjuvant anticancer therapies in individuals with PD-L1 positive tumors (combined positive score [CPS] ≥1).
5. To compare EFS as determined by the investigator and OS following administration of pembrolizumab and placebo, both in combination with the protocol-specified neoadjuvant and adjuvant anticancer therapies in individuals with PDL1 positive tumors (CPS ≥1).
6. To evaluate the safety and tolerability of pembrolizumab combined with neoadjuvant chemotherapy and adjuvant endocrine therapy within and across the neoadjuvant and adjuvant periods.
7. To evaluate health-related quality of life (QoL) assessments using the European Organisation for Research and Treatment of cancer (EORTC) QoL Questionnaire Core 30 (QLQ-C30) and the EORTC Breast Cancer-specific QoL Questionnaire (QLQ-BR23) within and across the neoadjuvant and adjuvant periods.

Conditions and MedDRA coding

ER+/HER2- Breast Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Has a localized invasive breast ductal adenocarcinoma, confirmed by the local pathologist, that includes either T1c-T2 (tumor size ≥2 cm), clinical node stage (cN)1-cN2, or T3-T4, cN0-cN2. - Note: Inflammatory breast cancer is allowed.
2. Has centrally confirmed ER+/HER2-, Grade 3 breast cancer of ductal histology, according to the most recent American Society of Clinical Oncology/College of American Pathologist guidelines.
3. Provides a new or recently obtained core needle biopsy, consisting of multiple cores, taken from the primary breast tumor(s) for central determination of HR status (ER and progesterone receptor), HER2, grade, and PD-L1 status. - Note: Sponsor agreement is required for formalin-fixed paraffin-embedded (FFPE) tumor tissue sample or slides that were obtained greater than 60 days prior to the date that the documented informed consent was obtained.
4. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, as assessed within 10 days prior to initiation of study treatment.
5. Male participants must agree to use contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment and refrain from donating sperm during this period.
6. Female participants must agree to use effective contraception during the treatment period and for at least 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment with pembrolizumab or placebo.
7. Has adequate organ function.

Exclusion criteria 23

1. Has a history of non-infectious pneumonitis that required treatment with steroids or has current pneumonitis.
2. Has breast cancer with lobular histology.
3. Has bilateral invasive breast cancer.
4. Has metastatic (Stage IV) breast cancer.
5. Has multi-centric breast cancer (presence of more than 1 tumor in different quadrants of the breast).
6. Has any of the following clinical lymph node staging per current American Joint Committee on Cancer (AJCC) staging criteria for breast cancer staging based on radiological and/or clinical assessment: cN3, cN3a, cN3b, or cN3c.
7. Has ER-, progesterone receptor positive breast cancer.
8. Has undergone excisional biopsy of the primary tumor and/or axillary lymph nodes or has undergone sentinel lymph node biopsy prior to study treatment.
9. Has a known additional, invasive, malignancy that is progressing or required active treatment in the last 5 years. - Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, ductal breast carcinoma in situ, or cervical carcinoma in situ that has undergone potentially curative therapy are not excluded.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment.
11. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs) Note: Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
12. Has a known history of active tuberculosis (Bacillus tuberculosis).
13. Has an active infection requiring systemic therapy.
14. Has left ventricular ejection fraction (LVEF) of <50% or below the institution limit of normal, as assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan performed at screening.
15. Has other significant cardiac disease, such as: 1) History of myocardial infarction, acute coronary syndrome, or coronary angioplasty/stenting/bypass within the last 6 months. or 2) Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA Class III or IV.
16. Has a known history of human immunodeficiency virus (HIV) infection.
17. Has a known history of hepatitis B or known active hepatitis C virus infection
18. Has received prior treatment for breast cancer.
19. Has received prior therapy with an anti-programmed cell death protein 1 (anti-PD-1), anti-programmed cell death-ligand 1 (anti-PD-L1), or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g. cytotoxic T-lymphocyte-associated protein 4 [CTLA-4], OX 40, CD137).
20. Has received a live vaccine within 30 days prior to the first dose of study treatment.
21. Has severe hypersensitivity (≥Grade 3) to any of the components or excipients used in the study treatments.
22. Is/was enrolled in a study of an investigational agent and received study therapy, or used an investigational device within 4 weeks (12 months for an investigational agent or device with anticancer or antiproliferative properties) prior to the first dose of study treatment.
23. Is pregnant, breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 12 months (for participants who received cyclophosphamide) or 6 months (for participants who did not receive cyclophosphamide) after the last dose of study treatment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Pathological Complete Response (pCR) Rate Using the Definition of ypT0/Tis ypN0
2. Event-Free Survival (EFS)

Secondary endpoints 12

1. Overall Survival (OS)
2. pCR Rate Using the Definition of ypT0ypN0
3. pCR Rate Using the Definition of ypT0/Tis
4. pCR Rate Using the Definitions of ypT0/Tis ypN0, ypT0/Tis, and ypT0 ypN0 in Participants With a Combined Positive Score [CPS] ≥1
5. EFS in Participants with a CPS ≥1
6. OS in Participants with a CPS ≥1
7. Number of Participants Experiencing an Adverse Event (AE)
8. Number of Participants Experiencing a Serious Adverse Event (SAE)
9. Number of Participants Experiencing an Immune-related AE (irAE)
10. Number of Study Treatment Discontinuations Due to AEs
11. Change from Baseline in European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life (QoL) Questionnaire Core 30 (QLQ-C30) Score
12. Change from Baseline in EORTC Breast Cancer-Specific QoL Questionnaire (QLQ-BR23) Score

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Kim Hirshfield

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Kim Hirshfield

Third parties 8

Locations

8 EU/EEA countries · 66 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 70 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

19 submissions — initial application plus substantial / non-substantial modifications