First-Line Ribociclib Plus Endocrine Therapy Versus Chemotherapy With or Without Subsequent Endocrine Therapy in Patients With Rapidly Progressive HR-Positive/HER2-Negative Advanced Breast Cancer

Efficacy and Safety of First-Line Ribociclib Plus Endocrine Therapy Versus Chemotherapy With or Without Subsequent Endocrine Therapy in Patients With Rapidly Progressive HR-Positive/HER2-Negative Advanced Breast Cancer: A Multicenter, Nonrandomized Phase II Study With an External Control

This phase II study focuses on women with rapidly progressive hormone receptor-positive and HER2-negative advanced breast cancer, including patients with symptomatic visceral metastases, rapidly increasing tumor burden, impending organ dysfunction, or highly symptomatic non-visceral disease. These patients often require prompt and effective systemic treatment.

The purpose of the study is to determine whether first-line ribociclib combined with endocrine therapy can provide effective and rapid tumor control compared with chemotherapy-based treatment. Women in the prospective study group receive ribociclib plus endocrine therapy, with ovarian function suppression when clinically indicated. Their outcomes are compared with data from patients previously treated at the same participating hospitals with combination chemotherapy, with or without subsequent endocrine maintenance therapy.

The main outcome is the objective response rate, defined as the proportion of patients whose tumors shrink or disappear. Other outcomes include progression-free survival, overall survival, clinical benefit, time to response, treatment safety, and quality of life.

This study focuses on patients with rapidly progressive hormone receptor-positive, HER2-negative advanced breast cancer, a population for whom prompt systemic disease control is clinically important. Rapid progression may include symptomatic visceral metastases, rapidly increasing tumor burden, impending organ dysfunction, or highly symptomatic non-visceral disease.

The study was initially designed as a prospective, multicenter, randomized phase II trial. Owing to difficulties in prospectively recruiting patients to the chemotherapy control arm, the protocol was amended to include a prospective ribociclib plus endocrine therapy cohort and a retrospective external control cohort. Following statistical consultation, objective response rate was designated as the primary endpoint, with progression-free survival retained as a key secondary endpoint.

Under the amended design, eligible patients receiving first-line ribociclib plus endocrine therapy are enrolled prospectively. Their outcomes are compared with an external control cohort selected from patients treated at the same participating hospitals who received first-line combination chemotherapy, with or without subsequent endocrine maintenance therapy. External control patients are identified from electronic medical records and institutional clinical databases and are required to meet eligibility criteria comparable to those applied to the prospective cohort. The historical control period extends from January 2020 to January 2024.

Objective response rate was designated as the primary endpoint because it directly evaluates early antitumor activity in this phase II setting and was used as the basis for the revised sample-size calculation. Progression-free survival remains a key secondary endpoint. To reduce confounding associated with the nonrandomized external-control design, the study will use predefined eligibility criteria, standardized outcome definitions, and propensity score-based methods, including inverse probability weighting and propensity score matching, with additional multivariable analyses as appropriate.

The major protocol amendment was incorporated into Protocol Version 4.0, dated 28 December 2025, and was approved by the Ethics Committee of the First Affiliated Hospital of Nanjing Medical University on 21 January 2026 under approval number 2023-SR-880.A1.

Inclusion criteria for the prospective cohort

1. Female patient aged 18 years or older.
2. ECOG PS of 0-2.
3. Histologically or cytologically confirmed recurrent, metastatic, or unresectable locally advanced breast cancer not amenable to curative surgery or radiotherapy.
4. HR-positive/HER2-negative disease: ER expression in at least 10% of tumor-cell nuclei; HER2 IHC 0 or 1+, or IHC 2+ with negative FISH/ISH. When metastatic-tissue pathology is available, the metastatic result is preferred.
5. At least one feature of rapid disease progression, as determined by the investigator: symptomatic visceral metastasis; rapidly progressive disease or impending visceral compromise; or markedly symptomatic nonvisceral disease.
6. No prior systemic anticancer therapy for recurrent or metastatic disease. Prior neoadjuvant or adjuvant therapy is permitted.
7. At least one measurable lesion according to RECIST 1.1.
8. Postmenopausal, premenopausal, or perimenopausal status. Premenopausal or perimenopausal patients must agree to receive OFS.
9. Adequate baseline organ function: hemoglobin at least 90 g/L; white blood cell count at least 3.5 × 10^9/L; absolute neutrophil count at least 1.5 × 10^9/L; platelet count at least 100 × 10^9/L; serum creatinine not above the institutional ULN; and clinically acceptable hepatic function.
10. Negative pregnancy test for patients of childbearing potential and agreement to use effective contraception according to applicable product information and institutional requirements.
11. Written informed consent and ability to comply with treatment and follow-up procedures.

Exclusion criteria for the prospective cohort

1. Prior systemic anticancer therapy for recurrent or metastatic disease.
2. Prior CDK4/6 inhibitor therapy in the neoadjuvant or adjuvant setting.
3. Symptomatic central nervous system metastasis requiring urgent local intervention. Treated, clinically stable, asymptomatic CNS metastasis may be permitted at investigator discretion.
4. Known contraindication or serious hypersensitivity to ribociclib or the selected endocrine agent.
5. Clinically significant uncontrolled cardiac disease, arrhythmia, congenital long-QT syndrome, uncorrected electrolyte abnormality, or baseline QTcF at or above 450 ms.
6. Severe or active cardiovascular, hepatic, respiratory, renal, hematologic, infectious, or psychiatric disease that may increase risk or interfere with efficacy assessment.
7. Inability to swallow oral medication or clinically significant gastrointestinal disease that may impair drug absorption.
8. Pregnancy or breastfeeding.
9. Clinical condition judged by the investigator to preclude safe systemic treatment.
10. Any other condition that, in the investigator's opinion, makes participation inappropriate.

Eligibility for the historical external control cohort

The external control cohort must satisfy the same core disease, treatment-line, biomarker, rapid-progression, and measurable-disease criteria as the prospective cohort. The following retrospective adaptations are permitted:

• ECOG PS may be taken from an explicit medical-record entry. If functional descriptions are mapped to ECOG PS according to a prespecified rule, the inferred status will be flagged and excluded in sensitivity analyses.
• Rapid disease progression will be determined from contemporaneous symptoms, laboratory findings, imaging descriptions, physician notes, and the treatment-decision context.
• Baseline laboratory values will be the closest available results within the prespecified window before the index chemotherapy date.
• At least one measurable lesion must be retrospectively assessable according to RECIST 1.1. Patients with unavailable or inadequate imaging will be excluded.
• Patients with critically missing baseline covariates, treatment details, tumor-response information, or follow-up outcomes will be excluded according to prespecified data-quality rules.