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Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab is an anti-PD-1 inhibitor approved for the treatment of NSCLC and cutaneous basal and squamous cell CA. Lymphocyte activation gene 3 (LAG-3) binds MHC class II leading to inhibition of T-cell proliferation and activation and is often co-expressed with PD-1. REGN3767 is a fully humanized mAb that binds to LAG-3 and blocks inhibitory T-cell signaling. Concurrent blockade of LAG-3 with an anti-PD-1 may enhance efficacy of an anti-PD-1. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included Paclitaxel 80 mg/m2 IV weekly x 12 and Cemiplimab 350 mg and REGN3767 1600 mg both given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. Cemiplimab/REGN3767 was eligible to graduate in 3 of 10 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. The statistical methods for evaluating I-SPY 2 agents has been previously described. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemiplimab/REGN3767 being superior to the dynamic control. Response predictive subtypes (Immune+ vs Immune-) were assessed using pre-treatment gene expression data and the ImPrint signature. Results: 73 HER2- patients (40 HR+ and 33 HR-) received Cemiplimab/REGN3767 treatment. The control group included [357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemiplimab/REGN3767 graduated in both HR-/HER2- and HR+/HER2- groups; estimated pCR rates (as of June 2022) are summarized in the table. Safety events of note for Cemiplimab/REGN3767 include hypothyroidism 30.8%, adrenal insufficiency (AI) 19.2%, hyperthyroidism 14.1%, pneumonitis 1.3%, and hepatitis 3.8%. All were G1/2 except for 6 (7.7%) G3 AI and 3 (3.8%) G3 colitis. Rash occurred in 62.8%, 9% G3 and 2 pts (2.6%) had pulmonary embolism. X% of adrenal insufficiency cases required replacement therapy. 40 patients (11 HR+ and 29 HR-) in Cemiplimab/REGN3767 were predicted Immune+; 32 (29 HR+ and 3 HR-) were predicted Immune-. In the HR+ group pCR was achieved in 10/11 (91%) patients with Immune+ subtype compared with 8/29 (28%) with Immune- subtype. Additional biomarker analyses are ongoing and will be presented at the meeting. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Dual immune blockade with a LAG-3 inhibitor and anti-PD1 therapy resulted in a high predicted pCR rate both in HR-/HER2- (60%) and HR+/HER2- (37%) disease. The novel Imprint signature identified a group of HR+ patients most likely to benefit from this active regimen. Table 1: Estimated pCR rates Citation Format: Claudine Isaacs, Rita Nanda, Jo Chien, Meghna S. Trivedi, Erica Stringer-Reasor, Christos Vaklavas, Judy C. Boughey, Amy Sanford, Anne Wallace, Amy S. Clark, Alexandra Thomas, Kathy S. Albain, Laura C. Kennedy, Tara B. Sanft, Kevin Kalinsky, Hyo S. Han, Nicole Williams, Mili Arora, Anthony Elias, Carla Falkson, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. Evaluation of anti-PD-1 Cemiplimab plus anti-LAG-3 REGN3767 in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-03.

Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within biomarker subtypes defined by hormone-receptor (HR), HER2, and MammaPrint (MP) status to evaluate novel agents as neoadjuvant therapy for high-risk breast cancer. The primary endpoint is pathologic complete response (pCR). Cemiplimab (Cemi) is a PD-1 inhibitor approved for the treatment of NSCLC, cutaneous basal, and squamous cell cancer. Here, we report current efficacy rates of Cemi in combination with paclitaxel followed by AC. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment; HR positive (HR+) patients had to be MP high risk. Treatment included paclitaxel 80 mg/m2 IV weekly x 12 and Cemi 350 mg IV given q3weeks x 4, followed by doxorubicin/cyclophosphamide (AC) every 2 weeks x 4. The control arm was weekly paclitaxel x 12 followed by AC every 2-3 weeks x 4. All patients undergo serial MRI imaging; and imaging response (at 3 weeks, 12 weeks and prior to surgery) were used along with accumulating pCR data to continuously update and estimate pCR rates for trial arms. Analysis was modified intent to treat. Patients who switched to non-protocol therapy count as non-pCR. The goal is to identify (graduate) regimens with ≥85% Bayesian predictive probability of success (i.e. demonstrating superiority to control) in a future 300-patient phase 3 neoadjuvant trial with a pCR endpoint within responsive signatures. Cemi was eligible to graduate in 3 pre-defined signatures: HER2-, HR-HER2-, and HR+HER2-. To adapt to changing standard of care, we constructed “dynamic controls” comprising ‘best’ alternative therapies using I-SPY 2 and external data and estimated the probability of Cemi being superior to the dynamic control. Results: 60 HER2- patients (28 HR+ and 32 HR-) received Cemi arm treatment. The control group included 357 patients with HER2- tumors (201 HR+ and 156 HR-) enrolled since March 2010. Cemi graduated in HR-/HER2- signature. Estimated pCR rates (as of June 2022) are summarized in the table. Immune-related endocrine disorders include: hypothyroid (14.5%), adrenal insufficiency (10%), hyperthyroid (4.8%),) and thyroiditis (3.2%). Only one grade 3 adrenal insufficiency was observed. All immune related AE’s were manageable. Additional biomarker analyses are ongoing and will be presented at the meeting. Response predictive subtypes (Immune+ vs Immune-) and additional predictive biomarkers were assessed. Associations with pCR will be presented at SABCS. Conclusion: The I-SPY 2 study aims to assess the probability that investigational regimens will be successful in a phase 3 neoadjuvant trial. Anti-PD-1 therapy with Cemi resulted in a higher predicted pCR rate in HR-/HER2- 55 rate% disease compared to control at 29%. Immune-mediated AE’s were observed. This data is consistent with previously published data using check point inhibitors in early-stage HR-/HER2- breast cancer. Estimated pCR rates Citation Format: Erica Stringer-Reasor, Rebecca A. Shatsky, Jo Chien, Anne Wallace, Judy C. Boughey, Kathy S. Albain, Hyo S. Han, Rita Nanda, Claudine Isaacs, Kevin Kalinsky, Zahi Mitri, Amy S. Clark, Christos Vaklavas, Alexandra Thomas, Meghna S. Trivedi, Janice Lu, Smita Asare, Ruixiao Lu, Maria Pitsouni, Amy Wilson, Jane Perlmutter, Hope Rugo, Richard Schwab, W. Fraser Symmans, Nola M. Hylton, Laura Van ’t Veer, Douglas Yee, Angela DeMichele, Donald Berry, Laura J. Esserman, I-SPY Investigators. PD11-01 Evaluation of the PD-1 Inhibitor Cemiplimab in early-stage, high-risk HER2-negative breast cancer: Results from the neoadjuvant I-SPY 2 TRIAL [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-01.

