Sponsor: Hoffmann-La Roche (industry)
Phase: 2/3
Start date: May 21, 2026
Planned enrollment: 650
Perzebertinib (ZN-A-1041; RG6596) is an orally administered, selective HER2 tyrosine kinase inhibitor designed to cross the blood–brain barrier (BBB). It is being developed for HER2‑positive solid tumors, with an emphasis on metastatic breast cancer with brain metastases (BCBM). Roche/Genentech acquired global rights from Zion Pharma in May 2023. (ascopubs.org)
Active clinical development includes: - First‑in‑human Phase 1 study of monotherapy and combinations with capecitabine plus trastuzumab, trastuzumab emtansine (T‑DM1), or trastuzumab deruxtecan (T‑DXd) in HER2‑positive advanced solid tumors (including BCBM): NCT04487236 and NCT05593094. Site listings indicate the program began in 2020, with current estimated study end around October 2026. (ascopubs.org) - A healthy‑volunteer Phase 1 relative bioavailability/food–PPI interaction study of new tablet formulations (NCT07051993; sponsor Genentech). (genentech-clinicaltrials.com)
An International Nonproprietary Name (INN) record lists the drug name as perzebertinib; synonyms include ZN‑A‑1041 and ZN‑1041 (CAS 2414056‑31‑6). (guidetopharmacology.org)
Perzebertinib is a selective small‑molecule inhibitor of HER2 kinase activity. Preclinical and early clinical reports emphasize BBB penetrance and lack of substrate behavior for the efflux transporters P‑gp (ABCB1) and BCRP (ABCG2), features intended to enhance CNS exposure; a cerebrospinal fluid unbound partition coefficient (Kpuu,CSF) of 4.9 was reported. (ascopubs.org)
Early clinical signals have been reported in ASCO 2023 meeting abstracts:
These are early, small cohorts without randomized controls; mature efficacy outcomes (e.g., progression‑free survival, duration of response) have not yet been reported in peer‑reviewed full manuscripts as of October 7, 2025. Ongoing Phase 1 trials (NCT04487236, NCT05593094) are designed to further characterize activity. (mycancergenome.org)
Across Phase 1a/1b experiences reported to date: - Monotherapy up to 800 mg BID showed no dose‑limiting toxicities; most treatment‑related adverse events (TRAEs) were grade 1, with nausea (43%) and vomiting (29%) common; ≥grade 2 diarrhea was not observed in the reported dataset. (ascopubs.org) - In the capecitabine + trastuzumab combination (Phase 1c, BCBM), grade ≥3 adverse reactions (≥5%) included hepatic function impairment (8.7%), headache (8.7%), hyperbilirubinemia (5.7%), elevations in ALT/AST/GGT (each 5.7%), and decreased WBC (5.7%). (ascopubs.org) - Combination with T‑DXd at 800 mg BID reported no dose‑limiting toxicities in the small cohort described. (ascopubs.org)
Comprehensive safety profiles (e.g., exposure‑adjusted AE rates, ILD/pneumonitis risk with antibody–drug conjugate combinations) will require larger and longer‑term datasets.
Notes: Publicly available data as of October 7, 2025 derive largely from conference abstracts and trial registries; peer‑reviewed, full‑length clinical publications were not identified. (ascopubs.org)
Last updated: Oct 2025
Goal: To determine whether the blood-brain barrier–penetrant HER2 tyrosine kinase inhibitor RO7771950, combined with trastuzumab and capecitabine, improves efficacy relative to tucatinib with the same backbone, while assessing safety, tolerability, patient-reported outcomes, and pharmacokinetics. The study is designed to evaluate both systemic and intracranial disease control.
Patients: Patients have centrally confirmed HER2-positive unresectable locally advanced or metastatic breast cancer after at least one prior metastatic anti-HER2 regimen. Prior anti-HER2 antibody-drug conjugate therapy is generally required; patients must be TKI-naïve in the advanced-disease setting, have ECOG performance status 0–1, LVEF at least 50%, and adequate organ and marrow function. Patients with previously treated, untreated, stable, or progressive CNS metastases, including leptomeningeal metastases, are eligible. Stage 1 requires RECIST-measurable disease, whereas stage 2 allows nonmeasurable disease.
