Background: In stage II/III TNBC, pembrolizumab when combined with chemotherapy (doxorubicin, cyclophosphamide, paclitaxel [ACT], and carboplatin) improves event free survival and pathologic complete response (pCR) rate (Keynote-522 study).1 Novel combination immunotherapy strategies may further improve outcome and/or afford the opportunity to de-escalate the chemotherapy backbone. We have previously reported safety and feasibility of pre-operative IRX-2, a novel cytokine-based therapeutic that can be administered locoregionally to enhance immune response.2 In a phase Ib study in stage I-III breast cancer, IRX-2 was safe, well tolerated, and associated with increased tumor infiltrating lymphocytes (sTILs, by H&E and multispectral immunofluorescence [mIF]), PD-L1 expression (Ventana SP142 assay, mIF), and lymphocyte activation (by RNA sequencing). These potential immunomodulatory effects support further study of IRX-2 in combination with ICI and chemotherapy in the neoadjuvant setting. Methods: Patients are randomized to a phase II, open-label trial to evaluate the clinical and immunological activity of pembrolizumab plus de-escalated chemotherapy (ACT) when combined with IRX-2 for TNBC. All patients (n=30) will receive pembrolizumab induction (single dose 200mg IV), followed by pembrolizumab every three 3 weeks in conjunction with ACT as neoadjuvant therapy prior to surgery. Patients randomized to arm A (n=15) will additionally receive peri-lymphatic locoregional injections of IRX-2 (1mL SQ x 2 daily, x 10 days) during the induction phase. Eligible subjects will have previously untreated, resectable stage II/III TNBC. The primary endpoint is pCR. The secondary endpoint is safety. On-treatment biopsies following induction (pembrolizumab +/- IRX-2) will permit a prospective, randomized validation of previously reported immunomodulatory effects of IRX-2 (sTILs, PD-L1, lymphocyte RNA signatures). As of 7/8/2021, n=6/30 subjects are enrolled (Providence Cancer Institute, Portland, OR, Providence St. John’s Cancer Institute, Santa Monica, CA, Baylor College of Medicine, Houston, TX). NCT04373031. 1Schmid, P. N Engl J Med 2020; 382:810-821. 2Page, DB. Clin Cancer Res 2020; 26.7:1595-1605.

Citation Format: Katherine Sanchez, Alison Conlin, Parvin Peddi, Sasha Stanton, Janet Ruzich, Kelly Perlewitz, Yaping Wu, Nicole Moxon, Staci Mellinger, Zhaoyu Sun, William Redmond, David B Page. The neoIRX trial:locoregional cytokine therapy to promote immunologic priming and enhanced response to neoadjuvant pembrolizumab plus chemotherapy in triple negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-03.