QL1706 Plus Neoadjuvant Endocrine Therapy in HR-Positive/HER2-Negative Breast Cancer With a Poor Response to Neoadjuvant Chemotherapy

Efficacy and Safety of QL1706 Combined With Neoadjuvant Endocrine Therapy in Patients With HR-Positive/HER2-Negative Breast Cancer Showing a Poor Response to Neoadjuvant Chemotherapy: A Prospective, Randomized Controlled Clinical Trial

This study will evaluate whether adding QL1706 (iparomlimab and tuvonralimab) to neoadjuvant endocrine therapy improves tumor response in patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer who have had a poor response to neoadjuvant chemotherapy.

Approximately 40 participants whose tumors have decreased by less than 40% on magnetic resonance imaging after two cycles of neoadjuvant TAC chemotherapy will be randomly assigned in a 1:1 ratio to receive either an aromatase inhibitor plus a CDK4/6 inhibitor or the same treatment combined with QL1706. Premenopausal and perimenopausal participants will also receive ovarian function suppression.

The main outcome is the objective response rate during the study treatment period. Pathological response, changes in Ki-67, treatment safety, and changes in the tumor immune microenvironment will also be evaluated.

Inclusion Criteria:

1. Female participants aged 18 to 75 years.
2. Histologically or pathologically confirmed HR-positive/HER2-negative early or locally advanced breast cancer, classified as stage IIB-IIIC, with a poor response to two cycles of neoadjuvant TAC chemotherapy. Chemotherapy sensitivity is defined as a reduction in tumor size of at least 40% on magnetic resonance imaging (MRI), whereas a poor response is defined as a reduction in tumor size of less than 40%.
3. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
4. No prior antitumor treatment other than the two cycles of neoadjuvant TAC chemotherapy specified in this study, including no prior immune checkpoint inhibitor therapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy of at least 12 weeks.
7. No coagulation abnormalities.
8. Normal cardiac function, a normal electrocardiogram, and a left ventricular ejection fraction of at least 55%.
9. Willingness to provide tumor tissue and/or blood samples at baseline and after treatment for biomarker analyses. Participants with insufficient tumor tissue or those unwilling to provide biological samples may be enrolled only with the investigator's approval.
10. Adequate major organ function, as defined by the following laboratory criteria: absolute neutrophil count greater than 1.5 × 10^9/L; platelet count greater than 100 × 10^9/L; hemoglobin greater than 100 g/L; total serum bilirubin less than 1.5 × the upper limit of normal (ULN); alanine aminotransferase and aspartate aminotransferase less than 3 × ULN; and serum creatinine no greater than 1.5 × ULN.
11. Ability to understand and comply with the study requirements and willingness to provide written informed consent.

Exclusion Criteria:

1. Known hypersensitivity to any study drug or any of its excipients.
2. Inflammatory breast cancer, bilateral breast cancer, or advanced breast cancer with distant metastases.
3. A history of another malignancy within the past 5 years, except for malignancies treated with curative intent.
4. Serious concomitant diseases, including extensive interstitial pneumonitis requiring pharmacological treatment; active or uncontrolled infection, including tuberculosis or human immunodeficiency virus infection; decompensated liver disease; active hepatitis; active bleeding; a history of cerebrovascular events or pulmonary embolism; active, known, or suspected autoimmune disease; or an active infection currently requiring systemic anti-infective therapy.
5. Active brain metastases or leptomeningeal metastases, unless the metastases have been treated and are stable.
6. Pregnancy, planned pregnancy, or breastfeeding.
7. Any other condition that, in the investigator's opinion, makes the participant unsuitable for enrollment.