Douglas, Emily

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

LBA520 Background: I-SPY 2 is a multicenter trial using response-adaptive randomization within biomarker subtypes including MammaPrint (MP) risk to evaluate novel neoadjuvant agents in high-risk breast cancer. Oral paclitaxel and encequidar (OPE) is an oral combination of paclitaxel (P) with a p-glycoprotein pump inhibitor, encequidar, to enhance gastrointestinal (GI) absorption. Dostarlimab (D) is an anti-PD-1 monoclonal antibody. Methods: Women with tumors ≥ 2.5cm and MP high-risk cancers were screened and treated starting Oct 5, 2020. Treatment included Oral Paclitaxel 205mg/m2 and encequidar 12.9 mg on days 1-3, Carboplatin (Cb) AUC 1.5 on day 1 weekly x 12, and Dostarlimab (D) 500 mg every 3 weeks x 4, followed by doxorubicin/ cyclophosphamide (AC) every 2-3 weeks x 4. The control arm was IV P weekly x 12 followed by AC every 2-3 weeks x 4. For patients with HER2+ disease, weekly Trastuzumab (T) was administered during the first 12 weeks. The arm was eligible for graduation [> 85% chance of success in a 300-person phase 3 neoadjuvant trial with a pathologic complete response (pCR) endpoint] in 10 predefined signatures. Results: 106 patients (44 HR+HER2-, 56 HR-HER2- (TN), 6 HER2+) received OPE/Cb/D ± T. The control arm included 388 historical controls (201 HR+HER2-, 156 TN, 31 HER2+). 22 patients (20 HR+, 2 HR-) in OPE/Cb/D were MP1 (MP high) and 84 patients (29 HR+, 55 HR-) were MP2 (MP ultra-high). OPE/Cb/D graduated in the TN signature and accrual was stopped. Conclusions: OPE/Cb/D graduated in the TN signature with a higher predicted pCR rate compared to control. OPE and D have been, individually, shown to have efficacy in other settings. The lower-than-expected pCR rate and lower irAEs with triplet therapy (taxane, platinum, immune checkpoint inhibitor [ICI]) in TN compared to prior IV chemo + ICI arms on I-SPY 2 suggests a possible interference of OPE with ICI. Changes in gut microbiome is being investigated as an explanation. Clinical trial information: NCT01042379 . [Table: see text]