Article
Author: Beineke, Philip ; Symmans, W. Fraser ; Elias, Anthony D. ; Clark, Amy S ; Vaklavas, Christos ; Williams, Nicole ; Li, Wen ; Rugo, Hope S ; Moore, Brian ; Albain, Kathy S. ; Esserman, Laura J. ; Elias, Anthony D ; Rugo, Hope S. ; Esserman, Laura J ; Omene, Coral ; Clark, Amy S. ; Perlmutter, Jane ; Norwood, Peter ; Matthews, Jeffrey B. ; Chen, Yunni Yi ; Boles, Sarah ; Yau, Christina ; Hirst, Gillian L ; DeMichele, Angela ; Yee, Douglas ; Roussos Torres, Evanthia T ; Rozenblit, Mariya ; Matthews, Jeffrey B ; Blackwood, M Michele ; Heditsian, Diane ; van ’t Veer, Laura J. ; Thomas, Brittani ; Parker, Catherine ; Howard, Frederick M. ; Pohlmann, Paula ; Beckwith, Heather ; Shatsky, Rebecca A ; Albain, Kathy S ; Chien, A. Jo ; Sanft, Tara ; Isaacs, Claudine ; Blackwood, M. Michele ; Stringer-Reasor, Erica ; Brown-Swigart, Lamorna ; Nanda, Rita ; Davidian, Marie ; Tseng, Jennifer ; Tsiatis, Butch ; van 't Veer, Laura J ; Roussos Torres, Evanthia T. ; Thomas, Alexandra ; Nangia, Chaitali ; Jahan, Nusrat ; Asare, Adam L. ; Price, Elissa ; LeStage, Barbara ; Falkson, Carla ; Yeung, Kay ; Sanford, Amy ; Hershman, Dawn L ; Boughey, Judy C. ; Hylton, Nola M. ; Hirst, Gillian L. ; Symmans, W Fraser ; Giridhar, Karthik ; Arora, Mili ; Trivedi, Meghna S. ; Kalinsky, Kevin ; Wallace, Anne M ; Onishi, Natsuko ; Howard, Frederick M ; Chien, A Jo ; Wallace, Anne M. ; Hershman, Dawn L. ; Shatsky, Rebecca A. ; Huppert, Laura ; Trivedi, Meghna S ; Boughey, Judy C ; Hylton, Nola M ; Asare, Adam L
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 .