Glycoprotein NMB (gpNMB) is an internalizable transmembrane protein overexpressed in ∼20% of breast cancer (BC) including ∼40% of TNBC. gpNMB is a poor prognostic marker in BC (Rose CCR 2010) and implicated in tumor invasion, metastasis, and angiogenesis. GV is a novel ADC delivering the potent cytotoxin MMAE to gpNMB expressing cancer cells. In a Phase 1/2 study and in the Phase 2 EMERGE study, GV was well tolerated and demonstrated promising activity, particularly in TNBC and/or gpNMB overexpressing (≥25% tumor cells; gpNMB+) BC. GV toxicity included rash, neutropenia and neuropathy (primarily grade 1 and 2). In EMERGE subset analyses, objective response rate (ORR) for GV vs. investigator's choice chemotherapy = 30% (7/23) vs. 9% (1/11) in gpNMB+ BC; 18% (5/28) vs. 0% (0/11) in TNBC; and 40% (4/10) vs. 0% (0/6) in gpNMB+ TNBC. Improvements in PFS (hazard ratio (HR) = 0.11; 95% CI, 0.02 to 0.57) and OS (HR = 0.14; 95% CI, 0.03 to 0.59) were also apparent in gpNMB+ TNBC. Trial design: The METRIC Trial (NCT#01997333) is an ongoing international, 2-arm Phase 2, registrational, TNBC study open in the USA, Canada, Australia, Spain and UK with sites planned in France, Germany and Italy. Pts are randomized 2:1 to GV (1.88 mg/kg IV q3w) or capecitabine (2,500 mg/m2 PO d1-14 q3w) until progression or intolerance. Eligibility Criteria Key eligibility criteria: ≥25% tumor epithelium gpNMB+ by central IHC screening; estrogen and progesterone receptors <10%; HER2 negative [0-1+ IHC, or ISH copy number <4.0/ratio <2.0] by local assessment; prior receipt of a taxane; anthracycline exposure (if indicated); ≤2 chemotherapy regimens for advanced BC; measurable disease; no persistent Grade ≥2 toxicity. Specific aims Primary endpoint is PFS per central review (RECIST 1.1). Secondary endpoints are ORR, DOR, OS, safety, PK, and PD. Exploratory endpoints are QoL and/or cancer-related pain (EORTC QLQ-C30 questionnaire). Statistical methods and target accrual The target sample size of 300 TNBC pts provides 85% power to detect PFS HR of 0.64 with two sided &agr; = 0.05. The hypothesized median PFS is 4.0 months for capecitabine and 6.25 months for GV. Clinical trial identification: NCT #01997333; EudraCT #2015-003693-33 Legal entity responsible for the study: Celldex Therapeutics, Inc. Celldex Therapeutics, Inc.

