{
  "abstract": "Importance\n\nThe 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).Objective\n\nTo evaluate the efficacy and safety of trastuzumab-deruxtecan (T-DXd), an antibody drug conjugate targeting low ERBB2 (formerly HER2) 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).Design, setting, and participants\n\nThis phase 2, multicenter, adaptively randomized neoadjuvant trial enrolled patients with high-risk stage II/III ERBB2-negative EBC (including those with ERBB2 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.Interventions\n\nParticipants 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).Main outcomes and measures\n\nThe primary end point was pathologic complete response (pCR). Safety assessments included adverse events (AEs), with focused monitoring for interstitial lung disease (ILD).Results\n\nA 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.Conclusions and relevance\n\nThis randomized clinical trial found that treatment with RT-DXd demonstrated promising activity, with mostly low-grade toxic effects in immune-positive, ERBB2-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.Trial registration\n\nClinicalTrials.gov Identifier: NCT01042379.",
  "abstract_shown": true,
  "affiliations": [
    "Mayo Clinic, Rochester, Minnesota.",
    "Emory University Winship Cancer Institute, Atlanta, Georgia.",
    "University of California, San Francisco.",
    "University of Alabama, Birmingham.",
    "University of Minnesota, Minneapolis.",
    "University of California, San Diego, La Jolla.",
    "University of Colorado, Aurora.",
    "University of Chicago, Chicago, Illinois.",
    "Georgetown University, Washington, DC.",
    "Rutgers Cancer Institute of New Jersey, New Brunswick.",
    "Cooperman Barnabas Medical Center, Livingston, New Jersey.",
    "University of Pennsylvania, Philadelphia.",
    "Wake Forest, Winston-Salem, North Carolina.",
    "Duke University, Durham, North Carolina.",
    "Moffitt Cancer Center, Tampa, Florida.",
    "New York University, New York.",
    "The Ohio State University, Columbus.",
    "Columbia University, New York, New York.",
    "UC Davis Health, Sacramento, California.",
    "University of Utah Huntsman Cancer Institute, Salt Lake City.",
    "City of Hope (Lennar), Duarte, California.",
    "Health Partners Institute-Hennepin, Minneapolis, Minnesota.",
    "Montefiore Medical Center, New York, New York.",
    "Oregon Health and Science University, Portland.",
    "University of Rochester Medical Center, Rochester, New York.",
    "University of Southern California, Los Angeles.",
    "Hoag Family Cancer Institute, Irvine, California.",
    "Loyola University Medical Center, Maywood, Illinois.",
    "Yale University, New Haven, Connecticut."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 88,
  "authors": [
    {
      "name": "I-SPY2 Trial Investigators and Advocates"
    },
    {
      "affs": [
        0
      ],
      "name": "Ciara C O'Sullivan"
    },
    {
      "affs": [
        1
      ],
      "name": "Kevin M Kalinsky"
    },
    {
      "affs": [
        2
      ],
      "name": "Christina Yau"
    },
    {
      "affs": [
        3
      ],
      "name": "Tejaswini Kulkarni"
    },
    {
      "affs": [
        4
      ],
      "name": "Douglas Yee"
    },
    {
      "affs": [
        5
      ],
      "name": "Anne M Wallace"
    },
    {
      "affs": [
        2
      ],
      "name": "A Jo Chien"
    },
    {
      "affs": [
        0
      ],
      "name": "Judy C Boughey"
    },
    {
      "affs": [
        6
      ],
      "name": "Anthony D Elias"
    },
    {
      "affs": [
        7
      ],
      "name": "Rita Nanda"
    },
    {
      "affs": [
        8
      ],
      "name": "Claudine Isaacs"
    },
    {
      "affs": [
        9,
        10
      ],
      "name": "Coral Omene"
    },
    {
      "affs": [
        3
      ],
      "name": "Erica Stringer-Reasor"
    },
    {
      "affs": [
        11
      ],
      "name": "Amy S Clark"
    },
    {
      "affs": [
        12,
        13
      ],
      "name": "Alexandra Thomas"
    },
    {
      "affs": [
        14
      ],
      "name": "Heather S Han"
    },
    {
      "affs": [
        15
      ],
      "name": "Nancy Chan"
    },
    {
      "affs": [
        16
      ],
      "name": "Nicole Williams"
    },
    {
      "affs": [
        17
      ],
      "name": "Meghna S Trivedi"
    },
    {
      "affs": [
        18
      ],
      "name": "Mili Arora"
    },
    {
      "affs": [
        19
      ],
