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

Patients with HR-positive/HER2-negative breast cancer may have an inadequate response to neoadjuvant chemotherapy, and an optimal subsequent neoadjuvant treatment strategy for this population has not been established. QL1706 is a bifunctional combination antibody consisting of iparomlimab, which targets programmed cell death protein 1 (PD-1), and tuvonralimab, which targets cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Simultaneous inhibition of these immune checkpoints may enhance antitumor immune activity. This study will explore whether the addition of QL1706 to endocrine therapy and CDK4/6 inhibition improves tumor response in patients who have had a poor early response to neoadjuvant chemotherapy.

This is an exploratory, open-label, prospective, randomized controlled study. Approximately 40 women with stage IIB-IIIC HR-positive/HER2-negative early or locally advanced breast cancer will be enrolled. Eligible participants must have received two cycles of neoadjuvant TAC chemotherapy and have a reduction in tumor size of less than 40% on magnetic resonance imaging. Participants will be randomly assigned in a 1:1 ratio to the experimental arm or the active comparator arm.

Participants in the active comparator arm will receive an aromatase inhibitor plus a CDK4/6 inhibitor. Participants in the experimental arm will receive the same treatment combined with QL1706 at 5 mg/kg by intravenous infusion on Day 1 of each 3-week cycle for six cycles. Premenopausal and perimenopausal participants will receive ovarian function suppression. Surgery will be performed after completion of neoadjuvant treatment based on clinical assessment.

The primary outcome is the objective response rate according to Response Evaluation Criteria in Solid Tumors version 1.1. Secondary outcomes include breast pathological complete response, total pathological complete response, Miller-Payne grade, residual cancer burden class, changes in Ki-67 expression, and the incidence of immune-related and other adverse events. Exploratory analyses will assess changes in the tumor immune microenvironment, including immune-cell infiltration and the expression of PD-1, programmed death-ligand 1, and CTLA-4, using blood and tumor specimens collected at protocol-specified time points.

• Iparomlimab and Tuvonralimab (QL1706) (Drug): Iparomlimab and tuvonralimab (QL1706) will be administered intravenously at 5 mg/kg on Day 1 of each 3-week cycle for six cycles.
• Aromatase Inhibitor (AI) (Drug), also known as Exemestane, Anastrozole, Letrozole: Participants will receive exemestane, anastrozole, or letrozole. The specific aromatase inhibitor, dose, and administration schedule will be selected according to the applicable prescribing information or clinical guidelines and will be continued throughout the approximately 18-week neoadjuvant treatment period.
• CDK4/6 inhibitor (Drug), also known as Abemaciclib, Ribociclib: Participants will receive abemaciclib or ribociclib. The specific CDK4/6 inhibitor, dose, and administration schedule will be selected according to the applicable prescribing information or clinical guidelines and will be continued throughout the approximately 18-week neoadjuvant treatment period.
• Ovarian function suppression (Drug), also known as Goserelin, Leuprorelin, Triptorelin: Premenopausal and perimenopausal participants will receive ovarian function suppression with goserelin, leuprorelin, or triptorelin. The specific agent, dose, and administration schedule will follow the applicable prescribing information or clinical guidelines.

Primary outcomes

• Objective Response Rate (ORR) [From randomization through the preoperative assessment after six treatment cycles, approximately 18 weeks]: The proportion of participants whose best overall response is complete response (CR) or partial response (PR), as assessed by computed tomography or magnetic resonance imaging according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). ORR will be calculated as the number of participants achieving CR or PR divided by the total number of participants included in the efficacy analysis, multiplied by 100%.

Secondary outcomes

• Breast Pathological Complete Response Rate (bpCR) [At surgery after completion of six treatment cycles, approximately 18 weeks after randomization]
• Total Pathological Complete Response Rate (tpCR) [At surgery after completion of six treatment cycles, approximately 18 weeks after randomization]
• Miller-Payne Grade [At surgery after completion of six treatment cycles, approximately 18 weeks after randomization]: Pathological response of the primary breast tumor will be assessed using the Miller-Payne grading system, which ranges from Grade 1 to Grade 5. Grade 1 indicates no or minimal reduction in tumor cells, whereas Grade 5 indicates no identifiable malignant cells at the primary tumor site. A higher grade indicates a better pathological response to treatment.
• Residual Cancer Burden (RCB) Class [At surgery after completion of six treatment cycles, approximately 18 weeks after randomization]: Residual cancer burden will be assessed in the resected breast and regional lymph nodes and classified as RCB-0, RCB-I, RCB-II, or RCB-III. RCB-0 indicates no residual invasive cancer, whereas RCB-III indicates extensive residual disease. A higher RCB class indicates a greater residual tumor burden and a worse pathological response to treatment.
• Incidence of Immune-Related Adverse Events [From the first dose of study treatment through 30 days after the last dose, approximately 22 weeks]
• Change From Baseline in Ki-67 Expression [From baseline to surgery after completion of six treatment cycles, approximately 18 weeks]: Ki-67 expression will be assessed by immunohistochemistry in tumor tissue obtained at baseline and at surgery and reported as the percentage of positively stained tumor cells (range, 0% to 100%). Change from baseline will be calculated as the value at surgery minus the baseline value and reported in percentage points (possible range, -100 to 100). A negative value indicates a reduction in Ki-67 expression, with a more negative value indicating greater suppression of tumor cell proliferation.

Other outcomes

• Change in Tumor Immune-Cell Infiltration [From baseline to surgery after completion of six treatment cycles, approximately 18 weeks]
• Change in PD-1 Expression [From baseline to surgery after completion of six treatment cycles, approximately 18 weeks]
• Change in PD-L1 Expression [From baseline to surgery after completion of six treatment cycles, approximately 18 weeks]
• Change in CTLA-4 Expression [From baseline to surgery after completion of six treatment cycles, approximately 18 weeks]
• Change in ESTIMATE Score [From baseline to surgery after completion of six treatment cycles, approximately 18 weeks]: The ESTIMATE score will be calculated from tumor gene-expression data using the ESTIMATE algorithm at baseline and at surgery. The ESTIMATE score is a continuous, data-dependent measure without fixed minimum or maximum values. A higher score indicates a greater overall proportion of immune and stromal components and lower estimated tumor purity; a positive change indicates an increase in these non-tumor components after treatment.

Sex: Female, ages: 18 Years to 75 Years

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.