Rebecca Moroose

Safety and Efficacy of Neratinib in Combination With Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

PURPOSE Neratinib is a potent irreversible pan-tyrosine kinase inhibitor with antitumor activity and acceptable tolerability in patients with human epidermal growth factor receptor 2 (HER2) -positive breast cancer. A multinational, open-label, phase I/II trial was conducted to determine the maximum-tolerated dose (MTD) of neratinib plus capecitabine in patients with solid tumors (part one) and to evaluate the safety and efficacy of neratinib plus capecitabine in patients with HER2-positive metastatic breast cancer (part two). PATIENTS AND METHODS Part one was a 3 + 3 dose-escalation study in which patients with advanced solid tumors received oral neratinib once per day continuously plus capecitabine twice per day on days 1 to 14 of a 21-day cycle at predefined dose levels. In part two, patients with trastuzumab-pretreated HER2-positive metastatic breast cancer received neratinib plus capecitabine at the MTD. The primary end point in part two was objective response rate (ORR). RESULTS In part one (n = 33), the combination of neratinib 240 mg per day plus capecitabine 1,500 mg/m(2) per day was defined as the MTD, which was further evaluated in part 2 (n = 72). The most common drug-related adverse events were diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%). In part two, the ORR was 64% (n = 39 of 61) in patients with no prior lapatinib exposure and 57% (n = 4 of 7) in patients previously treated with lapatinib. Median progression-free survival was 40.3 and 35.9 weeks, respectively. CONCLUSION Neratinib in combination with capecitabine had a manageable toxicity profile and showed promising antitumor activity in patients with HER2-positive metastatic breast cancer pretreated with trastuzumab and lapatinib.

Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Abstract CT236: Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results

Background: Sacituzumab govitecan (IMMU-132) is a new ADC comprising SN-38, the active metabolite of the topoisomerase inhibitor, camptothecin (irinotecan), conjugated to an anti-Trop-2 antibody. In vitro and in vivo preclinical data suggest that IMMU-132 is a unique ADC, being most efficacious at a high drug-antibody ratio (DAR) of 7.6, and capable of delivering up to 135-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft. In vitro studies also demonstrate specific double-stranded DNA breaks by the internalizing ADC. Methods: IMMU-132 is completing a phase I/II clinical trial with phase II expansion after MTD determination (ClinicalTrials.gov.NCT01631552) in patients with advanced cancers that typically express high levels of Trop-2, at doses of 8 and 10 mg/kg on days 1 and 8 of 21-day repeated cycles. Efficacy (N = 91) and safety (N = 130) results are provided. Results: The% of grades 3/4 AEs for both dose levels are neutropenia (16/4), febrile neutropenia (4/4), anemia (4/0), diarrhea (4/0), and fatigue (4/0) (Table 1). No patient discontinued therapy due to toxicity, and no patient showed immunogenicity despite repeated therapy. Patient dose reductions were 15-16%, and dose delays after first 2 cycles were 3-4%. Conclusions: IMMU-132 shows activity in patients with diverse cancers, even when they no longer responded to a topoisomerase inhibitor. It appears to have a manageable toxicity profile, with promising efficacy at a high therapeutic index in patients with heavily-pretreated metastatic cancers, especially TNBC, SCLC, and NSCLC. Based on these results, this ADC carrying a moderately-toxic drug that is the active metabolite of a currently-used camptothecin analogue represents a novel cancer therapeutic that challenges the current dogma of requiring ultratoxic drugs conjugated at low DARs for ADC therapy. Citation Format: Alexander N. Starodub, Allyson J. Ocean, Aditya Bardia, Michael J. Guarino, Wells Messersmith, Jordan Berlin, Vincent J. Picozzi, Sajeve S. Thomas, Gregory Masters, Linda T. Vahdat, Ingrid A. Mayer, Rebecca Moroose, Jennifer S. Diamond, Scott T. Tagawa, Manish A. Shah, Francois Wilhelm, William A. Wegener, Pius Maliakal, Robert M. Sharkey, David M. Goldenberg. Advanced solid cancer therapy with a novel antibody-drug conjugate (ADC), sacituzumab govitecan (IMMU-132): key preclinical and clinical results. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT236. doi:10.1158/1538-7445.AM2015-CT236

