Abstract PD3-06: Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC
Authors: Bardia A , Diamond JR , Mayer IA , Starodub AN , Moroose RL , Isakoff SJ , Ocean AJ , Guarino MJ , Berlin JD , Messersmith WA , Thomas SS , O'Shaughnessy JA , Kalinsky K , Maurer M , Chang JC , Forero A , Traina T , Gucalp A , Wilhelm F , Wegener WA , Maliakal P , Sharkey RM , Goldenberg DM , Vahdat LT 
Published: May 2016

Abstract
Background: Triple-negative breast cancer (TNBC) comprises about 15% of all breast cancer types, and has a particularly aggressive course. Following first-line therapy, the median PFS is &lt;3 months, and OS is &lt;10 months. Therefore, new treatment strategies are needed. Since Trop-2 is expressed in &gt;90% of TNBC, as measured by IHC, we conducted a trial to evaluate the safety and efficacy of a humanized anti-Trop-2 monoclonal antibody conjugated to a high concentration of SN-38, a camptothecin that is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan, with 2-3 logs higher potency than the prodrug.
Methods: After establishing the optimal repeated dose in a Phase I trial (ClinicalTrials.gov, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC. Patients received 8 or 10 mg/kg IMMU-132 i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible.
Results: As of May 10, 2015, 58 patients with TNBC, with a median of 4 prior therapies (range, 1-11), were treated with IMMU-132. Grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%). No patient developed antibodies to SN-38 or the antibody, and no patient discontinued therapy due to toxicity. Tumor responses were defined as ORR (CR+PR) in 31% of 49 evaluated patients, including 2 with CR, and a clinical benefit ratio (CR+PR+SD&gt;6 mo) of 49% (63% with SD&gt;4 mo; 23 patients continuing treatment after 1st assessment). The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient. Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining.
Conclusions: The Trop-2-targeting IMMU-132, delivering cytotoxic doses of the topoisomerase I inhibitor, SN-38, shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This ADC appears to have a high therapeutic index in heavily pretreated patients.
Citation Format: Bardia A, Diamond JR, Mayer IA, Starodub AN, Moroose RL, Isakoff SJ, Ocean AJ, Guarino MJ, Berlin JD, Messersmith WA, Thomas SS, O'Shaughnessy JA, Kalinsky K, Maurer M, Chang JC, Forero A, Traina T, Gucalp A, Wilhelm F, Wegener WA, Maliakal P, Sharkey RM, Goldenberg DM, Vahdat LT. Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-06.