Neoadjuvant dalpiciclib combined with aromatase inhibitors in stage I-III HER2 negative luminal B breast cancer (DANCER): Preliminary findings from an ongoing phase II study.

e12622 Background: CDK4/6 inhibitors, in combination with endocrine therapy, have shown efficacy as neoadjuvant treatment in HR+/HER2- breast cancer (BC). This study investigates the efficacy and safety of dalpiciclib, a CDK4/6 inhibitor, combined with aromatase inhibitors (AI) as a neoadjuvant treatment for luminal B BC (defined as ER+/HER2- BC, with either Ki67≥20% and/or PR<20%). Methods: This single-arm, single-center, phase II study (NCT05640778) enrolled patients aged 18-75 with clinical stage I-III luminal B BC, primary tumor size ≥2 cm, and ECOG PS 0-1. Eligible patients, regardless of menopausal status, received AI therapy (either anastrozole 1 mg daily or letrozole 2.5 mg daily) combined with dalpiciclib (150 mg daily on days 1-21) starting from cycle 1 day 1 (C1D1), for four 28-day cycles, followed by surgery. Pre-/peri-menopausal patients received AI therapy 14 days prior to the first dose of dalpiciclib (C0D1-C0D14), concurrent with a GnRH agonist administered every 28 days from C0D1. Ki67 levels were assessed through serial biopsies at baseline, C1D15, and surgery. MRI assessments were performed at baseline, C2D28, and before surgery per RECIST v1.1. Serial plasma samples were collected for circulating tumor DNA (ctDNA) analysis. The primary endpoint was the complete cell cycle arrest (CCCA: Ki67≤2.7%) rate at 2 weeks (C1D15). Results: From Oct 2022 to Dec 2023, 23 patients with a median age of 52 years (range 38-73) were enrolled and received study treatment. Of these patients, 11 (47.8%) were pre-/peri-menopausal. Sixteen (69.6%) were diagnosed with stage II and the remaining had stage III disease. High Ki67 expression (≥20%) was observed in 21 patients (91.3%). As of Jan 7, 2024, all patients underwent the C1D15 Ki67 evaluation and the CCCA rate was 82.6% (95% CI: 60.5%-94.3%). The ctDNA concentration at C2D28 and post-surgery was significantly higher in patients who did not achieve CCCA compared to those who achieved CCCA ( P = 0.003 and 0.011, respectively). Ki67 expression decreased by a geometric mean of 93.1% (95% CI:76.0%-98.8%) from baseline to C1D15. Out of 20 patients who completed 2 cycles of treatment and received an MRI scan, 12 achieved a partial response, yielding an ORR of 60.0% at C2D28. Among 17 who completed all neoadjuvant therapy and underwent surgery, the ORR before surgery was 82.4% with 14 partial responses; none demonstrated residual cancer burden (RCB) 0/1, seven exhibited RCB 2, and 10 had RCB 3; one reached breast pathological complete response (ypTisN1). Grade ≥3 treatment-emergent adverse events included neutrophil count decreased (16, 69.6%), white blood cell decreased (9, 39.1%), and oral mucositis (1, 4.3%). Conclusions: Dalpiciclib plus anastrozole or letrozole exhibited biological and clinical activity with manageable toxicities in neoadjuvant treatment for stage I-III luminal B/HER2- BC. Clinical trial information: NCT05640778 .