Abstract Background: Residual breast cancer after NAC is associated with a high risk of recurrence. Little evidence supports the use of further chemotherapy in this setting. Eribulin, an inhibitor of microtubule dynamics, demonstrated a survival advantage in patients with metastatic breast cancer who had progressed after previous anthracycline and taxane therapy. This phase 2 trial assessed the efficacy of eribulin (2-yr disease-free survival) administered postoperatively to breast cancer pts not achieving a pCR following standard NAC. Methods: Women with invasive breast cancer (stage T1-4b, N0-2, M0 at diagnosis) and evidence of residual cancer (>5 mm) in the breast or axillary lymph nodes (LN) following ≥4 cycles of standard anthracycline and/or taxane-containing NAC were eligible. Additional eligibility criteria: age ≥18 yrs, peripheral neuropathy < 1, adequate hematologic, hepatic, and renal function. 3 groups were studied: Cohort A-triple negative (TN), Cohort B-HR+/HER2-, Cohort C-HER2+. After recovery from definitive surgery, all pts received eribulin mesylate 1.4mg/m2 IV on days 1 and 8 every 21 days for 6 cycles. Cohort C pts also received trastuzumab 6mg/kg IV day 1 every 21 days for a total of 1 yr from start of NAC. Adjuvant hormonal therapy and loco-regional radiotherapy were administered per institutional guidelines. We hypothesized post-operative eribulin would result in a 40% increase over the reported 40% 2 yr DFS for TN, and a 15% increase over the reported 80% 2 yr DFS for HR+/HER2- pts who did not achieve pCR following standard NAC. Results: 127 pts were enrolled (54, Cohort A; 42, Cohort B; 31, Cohort C). Pts on Cohort C continue with study treatment. Here, we present the results of 95 pts treated on Cohorts A and B. Median age-52 yrs (range, 27-74). 87 pts (92%) had invasive ductal adenocarcinoma, 6 (6%) invasive lobular, 1 (1%) mucinous, and 1 (1 %) unknown; 34 pts (36%) had T3 or T4 tumors and 65 (68%) had N1-2 disease at diagnosis. NAC with anthracyclines was administered to 74 pts (78%), taxanes to 88 (93%), and 72 (76%) received both. 71 pts (75%) had mastectomies, 24 (25%) had breast conserving surgery. Median residual tumor was 17.5 mm (range 0.1 to 80); 60 pts (63%) were LN+. 78 pts (81%) completed the planned 6 cycles of eribulin. Adjuvant radiation was administered in 28 pts (30%). 3 pts discontinued treatment due to toxicity (1 each with G3 neutropenia, G3 nausea, and unknown grade neuropathy). The most common treatment-related G3/4 adverse events were neutropenia [29 pts (31%)] and leukopenia [10 pts (11%)]. 3 pts (3%) had G3/4 febrile neutropenia and 2 pts (2%) had G3/4 neuropathy. Growth factors were administered to 22 pts (24%). There were no treatment-related deaths. With a median follow up of 19.2 and 14.9 months for Cohorts A and B respectively, the 2 yr DFS probabilities calculated from date of surgery were 61.1 % (95% CI-41.2-76.0) for Cohort A; 82.2% (95% CI-60.2-92.7) for Cohort B. Conclusions: The addition of eribulin is safe and feasible in pts who do not achieve pCR following anthracycline and/or taxane based NAC. At a median follow up of 19.2 months, a statistically significant improvement in the estimated 2 yr DFS was evident in the TN (Cohort A) pts. Citation Format: Yardley DA, Peacock N, Shroff S, Molthrop, Jr DC, Anz B, Daniel BR, Young RR, Weaver R, Harwin W, Webb CD, Ward P, Shastry M, DeBusk LM, Midha R, Hainsworth JD, Burris III HA. A phase 2 study of eribulin in breast cancer not achieving a pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC). [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 P1-12-04.

