Neoadjuvant Dalpiciclib + AI → SHR-A1811 for HR+/HER2-Low Breast Cancer

Phase 2Not Yet RecruitingNCT07618923

Tang-Du Hospital20 enrolled

Overview

This is a phase II, single-arm, prospective exploratory study to evaluate the efficacy and safety of neoadjuvant dalpiciclib (a CDK4/6 inhibitor) plus an aromatase inhibitor (AI) followed by SHR-A1811 (an anti-HER2 antibody-drug conjugate) in patients with intermediate-to-high risk, hormone receptor-positive (HR+), HER2-low breast cancer. Patients will receive dalpiciclib (125 mg orally once daily, days 1-21, every 4 weeks) plus AI (anastrozole 1 mg, letrozole 2.5 mg, or exemestane 25 mg once daily) for 4 cycles, followed by SHR-A1811 (4.8 mg/kg intravenously every 3 weeks) for 4 cycles. The primary endpoint is objective response rate (ORR) per RECIST 1.1. Secondary endpoints include pathological complete response (pCR), breast-conserving surgery rate, event-free survival (EFS), change in Ki-67 index, and safety. A total of 20 participants will be enrolled.

This is a single-arm, open-label, phase II exploratory trial conducted at a single center (Second Affiliated Hospital of Air Force Medical University, China). The study aims to investigate the activity and safety of dalpiciclib plus an aromatase inhibitor (AI) followed by the HER2-directed antibody-drug conjugate (ADC) SHR-A1811 as neoadjuvant therapy for patients with intermediate-to-high risk, hormone receptor-positive (HR+), HER2-low breast cancer. Preclinical evidence suggests that CDK4/6 inhibition may enhance the immunogenic cell death induced by ADCs and overcome tumor heterogeneity. Dalpiciclib is a selective CDK4/6 inhibitor with a distinct piperidine structure associated with low hepatotoxicity and minimal gastrointestinal side effects. SHR-A1811 is a HER2-targeted ADC composed of a humanized anti-HER2 IgG1 monoclonal antibody (based on trastuzumab sequence), a cleavable maleimide tetrapeptide (GGFG) linker, and a DNA topoisomerase I inhibitor (SHR169265). It demonstrates bystander killing of HER2-low cells. The 4-cycle induction with dalpiciclib plus AI prior to SHR-A1811 is designed to reduce tumor proliferation and potentially prime the tumor microenvironment before ADC administration. Treatment administration * Dalpiciclib: 125 mg orally once daily on days 1-21 of each 28-day cycle (4 cycles total). Patients are instructed to take the tablet at approximately the same time each day, on an empty stomach (≥1 hour before or after food). Missed doses are not supplemented; vomiting within a short time after intake does not trigger a replacement dose. Interruption for \>21 consecutive days requires study discontinuation. Dose reductions follow a stepwise scheme: 125 mg → 100 mg → 75 mg. * Aromatase inhibitor (AI): Investigator's choice of anastrozole 1 mg daily, letrozole 2.5 mg daily, or exemestane 25 mg daily, taken continuously during the first 4 cycles. Premenopausal patients (mandatory) and perimenopausal patients (at investigator's discretion) receive concomitant LHRH agonists (e.g., goserelin or leuprolide). * SHR-A1811: 4.8 mg/kg intravenously over a standard infusion duration on day 1 of each 21-day cycle (4 cycles total). The dose is recalculated based on body weight measured immediately before each cycle. If weight change from baseline is \<10%, no dose adjustment is required. Dose reductions follow a 4.8 → 3.2 mg/kg step. Infusion-related reactions are managed according to a predefined algorithm (slow infusion, antihistamines, corticosteroids, or permanent discontinuation for grade ≥3 reactions).

