Evaluation of Trastuzumab Deruxtecan in Unresectable/Metastatic HER2-low or HER2 IHC0 Breast Cancer: A Multicenter, Open-label Study

Trial ID: 2023-505616-38-00
Protocol: DS8201-0001-CIS-MA
Sponsor: Daiichi Sankyo Inc.

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Diseases & Conditions

Breast cancer

Objectives

The primary objective of this study is to evaluate the efficacy of **trastuzumab deruxtecan** (T-DXd) in subjects with unresectable and/or metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 breast cancer (BC) across four cohorts. The outcome measure for this objective is the time to next treatment (TTNT), defined as the duration from the start of T-DXd to the initiation of subsequent anticancer treatment or death due to any cause. This measure is clinically relevant as it provides insight into the duration of benefit from T-DXd before the need for additional therapy, which is crucial for treatment planning and patient management.

Secondary objectives include:

Evaluating the efficacy of T-DXd by measuring real-world progression-free survival (PFS), which is the time from the start of T-DXd to disease progression or death, assessed by investigators using RECIST version 1.1.
Assessing the time to treatment discontinuation (TTD) for any reason, which is the time from the start of T-DXd to discontinuation of the drug or death.
Determining the objective response rate (ORR), which involves subjects with an objective report of response per investigator assessment based on RECIST version 1.1.
Evaluating the safety and tolerability of T-DXd by analyzing treatment-emergent adverse events (TEAEs) collected from the first dose to database lock, along with other safety parameters.
Assessing health economics and outcomes research (HEOR) endpoints, including patient-reported outcomes (PROs), for subjects treated with T-DXd.

These secondary objectives aim to provide a comprehensive understanding of the therapeutic impact, safety profile, and patient-centered outcomes associated with T-DXd treatment in this patient population.

Participants

The clinical trial involves a total of **129 participants** diagnosed with **unresectable and/or metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 breast cancer**. The study population includes both male and female subjects, aged 18 years and older, who are not considered part of a vulnerable population. Participants were selected based on specific inclusion criteria, such as having a left ventricular ejection fraction of at least 50% and adequate organ and bone marrow function. The trial does not impose specific lifestyle considerations such as diet or physical activity. Key inclusion criteria include the requirement for participants to have a pathologically documented breast cancer tumor that is unresectable or metastatic, with confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC0 status. Participants must not have been previously treated with anti-HER2 therapy in the metastatic setting. The trial aims to evaluate the efficacy of T-DXd treatment in this specific cohort.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **trastuzumab deruxtecan** in subjects with unresectable and/or metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 breast cancer. This is a Phase 4, multicenter, global, interventional, open-label study. The trial will involve a randomized, controlled design to ensure the reliability of the results. The estimated duration of the trial is from August 2024 to January 2028, with participant involvement expected to last up to 24 months, depending on individual response and progression.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as adequate organ function and a confirmed diagnosis of the target condition. Following successful screening, participants will receive the investigational product, DS-8201a, administered as a **solution for infusion** via the intravenous route. The primary endpoint is the time to next treatment (TTNT), with secondary endpoints including progression-free survival (rwPFS) and overall response rate (ORR).

Study visits will be scheduled regularly to monitor the participants' health status, treatment response, and any adverse events. Follow-up visits will include assessments such as tumor scans, laboratory tests, and patient-reported outcomes. The end-of-study visit will occur after the completion of the treatment period or upon early termination. Conditions that may lead to early termination include significant adverse events, disease progression, or withdrawal of consent by the participant.

Participants are required to comply with scheduled visits, drug administration plans, and study restrictions. The trial will ensure that all procedures adhere to ethical standards and regulatory requirements, with the primary objective of evaluating the treatment's efficacy and safety profile in the specified patient population.

Treatment

The clinical trial involves the administration of **trastuzumab deruxtecan**, commercially known as DS-8201a, which is an investigational medication. This pharmaceutical product is formulated as a **solution for infusion** and is administered via the **intravenous** route. The dosing regimen for DS-8201a is set at a maximum daily dose of 5.4 mg/kg, with a total maximum dose not exceeding 187 mg/kg over the course of the treatment. The treatment period is capped at 24 weeks. The active substance, trastuzumab deruxtecan, is a protein-based compound classified under the category of "Protein - Other." The investigational product is developed and supplied by Daiichi Sankyo, Inc.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The focus is solely on evaluating the efficacy of the investigational drug, DS-8201a, in subjects with unresectable and/or metastatic HER2-low or HER2 Immunohistochemistry (IHC) 0 breast cancer. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol and to assess the therapeutic outcomes accurately.

