Abstract C166: Combining an anti-Trop-2 antibody-SN-38 conjugate (sacituzumab govitecan) with microtubule inhibitors (paclitaxel and eribulin mesylate) or PARP inhibitor (olaparib) significantly improves therapeutic outcome in experimental triple-negative breast cancer (TNBC)
Authors: Cardillo Thomas M. , Govindan Serengulam V. , Zalath Maria , Arrojo Roberto , Sharkey Robert M. , Goldenberg David M. 
Published: May 2016

Abstract
Purpose: Determine whether combining sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate, with microtubule inhibitors (paclitaxel or eribulin mesylate) or a poly(adenosine diphosphoribose) polymerase (PARP) inhibitor (olaparib) in mice bearing human TNBC xenografts improves anti-tumor effects.
Experimental Procedures: Mice bearing human TNBC xenografts (MDA-MB-468 or HCC1806; ∼0.3 cm3) were treated with the maximum tolerated dose of paclitaxel (15 mg/kg weekly x 5 wks) and IMMU-132 at either 10 mg/kg or 12.5 mg/kg on days 1, 8, 22, and 29. Mice bearing HCC1806 tumors (∼0.28 cm3) were treated for 2 cycles with IMMU-132 (12.5 mg/kg) and 0.5 mg/kg of eribulin mesylate (equivalent to human dose of 1.4 mg/m2) weekly for 2 weeks on a 21-day cycle. Studies examining PARP inhibition used mice bearing MDA-MB-468 tumors (∼0.32 cm3) treated with olaparib (50 mg/kg, qdx5d, x 4 wks; 33% of human dose equaling 800 mg daily) and IMMU-132 (10 mg/kg, twice weekly x 4 wks). The primary endpoint was the median survival time (MST), defined as the time for tumors to progress to 1.0 cm3.
Results: Mice with MDA-MB-468 tumors given the combination of IMMU-132 and paclitaxel exhibited superior anti-tumor effects, with &gt;11-fold tumor shrinkage, in comparison to 1.4-fold shrinkage in the IMMU-132 group alone (P = 0.0003; area under the curve, AUC) or 11.4-fold increase in tumor size in mice treated with paclitaxel alone (P&lt;0.0001; AUC). In the rapidly-progressing HCC1806 xenografts, the combination improved MST to 38 days from 17.5 and 17.0 days for paclitaxel and IMMU-132, respectively (P&lt;0.0015; log-rank). Mice treated with the combination of IMMU-132 plus eribulin mesylate exhibited a significantly greater anti-tumor response than all other monotherapy groups (P&lt;0.0432; paired t-test). This resulted in a significant survival benefit for the combination (MST = 23 days) when compared to eribulin or IMMU-132 monotherapy (MST = 18 and 14 days, respectively; P&lt;0.0044; log-rank). Likewise, combining IMMU-132 therapy with olaparib was superior to single agent therapy in mice bearing MDA-MB-468 tumors (P&lt;0.0032; AUC). All the IMMU-132 combination treatments were well-tolerated.
Conclusions: IMMU-132 is a humanized anti-Trop-2 antibody conjugated to SN-38, the active metabolite of irinotecan, a topoisomerase I inhibitor. Clinically, IMMU-132 has shown manageable toxicity and encouraging responses in patients with relapsed/refractory TNBC (ClinicalTrials.gov, NCT01631552). Since preclinical studies indicate IMMU-132 can be combined with two different microtubule-inhibitors or a PARP-inhibitor with significantly enhanced anti-tumor activity, these data provide a rationale for future clinical evaluation of IMMU-132 in combination with these and other chemotherapeutics that likewise target cell division through microtubule inhibition or DNA-repair mechanisms in patients with TNBC.
Citation Format: Thomas M. Cardillo, Serengulam V. Govindan, Maria Zalath, Roberto Arrojo, Robert M. Sharkey, David M. Goldenberg. Combining an anti-Trop-2 antibody-SN-38 conjugate (sacituzumab govitecan) with microtubule inhibitors (paclitaxel and eribulin mesylate) or PARP inhibitor (olaparib) significantly improves therapeutic outcome in experimental triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C166.