Search

Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). Preclinical studies have shown a great range of efficacy with SG in mice bearing tumors with low, moderate, and high Trop-2 expression levels. We report subgroup analyses by Trop-2 expression from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with metastatic TNBC (mTNBC). Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, duration of response, overall survival (OS), and safety. Exploratory endpoints included biomarker assessments, including Trop-2 and BRCA1/2. Trop-2 expression was assessed using a validated immunohistochemistry assay. Results: Subgroup analyses by biomarker expression including Trop-2 and BRCA1/2 were performed, and outcomes by PFS, OS, ORR, and safety results will be reported. Conclusions: These analyses will provide further insights into the relationship of Trop-2 expression and the activity of SG in previously treated patients with mTNBC. Citation Format: Sara A. Hurvitz, Sara M. Tolaney, Kevin Punie, Delphine Loirat, Mafalda Oliveira, Kevin Kalinsky, Amelia Zelnak, Philippe Aftimos, Florence Dalenc, Sagar Sardesai, Erika Hamiltion, Priyanka Sharma, Sabela Recalde, Eva Ciruelos Gil, Tiffany Traina, Joyce O'Shaughnessy, Javier Cortés, Michaela Tsai, Linda Vahdat, Véronique Diéras, Lisa Carey, Hope S. Rugo, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Aditya Bardia. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-06.

Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, the active metabolite of irinotecan, via a unique hydrolyzable linker that allows SN-38 release intracellularly and in the tumor microenvironment (bystander effect). SG received accelerated approval in April 2020 for the treatment of patients with metastatic TNBC (mTNBC) who received at least 2 prior therapies for metastatic disease. The most common adverse events (AEs) observed with SG are neutropenia and gastrointestinal toxicity, also seen with irinotecan. To provide further information on SG, additional safety analyses from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with mTNBC, will be reported. Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, overall survival, and safety. An exploratory analysis of incidence of grade 3-5 AEs by UGT1A1 genotype was also performed. Post-hoc analysis of the time to onset and duration of key AEs will be performed, and descriptive analyses on alopecia, nausea and vomiting will also be provided. Results: Exploratory safety analyses by UGT1A1 allele status will be shown as well as time to onset and duration of neutropenia and diarrhea. Further descriptive analyses on alopecia, nausea, and vomiting will be provided along with AE management strategies. Conclusions: These analyses will provide further insights into the safety profile of SG and appropriate AE management strategies for patients with previously treated mTNBC to allow optimal therapeutic exposure. Citation Format: Hope S. Rugo, Sara M. Tolaney, Delphine Loirat, Kevin Punie, Aditya Bardia, Sara A. Hurvitz, Joyce O'Shaughnessy, Javier Cortés, Véronique Diéras, Lisa Carey, Luca Gianni, Martine J. Piccart, Sibylle Loibl, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Kevin Kalinsky. Impact of UGT1A1 status on the safety profile of sacituzumab govitecan in the phase 3 ASCENT study in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-09.

Background: Patients (pts) with metastatic triple-negative breast cancer (mTNBC) who have brain metastases represent a poor prognosis cohort with a high unmet clinical need. Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). SN-38 can cross the blood-brain barrier and is a drug partner in central nervous system (CNS) disease regimens (PMID: 18784279; PMID: 26080460). Although antibody-based therapy raises concerns regarding CNS penetration, activity with SG has been seen in intracranial xenograft models (Brenner Neurooncol Adv 2019). In a subgroup analysis from ASCENT, the efficacy and safety of SG were evaluated in pts with stable brain metastases. Methods: In the phase 3 ASCENT study (NCT02574455), 529 pts with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (TPC; capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. Brain MRIs were required in pts with known brain metastases who were eligible if they had stable CNS disease for ≥4 wk by MRI. Per protocol, stable disease was defined as ≥2 wk from discontinuation of antiseizure medication and corticosteroid dose (≤20 mg prednisone equivalent) that was stable or decreasing for ≥2 wk before randomization. In these pts, brain MRIs were required throughout the study. The primary endpoint was progression-free survival (PFS) per independent central review (RECIST v1.1) in brain metastases-negative pts. Secondary endpoints included PFS per investigator assessment, PFS in the full population (in pts with/without brain metastases) by central review, objective response rate (ORR), overall survival (OS), and safety. Results: Overall, 61 of 529 (12%) enrolled pts had stable brain metastases at screening and were randomized to SG (n=32) or TPC (n=29). Median age was 53 y for SG and 51 y for TPC; all pts were female and had a median of 5 prior anticancer regimens. In this subset, median PFS was 2.8 mo (95% CI, 1.5-3.9) for SG vs 1.6 mo (95% CI, 1.3-2.9) for TPC by central review, and median OS was 6.8 mo (95% CI, 4.7-14.1) for SG vs 7.5 mo (95% CI, 4.7-11.1) for TPC. ORR for SG vs TPC, respectively, was 3% (1/32) vs 0% by central review, with a clinical benefit rate of 9.4% vs. 3.4%. Stable disease was achieved in 15 (47%) pts with SG vs 9 (31%) pts with TPC. In 53 pts who received at least 1 dose of treatment (SG, n=30; TPC, n=23), any-grade treatment-emergent adverse events (>20% with SG) for SG vs TPC were fatigue (63% vs 52%), diarrhea (50% vs 13%), neutropenia (43% vs 35%), nausea (43% vs 26%), decreased appetite (30% vs 17%), decreased neutrophil count (33% vs 22%), anemia (23% vs 35%), alopecia (23% vs 13%), and constipation (23% vs 22%). There were no treatment-related deaths. Two pts treated with SG are continuing study treatment for 16.2 and 6.3 mo as of the data cutoff date. Conclusions: Data interpretation in this population with poor prognosis is limited by the small sample size. In this exploratory analysis of pts with brain metastases from the phase 3 ASCENT study, SG was numerically better than TPC for tumor response and PFS but not OS. The safety profile was similar to that of the population without brain metastases for both study arms. SG is currently under clinical investigation for pts undergoing elective craniotomy for breast cancer with brain metastases or recurrent glioblastoma (NCT03995706) based on promising preclinical and intracranial clinical data. Citation Format: Véronique Diéras, Robert Weaver, Sara M. Tolaney, Aditya Bardia, Kevin Punie, Adam Brufsky, Hope S. Rugo, Kevin Kalinsky, Tiffany Traina, Leonard Klein, Delphine Loirat, Filipa Lynce, Brooke Daniel, Foluso Ademuyiwa, Sara A. Hurvitz, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Lisa Carey. Subgroup analysis of patients with brain metastases from the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-07.

