Abstract CT175: Targeting inducible nitric oxide in a first-in-class phase 1/2 trial in triple-negative breast cancer patients diminishes M2 macrophage polarization and led to a robust clinical response

Targeting inducible nitric oxide in a first-in-class phase 1/2 trial in triple-negative breast cancer patients diminishes M2 macrophage polarization and led to a robust clinical response. Andrew W. Chung*, Kartik Anand*, Polly Niravath* (co-first authors), Nakul Gupta, Luz A Venta, Mary R. Schwartz, Wei Qian, Yitian Xu, Licheng Zhang, Qiuying Chen, Nabeel Attarwala, John Kuhn, Tejal Patel, Angel Rodriguez, Anna Belcheva, Jorge Darcourt, Joe Ensor, Eric Bernicker, Ping-Ying Pan, Virginia Kaklamani, Shu Hsia Chen, Jenny C ChangIntroduction:The inducible nitric oxide signaling (iNOS) pathway has been associated with poor prognosis in triple-negative breast cancer (TNBC). Inhibition of iNOS pathway by using the pan-NOS inhibitor NG-monomethyl-L-arginine (L-NMMA) in patient-derived xenograft (PDX) models has shown reduced tumor growth and enhanced survival. Here, we report a first-in-class phase 1/2 trial of L-NMMA plus taxane for patients with chemorefractory locally advanced (LA) TNBC or metastatic TNBC and present findings on molecular immune correlates and metabolites of response/resistance. Methods:Women with chemorefractory LA or metastatic TNBC without uncontrollable hypertension or heart disease, age >18 years, and ECOG performance status ≤2 were eligible. A Bayesian model averaging continuous reassessment method was used to determine the recommended phase 2 L-NMMA dose (RP2D). In phase 1, two dose levels of docetaxel (75 and 100 mg/m2) and seven dose levels of L-NMMA (5,7.5, 10, 15,17.5, and 20 mg/kg) were studied. Patients in phase 2 received a maximum of six (q 3 weeks) cycles of L-NMMA given via IV on D1-D5. All patients also received amlodipine (6 days/cycle) and aspirin daily, as hypertensive and thromboembolic prophylaxis. Toxicity was measured as per CTCAE v4.03. Pharmacokinetics/Pharmacodynamics, 38 circulating cytokines, and 30 differential metabolites were also assayed. Tissue imaging mass cytometry (IMC) with 35 cell surface markers was performed on paired biopsies. Results: From July 2016 to September 2020, a total of 35 patients were recruited (phase 1, n=15; phase 2, n= 24, including 4 RP2D patients from phase 1). RP2D dose was 20 mg/kg for L-NMMA and 100 mg/m2 for docetaxel. In phase 2, 54.2% had metastatic TNBC (with 5 median prior lines of chemotherapy) and 45.8% had LABC (anthracycline-refractory). Overall response rate (ORR) was 54.2% - 81.8% for LABC and 30.8% for metastatic TNBC. Radiologic complete response (CR) rate was 27.2% for