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Recruiting

Comparison of RO7771950 plus combination therapy versus tucatinib plus combination therapy in pretreated HER2-positive locally advanced or metastatic breast cancer

Trial ID: 2025-524498-17-00
Protocol: WO46069
Sponsor: F. Hoffmann-La Roche AG

Trial statistics

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Diseases & Conditions

HER2 positive breast cancer

Objectives

The primary objective is to evaluate the efficacy of RO7771950 in combination with trastuzumab and capecitabine compared to tucatinib in combination with trastuzumab and capecitabine regarding progression-free survival in the full analysis set. 5

Secondary objectives include:

Evaluation of intracranial efficacy in terms of progression-free survival in participants with central nervous system metastases.
Assessment of overall survival.
Evaluation of objective response rate, duration of response, and confirmed benefit rate in the full analysis safety set and participants with baseline central nervous system metastases.
Determination of the impact on patient-reported brain tumor-specific symptoms.
Evaluation of patient-reported outcomes concerning functioning and health-related quality of life.
Assessment of safety and tolerability. 4
Comparison of health utility to generate utility scores for economic models. 13
Characterization of plasma pharmacokinetics of RO7771950 and its metabolites. 6

Participants

The study population consists of 413 participants with HER2-positive breast cancer that is unresectable, locally advanced, or metastatic. This cohort includes both female and male individuals, including vulnerable populations, within the specified age ranges. Eligible participants must have pathologically documented disease and confirmed status via central laboratory testing. Inclusion requires having received at least one prior line of anti-HER2-based therapy and prior treatment with an antibody-drug conjugate, such as trastuzumab deruxtecan or trastuzumab emtansine. Participants may have received a tyrosine kinase inhibitor in the neoadjuvant or adjuvant setting if the interval since completion exceeds 12 months, though prior use for metastatic disease is prohibited. Disease must be assessable by RECIST v1.1 or RANO-BM criteria.

Plans and Procedures

This is a two-part, seamless, multicenter, randomized, open-label, adaptive Phase II/III study designed to evaluate the efficacy of RO7771950 in combination with trastuzumab and capecitabine compared to tucatinib in combination with trastuzumab and capecitabine. The study focuses on patients with pretreated unresectable locally advanced or metastatic HER2-positive breast cancer, with or without central nervous system metastases. The primary objective is to assess progression-free survival within the full analysis set. Participants must have confirmed HER2-positive status and have received at least one prior line of anti-HER2 therapy, including an antibody-drug conjugate. The trial is estimated to occur between April 2026 and January 2030. Secondary endpoints include overall survival, objective response rate, and various assessments of health-related quality of life and adverse events.

Treatment

RO7771950 is an experimental medication administered as an oral film-coated tablet or coated tablet. The specific dosage is not provided.

Trastuzumab is an experimental treatment administered via IV infusion at a dose of 8 mg/kg or via subcutaneous use at a dose of 600 mg.

Capecitabine is an experimental medication administered by the oral route at a dosage of 2000 mg/m2.

Tucatinib is a comparator treatment administered by the oral route at a dose of 600 mg.

Efficacy

The primary efficacy endpoint is progression-free survival in the full analysis set (PFS-FAS). Secondary efficacy parameters include progression-free survival in participants with central nervous system metastases (PFS-CNS), overall survival in the full analysis set (OS-FAS), objective response rate (ORR), duration of response (DOR), and clinical benefit rate (CBR). Specific assessments for participants with CNS metastases include ORR-CNS, DOR-CNS, and CBR-CNS.

Efficacy is further evaluated using several patient-reported outcomes and clinical assessments:

Mean and mean changes from baseline in symptoms for participants with brain tumors via the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Brain Neoplasm module (EORTC QLQ-BN20).
Mean and mean changes from baseline in function and health-related quality of life (HRQoL) by cycle and between treatment arms via the EORTC QLQ-C30.
Changes in symptomatic treatment toxicities using the patient-reported outcome - Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Proportion of participants reporting response options via the Functional Assessment of Cancer Therapy - General Population 5-item (FACT-GP5) scale.
Health utility scores measured by the European Quality of Life 5 Dimensions 5 Level Version (EQ-5D-5L).

