Despite major advances in breast cancer treatment, TNBC, which comprises approximately 15% of all breast cancer cases, continues to have a poor prognosis, with an increased risk of recurrence and mortality. IMMU-132 is a new ADC targeting Trop-2, an antigen found in high prevalence in many epithelial cancers, including TNBC, and conjugated to SN-38, a topoisomerase inhibitor and active metabolite of irinotecan, at a high drug:antibody ratio (7.6:1). Studies in mice bearing human pancreatic tumor xenografts (Capan-1) have shown IMMU-132 remains intact in the serum until internalized within the tumor cell where SN-38 is released (pH dependent), resulting in selective cancer cell death. IMMU-132 was found to deliver >120-fold higher amount of SN-38 to xenografted tumors than irinotecan. In animals bearing established MDA-MB-468 TNBC xenografts, IMMU-132 at well-tolerated doses improved responses (more robust regression and delayed progression), compared to irinotecan at a maximum therapeutic dose regimen or to an irrelevant antibody conjugate control. Animals that progressed after receiving the control responded to IMMU-132 therapy, even after those tumors had more than doubled from their initial size.

These encouraging pre-clinical data led to the development of the ongoing phase I/II clinical trial in patients (pts) with diverse relapsed/refractory epithelial cancers, including TNBC (NCT01631552). In dose escalation (8 to 18 mg/kg given on days 1 and 8 of a 3-week treatment regimen), dosing was limited primarily by neutropenia, with IMMU-132 being tolerated best for multiple cycles at 8 to 10 mg/kg. Since most (26/30) archival tumors from pts with TNBC expressed Trop-2 (30% ≥2+) and many cancer cell lines express abundant (i.e., >100,000) copies of Trop-2, no enrichment strategies for TNBC were employed to treat TNBC pts with IMMU-132. As of June 1, 2014, 10 pts with TNBC have completed their first response assessment by CT, with 6 having disease shrinkage as their best response; 2 pts had a partial response (-32 and -51% shrinkage of target lesions, with time to progression of 18+ and 30 wks, respectively), and 4 had stable disease (-3, -14 and -19 and -27% shrinkage for 18+, 14, 45, and 24 wks, respectively), according to RECIST. For all pts with diverse cancers treated to date at the phase II dose levels of 8 and 10 mg/kg, 6/25 (24%) had G3 neutropenia; G4 febrile neutropenia occurred in 1 pt. Alopecia, diarrhea, fatigue, nausea, and vomiting are the more common related non-hematological toxicities, but most occur at Grade ≤2. There has been no evidence of immunogenicity to the antibody or the drug, even over multiple cycles of treatment.

These promising results in pts who failed multiple prior therapies (median, 4; range, 1-8) suggest IMMU-132 is a safe and potentially effective drug for pts with TNBC, justifying continued evaluation of IMMU-132 in less refractory pts and also in combination with other agents.

Citation Format: David M Goldenberg, Linda T Vahdat, Alexander N Starodub, Aditya Bardia, Ellen Chuang, Rebecca L Moroose, Jennifer R Diamond, Robert M Sharkey, Pius P Maliakal, Steven A Hamburger, Allyson J Ocean. IMMU-132, a potential new antibody-drug conjugate (ADC) for the treatment of triple-negative breast cancer (TNBC): Preclinical and initial clinical results [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 P5-19-08.