Design: This is a multicenter, randomized, open-label, seamless adaptive phase II/III study. Participants are assigned to one of two RO7771950 dose groups or an active-control tucatinib group, each with trastuzumab and capecitabine. The adaptive two-part structure is intended to support dose selection and subsequent comparative efficacy assessment. Blinded independent central review is used for key radiographic endpoints.
Treatments: The experimental groups receive one of two dose levels of oral RO7771950 plus trastuzumab and capecitabine. RO7771950, also known as ZN-A-1041, is a selective HER2-targeted TKI engineered for blood-brain barrier penetration and is not a substrate of the P-gp or BCRP efflux transporters. Early-phase studies have reported intracranial activity, including a 73.7% intracranial response rate among 19 evaluable patients in one expansion cohort, with mostly low-grade nausea and vomiting in monotherapy testing; these preliminary, small-cohort findings remain unconfirmed. The comparator is oral tucatinib, an established HER2-selective TKI with demonstrated CNS activity, combined with trastuzumab and capecitabine.
Outcomes: The primary endpoint is progression-free survival by blinded independent central review using RECIST v1.1, assessed over approximately 35 months. Secondary efficacy endpoints include overall survival, objective response rate, clinical benefit rate, duration of response, and corresponding CNS-specific measures, including PFS-CNS, ORR-CNS, DOR-CNS, and CBR-CNS. Additional assessments include adverse-event incidence and severity, cardiac function, suicidality, RO7771950 pharmacokinetics, brain-tumor symptoms, global function and health-related quality of life, treatment-related symptoms and side-effect burden, and EQ-5D-5L health utility.
Burden on patient: Estimated burden is moderate to high. Treatment includes ongoing oral therapy plus repeated trastuzumab infusions, requiring regular clinic attendance, laboratory monitoring, and tumor and CNS imaging; pharmacokinetic blood sampling may add visits or extend selected visits. Serial echocardiography or MUGA, adverse-event evaluations, ECG and electrolyte monitoring as clinically required, and multiple quality-of-life and symptom questionnaires add further burden. No mandatory research biopsy is specified, so most procedures overlap with intensive standard monitoring for metastatic HER2-positive breast cancer, but the cumulative travel and assessment schedule is substantial.
Last updated: Sep 2026
Inclusion Criteria:
* Pathologically documented locally advanced inoperable (LAI) or metastatic breast cancer (MBC) with confirmed HER2-positive status by central laboratory.
* Measurable disease as per by RECIST v1.1 in stage 1. Non-measurable disease allowed in stage 2.
* Previously treated (stable or progressive) or previously untreated CNS metastases, or leptomeningeal metastases.
* At least one prior line of anti-HER2-based therapy for LAI or metastatic disease.
* Prior anti-HER2 antibody-drug conjugate (ADC), such as trastuzumab-deruxtecan (T-DXd) or trastuzumab emtansine (T-DM1), in any treatment setting. Participants without prior ADC therapy may only be enrolled if approved standard-of-care (SOC) anti-HER2 ADC is not locally accessible at screening, or if there is a prospectively documented clinical contraindication.
* Prior tyrosine kinase inhibitor (TKI) in the (neo)adjuvant setting provided completion is \> 12 months ahead of LAI occurrence. Prior treatment with TKIs for LAI/MBC is not permitted.
* Has protocol-defined adequate organ and bone marrow function.
* Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
* Baseline left ventricular ejection fraction (LVEF) ≥ 50%.
Exclusion Criteria:
* Concurrent anti-cancer treatment, or treatment with investigational therapy within 28 days prior to initiation of study treatment.
* Known active/untreated hepatitis B or C or chronic liver disease.
* Clinically significant cardiovascular disease or risk, including heart failure (New York Heart Association (NYHA) ≥ II), ischemic heart disease or recent coronary events/interventions, clinically significant arrhythmias or electrocardiogram (ECG) abnormalities, QT prolongation or risk of ventricular dysrhythmias, poorly controlled hypertension, peripheral arterial disease, dilated cardiomyopathy, or unstable angina.
* Clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.
* Concomitant use of any drug or herbal medicine known to strongly inhibit or induce CYP3A4 or CYP2C8 activity, oral coumarin-derivative anticoagulants.
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