Culmerciclib (CDK2/4/6 inhibitor) plus fulvestrant in HR+/HER2− advanced breast cancer after progression on CDK4/6i: Preliminary results from a phase II trial.

Abstract

1082 Background: CDK4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) have been the standard first line treatment for HR+/HER2- advanced breast cancer (ABC). However, there is currently no established standard treatment after progression on a CDK4/6i–based regimen. Culmerciclib (Culm), a novel potent CDK2/4/6 inhibitor, has shown significant PFS benefits when combined with Fulvestrant (Ful) in both first-line and later-line settings for HR+/HER2– ABC (ESMO 2025; CSCO 2024). Here we evaluated the combination in HR+/HER2- ABC following disease progression on prior CDK4/6i + ET. Methods: In this prospective, multicenter, single-arm phase II trial (TQB3616-II-04), eligible patients (pts) who had progressive disease on a CDK4/6i + ET as initial therapy for ABC or relapse on/after a CDK4/6i + ET as adjuvant therapy for early BC, previous up to 2 lines of ET and 1 line of chemotherapy for ABC, received Culm (180mg, qd) + Ful. The primary endpoint was ORR, and secondary endpoints included DCR, PFS, DOR, CBR and safety. Assuming a power of 0.9 to test the hypothesis that ORR would be 30.0% against the null hypothesis that it would be 8.0% or lower, with 0.025 as one-sided significance level; considering the dropout rate of 20%, a total of 33 pts was required. Results: 35 female pts were enrolled and treated, 31.4% were pre- or perimenopausal (received a concomitant GnRH agonist), 71.4% had visceral metastases (including 45.7% with liver metastases and 5.7% with brain metastases). All pts had received prior CDK4/6i +ET (AI and/or SERM) therapies, prior CDK4/6i was 68.6% palbociclib, 28.6% dalpiciclib, and 8.6% ribociclib (2 pts with dual CDK4/6i); 28.6% had received prior two lines endocrine therapy, also 37.1% had received prior chemotherapy for metastatic disease. As of data cutoff on Jan 17, 2026, median follow-up time was 7.3 months. Among 34 evaluable pts, the overall ORR was 29.4% (95% CI: 15.1, 47.5, p ＜0.0001 ), meeting the predefined primary endpoint, which significantly rejected the null hypothesis of ORR. The overall DCR was 88.2% (95% CI: 72.6, 96.7), and the CBR was 82.4% (95% CI: 65.5, 93.2). Median TTR was 3.7 months, mPFS and mDOR were not yet reached, while 6-month PFS rate was 72.5% (95% CI: 52.7, 84.7). Grade≥3 TRAEs and serious TRAEs were reported in 14 (40.0%), 3 (8.6%) pts, respectively. The most common TRAEs included diarrhea, neutropenia, vomiting etc. No new safety signals were observed, with findings consistent with the known safety profile of Culm. Dose reductions due to TRAEs occurred in 14.3% of pts, and no deaths or discontinuations related to TRAEs were reported. Conclusions: Culm combined with Ful demonstrated promising antitumor activity in HR+/HER2- ABC after progression on previous CDK4/6i + ET, offering a potential targeted therapeutic strategy for this population (NCT06702618). Clinical trial information: NCT06702618 .