Multicenter randomized phase 2 trial of rilvegostomig plus trastuzumab-deruxtecan for early-stage breast cancer

The I-SPY2.2 trial, at 30 sites in the US, tests personalized treatment strategies to improve outcomes while reducing exposure to standard chemotherapy in patients with high-risk early breast cancer (EBC). Outcomes with neoadjuvant rilvegostomig (R, a bispecific antibody targeting programmed cell death 1 protein and T-cell immunoglobulin and ITIM domain) plus trastuzumab-deruxtecan (T-DXd) as initial therapy in I-SPY2.2 have now been published. Patients with high-risk stage II/III HER2-negative EBC received up to 3 sequential blocks of therapy, based on response and subtype: RT-DXd (block A), taxane-based therapy with or without immunotherapy (block B), and doxorubicin-cyclophosphamide (AC) with or without immunotherapy (block C). The primary endpoint was pathologic complete response (pCR). A total of 182 individuals 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 ITT population with 105 and 107 evaluable participants. Among 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 immuno-positive patients who experienced pCR, 21 (62%) required only block A, and 33 (97%) avoided anthracycline-based chemotherapy. The most common adverse events were fatigue and nausea. The authors conclude that treatment with RT-DXd demonstrated promising activity, with mostly low-grade toxic effects in immune-positive, HER2-negative EBC. Unlike immune-negative patients, many immune-positive patients who experienced pCR avoided standard chemotherapy.