Background: Patients (pts) with HR+/HER2- MBC for whom first- and second-line treatments have failed need additional treatment approaches. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in breast cancer and linked to poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate comprising an anti-Trop-2 monoclonal antibody conjugated to SN-38 (active metabolite of irinotecan) in a high drug-to-antibody ratio of 7.6. It has a unique hydrolysable linker that allows release of SN-38 intracellularly and in the tumor microenvironment. In the HR+/HER2- MBC cohort in the IMMU 132-01 phase 1/2 basket study, SG showed a 31% objective response rate (ORR), median progression-free survival (PFS) of 6.8 mo, and a predictable and manageable safety profile with low discontinuation rates due to adverse events (Kalinsky 2018 SABCS). Trial Design: Trop-2 Investigation in Cancer with Sacituzumab (TROPiCS-02; NCT03901339) is a randomized, open-label, phase 3 study in pts with HR+/HER2- MBC and ≥1 measurable target lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 after failure of ≥2, but ≤4 prior chemotherapy regimens. Pts are randomized 1:1 to receive SG (10 mg/kg intravenously, days 1 and 8 every 21 days) or treatment of physician’s choice (TPC, determined pre-randomization: eribulin, capecitabine, gemcitabine, vinorelbine). Pts continue treatment until progression requiring discontinuation or unacceptable toxicity. Eligible pts are females or males ≥18 y old with documented evidence of HR+/HER2- MBC, Eastern Cooperative Oncology Group score of 0 or 1, and adequate safety laboratories. Pts must have received prior taxanes in any setting, ≥1 prior anticancer hormonal treatment, and ≥1 cyclin dependent kinase 4/6 inhibitor in the metastatic setting, with documented progression after most recent therapy. Pts also must be eligible to receive one of the TPC agents. The primary endpoints are PFS (local assessment) and ORR; additional endpoints include overall survival (OS), duration of response (DOR), and safety. The hazard ratio of the primary endpoint of PFS and its associated 95% confidence interval (CI) will be estimated using a Cox proportional-hazards model; the 2-sided 95% CIs of ORR will be calculated by the Clopper-Pearson exact method. Exploratory endpoints include Trop-2 expression and efficacy in relation to Trop-2 expression and blood and tumor biomarkers. Biomarker samples are taken at baseline, pre-dose at cycle 2, and at disease progression/end of treatment. Approximately 400 pts will be randomized across multiple countries. Citation Format: Hope S Rugo, Aditya Bardia, Sara M. Tolaney, Carlos Arteaga, Javier Cortes, Joohyuk Sohn, Frederik Marmé, Quan Hong, Scott Hofsess, Martin Olivo, André Fabrice, Peter Schmid. TROPiCS-02: phase 3 study of Sacituzumab Govitecan (IMMU-132) in relapsed/refractory hormonal receptor-positive (HR+) human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr OT1-07-05.

Background: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. Patients and methods: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. Results: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. Conclusions: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup., SCOPUS: ar.j, info:eu-repo/semantics/published

