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

Dalpiciclib Combined With Aromatase Inhibitor (AI) Followed by SHR-A1811 as Neoadjuvant Therapy in Patients With Intermediate-to-High Risk HR+/HER2-Low Breast Cancer: A Phase II Exploratory Study

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).

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.