Abstract PS5-02-02: Early use of CDK4/6 inhibitor combined with endocrine therapy plus anti-HER2 antibody may get more survival benefit in HR+/HER2+ advanced breast cancer: result from a phase II single-arm mini cohort study (CABC016)

Abstract Background: Based on anti-HER2 therapy, the combination of CDK4/6 inhibitors proved to be a potential regimen, which can simultaneously inhibit the crosstalk between the ER and HER2 pathways. PATINA study showed a meaningful prolonged PFS after a chemo-based induction therapy when added Palbociclib to the maintaining treatment, same kind of de-chemo treatment which also achieve better efficacy is still expected to be the initial regimen during metastatic setting. Methods: CABC016 is a phase II, single-arm, prospective cohort study (NCT05969184), assessing palbociclib combine with anti-HER2 antibody and endocrine therapy (ET) to treat HR+/HER2+ metastatic breast cancer (MBC). Patients are treated with palbociclib at a dose of 125 mg daily on days 1 - 21 of a 28 - day cycle, plus trastuzumab (H, trastuzumab or inetetamab) or trastuzumab plus pertuzumab (HP) intravenously on day 1 of each 21-day cycle. ET options included aromatase inhibitor (AI), tamoxifen or fulvestrant depend on endocrine sensitivety, with ovarian suppression required for premenopausal patients. The primary endpoint is investigator-assessed progression-free survival (PFS); key secondary endpoints were safety, response rate (ORR), disease control rate (DCR), and survival (OS). Result Analysis cutoff date is June 21, 2025. Enrolled 47 eligible MBC patients with a median age of 56 (32 - 74). 72.3% and 68.1% have 50% ER and 30% Ki - 67 expression. 72.3% patients had visceral and 17.0% had stable brain disease. At least one prior chemotherapy regimen was administered in 70.2% of patients, of whom 46.8% have been treated with taxane. The mPFS of ITT population is 16.5 m(95%CI, 11.3 - 21.9), with 19.3 m (95%CI, 15.5 - 22.5) of median follow - up. The mOS is 34.9 m(95%CI, 29.1 - 40.6), which is immature. Further analysis found that patients who were ET-naïve during metastatic setting had better mPFS (22.0 m95%CI, 16.3 - 27.6, n = 26) than who had been treated by ET (8.3 m95%CI, 3.2 - 13.5, n = 21) (P 0.001). mPFS is longer in the front lines than late lines (mPFS of 1, 2 and 3 or more prior ET is 11.1 m95%CI, 3.2 - 19.0; n = 12, 4.8 m95%CI, 3.7 - 6.1; n = 7 and 1.5 m95%CI, 0.3 - 2.7; n = 2, respectively (P 0.001). At a median of 3 lines of this cohort, mPFS is better in 1st- line treatment (18.9 m95%CI, 12.5 - 25.5; n = 17) than in second/third - line (15.8 m95%CI, 9.9 - 21.7; n = 18), than fourth or later(up to 12 lines)treatment (7.7 m95%CI, 1.5 - 13.9; n = 12) (P = 0.008). In front line (line 1-3) patients, mPFS is even longer in ET-naïve patients (24.1 m95%CI, 18.6 - 29.6, n = 23]) than those under ET treated (7.0 m95%CI, 3.3 - 10.8, n = 12). No significant difference in mPFS was observed between the inetetamab (13.9 m95%CI, 9.3 - 18.5; n = 26) and trastuzumab (14.5 m95%CI, 7.4 - 21.6; n = 21) (P = 0.28), or H and HP (11.3month95%CI, 6.0 - 16.5 vs. 18.1m95%CI, 11.0 - 25.1; P = 0.418). The ORR of ITT population is 34.1%, included 1 CR, and DCR is 87.8%. While in ET-naïve setting, the ORR rise to 45.5%, and DCR rise to 95.5%. For patients with stable brain disease, the longest survival reached 34.6 months, no significant difference in mPFS was observed between patients with or without brain disease (P= 0.293), with a 50% ORR and 62.5% DCR, respectively. The overall safety profile was manageable. The most common grade 3-4 AEs were neutropenia (44.2%) and thrombocytopenia (20.9%). Dose reduction of palbociclib (from 125mg to 100mg) had occurred in 18 patients (38.3%) because of myelotoxicity. No patient fell out because of AEs. Conclusion: This mini cohort study showed palbociclib plus ET plus anti-HER2 antibody could be one of the optimal initial treatment options for metastatic setting of HR+/HER2+ breast cancer, especially for early use during ET-based regimen, even for stable brain disease. Citation Format: Y. Liu, S. Guohong, R. Ran, J. Hanfang, S. Bin, X. Liang, Z. Jiayang, Z. Ruyan, L. Huiping. Early use of CDK4/6 inhibitor combined with endocrine therapy plus anti-HER2 antibody may get more survival benefit in HR+/HER2+ advanced breast cancer: result from a phase II single-arm mini cohort study (CABC016) [abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-02.