Background: Eribulin mesylate (ERI), a nontaxane microtubule inhibitor with effects on tumor biology (increased vascular perfusion, reversal of epithelial to mesenchymal transition), is approved as a monotherapy for the treatment of patients (pts) with metastatic breast cancer who received ≥2 prior chemotherapeutic regimens for metastatic disease. In a pooled analysis, ERI significantly prolonged OS compared with capecitabine or treatment of physician's choice in pts with metastatic triple-negative breast cancer (mTNBC; 12.9 vs 8.2 mo, n=428). Pembrolizumab (PEM) is a human programmed death (PD) receptor-1–blocking antibody approved for the treatment of several advanced cancers. In a phase (Ph) 2 study in mTNBC, PEM monotherapy as first-line therapy demonstrated ORR, 23%; median PFS, 2.1 mo [95% CI 2.0-3.9], and in pts pretreated with ≥1 prior chemotherapy demonstrated ORR, 5%; median OS, 8.9 mo [95% CI 7.2-11.2]). Methods:This open-label Ph 1b/2 trial enrolled pts (aged ≥18 yrs; ECOG PS ≤1) with mTNBC treated with ≤2 prior lines of chemotherapy for metastatic disease. Ph 1b included a safety cohort of ≥6 pts who received intravenous (IV) ERI 1.4 mg/m2 on day (d) 1 and d8 and IV PEM 200 mg on d1 of a 21-d cycle. In Ph 2, pts were enrolled based on prior chemotherapy in the metastatic setting [0 vs 1–2 lines]. Primary endpoints: safety, tolerability (Ph 1b), and ORR (Ph 2); secondary endpoints: PFS, OS, and efficacy in PD-L1+ pts. Results: We report data from 82 of 104 enrolled pts (data cut-off Nov 1, 2016).The RP2D was ERI 1.4 mg/m2 on d1 and d8 and PEM 200 mg on d1 of a 21-d cycle. Most common treatment-emergent adverse events (TEAEs) were fatigue (73.2%), nausea (51.2%), peripheral sensory neuropathy (46.3%), alopecia (43.9%), and pyrexia (36.6%). Most common Grade (G) 3 or 4 TEAEs related to ERI: neutropenia (29.3%), peripheral neuropathy (8.5%), and asthenia/fatigue (7.3%). G3/4 immune-related TEAEs related to PEM: 19.5% of pts. TEAEs that led to drug withdrawal/dose reduction: 18.3%/28.0% of pts. G5 events: 3 pts (respiratory failure, pleural effusion, and multiple organ failure; none related to study drug). Response was irrespective of PD-L1 status (Table1). Results of the final analysis will be available for presentation. Overall (n=82)No prior chemotherapy in metastatic setting (n=48)1-2 Prior lines of chemotherapy in metastatic setting (n=34)PD-L1+ (n=35)PD-L1- (n=36)ORR, n (%) [95% CIa]21 (25.6) [16.8, 35.4]12 (25.0) [14.0, 37.8]9 (26.5) [13.3, 41.8]9 (25.7) [12.9, 40.8]9 (25.0) [12.5, 39.8]CBRb, n (%)25 (30.5)13 (27.1)12 (35.3)10 (28.6)12 (33.3)DCRc, n (%)46 (56.1)28 (58.3)18 (52.9)19 (54.3)21 (58.3)Median PFS, mo [95% CI]4.1 [2.3-4.8]4.1 [2.2-4.9]3.9 [2.1-6.3]4.1 [2.1-4.8]4.1 [2.3-6.3]Median OS, mo [95% CI]NE [17.7-NE]17.7 [13.7-NE]NE [13.1-NE]----a Credible interval from Bayesian analysis; b clinical benefit rate = CR+PR+SD; c disease control rate = CR+PR+SD ≥24 weeks. NE, not estimable. Conclusions: ERI+PEM was well tolerated and demonstrated activity in pts with mTNBC. The combination resulted in improved ORR, with longer PFS, OS, and comparable TEAEs to those observed with either treatment as monotherapy. Further exploration of this combination is warranted. Citation Format: Tolaney SM, Kalinsky K, Kaklamani V, Savulsky C, Olivo M, Aktan G, Kaufman PA, Xing D, Almonte A, Misir S, Karantza V, Diab S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-13.

1077 Background: In pts with pretreated mTNBC, standard-of-care chemotherapy is associated with low objective response rates (ORRs) and short median progression-free survival (PFS). SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated FDA approval for treatment of pts with mTNBC who have received ≥2 prior therapies for metastatic disease. The confirmatory phase 3 ASCENT study (NCT02574455) in pts with relapsed/refractory mTNBC demonstrated a significant survival benefit of SG over TPC (median PFS: 5.6 vs 1.7 mo, HR 0.41, P< 0.0001; median overall survival [OS]: 12.1 vs 6.7 mo, HR 0.48, P< 0.0001) with a tolerable safety profile. Here we summarize efficacy results for SG vs each TPC agent in ASCENT to examine how each TPC agent performed individually. Methods: Pts had mTNBC refractory to or progressing after ≥2 prior standard chemotherapy regimens. Pts were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8, every 21 days) or single-agent TPC (eribulin, vinorelbine, capecitabine, or gemcitabine). Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Secondary endpoints were ORR per RECIST 1.1, duration of response, OS, and safety. Outcomes for each of the agents in the TPC arm were analyzed and compared with SG. Results: Of 529 pts enrolled, 468 were BMNeg. Among pts in the TPC cohort (n = 233), eribulin was the most commonly chosen chemotherapy (n = 126), followed by vinorelbine (n = 47), capecitabine (n = 31), and gemcitabine (n = 29). Treatment with eribulin, vinorelbine, capecitabine, and gemcitabine resulted in shorter median PFS vs SG (2.1, 1.6, 1.6, and 2.7 vs 5.6 mo, respectively); similar results were observed for median OS (6.9, 5.9, 5.2, and 8.4 vs 12.1 mo), ORR (5%, 4%, 6%, and 3% vs 35%), and clinical benefit rate (CBR; 8%, 6%, 10%, and 14% vs 45%). Key grade ≥3 treatment-related adverse events (TRAEs) with TPC overall vs SG included neutropenia (33% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), and anemia (5% vs 8%). Key grade ≥3 TRAEs with eribulin vs SG included neutropenia (30% vs 51%), leukopenia (5% vs 10%), fatigue (5% vs 3%), anemia (2% vs 8%), and peripheral neuropathy (2% vs none), respectively. The safety profiles of vinorelbine, capecitabine, and gemcitabine combined were consistent with that of TPC overall and with eribulin. One treatment-related death was reported for the TPC arm (eribulin) and none with SG. Conclusions: The efficacy benefit observed with SG vs TPC in pts with mTNBC was retained when evaluating each TPC chemotherapy agent individually. These results confirm that SG should be considered as a new standard of care in pts with pretreated mTNBC. Clinical trial information: NCT02574455 .

