Add-on bireociclib promising for HR+/HER2- ABC following ET failure

In the interim analysis of the phase III BRIGHT-2 study, adding the CDK4/6 inhibitor bireociclib to fulvestrant prolongs progression-free survival (PFS) in Chinese women with HR+/HER2- advanced breast cancer (ABC) who progressed on or after endocrine therapy (ET).

“[W]e found that HR+/HER2- ABC patients who had previously exhibited progressive disease (PD) on or after ET experienced a significant reduction in the risk of PD or death when treated with the bireociclib-fulvestrant (BF) regimen,” said the researchers.

The median PFS was longer in the BF vs placebo arm, both by investigator (12.94 vs 7.29 months; hazard ratio [HR], 0.56; p=0.001) and blinded independent central review (not reached vs 7.46 months; HR, 0.46; p<0.001). [Nat Commun 2025;doi:10.1038/s41467-025-58647-z]

On investigator assessment, the most significant effects were seen in women with primary resistance to ET (HR, 0.25) and bone-only (HR, 0.23) and liver metastases (HR, 0.38). “Sensitivity analysis supports the robustness of the PFS finding,” they said.

Objective response rates by investigator were greater in the BF than placebo arm, both in the intention-to-treat cohort (39.7 percent vs 13.9 percent; odds ratio [OR], 4.1; p<0.0001) and in women with measurable disease (43.8 percent vs 15.6 percent; OR, 4.3; p<0.0001). These results imply that add-on bireociclib yields strong and durable tumour shrinkage, which may help alleviate tumour-related symptoms and potentially translate into survival benefits, the researchers noted.

Grade ≥3 treatment-emergent adverse event (TEAE) rate was higher in the BF vs placebo arm (64.7 percent vs 18.8 percent). The most common grade 3/4 TEAEs with BF were neutropenia (31.4 percent), leukopenia (18.6 percent), anaemia (10.8 percent), hypokalaemia (8.3 percent), and diarrhoea (5.4 percent).

Of note, diarrhoea mainly occurred during the early stage of treatment, with its incidence gradually dropping with prolonged medication from the 3^rd cycle. “Most events resolved with supportive care or bireociclib dose adjustment. Only one patient was hospitalized due to grade 3 diarrhoea,” the researchers said.

Drug resistance despite optimal ET

About 16 percent of newly diagnosed BC occur in Chinese women, with peak diagnosis age between 40 and 59 years. [Chin J Oncol 2024;46:221-231; Breast Cancer Res Treat 2016;159:395-406] “Compared with Westerners, Asians have a higher proportion of luminal B BC, which has a worse prognosis and is more prone to ET resistance. Despite optimal ET, a certain percentage of patients fail to respond to treatment due to primary or secondary drug resistance,” said the researchers.

Evidence shows that combining a CDK4/6 inhibitor with fulvestrant offers significant efficacy benefits over fulvestrant alone in HR+/HER2- ABC patients with recurrence or progression post-ET. [Lancet Oncol 2016;17:425-439; J Clin Oncol 2017;35:2875-2884; N Engl J Med 2020;382:514-524; Ann Oncol 2022;33:S642-S643]

“Building on these findings, BRIGHT-2 was designed to better reflect the characteristics of the Chinese BC population, which is typically diagnosed at a younger age, with later-stage disease, a higher proportion of luminal B BC, increased chemo applications in advanced stages, and an elevated risk of recurrence,” they said.

A total of 305 participants (median age 55 years) were randomized 2:1 to BF or placebo plus fulvestrant. IM fulvestrant 500 mg was given on days 1 and 15 of the initial cycle and day 1 of the ensuing cycles. Bireociclib 360 mg or placebo BID was given during each 28-day cycle. About 26 percent had primary endocrine resistance, and three-quarters had secondary endocrine resistance. As of data cutoff for this analysis, median follow-up time from randomization was 8.7 months.

In this analysis, BF improved PFS, reduced the tumour burden, and had a tolerable and manageable safety profile in Chinese women with HR+/HER2- ABC. “These findings support BF as a promising option for these patients,” the researchers concluded.

Fifty-four percent of participants were still on treatment at the time of analysis. Overall survival data remain immature.