Abstract LB-C16: Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial

This abstract has been withheld from publication due to its inclusion in the AACR-NCI-EORTC Molecular Targets Conference 2015 Official Press Program. It will be posted online at the time of its presentation in a press conference or in a session: 12:30 PM ET Sunday, November 8. Citation Format: Aditya Bardia, Ingrid Mayer, Jennifer Diamond, Alexander Starodub, Rebecca Moroose, Steven Isakoff, Allyson Ocean, Michael Guarino, Kevin Kalinsky, Joyce O9Shaugnessy, Francois Wilhelm, Pius Maliakal, Robert Sharkey, David Goldenberg, Linda Vahdat. Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial. [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 LB-C16.

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)

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.

Patterns of Progression in Metastatic Estrogen Receptor Positive Breast Cancer: An Argument for Local Therapy

Purpose Despite advances in endocrine therapy (ET), metastatic estrogen receptor positive breast cancer (BrCA) remains incurable. Though the mechanisms of resistance to ET have been studied extensively, the anatomic pattern of disease progression remains poorly characterized. The purpose of this study was to characterize the pattern of progression for patients receiving ET for metastatic BrCA. Methods The records of 108 patients with metastatic BrCA who progressed on ET were reviewed. Progression was characterized as follows: diffuse progression, progression in greater than 3 sites; oligoprogression, progression in fewer than 3 sites with prior diffuse metastases; and oligometastatic disease with progression, progression in 3 or fewer sites with prior limited metastases. Results Seventy-four patients (69%) displayed only diffuse disease progression. Conversely, 23 patients (21%) displayed oligoprogression and 11 patients (10%) displayed oligometastases with progression at least once in their disease course. Further analysis of the patients with oligoprogression suggested that in 14 patients the sites of progression would have been amenable to local therapy. Conclusion Oligoprogressive disease occurs in a significant subset of patients with metastatic BrCA treated with ET. These patients with oligoprogressive disease may be eligible for local therapy, potentially obviating the need to change of systemic therapy.

Abstract P5-16-28: A single-institution clinical experience with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP): A safety and efficacy analysis

