Stopping Anti-HER2 Therapy to Improve Outcomes for Exceptional Responder Patients with Metastatic HER2-Positive Breast Cancer, The STOP-HER2 Trial

Status: closed to accrual

This phase II trial studies how well stopping anti-HER2 therapy works in improving outcomes of patients with HER2-positive breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic) and have experienced long-term benefit from first-line treatment (exceptional responders). Patients with metastatic HER2-positive breast cancer are currently treated with systemic drugs indefinitely. These drugs include chemotherapy and/or biological agents targeting the HER2 protein. The first drug combination administered after diagnosis of metastatic spread (i.e., first-line treatment) usually combines chemotherapy with anti-HER2 agents (trastuzumab with or without pertuzumab). Chemotherapy is administered for a limited number of months, and anti-HER2 agents are continued indefinitely as maintenance therapy. Some of these patients experience a long-term benefit from first-line treatment without cancer growth and can be defined as “exceptional responders.” Nevertheless, all patients with this type of tumor typically continue maintenance treatment with anti-HER2 therapy indefinitely. Exceptional responders usually receive treatment for many years. Information learned from this trial may help researchers understand whether maintenance anti-HER2 treatment can be safely stopped in patients with exceptional response to first-line therapy.

Inclusion Criteria

Age >= 18 years
Participants must have histologically or cytologically confirmed unresectable locally advanced or metastatic invasive breast carcinoma that is HER2-positive by American Society of Clinical Oncology/College of American Pathologists 2018 criteria, as assessed by standard institutional guidelines (central testing is not required). Both estrogen receptor (ER)-positive/HER2-positive and ER-negative/HER2-positive will be eligible
Participants with ER-positive disease may continue endocrine therapy
Participants must be currently receiving first-line anti-HER2 therapy (any regimen) for metastatic disease and must have been on this therapy for at least 3 years without evidence of progressive disease prior to registration in the judgement of the treating investigator. Participants may have switched anti-HER2 treatments during their first line of therapy, providing the change was due to reasons other than progressive disease. Participants must have received anti-HER2 therapy within 90 days of registration. The following exceptions apply
Participants with history of brain-only progressive disease previously treated with local therapy (surgery and/or radiation therapy) are eligible, provided they meet all the following study criteria: * Asymptomatic * Not requiring anti-convulsant for symptomatic control * Not requiring corticosteroids * No evidence of interim central nervous system (CNS) progression between the completion of CNS-directed therapy and screening radiographic study * Minimum of 2 years (24 months) between completion of CNS-directed therapy and study start
Participants with history of oligo-progression (i.e., progressive disease of a single lesion) outside CNS treated with local treatment and/or change of endocrine therapy only are eligible, provided they meet the following criteria: * No evidence of interval progression between completion of local treatment or endocrine therapy change and screening radiographic study * Minimum 2 years (24 months) between completion of local therapy or treatment switch and study start
CT scan within 30 days of registration without definitive evidence of progressive disease in the opinion of the treating investigator
Available, representative archival formalin-fixed paraffin-embedded (FFPE) tumor tissue block from primary and/or metastatic site. If tissue block is unavailable, 20 unstained 10uM slides will be accepted (less than 20 slides may be acceptable with documentation of Sponsor-Investigator approval and would not require an eligibility exception). Tumor tissue must be received by coordinating site prior to study enrollment
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
For intervention arm only (cohort 2): Willingness to stop anti-HER2 systemic therapy
Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
Ability to understand the study requirements and document informed consent indicating awareness of the investigational nature and the risks of this study
Participants with another prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of this trial are eligible

Exclusion Criteria

Participants who are receiving any investigational agents to treat breast cancer
Participants with psychiatric illness/social situations that would limit compliance with study requirements
All English-speaking participants will participate in the patient-reported outcome (PRO) measures. Participants that do not read or understand English are eligible to participate but will be exempt from the patient-completed questionnaires

PRIMARY OBJECTIVES:

I. To evaluate the 1-year progression-free survival (PFS) in participants with HER2-positive metastatic breast cancer (MBC) and exceptional response to anti-HER2 therapy who agree to stop anti-HER2 therapy (cohort 2).

II. To evaluate 1-year PFS in participants with HER2-positive MBC and exceptional response to anti-HER2 therapy continuing anti-HER2 therapy (cohort 1).

