Abstract OT-33-01: Combination ipatasertib and atezolizumab to prevent recurrence in triple negative breast cancer(TNBC): A phase II single arm trial
Authors: Mittendorf Elizabeth , Tolaney Sara , Wileyto Paul , DeMeo Michelle , Rugo Hope , Nanda Rita , Mayer Ingrid , Park Ben , MacArthur Heather , DeMichelle Angela 
Published: February 2021

Abstract
Background: TNBC patients with residual disease after neoadjuvant chemotherapy (NAC) have high recurrence rates. Targetable mechanisms likely responsible for NAC resistance must therefore be identified to identify new therapeutic options. Alterations in the PI3K/mTOR pathway as well as expression of the immune checkpoint PD-L1 have emerged as potential targets, with significant frequency of alteration in TNBC. Importantly, the AKT inhibitor ipatasertib (ipat) and the anti-PD-L1 antibody atezolizumab (atezo) have demonstrated activity against TNBC. Recent data suggests that the presence of circulating tumor cell-free DNA (cfDNA) following NAC correlates with residual disease and a higher recurrence risk. We have hypothesized that combination therapy with ipat and atezo will target micrometastatic disease, as determined by the presence of cfDNA after NAC, in TNBC patients. Trial design:Open label single-arm phase II study to evaluate combination therapy with ipat and atezo, in TNBC patients with detectable cfDNA after completion of NAC, definitive surgery, and adjuvant radiation and/or chemotherapy. Eligible patients will receive: atezo [840mg IV days 1 and 15 and ipat [400 mg orally daily on days 1-21, followed by one week off] in a 28-day cycle for 6 cycles; cfDNA will be evaluated after 3 and 6 cycles. Biomarkers including PD-L1 expression on tumor cells or infiltrating immune cells in the primary tumor or PD-L1 expression on circulating tumor cells will be assessed. Eligibility criteria:Patients ≥ 18 yrs of age with pathologically confirmed residual invasive TNBC (ER and PR negative defined as &lt;10% of cells expressing ER/PR by local assessment; HER2 negative according to ASCO/CAP guidelines) following NAC with evidence of cfDNA after completion of all local and systemic neoadjuvant and adjuvant therapy. Patients must enroll within 12 months of last therapy (definitive breast surgery, radiation and/or all intended adjuvant therapy). Prior treatment with immunotherapeutic agents is allowed. Specific aims:The primary objective is to evaluate the efficacy of 6 cycles of ipat + atezo in reducing micrometastatic disease (detectable cfDNA) in patients with residual breast and/or axillary disease after NAC and completion of all locoregional and/or systemic adjuvant therapy. Secondary objectives include: evaluating efficacy of ipat + atezo in reducing micrometastatic disease after 3 cycles; determining the recurrence risk after treatment with ipat + atezo; and determining the safety and tolerability of the combination. Correlative objectives include determining whether: 1) pretreatment circulating markers (mutations or copy number changes in PTEN/PI3K/AKT) are associated with response; 2) PD-L1 expression on tumor cells or infiltrating tumor cells in the primary tumor is associated with response; 3) PD-L1 expression on circulating tumor cells has utility as a pharmacodynamic biomarker; and 4) stool microbiome profiles are associated with response and/or survival. As an exploratory objective, patient attitudes and experience surrounding testing for tumor cfDNA and, for those testing positive, participation in a trial targeting cfDNA, will be assessed. Statistical methods:The primary objective is to determine the response rate defined as the proportion of patients with detectable cfDNA who become undetectable. We anticipate that 30% of patients screened will be tumor cfDNA-positive, thus anticipate screening ~ 120 patients to enroll 40. With 40 patients enrolled (assuming a one-sided alpha of 0.05), we will have 80% power to detect a 19.0% (81% positive versus 93% positive) clearance rate using a one-sample binomial exact test. Target Accrual:40 patients Contact:A. DeMichele (angela.demichele@pennmedicine.upenn,edu) Clinicaltrials.gov #: NCT04434040
Citation Format: Elizabeth Mittendorf, Sara Tolaney, Paul Wileyto, Michelle DeMeo, Hope Rugo, Rita Nanda, Ingrid Mayer, Ben Park, Heather MacArthur, Angela DeMichelle. Combination ipatasertib and atezolizumab to prevent recurrence in triple negative breast cancer(TNBC): A phase II single arm trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-33-01.