1011 Background: Approximately 20% of pts diagnosed with TNBC are aged ≥65 y. Often, older pts are less fit for chemotherapy due to a greater rate of comorbidities, increased use of medications, and pre-existing frailty or functional loss. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. The landmark phase 3 ASCENT study (NCT02574455) showed improved outcomes with SG vs single-agent chemotherapy of physician’s choice (TPC) in pts with relapsed/refractory mTNBC (median progression-free survival [PFS], 5.6 vs 1.7 mo; median overall survival [OS], 12.1 vs 6.7 mo). Here we assess the impact of age on the efficacy and safety of SG in ASCENT. Methods: Pts with mTNBC refractory/relapsing after ≥2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Safety outcomes were assessed in all treated pts. This prespecified subgroup analysis assessed the impact of age (pts ≥65 y) on PFS, OS, and safety. Results: Of 529 pts enrolled, 468 were BMNeg (median age, 54 y); of these, 44/235 pts (19%) who received SG and 46/233 pts (20%) who received TPC were aged ≥65 y. SG treatment improved median PFS vs TPC in pts ≥65 y (7.1 vs 2.4 mo; HR, 0.22; 95% CI, 0.12-0.40). SG vs TPC treatment also improved median OS in pts ≥65 y (15.3 vs 8.2 mo; HR, 0.37; 95% CI, 0.22-0.64). Treatment with SG vs TPC resulted in higher ORR (50% vs 0%) and clinical benefit rate (CBR, 61% vs 9%) in pts ≥65 y. Of the 7 pts ≥75 y who received SG, 2 had partial response, 4 had stable disease [SD], and 1 had SD > 6 mo as best response. In pts < 65 y, median PFS for SG vs TPC was 4.6 vs 1.7 mo (HR, 0.46; 95% CI, 0.35-0.59), and median OS was 11.2 vs 6.6 mo (HR, 0.50; 95% CI, 0.40-0.64), respectively; the ORR and CBR were 31% vs 6% and 41% vs 9%, respectively. Pts ≥65 y treated with SG vs TPC had similar rates of all grade and grade ≥3 treatment-emergent adverse events (TEAEs). TEAEs leading to dose reduction were similar in pts ≥65 y in the SG vs TPC arms (35% vs 33%) and were lower in pts < 65 y (19% vs 24%). Key treatment-related TEAEs leading to dose reduction in pts ≥65 y in the SG vs TPC arms were neutropenia (including febrile neutropenia; 14% vs 25%), fatigue (10% vs 4%), diarrhea (6% vs 0%), and nausea (4% vs 0%). TEAEs leading to treatment discontinuation with SG vs TPC were low in pts ≥65 y (2% vs 2%) and < 65 y (5% vs 6%). There were no treatment-related AEs leading to death in any SG-treated age group. Conclusions: Irrespective of age, pts who received SG had a significant survival benefit vs TPC, with a tolerable safety profile. Proactive AE monitoring and management will allow optimal therapeutic exposure to SG in older pts. Clinical trial information: NCT02574455 .

1080 Background: mTNBC is a heterogenous disease with few treatment options and poor outcomes. Pts who recur ≤ 12 mo after completing (neo)adjuvant chemotherapy may represent a subset with more aggressive disease. SG is an antibody-drug conjugate composed of an anti–Trop-2 antibody coupled to the cytotoxic SN-38 payload via a proprietary, hydrolyzable linker. SG received accelerated approval for pts with mTNBC who received ≥ 2 prior therapies for metastatic disease; clinical benefit for SG over treatment of physician's choice (TPC) was confirmed in the phase 3 ASCENT study (NCT02574455) for median progression-free survival (PFS; 5.6 vs 1.7 mo), median overall survival (OS; 12.1 vs 6.7 mo), objective response rate (ORR; 35% vs 5%), clinical benefit rate (CBR; 45% vs 9%), and median duration of response (6.3 vs 3.6 mo). This ASCENT subanalysis of pts with mTNBC who recurred ≤ 12 mo after (neo)adjuvant chemotherapy and then only received 1 line of therapy in the metastatic setting assessed the benefit of SG in this subgroup vs the overall trial population. Methods: In ASCENT, pts with mTNBC refractory/relapsing after ≥ 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg IV on days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine). Per protocol, a pt was eligible after only 1 prior regimen in the metastatic setting if their disease recurred within 12 months of completing (neo)adjuvant therapy. Primary endpoint was PFS per RECIST 1.1 by independent review in brain metastases-negative (BMNeg) pts. Efficacy and safety was assessed in a subset of pts who recurred ≤ 12 mo after (neo)adjuvant chemotherapy and then received 1 line of therapy in the metastatic setting. Results: In total, 33 and 32 BMNeg pts with a median age of 49 and 51 yrs received SG and TPC in this subgroup, respectively. In this subgroup, treatment with SG (vs TPC) improved PFS (median 5.7 vs 1.5 mo; HR, 0.41; 95% CI, 0.22-0.76; P = 0.0049) and OS (median 10.9 vs 4.9 mo; HR, 0.51; 95% CI, 0.28-0.91; P = 0.0227). We also observed higher ORR (30% vs 3%) and CBR (42% vs 6%) with a median response duration of 6.7 mo with SG vs not calculable with TPC. The efficacy results from this subgroup are similar to those for SG vs TPC in the overall BMNeg population. The safety profile of SG in pts in this subgroup was consistent with prior reports. There were no treatment-related deaths with SG. Conclusions: Pts with mTNBC who recurred ≤ 12 mo after (neo)adjuvant therapy and then had 1 line of prior therapy in the metastatic setting may represent a subset with more aggressive disease. In this subgroup, pts had superior outcomes with SG vs TPC in the second-line metastatic setting, consistent with the benefit seen in the overall BMNeg population. Studies are ongoing (NeoSTAR, NCT04230109; SASCIA, NCT04595565) to evaluate SG as an earlier-line treatment option for TNBC. Clinical trial information: NCT02574455 .