Eligibility

Sex: FEMALEMin age: 18 YearsMax age: 70 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age ≥18 and ≤70 years 2. Histologically confirmed invasive breast cancer, HR+ (ER ≥1% and/or PR ≥1%) and HER2-low (IHC 1+ or IHC 2+/ISH-) 3. No prior systemic anti-tumor therapy for breast cancer 4. Stage II-III (T1cN1-2M0, T2-4N0-2M0) per AJCC 8th edition 5. At least one of the following intermediate-to-high risk factors: * Axillary lymph node involvement ≥1 * Tumor size≥2 cm * Grade 3 tumor * Ki-67 ≥20% 6. At least one measurable lesion per RECIST 1.1 7. ECOG PS 0-1 8. Adequate organ function (ANC ≥1.5×10⁹/L, platelets ≥100×10⁹/L, Hb ≥90 g/L, TBIL ≤1.5×ULN, ALT/AST ≤2.5×ULN, Cr ≤1.5×ULN or CrCl ≥60 mL/min, LVEF ≥50%, QTcF ≤470 ms in females, DLCO ≥50% predicted 9. Negative pregnancy test (for women of childbearing potential) and agreement to use adequate contraception during and for 6 months after treatment 10. Willing and able to provide informed consent and comply with study procedures Exclusion Criteria: 1. Non-pathologically confirmed breast cancer 2. Bilateral, inflammatory, or occult breast cancer 3. Prior anticancer therapy (chemotherapy, radiotherapy, targeted therapy, endocrine therapy, etc.) 4. Concurrent use of other anticancer treatments 5. Other malignancy within 5 years (except cured basal cell carcinoma or cervical carcinoma in situ) 6. Participation in another interventional clinical trial within 4 weeks prior to first dose 7. Use of immunosuppressive agents or systemic corticosteroids (\>10 mg/day prednisone or equivalent) within 2 weeks prior to first dose 8. Live or attenuated vaccine within 4 weeks prior to first dose 9. Major surgery unrelated to breast cancer within 4 weeks prior to first dose 10. Active or history of autoimmune disease requiring systemic treatment 11. Known immunodeficiency (e.g., HIV positivity) or history of organ transplantation 12. Uncontrolled or significant cardiovascular disease (e.g., NYHA class III/IV heart failure, myocardial infarction, unstable angina, arrhythmia requiring treatment, QTcF \>470 ms, uncontrolled hypertension) 13. Known or suspected interstitial lung disease (ILD) or significant pre-existing pulmonary disease 14. Active hepatitis B (HBsAg positive and HBV DNA ≥500 IU/mL) or hepatitis C (HCV RNA above ULN), cirrhosis, or uncontrolled severe infection 15. Known bleeding or thrombotic tendency 16. Allergy or contraindication to any study drug or excipient 17. Pregnancy, breastfeeding, or positive pregnancy test at baseline 18. Any concurrent condition that may compromise patient safety or study compliance (e.g., uncontrolled hypertension, severe diabetes, active infection) 19. History of neurological or psychiatric disorders (e.g., epilepsy, dementia) or any condition deemed unsuitable by the investigator.

Outcomes

Primary Outcomes

Objective Response Rate (ORR)

Proportion of patients achieving complete response (CR) or partial response (PR) per RECIST 1.1

Time frame: After completion of 8 cycles of neoadjuvant therapy (Cycles 1-4: 28 days/cycle; Cycles 5-8: 21 days/cycle), within 4 weeks prior to surgery

Secondary Outcomes

Pathological Complete Response Rate (pCR): ypT0-is/ypN0

pCR is defined as absence of invasive carcinoma in the breast primary tumor (ypT0/is) and absence of tumor cells in axillary lymph nodes (ypN0) on pathological examination of the surgical specimen after neoadjuvant therapy. Presence of ductal carcinoma in situ (DCIS) alone is allowed.

Time frame: At the time of surgery, performed within 4 weeks after completion of 8 cycles of neoadjuvant therapy (Cycles 1-4: 28 days/cycle; Cycles 5-8: 21 days/cycle).

Breast-Conserving Surgery Rate

Proportion of participants who undergo breast-conserving surgery (BCS) after neoadjuvant therapy. BCS is defined as surgical resection of the primary tumor with negative margins while preserving the breast contour, as opposed to total mastectomy.

Time frame: At the time of surgery

Event-Free Survival (EFS)

EFS is defined as the time from enrollment to the first occurrence of any of the following events: disease progression (local, regional, or distant) during neoadjuvant therapy, disease recurrence after surgery (local, regional, or distant), contralateral breast cancer, any secondary malignancy, or death from any cause. Participants without an event at the time of last follow-up are censored.

Time frame: From enrollment up to 5 years after last patient enrollment (assessed every 3 months during the first year, then every 6 months thereafter

Ki-67 Index Change

Ki-67 index is measured by immunohistochemistry (IHC) as the percentage of tumor cells with positive nuclear staining. The scale is the Ki-67 proliferation index, which ranges from 0% (minimum) to 100% (maximum). Higher scores indicate a worse outcome (higher proliferative activity). The change is calculated as Ki-67 index at surgery minus Ki-67 index at baseline. A negative value (reduction) indicates a better outcome (decreased proliferation), while a positive value (increase) indicates a worse outcome.

Time frame: Baseline (pre-treatment core needle biopsy) and at surgery (post-neoadjuvant surgical specimen).

Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs)

Safety outcomes include: incidence of any AE, incidence of grade ≥3 AE (per NCI-CTCAE version 6.0), incidence of SAEs, incidence of AE leading to treatment discontinuation or dose modification, and incidence of AE by system organ class and preferred term. Laboratory abnormalities, vital signs, ECG parameters (QTcF, heart rate), and left ventricular ejection fraction (LVEF) are also summarized.

Time frame: From signing of informed consent through 30 days after the last dose of study drug, or until initiation of new anticancer therapy, whichever occurs first.