Pembrolizumab and Trastuzumab Emtansine in Treating Patients with Metastatic HER2-Positive Breast Cancer

Status: Active


This phase Ib trial studies the side effects and best way to give pembrolizumab and trastuzumab emtansine in treating patients with HER2-positive breast cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as pembrolizumab and trastuzumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Eligibility Criteria

Inclusion Criteria

  • Patients must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease; patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation
  • Either the primary tumor and/or the metastasis must have been tested for estrogen receptor (ER), progesterone receptor (PR) and HER2; patient must have HER2+ breast cancer per American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines 2013
  • Prior chemotherapy: * History of prior therapy with trastuzumab and a taxane, separately or in combination, is required * Patients must have either received one line of prior therapy for metastatic breast cancer, or have developed a disease recurrence during or within 6 months after completing adjuvant therapy * No prior treatment with T-DM1 is allowed * Last dose of chemotherapy must be at least 21 days prior to registration
  • Prior biologic therapy: * Patients must have discontinued all biologic or investigational therapy at least 21 days before registration
  • Prior radiation therapy: * Patients may have received prior radiation therapy in either the metastatic or early-stage setting * Radiation therapy must be completed at least 14 days prior to registration
  • In the dose de-escalation cohort: subjects must have evaluable disease
  • In the expansion cohort: subjects must have at least one lesion that is not within a previously radiated field that is measurable on computerized tomography (CT) or magnetic resonance imaging (MRI) scan per RECIST version 1.1; bone lesions are not considered measurable by definition
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Absolute neutrophil count >= 1,500/ul
  • Platelets >= 100,000/ul
  • Hemoglobin >= 9 g/dL
  • Total bilirubin =< 1.5 mg/dL (=< 2.0 in patients with known Gilbert's syndrome)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal (ULN); =< 5.0 x institutional ULN for patients with documented liver metastases
  • Albumin > 2.5 mg/dL
  • Serum creatinine =< 1.5 mg/dL or calculated glomerular filtration rate (GFR) >= 60 mL/min
  • International normalized ratio (INR)/prothrombin time (PT) =< 1.5 times ULN unless participant is receiving anticoagulant therapy, as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated partial thromboplastin time (aPTT)/PTT =< 1.5 times ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Participants enrolling in the dose expansion must have tissue that is amenable to biopsy and be willing to undergo a fresh tissue biopsy at baseline; participants who undergo an attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in order to continue on protocol
  • Women of child-bearing potential and men of childbearing potential must agree to use adequate contraception starting with the first dose of study therapy, for the duration of study participation, and for an additional 120 days after the last dose of study medication; note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject * Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the treating physician and principal investigator should be informed immediately * While on the study, women should not breast-feed * Subjects of childbearing potential are defined as those who have not been surgically sterilized and/or have had a menstrual period in the past year
  • Female subject of child-bearing potential, as defined above, must have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication; if a urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
  • Patients on bisphosphonates may continue receiving bisphosphonate therapy during study treatment
  • Left ventricular ejection fraction (LVEF) must be >= 50 as assessed by echocardiogram or multigated acquisition scan (MUGA) documented within 28 days prior to first dose of study drug
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

  • The subject has received another investigational agent within 21 days of the first dose of study drug
  • The subject has received prior pembrolizumab or any other anti-PD-1, anti-PD-L1, or anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumab
  • Pre-existing neuropathy greater than or equal to grade 2
  • Hypersensitivity to pembrolizumab or T-DM1 or any of their excipients
  • The subject has any history or evidence of active, non-infectious pneumonitis or interstitial lung disease
  • Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms; participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial therapy initiation, are neurologically stable with an absence of new neurological symptoms for at least 4 weeks prior to study entry, and have recovered from effects of radiotherapy or surgery; any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for >= 2 weeks before the first study drug; treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician
  • Known carcinomatous meningitis
  • The subject has an uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure (New York Heart Association class III or IV), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe malnutrition
  • Concurrent use of potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment with T-DM1
  • Active infection requiring intravenous antibiotics at cycle 1 day 1
  • Individuals with a history of a second malignancy are ineligible except for the following circumstances; individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin; patients with other cancers diagnosed within the past 5 years and felt to be at low risk of recurrence should be discussed with the study sponsor to determine eligibility
  • The subject has a medical condition that requires chronic systemic steroid therapy or any other form of immunosuppressive medication including disease modifying agents; replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • The subject has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents
  • The participant is positive for hepatitis B surface antigen, or hepatitis C ribonucleic acid (RNA)
  • Known human immunodeficiency virus (HIV)-positive participants; appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated
  • The subject has received a live vaccine within 28 days of planned start of study therapy * Note: seasonal influenza vaccines for infection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (i.e. Flu-Mist) are live attenuated vaccines, and are not allowed