Background Patients with human epidermal growth factor receptor-2–negative metastatic breast cancer (MBC), whose disease progressed on prior chemotherapy, have a poor prognosis. Eribulin, a microtubule dynamics inhibitor, extends overall survival in previously treated MBC. The most common adverse event associated with eribulin is neutropenia, which may result in dose interruptions or reductions. A modified biweekly dosing schedule of eribulin was assessed for efficacy as well as improvements in hematologic toxicity. Patients and Methods In this open-label, single-arm, multicenter, phase II study, previously treated (2-5 chemotherapy regimens for metastatic disease) patients with human epidermal growth factor receptor-2–negative MBC received intravenous eribulin 1.4 mg/m2 over 2 to 5 minutes on days 1 and 15 of each 28-day cycle. The primary study endpoints were objective response rate (ORR; complete response [CR] + partial responses [PR]) and disease control rate (DCR; CR + PR + stable disease [SD]). Results Among 58 treated patients, the ORR was 12% (95% confidence interval [CI], 5%-24%), DCR (CR, n = 1; PR, n = 6; SD, n = 30) was 65%, and the median progression-free survival was 3.6 months (95% CI, 2.9-4.1 months). Grade 3 or 4 neutropenia was 31%; 50% of all patients, and 78% of patients with neutropenia (all grades), received hematopoietic growth-factor support. Conclusion The efficacy and safety results obtained with a biweekly eribulin schedule in this phase II trial appear similar to those associated with the approved eribulin schedule (1.4 mg/m2 on days 1 and 8 of a 21-day cycle) reported in the EMBRACE study.

Purpose This phase III randomized trial (ClinicalTrials.gov identifier: NCT00337103) compared eribulin with capecitabine in patients with locally advanced or metastatic breast cancer (MBC). Patients and Methods Women with MBC who had received prior anthracycline- and taxane-based therapy were randomly assigned to receive eribulin or capecitabine as their first-, second-, or third-line chemotherapy for advanced/metastatic disease. Stratification factors were human epidermal growth factor receptor-2 (HER2) status and geographic region. Coprimary end points were overall survival (OS) and progression-free survival (PFS). Results Median OS times for eribulin (n = 554) and capecitabine (n = 548) were 15.9 and 14.5 months, respectively (hazard ratio [HR], 0.88; 95% CI, 0.77 to 1.00; P = .056). Median PFS times for eribulin and capecitabine were 4.1 and 4.2 months, respectively (HR, 1.08; 95% CI, 0.93 to 1.25; P = .30). Objective response rates were 11.0% for eribulin and 11.5% for capecitabine. Global health status and overall quality-of-life scores over time were similar in the treatment arms. Both treatments had manageable safety profiles consistent with their known adverse effects; most adverse events were grade 1 or 2. Conclusion In this phase III study, eribulin was not shown to be superior to capecitabine with regard to OS or PFS.

Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose-independent, three-compartment model with allometric relationship for body weight, was similar for all tumor types. Inter-individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulin's effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure-efficacy relationships to inform physicians treating patients with MBC.

Withdrawn by Author. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-08.

PURPOSE AND METHODS: Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/ metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m2 on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m2 on days 1–14 (21-day cycles). RESULTS: In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms. CONCLUSIONS: Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies. TRIAL REGISTRATION (PRIMARY STUDY): This study reports the subgroup analyses of eribulin versus capecitabine from a phase 3, open-label, randomized study (www.clinicaltrials.gov; ClinicalTrials.gov identifier: NCT00337103)., SCOPUS: ar.j, info:eu-repo/semantics/published

Introduction: Progression-free survival (PFS) and overall survival (OS) endpoints often only weakly correlate. This analysis investigates how different progression events impact on OS, using data from two phase 3 studies with eribulin in women with advanced/metastatic breast cancer (MBC). Methods: In Study 301, 1102 women with ≤2 prior chemotherapies for advanced/MBC were randomized to eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) or capecitabine (1.25 g/m2 twice daily on days 1-14 every 21 days). Study 305/EMBRACE enrolled 762 patients following two to five prior chemotherapies for advanced/MBC, randomized to eribulin (as above) or treatment of physician's choice. We analyzed OS and PFS post hoc for patients whose disease progressed due to development of "new" metastases, growth of pre-existing lesions, and patients with no reported disease progression. Results: In both clinical studies, development of new metastases was associated with an increased risk of death (p < 0.0001). The time to development of new metastasis or death was significantly longer with eribulin than the comparator in Study 305 (p = 0.0017), but not in Study 301 (p = 0.46). Significantly longer OS was observed in the eribulin compared with the comparator arm for the new metastases subgroup in Study 301 (p = 0.008), but not in Study 305 (p = 0.16), compared with other progression subgroups. Conclusions: Patients with MBC progressing with new metastases have a worse prognosis than those whose disease progresses due to growth of existing lesions or patients with no reported disease progression. These findings have potentially important implications for the interpretation of clinical study data and clinical practice., SCOPUS: ar.j, info:eu-repo/semantics/published

