Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer: The I-SPY2.2 Randomized Clinical Trial.
29 affiliations
- 1Mayo Clinic, Rochester, Minnesota.
- 2Emory University Winship Cancer Institute, Atlanta, Georgia.
- 3University of California, San Francisco.
- 4University of Alabama, Birmingham.
- 5University of Minnesota, Minneapolis.
- 6University of California, San Diego, La Jolla.
- 7University of Colorado, Aurora.
- 8University of Chicago, Chicago, Illinois.
- 9Georgetown University, Washington, DC.
- 10Rutgers Cancer Institute of New Jersey, New Brunswick.
- 11Cooperman Barnabas Medical Center, Livingston, New Jersey.
- 12University of Pennsylvania, Philadelphia.
- 13Wake Forest, Winston-Salem, North Carolina.
- 14Duke University, Durham, North Carolina.
- 15Moffitt Cancer Center, Tampa, Florida.
- 16New York University, New York.
- 17The Ohio State University, Columbus.
- 18Columbia University, New York, New York.
- 19UC Davis Health, Sacramento, California.
- 20University of Utah Huntsman Cancer Institute, Salt Lake City.
- 21City of Hope (Lennar), Duarte, California.
- 22Health Partners Institute-Hennepin, Minneapolis, Minnesota.
- 23Montefiore Medical Center, New York, New York.
- 24Oregon Health and Science University, Portland.
- 25University of Rochester Medical Center, Rochester, New York.
- 26University of Southern California, Los Angeles.
- 27Hoag Family Cancer Institute, Irvine, California.
- 28Loyola University Medical Center, Maywood, Illinois.
- 29Yale University, New Haven, Connecticut.
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.
Related
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- Adjuvant Trastuzumab Deruxtecan Versus Trastuzumab Emtansine by Residual Cancer Burden in HER2-Positive Early Breast Cancer: A Decision Analysis
- First-line durvalumab in combination with trastuzumab deruxtecan in women with locally advanced unresectable or metastatic, hormone-receptor-negative, HER2-low breast cancer: multicenter, open-label, phase 1b/2 BEGONIA platform trial
- Equivocal and definite interstitial lung abnormalities as risk factors for trastuzumab deruxtecan-related interstitial lung disease in breast cancer
- Managing trastuzumab deruxtecan-related adverse events in patients with metastatic breast cancer: insights from a worldwide survey of the Hermione EDUcational project
BibTeX
@article{advocates2026rilvegostomig,
title = {{Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer: The I-SPY2.2 Randomized Clinical Trial.}},
author = {I-SPY2 Trial Investigators and Advocates and Ciara C O'Sullivan and Kevin M Kalinsky and Christina Yau and Tejaswini Kulkarni and Douglas Yee and Anne M Wallace and A Jo Chien and Judy C Boughey and Anthony D Elias and Rita Nanda and Claudine Isaacs and Coral Omene and Erica Stringer-Reasor and Amy S Clark and Alexandra Thomas and Heather S Han and Nancy Chan and Nicole Williams and Meghna S Trivedi and Mili Arora and Christos Vaklavas and Jennifer Tseng and Satya Bommakanti and Jesus D Anampa Mesias and Alexandra Zimmer and Carla Falkson and Evanthia Roussos Torres and Chaitali Nangia and Kathy S Albain and Mariya Rozenblit and Somaye Zare and Soudabeth Fazelli and Yunni-Yi Chen and Laura A Huppert and An L Church and Heather Beckwith and Evelyn Carroll and Malvika Solanki and Virginia F Borges and Sarah E A Tevis and Nan Chen and Jay C Zeck and Maria J Kowzun and Jessica Sullivan and Natalie Marshall and Molly E Klein and Karthik V Giridhar and Radhika Acharya-Leon and Betty Fan and Elaine M Walsh and Anya Litvak and Nusrat Jahan and Elizabeth McDonald and Emily Hughes Douglas and Jameel Zena and Amber Guth and Kai Johnson and Julia E McGuinness and Kant Matsuda},
journal = {JAMA oncology},
year = {2026},
month = oct,
doi = {10.1001/jamaoncol.2026.4258},
url = {https://europepmc.org/article/MED/42911610},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer: The I-SPY2.2 Randomized Clinical Trial.
AU - I-SPY2 Trial Investigators and Advocates
AU - Ciara C O'Sullivan
AU - Kevin M Kalinsky
AU - Christina Yau
AU - Tejaswini Kulkarni
AU - Douglas Yee
AU - Anne M Wallace
AU - A Jo Chien
AU - Judy C Boughey
AU - Anthony D Elias
AU - Rita Nanda
AU - Claudine Isaacs
AU - Coral Omene
AU - Erica Stringer-Reasor
AU - Amy S Clark
AU - Alexandra Thomas
AU - Heather S Han
AU - Nancy Chan
AU - Nicole Williams
AU - Meghna S Trivedi
AU - Mili Arora
AU - Christos Vaklavas
AU - Jennifer Tseng
AU - Satya Bommakanti
AU - Jesus D Anampa Mesias
AU - Alexandra Zimmer
AU - Carla Falkson
AU - Evanthia Roussos Torres
AU - Chaitali Nangia
AU - Kathy S Albain
AU - Mariya Rozenblit
AU - Somaye Zare
AU - Soudabeth Fazelli
AU - Yunni-Yi Chen
AU - Laura A Huppert
AU - An L Church
AU - Heather Beckwith
AU - Evelyn Carroll
AU - Malvika Solanki
AU - Virginia F Borges
AU - Sarah E A Tevis
AU - Nan Chen
AU - Jay C Zeck
AU - Maria J Kowzun
AU - Jessica Sullivan
AU - Natalie Marshall
AU - Molly E Klein
AU - Karthik V Giridhar
AU - Radhika Acharya-Leon
AU - Betty Fan
AU - Elaine M Walsh
AU - Anya Litvak
AU - Nusrat Jahan
AU - Elizabeth McDonald
AU - Emily Hughes Douglas
AU - Jameel Zena
AU - Amber Guth
AU - Kai Johnson
AU - Julia E McGuinness
AU - Kant Matsuda
PY - 2026
DA - 2026/10/22
JO - JAMA oncology
DO - 10.1001/jamaoncol.2026.4258
UR - https://europepmc.org/article/MED/42911610
AB - 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.
SN - 2374-2437
SN - 2374-2445
ER -