Efficacy

The efficacy of Trastuzumab Deruxtecan (T-DXd) in the clinical trial will be assessed primarily through the endpoint of Time to Next Treatment (TTNT). TTNT is defined as the duration from the initiation of T-DXd treatment to the commencement of subsequent anticancer therapy or death from any cause. Subjects who have not received any subsequent therapy and are alive at the time of analysis will be censored at their last contact date. An interim analysis will be conducted when 60% of subjects in each cohort have experienced the primary endpoint.

Secondary efficacy endpoints include Real-world Progression-free Survival (rwPFS), Time to Treatment Discontinuation (TTD), and Overall Response Rate (ORR). rwPFS is measured from the first administration of T-DXd to the first observed disease progression or death, with disease progression determined by investigator assessment using RECIST version 1.1 criteria. TTD is the time from the first dose of T-DXd to discontinuation of the drug or death. ORR is defined as the proportion of subjects achieving a Best Overall Response (BOR) of confirmed Complete Response (CR) or Partial Response (PR) according to RECIST version 1.1 criteria.

Patient-reported outcomes (PRO) will also be analyzed, including changes in status on EORTC questionnaire scales, time to first and definitive deterioration from baseline, and responses to EQ-5D-5L items. These assessments will provide additional insights into the impact of T-DXd on patients' quality of life and symptom management.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Subject must sign and date the main ICF prior to the start of any study-specific qualification procedures.
Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
Must agree to provide a newly obtained or archival baseline biopsy from primary and/or metastatic lesion. All subjects must provide a formalin-fixed paraffin-embedded (FFPE) tumour sample that meets the tissue requirements for tissue-based analysis (including but not restricted/limited to IHC staining to determine HER2 expression, ISH staining when necessary for HER2-low status, and other predictive biomarkers as well as tumour mutational analysis). A newly acquired sample from a fresh biopsy will be used if available; however, submission of the subject’s most recent biopsy prior to the date of Screening and after the subjects’ last treatment regimen as per ASCO CAP 2018 guidelines is permitted for testing in a local laboratory. This archival sample for Tissue Screening must have been obtained post last line of systemic therapy. If a previously collected sample does not have sufficient material for a minimum of 15 × 4-micron sections (or block equivalent), a fresh biopsy must be collected.
Pathologically documented BC tumour that: a. Is unresectable or metastatic. b. Is hormone receptor-negative or hormone receptor-positive. c. Has confirmed HER2 IHC 1+ or IHC 2+/ISH- (HER2-low) status or HER2 IHC0 status as determined according to ASCO CAP 2018 guidelines based on sample collected during Tissue Screening as described above in Inclusion Criterion No. 3. d. Was never previously HER2-positive (IHC 3+ or IHC 2+/ISH+) on prior pathology testing (per ASCO CAP guidelines). e. Was never previously treated with anti-HER2 therapy in the metastatic setting.
a. Cohorts 1,2 and 4: hasHas had at least one and up to two prior lines of therapy in the metastatic setting. Targeted agents (such as mTOR inhibitors, PARP inhibitors, PD-1 inhibitors, PD-L1 inhibitors, histone deacetylase inhibitors, or CDK4/6 inhibitors) or endocrine therapy count as a line of therapy. b.a. Cohort 3:In subjects with hormone receptor-positive HER2-low metastatic BC (Cohort 3): − Has recurrent disease <2 years from the initiation of adjuvant endocrine therapy (ET) OR − Has disease progression on CDK4/6 inhibitor-based regimen within 12 months of completion of adjuvant therapy with a CDK4/6 inhibitor OR - Has disease progression within the first 12 months of CDK4/6 in the first line metastatic setting.
Presence of at least one measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) as assessed by the investigator, per RECIST v1.1 OR - At least 1 lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements, or non-measurable, bone-only disease that can be assessed by CT or MRI or X-Ray. Lytic or mixed lytic bone lesions that can be assessed by CT or MRI or X-Ray in the absence of measurable disease as defined above is acceptable; subjects with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
Subjects with brain metastases are allowed in the study. The brain lesion(s) should be small (< 2 cm), untreated, asymptomatic, not requiring urgent medical intervention, and/or are asymptomatic and clinically stable.
Has an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1.
Has a minimum life expectancy of 12 weeks at Screening.
Has a left ventricular ejection fraction (LVEF) ≥ 50% within 28 days before enrollment.
Has adequate organ and bone marrow function within 7 days before enrollment. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to Screening assessment. Organ and bone marrow function criteria must also be met when laboratory tests are repeated within 3 days before dosing as appropriate. Adequate organ/bone marrow function are defined in the protocol.
Has adequate treatment washout period before enrollment, as defined in protocol.
A male participant capable of producing sperm is eligible to participate if he agrees to avoid donating sperm or to adhere to contraception methods as defined in the protocol, for at least the time needed to eliminate the trial intervention. The length of time required to continue contraception after last dose for the trial intervention is 4 months.
A female POCBP is eligible to participate if the following conditions are met: a. Participant is not pregnant as confirmed by highly sensitive pregnancy test. b. Participant does not breastfeed during the trial intervention period, and for at least 7 months after last dose of trial intervention. c. Participant agrees to adhere to a contraceptive method that is highly effective and agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during the intervention period and for at least the time needed to eliminate the trial intervention after the last dose. The length of time required to continue contraception after last dose for the trial intervention is 7 months. Preservation of eggs may be considered prior to first dose of trial intervention.
Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.

