Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.

Journal

Nature medicine

ISSN: 1546-170X

Titre abrégé: Nat Med

Pays: United States

ID NLM: 9502015

Informations de publication

Date de publication:
14 Sep 2024

Historique:

received: 07 08 2024

accepted: 23 08 2024

medline: 15 9 2024

pubmed: 15 9 2024

entrez: 14 9 2024

Statut: aheadofprint

Résumé

Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change 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 pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype.ClinicalTrials.gov registration: NCT01042379 .

Identifiants

DOI: 10.1038/s41591-024-03267-1 PMID: 39277672

pubmed: 39277672

doi: 10.1038/s41591-024-03267-1

pii: 10.1038/s41591-024-03267-1

doi:

Banques de données

ClinicalTrials.gov

['NCT01042379']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : U.S. Department of Health & Human Services | National Institutes of Health (NIH)

ID : P01CA210961

Informations de copyright

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