Year: 2026
Type: article
Study design: Clinical Trial
Abstract: Importance: 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). Objective: To 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: This 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: 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). Main Outcomes and Measures: The primary end point was pathologic complete response (pCR). Safety assessments included adverse events (AEs), with focused monitoring for interstitial lung disease (ILD). Results: 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. Conclusions and Relevance: This 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: ClinicalTrials.gov Identifier: NCT01042379.
Source: JAMA Oncology
Authors: I-SPY2 Trial Investigators and Advocates, Ciara C. O’Sullivan, Kevin M. Kalinsky, Christina Yau, Tejaswini Kulkarni, Douglas Yee, Anne M. Wallace, A. Jo Chien, Judy C. Boughey, Anthony D. Elias, Rita Nanda, Claudine Isaacs, Coral Omene, Erica Stringer-Reasor, Amy S. Clark, Alexandra Thomas, Heather S. Han, Nancy Chan, Nicole Williams, Meghna S. Trivedi, Mili Arora, Christos Vaklavas, Jennifer Tseng, Satya Bommakanti, Jesus D. Anampa Mesias, Alexandra Zimmer, Carla Falkson, Evanthia Roussos Torres, Chaitali Nangia, Kathy S. Albain, Mariya Rozenblit, Somaye Zare, Soudabeth Fazelli, Yunni-Yi Chen, Laura A. Huppert, An L. Church, Heather Beckwith, Evelyn Carroll, Malvika Solanki, Virginia F. Borges, Sarah E. A. Tevis, Nan Chen, Jay C. Zeck, Maria J. Kowzun, Jessica Sullivan, Natalie Marshall, Molly E. Klein, Karthik V. Giridhar, Radhika Acharya-Leon, Betty Fan, Elaine M. Walsh, Anya Litvak, Nusrat Jahan, Elizabeth McDonald, Emily Hughes Douglas, Jameel Zena, Amber Guth, Kai Johnson, Julia E. McGuinness, Kant Matsuda, Shadi Shakeri, Jairam Krishnamurthy, Irene Kang, Abigail Madans, Sheldon Feldman, Monica Johnson, Hani Katerji, Yangling Ma, Jeffrey B. Matthews, Amy L. Delson, Barbara LeStage, Jane Perlmutter, Emanuel F. Petricoin, Rebecca A. Shatsky, Elissa Price, Amrita Basu, Adam L. Asare, Teresa Helsten, Marisa Howard McNatt, Rita A. Mukhtar, W. Fraser Symmans, Alexander D. Borowsky, Dawn L. Heshman, Angela M. DeMichele, Hope S. Rugo, Nola M. Hylton, Laura J. van ’t Veer, Laura J. Esserman
Institutions: Mayo Clinic, Winship Cancer Institute, University of California, San Francisco, University of Alabama at Birmingham, University of Minnesota, University of California San Diego, University of Chicago, Georgetown University, Saint Barnabas Medical Center, Rutgers Cancer Institute, University of Pennsylvania, Duke University, Wake Forest University, Moffitt Cancer Center, New York University, The Ohio State University, Columbia University, UC Davis Health, University of Utah, Huntsman Cancer Institute, City Of Hope National Medical Center, City of Hope, Montefiore Medical Center, Oregon Health & Science University, University of Rochester Medicine, University of Rochester, University of Southern California, Loyola University Medical Center, Yale University, George Mason University, Quantum Leap Healthcare Collaborative, The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W7223241664