Abstract P5-19-27: 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

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 > 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 <5% 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.

Enhanced Delivery of SN-38 to Human Tumor Xenografts with an Anti-Trop-2–SN-38 Antibody Conjugate (Sacituzumab Govitecan)

“…ELISA monitoring of IgG in the serum found that it clears more slowly, staying in the circulation for a longer period. Similar results are being found in patient samples (34)(35)(36)(37), where (i) the IgG component clears more slowly than the conjugate, (ii) >95% of the total SN-38 in the serum is bound to the IgG, (iii) the amount of free SN-38G in the serum is only a fraction of the free SN-38, and (iv) there is no evidence of glucuronidation of SN-38 bound to IgG. Analysis of serum samples taken from patients given 8 to 10 mg/kg of IMMU-132 on days 1 and 8 of 21-day cycles has found free SN-38 concentrations at levels of about 100 ng/mL 30 minutes after the end of a 2-to 3 h-infusion, whereas the total SN-38 levels average about 4,000 ng/mL (34).…”

“…IMMU-132 was found to deliver much higher levels of SN-38 to tumors than irinotecan and, importantly, all of the SN-38 delivered to the tumor by IMMU-132 is released in its most potent form. In relationship to gastrointestinal toxicity, the much lower amounts of SN-38G in the serum and significantly lower amounts of SN-38/SN38G in the intestine with IMMU-132 are expected to reduce the risk for severe diarrhea in patients, which is confirmed in clinical studies (34)(35)(36)(37)(38). Thus, IMMU-132 is an ADC that appears to have unique properties that combine to make an effective therapeutic agent in the solid cancers tested.…”

“…Because SN-38G levels in the serum are also very low with IMMU-132, we suspect that this reduces the pool of drug available for enterohepatic recirculation. These 2 factors likely combine to explain the lower incidence and severity of diarrhea observed clinically with IMMU-132 than other agents delivering SN-38 (34)(35)(36)(37).…”

First-in-Human Trial of a Novel Anti-Trop-2 Antibody-SN-38 Conjugate, Sacituzumab Govitecan, for the Treatment of Diverse Metastatic Solid Tumors

“…However, responses in patients with TNBC and SCLC are of particular interest, given the need for targeted therapies in these indications. Indeed, additional partial responses in patients with TNBC and SCLC observed in the ongoing expansion phase of this trial (16, 17) have suggested further emphasis on these cancers, but encouraging responses in NSCLC, EAC, UBC, and CRC are also being followed. Indeed, in a recent update of the ongoing phase II trial of sacituzumab govitecan, an overall response rate (PR) of 30%, with 40% clinical benefit rate (PR + SD ≥6 months) has been observed in 23 patients with metastatic TNBC (16).…”

“…Indeed, additional partial responses in patients with TNBC and SCLC observed in the ongoing expansion phase of this trial (16, 17) have suggested further emphasis on these cancers, but encouraging responses in NSCLC, EAC, UBC, and CRC are also being followed. Indeed, in a recent update of the ongoing phase II trial of sacituzumab govitecan, an overall response rate (PR) of 30%, with 40% clinical benefit rate (PR + SD ≥6 months) has been observed in 23 patients with metastatic TNBC (16). Long-term survival (15-20+ months) was observed for almost 25% (6/25) of the patients studied, and included 2 with PRs and 4 with SD, including patients with TNBC (N=2), CRC (N=3), and HRPC (N=1).…”