Locations & Contacts


Beth Israel Deaconess Medical Center
Status: Active
Contact: Gerburg M. Wulf
Phone: 617-667-1910
Brigham and Women's Hospital
Status: Active
Contact: Sara Michell Tolaney
Phone: 617-632-2335
Dana-Farber Cancer Institute
Status: Active
Contact: Sara Michell Tolaney
Phone: 617-632-2335

Trial Objectives and Outline


I. To evaluate the safety and tolerability of pembrolizumab in combination with trastuzumab emtansine (trastuzumab-DM1) (T-DM1) in patients with metastatic HER2+ breast cancer.


I. To explore the activity of pembrolizumab in combination with T-DM1, as defined by objective response rate, in patients with metastatic HER2+ breast cancer.

II. To explore the activity of pembrolizumab in combination with T-DM1, as defined by progression free survival (PFS), duration of response, disease control rate (defined as partial responses + complete responses + stable disease at 18 weeks), and overall survival (OS) in patients with metastatic HER2+ breast cancer.

III. To characterize a broad array of immune markers in metastatic HER2-positive breast tumors (characterization will be based on histology, protein expression, messenger ribonucleic acid [mRNA] expression, and genomic analysis).

IV. To explore how different immunosuppressive and/or immune-stimulating immune marker profiles at baseline correlate with disease response to therapy (response assessed by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 and immune-related RECIST [irRECIST]).

V. To characterize changes in immune marker profile in peripheral blood mononuclear cells (PBMCs) from baseline to over the course of trial therapy.

VI. To explore whether induction of changes in the immunosuppressive and/or immune-stimulating immune marker profile in PBMCs at baseline compared to on-therapy correlates with disease response to therapy (response assessed by RECIST 1.1 and irRECIST).

VII. To investigate whether there is an immune marker in circulating PBMCs that corresponds to tumor infiltrating lymphocyte (TIL) percentage in baseline tumor.

VIII. In the cohort of patients who have re-biopsy at week 6 of treatment: to characterize changes in a broad array of immune markers from baseline (as characterized in aim [1]) to 6 weeks on trial therapy, and explore changes in the tumor microenvironment that correlate with disease response to therapy.

IX. To characterize the structure and function of the gut microbiome in patients with breast cancer prior to starting this clinical trial.

X. To determine whether pre-treatment characteristics of the structure and function of the gut microbiome in patients with breast cancer is associated with efficacy of pembrolizumab plus T-DM1.

XI. To characterize changes in the structure and function of the gut microbiome of patients with breast cancer after two cycles of therapy compared to baseline.

XII. To determine whether changes in the overall diversity of the gut microbiome, estimated by the Shannon Index, of patients with breast cancer after two cycles of therapy regimens is associated with efficacy of pembrolizumab plus T-DM1.

XIII. To determine if the abundance and functional profile of specific gut bacteria are associated with objective response to pembrolizumab plus T-DM1.

XIV. To evaluate the functional pathways that may play a role as a predictive biomarker of response to pembrolizumab plus T-DM1.

XV. To explore whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel is correlated with patient outcomes (PFS, overall response rate [ORR], and OS).


Patients receive pembrolizumab intravenously (IV) over 30 minutes, and then patients receive trastuzumab emtansine IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6-9 weeks and annually thereafter.

Trial Phase & Type

Trial Phase

Phase I

Trial Type


Lead Organization

Lead Organization
Dana-Farber Harvard Cancer Center

Principal Investigator
Sara Michell Tolaney

Trial IDs

Primary ID 16-492
Secondary IDs NCI-2017-00402 ID NCT03032107