Rilvegostomig Plus Trastuzumab-Deruxtecan for Early-Stage Breast Cancer: The I-SPY2.2 Randomized Clinical Trial.

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.