Additional assessments include changes from baseline in clinical laboratory tests, vital signs, echocardiogram, multiple-gated acquisition (ECHO/MUGA), electrocardiogram (ECG), and the Columbia Suicide Severity Rating Scale (C-SSRS). Plasma concentration of RO7771950 and its metabolites are measured at specified timepoints.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Pathologically documented breast cancer that is locally advanced inoperable (LAI) or metastatic breast cancer (MBC)
Confirmed HER2-positive status, as determined according to American Society of Clinical Oncology/College of American Pathologists guidelines, by central laboratory testing of formalin-fixed, paraffin-embedded (FFPE) tumor tissue sample. HER2-positive status will be defined as 3+ by IHC and/or positive by HER2 amplification by in situ hybridization (ISH) with a ratio of ≥ 2 for the number of HER2 gene copies to the number of signals for chromosome 17 copies
Stage 1 participants: Measurable disease only, assessable by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and/or Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) Stage 2 participants: Measurable or non-measurable disease assessable by RECIST v1.1 and/or RANO-BM For both stages: Lytic or mixed lytic bone lesions that can be assessed by computed tomography (CT), magnetic resonance imaging (MRI), or X-ray can be accepted as measurable disease in the absence of other measurable lesions.
Participants must have received at least one prior line of anti-HER2-based therapy for LAI or metastatic disease
Participants must have received prior treatment with an anti-HER2 antibody-drug conjugate (ADC), such as trastuzumab-deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1), administered in the neoadjuvant, adjuvant, or metastatic setting. However, participants for whom prior ADC therapy was not appropriate (e.g., due to lack of access or being medically unfit) may be considered for enrollment.
Prior treatment with a tyrosine kinase inhibitor (TKI) in the neoadjuvant/adjuvant setting is acceptable, provided that the interval between the completion of TKI treatment and development of locally advanced inoperable (LAI) or metastatic disease is > 12 months. Prior treatment with TKIs for LAI/metastatic breast cancer (MBC) is not permitted.

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Exclusion Criteria

Treatment with investigational therapy within 28 days prior to initiation of study treatment
Concurrent anti-cancer treatment. Concurrent use of hormonal therapy for noncancer-related conditions (i.e., hormone replacement therapy for hypothyroidism) or for ovarian function suppression is allowed. Ongoing or planned bisphosphonate treatment is allowed in participants with bone metastases.
Based on screening brain MRI, any of the following criteria for participants with brain metastasis: – Progressive neurologic impairment or increased intracranial pressure, which is symptomatic (including nausea, vomiting, blurred vision, headache, epilepsy, etc.) – Any intracranial lesion that is expected to require immediate local therapy. After local therapy, the participant can be re-screened for the protocol. – Requirement for systemic corticosteroids for management of CNS symptoms at a total daily dose of 2 mg of dexamethasone (or equivalent). A stable or tapering dose of 2 mg is permitted. – Requirement for anti-epileptic medication for seizure control, with the exception of stable-dose levetiracetam
Participants who meet one of the following cardiac criteria: – Congestive heart failure (CHF; New York Heart Association [NYHA] functional classification) of 2 – Clinically significant peripheral arterial disease, like coronary artery disease, hypertrophic cardiomyopathy, or dilated cardiomyopathy – Abnormalities in the ECG measurements: such as first-degree heart block, second degree heart block, third-degree heart block, prolonged PR interval: 0.20 s – Any clinically significant supraventricular arrhythmia or ventricular arrhythmia requiring treatment or intervention – Unstable angina – Myocardial infarction within the past 6 months – Percutaneous transluminal coronary angioplasty/stenting, coronary artery bypass graft within 6 months of the first dose of the study treatment – QT interval corrected through use of Fridericia's formula (QTcF) prolongation (470 ms for women and 450 ms for men), a known history of QTcF prolongation or Torsade de Pointes; or is on drugs that are required for existing medical conditions and that may result in QT prolongation (e.g., anti-arrhythmic drugs) – Poorly controlled hypertension (e.g., systolic  180 mm Hg or diastolic  100 mmHg) – History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias such as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular hypertrophy) – Coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing) – Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome
Participants with known active and/or untreated hepatitis B or hepatitis C or chronic liver disease are ineligible. Participants with a diagnosis of hepatitis B or C that has been treated and cleared (viral genetic test should fulfil the local laboratory definition for "cleared"), and normal liver function are eligible to participate in the study if the other eligibility parameters are met. Virologic testing should be conducted according to local institutional practices

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Recruiting	20 Apr 2026	12
Belgium	Recruiting	20 Apr 2026	20
Czechia	Recruiting	20 Apr 2026	10
France	Not Yet Recruiting	20 Apr 2026	24
Germany	Recruiting	20 Apr 2026	40
Hungary	Recruiting	20 Apr 2026	12
Italy	Recruiting	20 Apr 2026	37
Poland	Recruiting	20 Apr 2026	20
Portugal	Recruiting	20 Apr 2026	16
Romania	Not Yet Recruiting	20 Apr 2026	12

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Sites & Investigators

Research sites

Institut Jules Bordet Istituto Oncologico Veneto Hospital Vall d’Hebron IRCCS Humanitas Research Hospital

Investigators

Coralie F.Joao M. P.Claudio V.Vlastimila Č.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
TUCATINIB	Comparator	—	ORAL	600	34	SUB177913
CAPECITABINE	Test	—	ORAL	2000	48	SUB12474MIG
TUCATINIB	Comparator	—	ORAL	600	34	SUB177913
RO7771950	Test	COATED TABLET	ORAL	0	1	PRD13110177
RO7771950	Test	FILM-COATED TABLET	ORAL	0	1	PRD13110176
TRASTUZUMAB	Test	—	SUBCUTANEOUS USE	600	48	SUB12612MIG
CAPECITABINE	Test	—	ORAL	2000	48	SUB12474MIG
TRASTUZUMAB	Test	—	IV INFUSION	8	48	SUB12612MIG