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Exclusion Criteria

Prior treatment with an ADC that consists of an exatecan derivative that is a topoisomerase I inhibitor (other than sacituzumab govitecan) including prior participation in a study involving an ADC produced by Daiichi Sankyo and/or AstraZeneca.
Uncontrolled or significant cardiovascular disease including any of the following: a. Subjects with a medical history of myocardial infarction within 6 months before randomization or symptomatic CHF (NYHA Class II to IV). Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial infarction related symptoms, should have a cardiologic consultation before randomization to rule out myocardial infarction. b. Uncontrolled and/or clinically important cardiac arrhythmias.
Has a corrected QT interval (QTc) prolongation to >470 ms (females) or >450 ms (males) based on average of the Screening triplicate 12-lead electrocardiogram (ECG).
Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.
Has spinal cord compression or clinically active central nervous system metastases, defined as symptomatic or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms. Subjects with clinically inactive brain metastases may be included in the study. Subjects with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants may be included in the study if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2 weeks must have elapsed between the end of whole brain radiotherapy and study enrollment.
Has primary malignancies within 3 years, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, other solid tumours curatively treated, or contralateral BC.
Has a history of severe hypersensitivity reactions to either the drug substances or inactive ingredients in the drug product.
Has a history of severe hypersensitivity reactions to other monoclonal antibodies.
Has an uncontrolled infection requiring systemic antibiotics, antivirals, or antifungals.
Has active or uncontrolled hepatitis B virus (HBV) infection. Hepatitis B screening tests are not required, unless there is a known history of HBV infection or if mandated by local health authority. Participants are eligible if they fulfil the conditions as described in the study protocol.
Has active or uncontrolled hepatitis C virus (HCV) infection. Hepatitis C screening tests are not required unless there is a known history of HCV infection or if mandated by local health authority. Participants are eligible if they meet the criteria as described in the study protocol.
Has active or uncontrolled human immunodeficiency virus (HIV) infection. Subjects must be tested for HIV viral load during the Screening Period if acceptable by local regulations or institutional review boards/independent ethics committees. Participants are eligible if they meet the criteria as described in the study protocol.
Has history of receiving a live, attenuated vaccine (messenger RNA and replication-deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first exposure to study drug.
Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to Grade ≤1 or baseline. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade > 2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy including the following: a. Chemotherapy-induced neuropathy b. Fatigue c. Residual toxicities from prior immune-oncology (IO) treatment: Grade 1 or Grade 2 endocrinopathies, which may include the following: Hypothyroidism/hyperthyroidism; Type 1 diabetes; Hyperglycemia; Adrenal insufficiency; Adrenalitis; Skin hypopigmentation (vitiligo).
Is pregnant or breastfeeding or planning to become pregnant.
Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of the study randomisation, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, and pleural effusion, etc).
Any autoimmune, connective tissue or inflammatory disorders (eg, rheumatoid arthritis, Sjogren’s, sarcoidosis, etc) where there is documented or a suspicion of pulmonary involvement at the time of Screening. Full details of the disorder should be recorded in the electronic case report form (eCRF) for subjects who are included in the study.
Prior complete pneumonectomy.
As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including ongoing or active infection, uncontrolled hypertension, renal transplant, active bleeding diseases, or serious chronic gastrointestinal conditions associated with diarrhea) substantially increasing risk of incurring AEs, which, in the investigator’s opinion, makes it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol.
Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject’s participation in the clinical study or evaluation of the clinical study results.
Social, familial, or geographical factors that would interfere with study participation or follow-up.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	30 Aug 2024	17
Ireland	Not Recruiting	30 Aug 2024	14
Italy	Not Recruiting	30 Aug 2024	26
The Netherlands	Not Recruiting	30 Aug 2024	—
Portugal	Not Recruiting	30 Aug 2024	10
Spain	Not Recruiting	30 Aug 2024	54
Netherlands	—	—	18