Background: Pertuzumab, a monoclonal antibody targeting subdomain II of HER2 and blocking dimerization , was approved by the FDA in 2013 for use in combination with trastuzumab and docetaxel as neoadjuvant therapy for pts with HER2+, locally advanced, inflammatory or early-stage breast cancer (>2cm and/or node-positive). This accelerated approval was based on results from the NeoSphere and the TRYPHAENA trials. In NeoSphere, pathologic complete response in the breast and nodes [pCR] was 39.3% after 4 cycles of neoadjuvant pertuzumab/trastuzumab/docetaxel. In TRYPHAENA, pCR was 63.6% among 76 patients treated with 6 cycles of neoadjuvant TCHP(47.5% in pts with ER+and/or PR+/HER2+ tumors and 81.1% in those with ER-/PR-/HER2+ tumors). Aside from TRYPHAENA, we have limited information on clinical outcomes, with neoadjuvant TCHP. Here we report our institutional experience at UF Health Cancer Center, Orlando (UFHCC) with Neoadjuvant TCHP in patients with operable or locally advanced breast cancer. Patients and Methods: After IRB approval, electronic medical record search was performed in order to identify HER2+ patients with tumors T2-T4/N0-3 or Tany/N1-3, treated with neoadjuvant TCHP between 10/13 and 5/16. Information from chart review included patient and tumor characteristics at the time of diagnosis , details of neoadjuvant chemotherapy plus anti-HER2 therapy, clinical, radiologic and pathologic assessment of tumor response to neoadjuvant TCHP, type of breast and axillary nodal surgery, surgical outcomes as well as disease outcomes. Results: 76 patients (75 female, 1 male) met the inclusion criteria; median age: 52 yrs; 83% of pts presented with clinical stage II and 17% with clinical stage III; 62% were ER+ and/or PR+ and 38% were ER-/PR-negative. 49 patients received all planned 6 cycles without dose reduction. The remaining 27 patients required dose reduction due to rash, diarrhea, nausea, vomiting, neuropathy or neutropenia; 5 patients requested dose reduction due to poor quality of life and fatigue; 2 patients required dose delay due to asymptomatic cardio-toxicity with ≥ 10% drop in EF. None had symptomatic CHF; 37% of patients underwent breast conserving surgery, 7% unilateral mastectomy and 55% bilateral mastectomy. Surgical lymph node assessment was performed after neoadjuvant chemotherapy and included sentinel lymph node biopsy (SLNB) in 74%, axillary dissection (ALND) in 8% or both in 18% of pts. Overall pCR rate (ypT0/is, ypN0) was 63.2%. pCR rate was 53.1% in pts with ER+ and/or PR+ tumors and 79.3% in those with ER-/PR- tumors. pCR by stage was 61% for Stage IIA, 65% for Stage IIB, 67% for Stage IIIA and 71% for Stage IIIC. Toxicity profile was consistent with what has been observed in the TRYPHAENA trial with fatigue, nausea, vomiting and neuropathy being the more commonly noted grade 3/4 toxicities. With median follow up of 18 months, all patients are disease-free with no documented recurrences observed. Conclusion: Our clinical experience with neoadjuvant TCHP confirms the efficacy and safety data from the TRYPHAENA trial in a single-institution, tertiary care center setting. Citation Format: Tariq R, Ajaz B, Shah N, Mamounas E, Moroose R. A single-institution clinical experience with neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP): A safety and efficacy analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-16-28.

Abstract P4-22-15: Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results

Background . mTNBC has an aggressive course with limited effective therapy options and a median progression-free survival (PFS) of 2-4 months (mos) with standard therapy. Sacituzumab govitecan (IMMU-132) is an ADC targeting Trop-2, an antigen present in many epithelial cancers, including TNBC, and delivering SN-38, a topoisomerase I inhibitor as its therapeutic moiety. IMMU-132 was awarded Breakthrough Therapy designation by FDA based on its previously reported activity in relapsed/refractory mTNBC patients. Here we present updated results from the mTNBC cohort of an ongoing phase I/II study (ClinicalTrials.gov, NCT01631552). Methods . mTNBC patients (pts) received IMMU-132 10 mg/kg on days 1 and 8 every 21 days. Trop-2 expression was not required for enrollment, but available tumor specimens underwent immunohistological (IHC) testing. Efficacy was assessed locally by RECIST 1.1; ORR, PFS and overall survival (OS) were determined for all pts. Pharmacokinetic parameters were estimated in select pts with adequate blood sampling. Immunogenicity to IMMU-132 was examined in all pts. Results . We previously reported preliminary efficacy results in 51 mTNBC patients. Here we present data on 69 patients with data cutoff June 5, 2016. Median age was 56 years (31-81) and a median of 5 prior therapies (range 1-12), with 66 evaluable for response; ORR was 29% (19/66) 2 confirmed complete (CR) and 17 confirmed partial responses (PR). The median intention-to-treat PFS is 5.6 mos (95% CI, 3.6-7.1 mos) and median OS is 14.3 mos (95% CI, 10.5-18.8 mos). PRs included 2 pts whose tumors did not respond to anti-PD-L1 therapy. The duration of response in the 19 confirmed responders (8 continuing therapy) is 11.5 mos (95% CI = 7.6 to 12.7). The clinical benefit rate (CR+PR+SD>6 mos) for the 66 assessable patients is currently 45.5%. The majority (88%) of archival tumor specimens were moderately (2+) to strongly (3+) positive by IHC for Trop-2, precluding using Trop-2 expression as a selection criterion. Among current adverse events, grade >3 drug-related toxicities included neutropenia (35%), leukopenia (16%), anemia (13%), vomiting (9%), diarrhea (10%), and febrile neutropenia (4%). Clearance kinetics in 8 pts showed IMMU-132 and IgG had a terminal half-life of 15.3 ± 2.7 h and 86.5 ± 40.5 h, respectively, with area under the curve for free SN-38 (unbound) only 3% of the total amount of SN-38 (e.g., IgG bound). Thus, most SN-38 remains bound to the conjugate, and is released at a rate predicted from in vitro serum stability studies. No pt developed anti-IMMU-132 antibodies. Conclusion The Trop-2-targeting ADC, IMMU-132, delivering cytotoxic doses of SN-38, shows high objective and durable tumor responses with manageable toxicity in heavily-pretreated pts with mTNBC in this updated cohort, supporting further development in this population with an unmet medical need. Citation Format: Bardia A, Diamond JR, Mayer IA, Isakoff SJ, Abramson V, Starodub AN, O9Shaughnessy J, Kalinsky K, Moroose R, Shah N, Juric D, Shapiro GI, Guarino M, Ocean AJ, Messersmith WA, Berlin JD, Wegener WA, Sharkey RM, Goldenberg DM, Vahdat LT. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-15.