Pharmacometric investigation of eribulin was undertaken in patients with metastatic breast cancer (MBC) and other advanced solid tumors. A population pharmacokinetic (PK) model used data combined from seven phase 1 studies (advanced solid tumors; n = 129), and one phase 2 (MBC; n = 211), and one phase 3 study (MBC; n = 173). Phase 3 data were also used in a PK/pharmacodynamic (PD) model of efficacy and tumor response (sum of longest diameters of target lesions). All analyses used NONMEM 7.2. Eribulin PK, described by a dose-independent, three-compartment model with allometric relationship for body weight, was similar for all tumor types. Inter-individual variability (IIV) was 52% for both exposure and clearance. Liver function markers (albumin, alkaline phosphatase, bilirubin) significantly influenced eribulin PK (7.3% of IIV in clearance). Tumor shrinkage correlated with eribulin exposure; a 36% decrease in tumor size from baseline was modeled at week 36. No patient/disease factors significantly predicted eribulin's effect on tumor size. At week 6, a decrease in tumor size was associated with longer survival than an increase (P = .0055), suggesting survival may relate indirectly to eribulin exposure. These pharmacometric analyses provide a detailed overview of eribulin exposure-efficacy relationships to inform physicians treating patients with MBC.

Purpose To evaluate the safety and efficacy of oral everolimus, a mammalian target of rapamycin (mTOR) inhibitor, in two different schedules in minimally pretreated patients with metastatic breast cancer and to explore for possible biologic correlates of response. Patients and Methods Patients who received no or one prior chemotherapy regimen for metastatic breast cancer were entered onto this multicenter, noncomparative, randomized phase II study of everolimus 10 mg daily versus 70 mg weekly; the multinomial end points of response and progression were evaluated at 8 weeks. A two-stage accrual design was used, with 15 evaluable patients in each schedule in stage 1. Only daily therapy met criteria for continuing, and another 15 patients were added. pAKT, PTEN, carbonic anhydrase 9, estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) were evaluated for possible correlation with response. Results The most common drug-related toxicities were fatigue, rash, anorexia, diarrhea, stomatitis, cough, and pneumonitis. Pneumonitis occurred at higher than expected rates and seemed to be schedule dependent, with the highest incidence on the daily schedule. Response rate with daily therapy was 12% (95% CI, 3.4% to 28.2%) compared with 0% (95% CI, 0.0% to 20.6%) for weekly therapy. Twenty-seven percent of patients on daily therapy discontinued treatment compared with 13% on weekly therapy (16% v 6% with pneumonitis, respectively). No biologic correlates of response could be identified, although there were trends favoring benefit in ER-positive and HER2-negative metastatic breast cancer. Conclusion Oral everolimus has activity in metastatic breast cancer that is schedule dependent. Daily therapy with 10 mg is worthy of further study in this patient population.

Data from two phase 3 studies of eribulin were pooled in analyses initially requested by the European Medicines Agency to assess whether specific patient subgroups, previously treated with an anthracycline and a taxane, benefited from eribulin. Study 305/EMBRACE included women after two-to-five lines of chemotherapy for advanced breast cancer who were randomized to eribulin mesylate (1.4 mg/m(2) on days 1 and 8 every 21 days) or treatment of physician's choice. In Study 301, patients who had received up to two prior chemotherapy regimens for advanced disease were randomized to eribulin (as above) or capecitabine (1.25 g/m(2) b.i.d. on days 1-14 every 21 days). In the pooled population, overall survival (OS), progression-free survival and response rates were analysed in the intent-to-treat population and selected subgroups. Overall, 1,062 patients were randomized to eribulin and 802 patients to control. Median OS was 15.2 months with eribulin versus 12.8 months with control (hazard ratio [HR] 0.85; 95% CI 0.77, 0.95; P = 0.003). In all subgroups assessed, OS data favoured eribulin; significant improvements occurred in some subgroups, notably in women with human epidermal growth factor receptor 2 (HER2)-negative disease (HR 0.82; P = 0.002), although the effect in those with HER2-negative but hormone-receptor-positive disease did not reach statistical significance; benefits were also seen, among others, in those with estrogen-receptor-negative and triple-negative disease. Eribulin improves OS in various patient subgroups with advanced/metastatic breast cancer who had previously received an anthracycline and a taxane. Women with HER2-negative disease are among those who may obtain benefit from eribulin.

147 Background: PN is a known adverse effect of various antimicrotubule agents, including eribulin. We report here the incidence and resolution of PN in breast cancer pts treated with eribulin in completed phase 2 and 3 studies, and the efficacy of eribulin in pts with PN in the phase 3 EMBRACE and 301 studies. Methods: In EMBRACE, women had received 2-5 lines of chemotherapy for advanced disease. In this ≥ 3rd-line setting, pts randomized to eribulin mesylate received it at 1.4 mg/m2 iv, days 1 and 8 every 21 days. The dosing schedule was the same in study 301, which involved pts who had received 0-2 prior chemotherapies for advanced disease. Overall survival (OS) and progression-free survival (PFS) were analyzed by stratified log-rank test. Data from EMBRACE and 301 were pooled with data from 2 phase 2 studies to assess time to improvement (a decrease of ≥ 1 grade) and resolution (decrease in grade to 0, 1 or baseline) of grade 3 or 4 PN. Results: In the pooled safety analysis, 7.7% (116/1503) of pts treated with eribulin had grade 3 or 4 PN; 63.8% of these experienced improvement in PN and 50% had resolution. Median time to improvement was 2.1 weeks and to resolution was 7.7 weeks. Characteristics were similar in pts with or without PN in EMBRACE and 301. Those with PN had longer exposure to eribulin vs pts without PN (median exposure [months], study 301: 4.9 vs 3.2; EMBRACE: 4.8 vs 2.9). OS and PFS were significantly longer in pts with PN (Table). Conclusions: Pts who had a favourable therapeutic response to eribulin, received a longer course of treatment and thus had a greater risk of PN. Severity of PN improved in most pts within a short period. Regarding PN, the risk–benefit ratio for eribulin supports treatment. Clinical trial information: NCT00337103, NCT00388726. [Table: see text]

