Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer

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