Abstract 3734: Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors

BACKGROUND: Sacituzumab govitecan (IMMU-132), an ADC targeting Trop-2, an antigen present in many solid tumors, uses SN-38, a topoisomerase I inhibitor that has nanomolar potency derived from irinotecan (IRI), and a pH sensitive linker that releases SN-38 gradually (in vitro, 50% released per 1 day in serum). Clinical studies in patients (pts) with diverse solid tumors have shown manageable toxicity (dose-limiting neutropenia, diarrhea but lower incidence than IRI) and encouraging efficacy. METHODS: Conjugate and IgG were monitored in pts given 8 (N = 24) or 10 mg/kg (N = 29) by ELISA. SN-38 and glucuronidated SN-38 (SN-38G) were measured by reversed-phase HPLC. SN-38 and SN-38G levels are expressed as the amount of drug dissociated from the conjugate (i.e., Free SN-38) and the amount bound to the IgG (Total SN-38). UGT1A1 status was determined in baseline blood sample from 146 pts. RESULTS: IMMU-132 cleared with a half-life of 11.7-18.9 h, depending on the assay, while the IgG half-life was 4-5 days, which agrees with in vitro drug-release data. Levels of Free SN-38 at 30 min or 1 d after injection were CONCLUSION: IMMU-132 cleared as predicted from in vitro serum stability data, with no difference between the 8 and 10 mg/kg groups. Current data show neutropenia did not correlate with Free SN-38 levels in serum at 30 min, and low SN-38G levels support the lower incidence of severe diarrhea. While pts with the *28*28 haplotype had a somewhat higher incidence of severe neutropenia or diarrhea than *1*1 and *1*28 pts, the overall incidence of each is small, suggesting toxicity management rather than screening is appropriate. With no major difference in safety and PK, but improved responses with 10 mg/kg, 10 mg/kg is selected for future clinical studies. Citation Format: Robert M. Sharkey, Allyson J. Ocean, Alexander N. Starodub, Aditya Bardia, Michael Guarino, Wells A. Messersmith, Jordan D. Berlin, Vincent J. Picozzi, Rebecca Moroose, William A. Wegener, Pius Maliakal, Serengulam V. Govindan, David M. Goldenberg. Pharmacokinetics of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC) targeting Trop-2, in patients with diverse advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3734. doi:10.1158/1538-7445.AM2017-3734

Abstract PD3-06: Safety and efficacy of anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in heavily pretreated patients with TNBC

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 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>6 mo) of 49% (63% with SD>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, O9Shaughnessy 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.