Editor’s Note
In the second-line treatment of hormone receptor–positive, HER2-negative (HR+/HER2–) advanced breast cancer, CDK4/6 inhibitors combined with fulvestrant have become the standard of care. However, variations in efficacy and safety profiles among different inhibitors remain an important clinical consideration.
At the 2025 European Society for Medical Oncology (ESMO) Annual Congress, held in Berlin from October 17 to 21, a study led by Prof. Jiayu Wang from the Cancer Hospital, Chinese Academy of Medical Sciences, was selected for poster presentation (Abstract #600P). The study presented a matching-adjusted indirect comparison (MAIC) of bireociclib plus fulvestrant versus dalpiciclib plus fulvestrant as second-line treatment for HR+/HER2– advanced breast cancer.
Results showed that bireociclib achieved comparable or even superior survival outcomes to dalpiciclib, while significantly reducing hematologic toxicity. These findings suggest that bireociclib could be an optimal option for patients at risk of bone marrow suppression, providing new evidence to guide individualized therapy. The study also reflects the growing contributions of Chinese researchers to the field of precision oncology.
Study Overview
Background
HR+/HER2– advanced breast cancer is the most common subtype of metastatic breast cancer, representing approximately 70% of all cases. For patients who progress on prior endocrine therapy, combining CDK4/6 inhibitors with fulvestrant has become the established standard of care, significantly prolonging both progression-free survival (PFS) and overall survival (OS).
Dalpiciclib is a selective CDK4/6 inhibitor. In the phase III DAWNA-1 trial (NCT03927456), dalpiciclib plus fulvestrant achieved a median PFS of 15.7 months compared with 7.2 months in the placebo plus fulvestrant group (HR 0.42; 95% CI 0.31–0.58; P < 0.0001). However, this regimen was associated with a high rate of hematologic toxicities, including grade ≥3 neutropenia (84.2%) and leukopenia (62.1%), though gastrointestinal events were rare.
Bireociclib is a next-generation, highly selective CDK4/6 inhibitor with an 18-fold stronger inhibitory effect on CDK4 compared to CDK6, and additional activity against CDK2 and CDK9, potentially conferring distinct biological properties. In the phase III BRIGHT-2 trial (NCT05077449), bireociclib plus fulvestrant demonstrated encouraging efficacy, achieving a median PFS of 14.69 months versus 7.33 months for placebo (HR 0.462; 95% CI 0.333–0.642; P < 0.0001). Unlike other CDK4/6 inhibitors, bireociclib showed relatively low hematologic toxicity but a higher incidence of gastrointestinal and hepatic events.
Given the absence of head-to-head clinical trials, this MAIC analysis aimed to indirectly compare the efficacy and safety of bireociclib plus fulvestrant and dalpiciclib plus fulvestrant as second-line therapy for HR+/HER2– advanced breast cancer.
Study Design and Methods
The MAIC analysis used individual patient-level data from the BRIGHT-2 trial (bireociclib + fulvestrant, n=204; placebo + fulvestrant, n=101) and aggregated data from the DAWNA-1 trial (dalpiciclib + fulvestrant, n=241; placebo + fulvestrant, n=120).
Patients from BRIGHT-2 were statistically reweighted to match key baseline characteristics of the DAWNA-1 population, including age, ECOG performance status, type of endocrine resistance (primary vs. secondary), presence of visceral metastases, prior chemotherapy for advanced disease, and menopausal status. After adjustment, the effective sample size (ESS) was 227 patients, confirming balanced cohorts.
The primary endpoint was investigator-assessed PFS per RECIST 1.1 criteria, while secondary endpoints included independent review committee (IRC)-assessed PFS and safety outcomes (treatment-emergent adverse events [TEAEs]) reported as odds ratios (OR) with 95% confidence intervals (CIs).
Key Findings
After matching, bireociclib plus fulvestrant achieved a median investigator-assessed PFS of 17.5 months, compared with 15.7 months for dalpiciclib plus fulvestrant. In the IRC-assessed analysis, bireociclib’s median PFS reached 23.1 months, significantly longer than 13.6 months for dalpiciclib. The six- and twelve-month PFS rates were 76.6% and 60.1% for bireociclib, compared with 76.4% and 51.8% for dalpiciclib, respectively.
In terms of safety, bireociclib demonstrated a clearly more favorable hematologic profile. The risks of neutropenia, leukopenia, and thrombocytopenia were substantially reduced, with odds ratios of 0.23, 0.24, and 0.46, respectively. For grade ≥3 neutropenia and leukopenia, the odds ratios were as low as 0.11 and 0.18, corresponding to a six- to ninefold reduction compared with dalpiciclib.
However, bireociclib was associated with a higher incidence of anemia (any grade OR 1.77; grade ≥3 OR 6.73) and gastrointestinal and hepatic adverse events. Diarrhea occurred in 93.6% of patients (grade ≥3 in 7.7%), whereas it was rare in the dalpiciclib group. Elevations in ALT and AST were also more frequent in the bireociclib arm, but these toxicities were typically manageable with supportive care and dose adjustments.
Conclusions
This MAIC analysis suggests that bireociclib plus fulvestrant is a promising second-line treatment option for patients with HR+/HER2– advanced breast cancer who have progressed after endocrine therapy. Bireociclib achieved comparable or better efficacy than dalpiciclib, particularly in IRC-assessed PFS, while showing a distinct safety advantage in reducing hematologic toxicity.
The notably lower rates of severe neutropenia and leukopenia may improve treatment adherence and reduce dose interruptions—key factors for maintaining long-term disease control in advanced settings. Although gastrointestinal and hepatic events were more common, these were largely mild to moderate and manageable.
Overall, bireociclib’s differentiated safety profile makes it a particularly attractive option for patients at risk of bone marrow suppression. These findings warrant further head-to-head comparative trials and real-world validation to better define bireociclib’s position in the HR+/HER2– treatment landscape.
Investigator’s Commentary
“CDK4/6 inhibitors combined with fulvestrant have become the standard second-line treatment for HR+/HER2– advanced breast cancer,” said Prof. Jiayu Wang. “As more agents become available, optimizing the balance between efficacy and safety is increasingly critical to achieving individualized care.”
“Bireociclib, as a new-generation, highly selective CDK4/6 inhibitor, stands out with its greater CDK4 selectivity and additional CDK2/CDK9 inhibition. This dual mechanism may explain its differentiated therapeutic profile.”
“The MAIC analysis is the first to indirectly compare bireociclib and dalpiciclib. Bireociclib showed a trend toward longer PFS and a significantly reduced risk of severe neutropenia, providing a safer, more tailored option for patients—especially those prone to myelosuppression but with good gastrointestinal tolerance.”
“While elevations in liver enzymes and anemia require monitoring, these are generally manageable through dose adjustments. Combined with earlier ASCO data showing a more than three-month PFS advantage over abemaciclib in indirect comparison, bireociclib demonstrates strong potential as a preferred second-line CDK4/6 inhibitor.”
“Looking ahead, research on front-line combinations, biomarker-guided patient selection, and real-world outcomes will further clarify bireociclib’s clinical value. As evidence builds, this domestically developed CDK4/6 inhibitor may offer Chinese patients an effective, safer, and more economically favorable treatment choice—advancing the overall quality of breast cancer care in China.”
Prof. Jiayu Wang Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences
