Neoadjuvant dalpiciclib combined with letrozole and dual HER2 blockade in HR+/HER2+ breast cancer: First-stage results of the HELEN HER2 017 trial.

1054 Background: Triple-positive breast cancer (TPBC; HR+/HER2+) represents a distinct subtype with suboptimal responses to conventional neoadjuvant chemotherapy combined with anti-HER2 therapy, with reported pCR rates of only 26%–43.8%, and is associated with significant treatment-related toxicities 1-3 . This highlights an urgent need for more effective and less toxic therapeutic strategies. We hypothesize that simultaneously targeting ER, HER2, and CDK4/6 pathways may enhance antitumor efficacy while enabling chemotherapy de-escalation. This phase II study investigates a response-guided, chemotherapy-free neoadjuvant regimen using dalpiciclib (a CDK4/6 inhibitor), aromatase inhibitor (AI), and dual HER2 blockade. Methods: This prospective, single-arm, two-stage Simon optimal design study planned to enroll 71 patients. In stage one, 20 patients were enrolled; proceeding to stage two required ≥6 pCRs. The final success threshold is ≥24 pCRs in 71 patients (α=0.05, power=80%, H0: pCR≤25% vs. H1: pCR≥40%). Eligible patients had stage II–IIIa HR+/HER2+ invasive breast cancer. Treatment included oral dalpiciclib (150 mg/day, 3 weeks on/1 week off), oral letrozole (2.5 mg/day; with ovarian suppression if premenopausal), and IV trastuzumab (loading 8 mg/kg, then 6 mg/kg) plus pertuzumab (loading 840 mg, then 420 mg) every 3 weeks. This was a response-adaptive design: after 2 cycles, MRI assessed tumor response. Patients achieving PR (≥30% reduction per RECIST 1.1) continued the same regimen for 6 cycles; non-responders switched to TCHP chemotherapy (docetaxel, carboplatin, trastuzumab, pertuzumab). The primary endpoint was pCR (ypT0/is ypN0) in the all-treated population. Secondary endpoints included ORR, RCB 0-1, EFS, and safety. Results: In the first stage, 20 patients were enrolled. Median age was 48 years (range 34–59). All were ER+ and HER2+ by central review. After 2 cycles, 15 of 20 patients (75%) achieved PR and continued on the dalpiciclib, letrozole, and dual HER2 blockade regimen. Of the 20 patients, 8 achieved pCR, with a rate of 40%. Among the MRI responders who continued the experimental arm, the pCR rate was 40% (6/15). Treatment was generally well-tolerated; the most common adverse events were neutropenia, leukopenia, anemia, and thrombocytopenia. No treatment-related discontinuations or cardiac toxicity of grade 3 or higher were observed. Conclusions: The first stage of this response-guided study met its predefined efficacy threshold (≥6 pCR in 20 patients). The neoadjuvant regimen combining dalpiciclib, an AI, and dual HER2 blockade shows promising pCR rates and a favorable safety profile in TPBC, supporting continued evaluation in the second stage of the trial. Clinical trial information: NCT06276868 .