SECONDARY OBJECTIVES:

I. To determine the clinical benefit rate (CBR) of re-initiation of anti-HER2 therapy for participants who experience disease progression after stopping anti-HER2 therapy.

II. To determine 3-year overall survival (OS) in participants in cohorts 1 and 2.

III. To determine 3-year PFS in participants in cohorts 1 and 2.

IV. To determine the probability of restarting anti-HER2 therapy without progression of disease in participants stopping anti-HER2 therapy.

EXPLORATORY OBJECTIVES:

I. To characterize the clinical and biological profile of persistent remission (i.e., maintained response or disease stability according to Response Evaluation Criteria in Solid Tumors [RECIST 1.1] criteria) in participants stopping anti-HER2 therapy.

II. To characterize the clinical and biological profile of disease recurrence in participants stopping anti-HER2 therapy.

III. To determine saved treatment costs in participants stopping anti-HER2 therapy.

IV. To characterize patterns and frequency of disease recurrence in participants stopping anti-HER2 therapy by length of time on anti-HER2 therapy.

V. To describe the proportion of participants choosing to stop or continue anti-HER2 therapy while both Cohorts 1 and 2 are open.

EXPLORATORY CORRELATIVE OBJECTIVES:

I. To explore minimal residual disease (MRD) status before and throughout the study period as a predictor of durable response.

Ia. The proportion of participants who are MRD-positive at baseline;

Ib. The relationship between serial MRD status and clinical outcomes (PFS, OS).

II. To characterize the mutational profile via circulating tumor deoxyribonucleic acid (DNA) (ctDNA) in participants who develop progression of disease.

III. To explore blood biomarkers of antitumoral immune activity as predictors of durable response or progression.

PATIENT-REPORTED OUTCOMES OBJECTIVES:

I. To evaluate change in illness intrusiveness in exceptional responders with HER2-positive MBC who stop anti-HER2 therapy.

II. To evaluate financial toxicity in exceptional responders with HER2-positive MBC who stop anti-HER2 therapy.

III. To describe anxiety in exceptional responders with HER2-positive MBC who stop anti-HER2 therapy.

IV. To describe symptoms, anxiety and quality of life (QOL) in exceptional responders with HER2-positive MBC who do and do not stop anti-HER2 therapy.

V. To describe decision regret in exceptional responders with HER2-positive MBC who stop anti-HER2 therapy.

VI. To describe distress about cancer progression in exceptional responders with HER2-positive MBC who do and do not stop anti-HER2 therapy.

VII. To describe illness intrusiveness in exceptional responders with HER2-positive MBC who continue anti-HER2 therapy.

VIII. To describe financial toxicity in exceptional responders with HER2-positive MBC who continue anti-HER2 therapy.

IX. To describe factors that impact exceptional responders' decisions to stop or continue anti-HER2 therapy.

X. To describe participants' perceptions about the risk of progression of HER2-positive MBC in the setting of continued treatment or a treatment break and about the success of resumption of anti-HER2 therapy following a treatment break.

XI. To describe exceptional responders' perceptions regarding their providers' preferences about stopping or continuing anti-HER therapy.

OUTLINE: Patients who choose to continue anti-HER2 therapy are assigned to Cohort 1, while patients who choose to discontinue anti-HER2 therapy are assigned to Cohort 2.

COHORT 1: Patients continue receiving anti-HER2 therapy on study as per standard of care. Patients also undergo collection of blood samples on study and during follow up, and undergo computed tomography (CT) or positron emission tomography (PET) scans throughout the trial. Patients with stable brain metastases also undergo magnetic resonance imaging (MRI) scans throughout the trial.

COHORT 2: Patients discontinue anti-HER2 therapy and undergo surveillance on study. Patients experiencing disease progression while on surveillance may re-initiate anti-HER2 therapy as clinically indicated. Patients who re-initiate anti-HER2 therapy may undergo an optional tumor tissue biopsy on study. Patients also undergo collection of blood samples on study and during follow up, and undergo CT or PET scans throughout the trial. Patients with stable brain metastases also undergo MRI scans throughout the trial.

Patients may be followed every 6 months regardless of disease status for a minimum of 3 years and up to 10 years, or until death, whichever occurs first.

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Stopping Anti-HER2 Therapy to Improve Outcomes for Exceptional Responder Patients with Metastatic HER2-Positive Breast Cancer, The STOP-HER2 Trial

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