Faculty, Staff and Student Publications

Language

English

Publication Date

12-1-2024

Journal

Nature Medicine

DOI

10.1038/s41591-024-03266-2

PMID

39277671

PMCID

PMC12044543

PubMedCentral® Posted Date

6-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Among the goals of patient-centric care are the advancement of effective personalized treatment, minimising toxicity. The phase-2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimising individual outcomes. Here we tested datopotamab-deruxtecan (Dato-Dxd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomisation trial (SMART) design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent (Block A), a taxane-based regimen tailored to the tumour subtype (Block B), and doxorubicin/cyclophosphamide (Block C). Patients are randomised into different arms consisting of different investigational Block A treatments. Algorithms based on MRI and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response (pCR), the primary endpoint. There are two primary efficacy analyses: after Block A and across all blocks for the 6 pre-specified breast cancer subtype groups (defined by clinical HR/HER2 status and/or the response predictive subtypes). We report results of 103 patients treated with Dato-Dxd. While Dato-Dxd did not meet the prespecified threshold for success (graduation) after Block A in any subtype, the treatment strategy across all blocks graduated in the HER2-negative Immune-negative DNA repair deficiency (DRD)-negative subtype with an estimated pCR rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato was particularly active in the HR-HER2-Im-DRD− signature, warranting further investigation, and was safe in other subtypes, in patients who followed the treatment strategy.

Keywords

Humans, Female, Breast Neoplasms, Middle Aged, Neoadjuvant Therapy, Adult, Neoplasm Staging, Antineoplastic Combined Chemotherapy Protocols, Aged, Antibodies, Monoclonal, Humanized, Treatment Outcome, Doxorubicin, Erb-b2 Receptor Tyrosine Kinases, Cyclophosphamide, Immunoconjugates, Trastuzumab, Camptothecin

Comments

ClinicalTrials.gov identifier: NCT01042379

Published Open-Access

yes

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