Abstract Background Glycoprotein NMB (gpNMB) is an internalizable transmembrane protein overexpressed in approximately 20% of breast cancer (BC), including approximately 40% of TNBC. gpNMB is a poor prognostic marker in BC (Rose CCR 2010) and preclinically has been implicated in tumor invasion, metastasis, and angiogenesis. GV is a novel antibody-drug conjugate targeting the potent cytotoxin monomethylauristatin E (MMAE) to gpNMB overexpressing cancer cells. In a Phase I/II study and the Phase II "EMERGE" study, GV demonstrated promising activity with TNBC patients (pts) deriving the greatest benefit and exhibiting the highest degree of gpNMB overexpression. GV was well-tolerated with the most frequent treatment-related toxicities consisting of rash, neutropenia, and neuropathy. In subset analyses of the EMERGE trial, objective response rate (ORR) was 30% (7/23) for GV vs. 9% (1/11) for investigator's choice in tumors with gpNMB overexpression (>25% of tumor epithelium); 18% (5/28) vs. 0% (0/11) in TNBC; and 40% (4/10) vs. 0% (0/6) in gpNMB-overexpressing TNBC for GV and IC respectively, with apparent improvements in progression-free survival (PFS; hazard ratio (HR) = 0.11) and overall survival (OS; HR = 0.14). Trial design The METRIC Trial (NCT#01997333) is an international (USA, CA, Aus), two-arm phase II study. Pts are randomized 2:1 to GV (1.88 mg/kg IV q 21 days) or capecitabine, a current standard of care for this population (2,500 mg/m2 daily for d1-14, q21 days) until progression or intolerance. Crossover is not permitted. Eligibility criteria Key eligibility criteria include: >25% of tumor epithelium gpNMB+ by central immunohistochemistry (IHC) screening of archival tissue; estrogen receptor and progesterone receptor <10% and HER2 negative [0-1+ IHC, or ISH copy number <4.0/ratio <2.0] by local assessment; ECOG 0-1; taxane resistance; anthracycline exposure (if indicated); <2 chemotherapy regimens for advanced BC; measurable disease; no persistent Grade >2 toxicity. Specific aims The primary endpoint is PFS per independent, blinded central review committee according to RECIST 1.1. Secondary endpoints are ORR, duration of response, OS, safety, pharmacokinetics and pharmacodynamics. Exploratory endpoints are quality of life and/or cancer-related pain. Statistical methods and target accrual The trial has 85% power to detect a PFS HR of 0.64 with two sided α = 0.05. The hypothesized median PFS is 4.0 months for capecitabine and 6.25 months for GV. Target accrual is open for 300 pts. Citation Format: Melisko M, Yardley DA, Blackwell K, Forero A, Ma C, Montero A, Daniel BR, Wright G, Fehrenbacher L, Chew H, Ferrario C, Nanda R, Seiler Jr M, Guthrie T, Vance K, Ouellette G, He Y, Bagley RG, Zhang J, Vahdat LT. The METRIC trial: A randomized international study of the antibody-drug conjugate glembatumumab vedotin (GV or CDX-011) in patients with metastatic gpNMB-overexpressing triple-negative breast cancer (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 OT1-03-15.

1103 Background: Ixabepilone (Ixa) is a potent tubulin polymerizer active in taxane refractory and locally advanced breast cancer as well as in TNBC. The clinical activity and toxicity profile of Ixa are similar to the taxanes with neuropathy and myelosuppression as dose-limiting toxicities. We present the preliminary toxicity of Ixa compared to weekly paclitaxel (Pac) following AC x 4, performed as part of the data safety monitoring in this trial. METHODS Eligibility criteria: TNBC (defined as ER and PR <10% by IHC and HER2 IHC 0-1+ or FISH negative), node positive or node negative with any tumor size, post surgery with no evidence metastatic disease. Patients (pts) were randomized to AC (60/600mg/m2) q3wks x4 followed by Ixa (40mg/m2 q 3wks x4) or weekly Pac (80mg/m2 x12 weeks). Growth factor support was permitted. Analysis is based on the first 226 women completing therapy (AC/Ixa, 120; AC/Pac, 106). RESULTS Median pt age was 54 years; 36% lymph node positive; 50% T2; 88% ductal histology. 10 pts (8%) did not complete AC/Ixa due to toxicity (hematologic - 2; nonhematologic - 8) versus 18 (17%) with AC/Pac (hematologic - 3; nonhematologic - 15). Neuropathy was the most common cause of treatment discontinuation in both arms, occurring more frequently in Pac pts (10 pts vs. 3 Ixa pts). Other discontinuation events were similar between the arms and included hypersensitivity, fatigue, rash, and pain. Toxicities were reported in their expected frequencies during AC, including 6 pts with G3 febrile neutropenia. Grade 3/4 toxicity during Pac and Ixa portions of treatment is summarized in the table. CONCLUSIONS As part of adjuvant chemotherapy, Ixa is feasible with a toxicity profile similar to weekly Pac. Neuropathy was the most frequent cause of study discontinuation, and occurred more frequently in pts receiving Pac. [Table: see text].