      "name": "Christos Vaklavas"
    },
    {
      "affs": [
        20
      ],
      "name": "Jennifer Tseng"
    },
    {
      "affs": [
        21
      ],
      "name": "Satya Bommakanti"
    },
    {
      "affs": [
        22
      ],
      "name": "Jesus D Anampa Mesias"
    },
    {
      "affs": [
        23
      ],
      "name": "Alexandra Zimmer"
    },
    {
      "affs": [
        24
      ],
      "name": "Carla Falkson"
    },
    {
      "affs": [
        25
      ],
      "name": "Evanthia Roussos Torres"
    },
    {
      "affs": [
        26
      ],
      "name": "Chaitali Nangia"
    },
    {
      "affs": [
        27
      ],
      "name": "Kathy S Albain"
    },
    {
      "affs": [
        28
      ],
      "name": "Mariya Rozenblit"
    },
    {
      "affs": [
        5
      ],
      "name": "Somaye Zare"
    },
    {
      "affs": [
        5
      ],
      "name": "Soudabeth Fazelli"
    },
    {
      "affs": [
        2
      ],
      "name": "Yunni-Yi Chen"
    },
    {
      "affs": [
        2
      ],
      "name": "Laura A Huppert"
    },
    {
      "affs": [
        4
      ],
      "name": "An L Church"
    },
    {
      "affs": [
        4
      ],
      "name": "Heather Beckwith"
    },
    {
      "affs": [
        0
      ],
      "name": "Evelyn Carroll"
    },
    {
      "affs": [
        0
      ],
      "name": "Malvika Solanki"
    },
    {
      "affs": [
        6
      ],
      "name": "Virginia F Borges"
    },
    {
      "affs": [
        6
      ],
      "name": "Sarah E A Tevis"
    },
    {
      "affs": [
        7
      ],
      "name": "Nan Chen"
    },
    {
      "affs": [
        8
      ],
      "name": "Jay C Zeck"
    },
    {
      "affs": [
        10
      ],
      "name": "Maria J Kowzun"
    },
    {
      "affs": [
        5
      ],
      "name": "Jessica Sullivan"
    },
    {
      "affs": [
        2
      ],
      "name": "Natalie Marshall"
    },
    {
      "affs": [
        4
      ],
      "name": "Molly E Klein"
    },
    {
      "affs": [
        0
      ],
      "name": "Karthik V Giridhar"
    },
    {
      "affs": [
        6
      ],
      "name": "Radhika Acharya-Leon"
    },
    {
      "affs": [
        7
      ],
      "name": "Betty Fan"
    },
    {
      "affs": [
        8
      ],
      "name": "Elaine M Walsh"
    },
    {
      "affs": [
        10
      ],
      "name": "Anya Litvak"
    },
    {
      "affs": [
        3
      ],
      "name": "Nusrat Jahan"
    },
    {
      "affs": [
        11
      ],
      "name": "Elizabeth McDonald"
    },
    {
      "affs": [
        12
      ],
      "name": "Emily Hughes Douglas"
    },
    {
      "affs": [
        14
      ],
      "name": "Jameel Zena"
    },
    {
      "affs": [
        15
      ],
      "name": "Amber Guth"
    },
    {
      "affs": [
        16
      ],
      "name": "Kai Johnson"
    },
    {
      "affs": [
        17
      ],
      "name": "Julia E McGuinness"
    },
    {
      "affs": [
        9
      ],
      "name": "Kant Matsuda"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1270dqmbaaz1w.bib",
  "cited_by": 0,
  "doi": "10.1001/jamaoncol.2026.4258",
  "fulltext_url": "https://europepmc.org/articles/PMC13691915",
  "id": "1270dqmbaaz1w",
  "issns": [
    "2374-2437",
    "2374-2445"
  ],
  "landing_url": "https://europepmc.org/article/MED/42911610",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1306|Breast Cancer Treatment Studies"
    ]
  ],
  "openalex": "W7223241664",
  "pdf_url": "https://jamanetwork.com/journals/jamaoncology/articlepdf/2855652/jamaoncology_osullivan_2026_oi_260059_1792008490.3891.pdf",
  "pmcid": "PMC13691915",
  "pmid": "42911610",
  "published": "2026-10-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/1270dqmbaaz1w.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:10Z",
      "native_id": "MED:42911610",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42911610"
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  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1306|Breast Cancer Treatment Studies",
      "subfield": "oncology"
    }
  ],
  "title": "Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer: The I-SPY2.2 Randomized Clinical Trial.",
  "title_text": "Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer: The I-SPY2.2 Randomized Clinical Trial.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:10Z",
  "url": "https://research.draconitic.com/paper/1270dqmbaaz1w",
  "venue": "JAMA oncology",
  "versions": []
}