Aim: Eribulin (E) is under review by the European Medicines Agency for use as a second-line and later therapy for pts with locally advanced/MBC who have advanced after prior chemotherapy. To assess the efficacy of E in this setting, we conducted pooled analyses of data from 2 phase 3 open-label studies in pts with locally advanced/MBC. Methods: In study 1, pts who had received 0–2 chemotherapies for advanced disease were randomized 1:1 to E mesilate (1.4 mg/m2 iv on days 1 and 8 every 21 days) or capecitabine (1.25 g/m2 orally bid on days 1–14 every 21 days). In study 2, pts had received 2–5 chemotherapies, and were randomized 2:1 to E (as above) or treatment of physician's choice. For this analysis, overall survival (OS) was assessed by Cox regression and stratified log-rank tests for the overall intent-to-treat population and by HER2, HR and triple negative (TNBC) status. Results: In all, 1644 pts (median age 55.0 yrs) were included, most in the 2nd (35.8%) or 3rd (37.0%) -line settings for advanced disease. E significantly improved OS vs control in the overall, HER2 - , HR+ and TNBC groups (Table). Similar OS data were seen in the HR- and non-TNBC groups (data not shown). E significantly improved progression-free survival (PFS) overall (3.9 vs 3.2 months; HR: 0.88; 95%CI: 0.78, 0.98; p = 0.020), and for HER2- (3.7 vs 2.9 months; HR: 0.84; 95% CI: 0.73, 0.96; p = 0.009), HR+ (4.1 vs 3.5 months; HR: 0.85; 95% CI: 0.73, 0.98; p = 0.028) and TNBC (2.8 vs 2.5 months; HR: 0.76; 95% CI: 0.60, 0.97; p = 0.026) but not HER2+ pts (3.8 vs 4.2 months; HR: 1.0; 95%CI: 0.75, 1.35; p = 0.970). Overall HER2 - HER2 + HR + TNBC E Con E Con E Con E Con E Con n 946 698 663 497 150 104 574 432 199 153 Median OS,amonths 15.1 12.5 15.1 12.0 13.5 11.7 15.7 13.5 12.4 8.1 HR (95% CI)b 0.84 (0.76, 0.94) 0.84 (0.74, 0.96) 0.75 (0.57, 1.00 0.85 (0.74, 0.99) 0.70 (0.55, 0.86) pb 0.003 0.011 0.054 0.038 0.003 aBased on survival curves adjusted by study; bstratified by region, prior capecitabine use and study (and HER2 status for the overall group). E, eribulin; Con, control; HR, hazard ratio; OS, overall survival. Conclusions: In this pooled analysis, E significantly improved OS in a second-line or later setting vs available therapies in the overall, HER2 - , HR + , HR - , TNBC and non-TNBC groups. Treatment differences were not significant in HER2+ pts, but there were fewer pts. Eribulin was thus superior to available therapies in a second-line or later setting in pts with locally advanced/MBC who have advanced after ≥ 1 chemotherapy for advanced disease. Disclosure: C. Twelves: has disclosed a consultant or advisory role with Eisai for which he has been compensated. He has also received honoraria and other remuneration from Eisai; J. Cortes: has disclosed a consultant or advisory relationship with Novartis, Celgene and Roche for which he has been compensated. He has also received honoraria from Novartis, Celgene, Roche and Eisai; M. Olivo: Martin Olivo is an employee of Eisai Inc.; Y. He: Yi He is an employee of Eisai Inc. All other authors have declared no conflicts of interest.

137 Background: Eribulin (E) has been assessed in two phase 3, open-label trials in pts with locally recurrent or MBC progressing after an anthracycline (A) and taxane (T). E significantly increased overall survival (OS) compared with treatment of physician’s choice (TPC) in one study (EMBRACE) and there was a non-significant trend for improved OS with E vs capecitabine (cape) in the other (Study 301). We present an unplanned pooled analysis of these data. Methods: In the EMBRACE trial, women had received 2–5 lines of chemotherapy for advanced disease. In this ≥ 3rd line setting, pts were randomized 2:1 to E mesylate (1.4 mg/m2 iv on days 1 and 8 every 21 days) or TPC. In study 301, pts who had received 0-2 prior chemotherapies for advanced disease were randomized 1:1 to either E (as above) or cape (1.25 g/m2orally b.i.d. days 1–14 every 21 days). We analysed OS by 2-sided stratified log-rank tests and Cox regression in the overall intent-to-treat population and in the HER2-, triple negative (TNBC) and HER2+ subgroups. Results: 1,864 pts (median age 54 yrs) were included; most had been treated in the 2nd (31.5%) or 3rd line (32.7%) MBC settings. Overall, E provided significantly improved OS vs control; this benefit was also significant in HER2− and TNBC, but not HER2+ pts (Table). E improved progression-free survival overall (4.0 vs 3.4 months, HR = 0.90, 95%CI = 0.81, 0.997, p = 0.046), in HER2– (3.7 vs 3.0 months, HR = 0.84, 95%CI = 0.74, 0.95, p = 0.006) and TNBC pts (2.8 vs 2.6 months, HR = 0.78, 95%CI = 0.63, 0.96, p= 0.018). As reported before, the E safety profile was similar in the studies. Conclusions: E significantly improved OS vs standard therapies in MBC pts with HER2− and TNBC in this pooled analysis; in pts with HER2+ disease the difference did not reach statistical significance but numbers were smaller. Clinical trial information: NCT00337103 and NCT00388726. [Table: see text]

