The Exploratory Randomized Phase II Study of Trastuzumab Deruxtecan Versus Endocrine Therapy of Physician's Choice in Low-HER2 Expressing Hormone Receptor-positive Advanced Breast Cancer Patients
This is a randomized phase II, two-arm, open label, clinical trial to identify LP-WGS ctDNA biomarker to predict T-DXd response in low-HER2 expressing advanced breast cancer patients compared with endocrine therapy. The hormone receptor (HR)-positive low-HER2 advanced breast cancer patients (HER2 IHC 1+ or 2+ \& ISH negative, n=141) who progressed on 1st line endocrine + CDK4/6 inhibitor therapy and received no other systemic therapy for advanced disease are enrolled in this study. Patients are 2:1 randomized to receive T-DXd (5.4mg/kg every 3 weeks, n=94) or endocrine therapy of physician's choice (TPC: fulvestrant, fulvestrant + alpelisib, Fulvestrant + Capivasertib, exemestane, exemestane + everolimus, or tamoxifen, n=47, fulvestrant + alpelisib can be selected in PIK3CA activating mutation positive patients, Fulvestrant + Capivasertib can be selected in 1 or More mutation positive of PIK3CA/AKT1/PTEN). The mandatory baseline archival tissue and ctDNA collection followed by on-treatment ctDNA collection (Cycle 1, Cycle 2, and Cycle 6) and ctDNA collection at progression will be performed in this study. The primary endpoint is PFS after randomization in two treatment arms. The secondary endpoints include overall survival (OS), objective response rate (ORR), progression-free survival (PFS2), adverse events by CTCAE 5.0 criteria, and Quality of life (QoL) measured by EORTC-QLQ-C30 and EORTC-QLQ-BR23 evaluated by questionnaire. The exploratory endpoints are to identify ctDNA biomarkers to predict the TDxd treatment outcome (PFS, OS, ORR) compared to endocrine therapy in HER2-low advanced breast cancer patients and to assess the accordance of genomic profiles between ctDNA and tumor tissues. Predictive biomarkers include copy number aberration (CNA) of gene loci, total ctDNA CNA burden, mutations, ctDNA-based molecular subtype, or HER2 amplicon copy number on LP-WGS ctDNA analysis. The investigator believe this trial will identify crucial circulating biomarkers for T-DXd treatment response in low-HER2 patients, which can guide right patient selection and potential molecular target identification to maximize T-DXd response and to overcome T-DXd resistance.
• Histologically or cytologically confirmed hormone receptor-positive advanced breast cancer patients
∙ Have recurrent, metastatic, or unresectable disease
‣ Have HER2-low expression status, defined as IHC 2+/ISH- or IHC 1+,with a validated assay by ASCO/CAP guidelines
‣ Have no previous history of HER2-positive breast cancer (IHC 3+ or ISH+) by ASCO/CAP guidelines
‣ The hormone receptor (HR) status is defined by ER/PR IHC nuclear staining, and ER or PgR ≥1% is defined as hormone receptor-positive status
• Patients who progressed on 1st line endocrine + CDK4/6 inhibitor therapy for advanced breast cancer and received no other systemic therapy for advanced breast cancer. The all FDA-approved CDK4/6 inhibitors (palbociclib, ribociclib, and Abemaciclib) are allowed, and combination with aromatase inhibitors or fulvestrant are both allowed.
• Patients who have received chemotherapy or adjuvant endocrine therapy in the neo-adjuvant or adjuvant setting are eligible.
• Female patients with ≥19 years of age
• Radiologic or objective evidence of disease progression on or after the last systemic therapy prior to starting study treatment
• Patients must have at least one measurable lesion by RECIST 1.1 criteria, which was not previously irradiated or showed objective progression after irradiation to that lesion
• Patients must have an adequate tumor tissue sample available for assessment of HER2 by central laboratory and other exploratory biomarker analyses
• Patients with ECOG performance status 0 or 1
• Both pre- and post-menopausal patients are eligible, and pre-menopausal patients should receive ovarian function suppression treatment (GnRH agonist injection or surgical bilateral oophorectomy) while receiving fulvestrant or aromatase inhibitor treatment in the control arm.
⁃ Adequate organ function for treatment Adequate organ and bone marrow function within 14 days before randomization/enrolment as described below:
⁃ a) Haemoglobin: ≥ 9.0 g/dL NOTE: Participants requiring ongoing transfusions or growth factor support to maintain haemoglobin ≥9.0 g/dL are not eligible. (Red blood cell transfusion is not allowed within 1 week prior to C1D1) b) Serum albumin: ≥ 2.5 g/dL c) International normalised ratio or Prothrombin time and either partial thromboplastin or activated partial thromboplastin time: ≤ 1.5 × ULN d) Absolute neutrophil count (ANC) ≥1500 cells/mm3
‣ granulocyte-colony stimulating factor administration is not allowed within 1 week prior to C1D1 ) e) Platelets ≥100,000 cells/mm3
‣ Platelet transfusion is not allowed within 1 week prior to C1D1) f) Estimated creatinine clearance ≥50 mL/min, or serum creatinine \<1.5x institution upper limit of normal (ULN) g) Bilirubin≤1.5 x ULN
‣ if no liver metastases or \< 3×ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline h) AST (SGOT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases) i) ALT (SGPT) ≤2.5 x ULN (5.0 x ULN if hepatic metastases)
⁃ 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant changes that do not require medical intervention
⁃ QTc interval ≤470 msec and without history of Torsades de pointes based on average of the screening triplicate 12-lead ECG
⁃ Pointes or other symptomatic QTc abnormality
⁃ LVEF (by MUGA or echocardiogram) of ≥50% within 28 days before randomization/enrollment
⁃ No history of pneumonitis other than radiation pneumonitis
⁃ The patient has provided signed informed consent
⁃ Neither pregnant or breastfeeding female patients
⁃ Fertile women who are not in pregnancy or breastfeeding should use effective contraception for a period from two weeks before the start of research treatment, during treatment and up to seven months after last dose of study treatment
⁃ No other concurrent severe and/or uncontrolled medical disease which could compromise study participation, including any of the following:
⁃ Adequate treatment washout period before enrollment are below -Major surgery ≥ 4 weeks -Radiation Therapy including palliative stereotactic radiation therapy to chest ≥ 4 weeks -Palliative stereotactic radiation therapy to other anatomic areas including whole brain radiation ≥ 2 weeks -Anti-Cancer chemotherapy \[Immunotherapy (non-antibody based therapy)\], retinoid therapy, hormonal therapy ≥ 3 weeks -Antibody based anti-cancer therapy ≥ 4 weeks -Targeted agents and small molecules ≥ 2 weeks or 5 half-lives, whichever is longer -Nitrosoureas or mitomycin C ≥ 6 weeks -Chloroquine/Hydroxychloroquine ≥ 14 days -Cell-free and CART, peritoneal shunt or drainage of pleural effusion, ascites or pericardial effusion ≥ 2 weeks prior to screening assessment