Background. Immunotherapy has emerged as an important component of neoadjuvant therapy for some patients with breast cancer (BC). As a result, immune-related adverse events (irAEs) are increasing and have effects on both short and long term symptoms significantly impacting patient quality of life. BC patients may develop new conditions including arthralgias, gastrointestinal issues, endocrinopathies, and fatigue during or after cancer therapy that may be acute or long-lasting in nature. Monitoring for early onset and severity of symptoms, and adjusting treatment and symptom management could optimize therapy for a particular patient, maximizing potential efficacy while mitigating toxicity. We sought to identify patient demographic characteristics and symptom patterns associated with risk for development of irAEs in the context of a randomized trial for patients with early-stage high-risk breast cancer. Methods. I-SPY2 is a multi-center, phase 2 trial using response-adaptive randomization for high-risk early-stage women with BC. The study population for this analysis includes enrolled patients receiving combinations of experimental immunotherapy and chemotherapy. Groups considered for statistical comparisons included those that developed an irAE versus those that did not develop an irAE up until the surgery timepoint. In I-SPY adverse events are documented through the Common Terminology Criteria for Adverse Events (CTCAEv5.0). Hypothyroidism, adrenal insufficiency, and pneumonitis were the irAEs considered in this study. A chi-square test was used to assess associations between race and ethnicity (White, Asian, Black, non-Hispanic) and irAEs. One-way ANOVA was used to evaluate the association between age (>50 vs < 50) and irAEs. 33 symptoms reported at CTCAE grade 2 or higher were included in the analyses and a symptom burden score was calculated using area under curve (AUC) which combined the duration of each symptom between baseline and week 6 of treatment, and grade of adverse event. Regularized regression using leave-one out cross validation was used to evaluate early symptoms (as quantified by the symptom burden score) as predictors, and irAEs as surrogate responses. Results. Out of 461 patients, percentages of patients wth irAEs of interest included hypothyroidism (13%), adrenal insufficiency (9%), and pneumonitis (4%). Demographic information was available for 333 patients, of which 270 (81%) were White, 23 (7%) were Asian, 37 (11%) were African American (AA) and 278 (17%) were non-Hispanic. There were proportionately higher number of white patients that developed hypothyroidism than non-white patients (35 of 265 (13%) vs 2 of 63 (3%), P < 0.04). Pneumonitis was more common in patients over 50 years old than under 50 years old (P < 0.02). Symptoms that were most commonly reported up to week 6 of treatment among patients who developed an irAE included: diarrhea (36%), fatigue (15%), dizziness (12%) and shortness of breath (SOB) (11%). Symptoms associated with the development of hypothyroidism included fatigue (15%, mean AUC=11.8 vs 5.8 for those that did not develop irAE), SOB (11%, 4.3 vs 2.8), and blurry vision (1%, 1.0 vs 0.12). Development of adrenal insufficiency was associated with early reports of diarrhea (36%, 19.0 vs 10.5), SOB (11%, 7.8 vs 2.6), joint pain (3%, 2.29 vs 0.58), decreased appetite (3%, 3.55 vs 0.91), and constipation (1%, 3.6 vs 0.02). No significant early symptoms emerged for pneumonitis due to a limited number of events. Conclusion. Our study utilizes an analysis framework that is aimed to determine symptom clusters that predict the development of irAEs. We describe specific symptoms presenting early with the development of hypothyroidism and adrenal insufficiency, in recognition of allowing physicians to be more diligent in active and post treatment monitoring. Citation Format: Amrita Basu, Saumya Umashankar, Michelle Melisko, Ruixiao Lu, Hongmei Yu, Christina Yau, Smita Asare, Maria Pitsouni, Rebecca A. Shatsky, Claudine Isaacs, Angela DeMichele, Dawn Hershman, Rita Nanda, Mi-Ok Kim, Laura J. Esserman, Hope Rugo. Identification of symptoms that are associated with irAEs in the I-SPY clinical trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-04.