1055^ Background: Key properties of QoL instruments in a clinical trial setting are reliability, the ability to detect a change, and content validity. Using data from the Study 301 phase III breast cancer trial, we report here content validity and ability to detect a change for the EORTC QLQ-C30 and breast cancer-specific QLQ-BR23 questionnaires. Methods: Patients with locally advanced or metastatic breast cancer were randomized to 21-day cycles of either eribulin mesylate 1.4 mg/m2 given on Days 1 and 8, or capecitabine 1.25 g/m2BID orally on Days 1-14. QoL questionnaires were completed at baseline and at 6 weeks, 3, 6, 12, 18, and 24 months. Objective tumor response was evaluated (complete response [CR]; partial response [PR]; stable disease [SD]; progressive disease [PD]). Univariate and multivariate longitudinal analyses using weighted generalized estimating equations were employed to assess the responsiveness of the QoL scales to objective tumor response. Results: 1,102 patients were randomized (554 eribulin, 548 capecitabine). Global health status (GHS)/QoL scores were low at baseline (55). GHS/QoL scores were highest for patients with CR (70.8), followed by those patients with PR (63.5), SD (60.5), and PD (58.1). Physical functioning followed the same pattern: CR (98.3); PR (79.1); SD (72.8); PD (71.0). Role and social functioning scores were also responsive. Pain increased, while fatigue and body image worsened, with poorer tumor responses. Using the weighted generalized estimating equations, there were improvements in physical (34.78; p

1050^ Background: In a phase III trial comparing eribulin (E) vs. capecitabine (C) in pts with locally advanced or MBC, a trend for improved OS was observed but a statistically significant superiority was not demonstrated with E vs. C for OS or PFS. The AE profiles were consistent with known side effects. We now report QoL results from this trial. Methods: Pts received eribulin mesylate 1.4 mg/m2 on Days 1 and 8, or C 1.25 g/m2 BID orally on Days 1-14, of a 21-day cycle. Eligible pts had received prior therapy including an anthracycline and taxane, and were receiving study drug as 1st-, 2nd-, or 3rd-line therapy for advanced disease. QoL, a secondary objective, was assessed using EORTC QLQ-C30 and QLQ-BR23 questionnaires at baseline, 6 weeks, 3, 6, 12, 18, and 24 months after starting treatment (or until progressive disease or treatment change), and at unscheduled visits. Longitudinal analyses were carried out using weighted generalized estimating equations adjusted for non-random attrition due to death within 12 months. Model covariates were time (visit), region, and baseline QoL. The primary endpoint was change from baseline for Global Health Status (GHS)/overall QoL; exploratory endpoints were change from baseline for each functional domain, and signs/symptoms. Results: 1,102 pts were randomized (E 554; C 548). GHS/QoL scores were low at baseline for E (56.3) and C (54.7) on a scale of 0 (worse) to 100 (best). GHS/QoL and cognitive functioning improved significantly more in pts receiving E vs. C, (6.5 [p=0.048] and 15.3 [p

1049^ Background: This phase III study, comparing eribulin versus capecitabine, showed a non-significant trend for superior overall survival (OS; hazard ratio [HR] 0.88 [95% confidence interval (CI) 0.77, 1.00]; p = 0.056) but not progression-free survival (PFS; HR 1.08 [95% CI 0.93, 1.25]; p = 0.31). Pre-specified exploratory subgroup analyses previously presented showed that patients with triple-negative, ER-negative or HER2-negative disease may have a greater benefit in OS with eribulin compared with capecitabine. Here we present further pre-specified exploratory analyses of OS and PFS. Methods: Patients (eribulin n=554; capecitabine n=548) with locally advanced or MBC had received ≤3 prior chemotherapy regimens (≤2 for advanced disease), including an anthracycline and a taxane. Patients were randomized (stratified for geographic region and HER2 status) 1:1 to 21-day cycles of eribulin mesylate 1.4 mg/m2 i.v. on days 1 and 8 or capecitabine 1.25 g/m2BID orally on days 1-14. Further pre-specified exploratory subgroups included: age; receptor status; number and setting of prior chemotherapy regimen(s); sites of disease; number of organs involved; and time to progression after last chemotherapy. Results: From analyses for OS, patients with only non-visceral disease (HR 0.51; 95% CI 0.33, 0.80), with >2 organs involved (HR 0.75; 95% CI 0.62, 0.90), who had progressed >6 months after last chemotherapy (HR 0.70; 95% CI 0.52, 0.95), or who had received an anthracycline and/or a taxane in the metastatic setting (HR 0.84; 95% CI 0.72, 0.98), appeared to benefit more from treatment with eribulin compared with capecitabine. For OS, in no subgroup was a trend favoring capecitabine seen. Data for other pre-specified subgroups for both OS and PFS will be presented. Conclusions: In addition to patients with triple-, ER-, or HER2-negative disease, further pre-specified exploratory analyses suggest that other patient subgroups may particularly benefit from treatment with eribulin; further studies are warranted to address these hypotheses. Clinical trial information: NCT00337103.