{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:46:45Z","timestamp":1792684005428,"version":"4.5.0"},"reference-count":35,"publisher":"American Medical Association (AMA)","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"abstract":"\n Importance<\/jats:title>\n The I-SPY2.2 trial tests personalized treatment strategies to improve outcomes while reducing exposure to standard chemotherapy in patients with high-risk early breast cancer (EBC).<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n \n To evaluate the efficacy and safety of trastuzumab-deruxtecan (T-DXd), an antibody drug conjugate targeting low\n ERBB2<\/jats:italic>\n (formerly\n HER2<\/jats:italic>\n ) expression, combined with rilvegostomig (R), a bispecific antibody targeting programmed cell death 1 protein and T-cell immunoglobulin and ITIM domain as initial therapy in I-SPY2.2 (RT-DXd).\n <\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n \n This phase 2, multicenter, adaptively randomized neoadjuvant trial enrolled patients with high-risk stage II\/III\n ERBB2<\/jats:italic>\n -negative EBC (including those with\n ERBB2<\/jats:italic>\n low\/ultralow tumors), as stratified by hormone receptor (HR) status and response-predictive subtypes. It was conducted at 30 sites in the US; efficacy data were analyzed continuously during the trial to update probabilities and other analyses before publication.\n <\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Participants received up to 3 sequential treatment blocks, based on response and subtype: RT-DXd (block A), taxane-based therapy with\/without immunotherapy (block B), and doxorubicin-cyclophosphamide (AC) with\/without immunotherapy (block C).<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n The primary end point was pathologic complete response (pCR). Safety assessments included adverse events (AEs), with focused monitoring for interstitial lung disease (ILD).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n A total of 182 individuals (mean [SD] age: RT-DXd, 48.1 [13.1] years; control, 50.9 [12.0] years) participated in the trial. Eighty-eight were randomized to the contemporary control arm, and 108 of 289 remaining participants (37%) were randomized to RT-DXd; 3 participants did not receive block A treatment, and 11 did not receive the assigned control treatment, leaving the intention-to-treat population with 105 and 77 evaluable participants. Among 105 patients treated with RT-DXd in block A, the modeled pCR rate was 54% in immune-positive tumors, which met the predefined threshold for success. Similar pCR rates were observed in HR-positive, immune-positive disease (57%) and HR-negative, immune-positive disease (52%). Across all treatment blocks, overall pCR rates were similar to control regimens; however, among immune-positive patients who experienced pCR, 21 (62%) required only block A, and 33 (97%) avoided anthracycline-based chemotherapy. Enrollment was paused twice to evaluate grade 2 or higher ILD and resumed after data safety monitoring board approval. The most common AEs were fatigue and nausea. Serious AEs included pulmonary embolism and ILD (3 of 105 [2.9%] each). ILD occurred in 13 (12.4%), including 1 grade 3 event, and was identified early with serial chest computed tomography monitoring.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n \n This randomized clinical trial found that treatment with RT-DXd demonstrated promising activity, with mostly low-grade toxic effects in immune-positive,\n ERBB2<\/jats:italic>\n -negative EBC. Unlike immune-negative patients, many immune-positive patients who experienced pCR avoided standard chemotherapy, including anthracyclines, supporting further evaluation in biomarker-selected populations.\n <\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT01042379<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaoncol.2026.4258","type":"journal-article","created":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T15:30:40Z","timestamp":1792683040000},"source":"Crossref","is-referenced-by-count":0,"title":["Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer"],"prefix":"10.1001","author":[{"name":"I-SPY2 Trial Investigators and Advocates","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciara C.","family":"O\u2019Sullivan","sequence":"additional","affiliation":[{"name":"Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin M.","family":"Kalinsky","sequence":"additional","affiliation":[{"name":"Emory University Winship Cancer Institute, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Yau","sequence":"additional","affiliation":[{"name":"University of California, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejaswini","family":"Kulkarni","sequence":"additional","affiliation":[{"name":"University of Alabama, Birmingham"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas","family":"Yee","sequence":"additional","affiliation":[{"name":"University of Minnesota, Minneapolis"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne M.","family":"Wallace","sequence":"additional","affiliation":[{"name":"University of California, San Diego, La Jolla"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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