Immu-132, A New Antibody-Drug Conjugate (Adc) Against Trop-2, As A Novel Therapeutic For Patients With Relapsed/Refractory, Metastatic, Triple-Negative Breast Cancer (Tnbc): Results From Phase I/Ii Clinical Trial (Nct01631552)

Background: TNBC, comprising 15-20% of all invasive breast cancers, represents an aggressive phenotype with high risk of recurrence and mortality. Trop-2 is a cell-surface glycoprotein expressed on many human carcinomas, including TNBC. High Trop-2 expression is associated with more aggressive disease and poor prognosis in several cancers, including breast cancer. We report interim results from a Phase I/II trial evaluating a novel ADC, IMMU-132 (isactuzumab govitecan), comprising a humanized anti-Trop-2 antibody conjugated to the topoisomerase I inhibitor, SN-38 (active metabolite of irinotecan). The drug:antibody ratio of 7.6 facilitates the delivery of high-dose chemotherapy preferentially to the tumor cells. Methods: Patients (pts) with relapsed/refractory metastatic epithelial tumors were enrolled at escalating IMMU-132 doses (8 to 18 mg/kg), given on days 1 and 8 of a 21-day cycle. The Phase II dose at this schedule was 10 mg/kg. CT scans were performed every 6-8 weeks to assess response using RECIST 1.1. During the dose-escalation portion, evidence of antitumor activity, including 3 partial responses (TNBC, small-cell lung cancer and colorectal cancer) and many with durable stable disease (SD), was observed, leading to Phase II expansion. Results: As of Sept. 25, 2014, a total of 132 pts have been enrolled, including 30 with advanced/metastatic TNBC. Currently evaluable TNBC pts (N=17) had a median age of 50 (33-77), with a median of 4 prior drug regimens (range 1-8), and 67% having received prior platinum-containing regimens. In this heavily pre-treated population, there were 4 PRs (25%) and 9 SDs (56.3%) per RECIST v1.1, representing a disease control (PR+SD g 4 mos) of 53% among evaluable pts with adequate follow-up. A maximum shrinkage of target lesions of 33%, 44%, 51%, and 60% for pts with PRs, and 14%, 19%, and 27% for 3 pts with SD, was determined. Biomarker CA15.3 directional changes correlated with RECIST. All but one pathology specimen were Trop-2 + by immunohistochemistry. HPLC analysis of serum samples found l5% unbound SN-38. The half-life of IMMU-132 was 23 h, which is similar to the predicted half-life from in vitro serum stability studies. Grade 3/4 toxicities were: neutropenia (G3, 4 pts, 23.5%) with 1 febrile neutropenia (5.9%), and lymphocytopenia (1 Gr 3, 1 pt, 5.9%). Grade 1/2 events were fatigue (35.3%), diarrhea (41.2%), and alopecia (29.4%). No pt discontinued therapy due to toxicity. Conclusions: Based on laboratory and initial clinical results, IMMU-132 is an ADC that selectively delivers a topoisomerase I inhibitor to cancer cells without the need for enrichment by a companion diagnostic. It is safe, well-tolerated, with preliminary evidence of encouraging efficacy in heavily-pretreated pts with relapsed/refractory metastatic TNBC. Randomized Phase III and combination trials are being planned. Citation Format: Aditya Bardia, Alexander Starodub, Rebecca L Moroose, Ingrid A Mayer, Jennifer R Diamond, Ellen Chuang, Serengulam V Govindan, Robert M Sharkey, Pius Maliakal, William A Wegener, Steven A Hamburger, Allyson J Ocean, David M Goldenberg, Linda T Vahdat. IMMU-132, a new antibody-drug conjugate (ADC) against Trop-2, as a novel therapeutic for patients with relapsed/refractory, metastatic, triple-negative breast cancer (TNBC): Results from Phase I/II clinical trial (NCT01631552) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-27.