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1006 Background: IMpassion130 was the first randomized phase 3 study to show clinical benefit of cancer immunotherapy (CIT) in untreated PD-L1+ mTNBC. Enhanced A + nP efficacy vs placebo (P) + nP was seen in pts with a richer immune TME but was confined to PD-L1 IC+ pts (PD-L1–expressing immune cells on ≥1% of tumor area; Emens JNCI 2021). While TNBC molecular subtyping and CD8 localization are prognostic in early TNBC, it is unknown whether these features are associated with CIT benefit in mTNBC. This exploratory analysis aimed to identify TME components associated with A + nP efficacy in IMpassion130. Methods: IHC was used to assess PD-L1 status (VENTANA SP142) and immune phenotypes (inflamed/excluded/desert per CD8 stromal/intratumoral localization; Mariathasan Nature 2018). RNA-seq was used for molecular subtyping (Burstein CCR 2015) and pathway analyses (MSigDB Hallmark). Cox regression was used to compare PFS/OS between A + nP vs P + nP, adjusted for prior taxanes, liver mets. Results: Sample classification and PD-L1 distribution are shown (Table). Improved PFS with A + nP vs P + nP was seen in PD-L1 IC+ inflamed and excluded tumors, but improved OS was limited to PD-L1 IC+ inflamed tumors. PD-L1 IC+ basal-like immune activated (BLIA) and immune suppressed (BLIS) subgroups derived PFS benefit, but OS benefit was limited to PD-L1 IC+ BLIA subgroups. In PD-L1 IC+ pts, pathway analysis identified proliferation/DNA damage repair (basal-like tumor features) and angiogenesis/ER response (higher in luminal androgen receptor [LAR]/ mesenchymal [MES] tumors) were associated with improved and reduced PFS, respectively. Conclusions: PD-L1 IC+ immune-inflamed tumors and PD-L1 IC+ BLIA tumors show highest CIT sensitivity, and LAR tumors may be resistant to CIT. These data warrant further study and validation. Clinical trial information: NCT02425891 .[Table: see text]

TPS1103 Background: Modulating estrogen synthesis and/or ER activity is the mainstay of treatment for pts with ER+ BC. Despite substantial progress, many pts experience relapse during/after adjuvant endocrine therapy. However, even though resistant to aromatase inhibitors (AIs) or tamoxifen, growth and survival of the majority of tumors are thought to remain dependent on ER signaling. Therefore, pts with ER+ BC can still respond to second- or third-line endocrine treatment after progression on prior therapy (Di Leo 2010; Baselga 2012). Therapeutic resistance can arise from mutations in ESR1, which can drive estrogen-independent transcription and proliferation. The highly potent, non-steroidal oral selective ER degrader giredestrant achieves robust ER occupancy and is active regardless of ESR1 mutation status. Phase I data indicate that giredestrant is well tolerated, with encouraging activity as a single agent and in combination with the CDK4/6 inhibitor palbociclib (Lim 2020). Single-agent activity was observed after prior treatment with fulvestrant and/or a CDK4/6 inhibitor (Jhaveri 2019). Methods: persevERA BC (NCT04546009) is a double-blind, placebo-controlled, randomized, multicenter phase III study designed to evaluate the efficacy and safety of first-line giredestrant + palbociclib in pts with ER+/HER2– LA/mBC. Randomization: 1:1 to either giredestrant (30 mg PO) plus letrozole placebo QD or letrozole (2.5 mg PO) plus giredestrant placebo QD on Days 1–28 of each 28-day cycle, with palbociclib (125 mg PO QD) on Days 1–21 of each 28-day cycle. Men and premenopausal women will receive an LHRH agonist. Eligibility: females or males ≥18 years old with measurable disease or evaluable bone disease and no prior treatment for advanced disease. Pts who received prior fulvestrant or who have relapsed within 12 months of completion of (neo)adjuvant therapy with an AI and/or prior therapy with CDK4/6 inhibitor are not eligible; relapse during tamoxifen therapy but > 24 months after the start of tamoxifen therapy is allowed. Stratification: site of disease, disease-free interval since the end of (neo)adjuvant therapy, menopausal status, and geographic region. Primary efficacy endpoint: progression-free survival (determined locally by the investigator per RECIST v1.1). Secondary endpoints include overall survival, objective response rate, duration of response, clinical benefit rate, QoL, and safety. Enrollment is open (first patient in: Oct 9, 2020); target recruitment is 978 pts across all sites in a global enrollment phase. After completion of the global enrollment, additional pts may be enrolled in China. Clinical trial information: NCT04546009 .

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 Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

1097 Background: In BROCADE3 (NCT02163694), addition of the PARP inhibitor (PARPi) V to CP improved PFS in patients (pts) with g BRCA-associated advanced breast cancer (hazard ratio 0.71 [95% CI 0.57–0.88], p = 0.002). Reversion mutations may account for resistance to platinum-based CT and PARPi. Efficacy, safety, and exploratory biomarker analyses for pts randomized to PL + CP who received crossover (Cx) V monotherapy after progression are reported. Methods: 513 total pts were randomized 2:1 to V + CP or PL + CP. V/PL, C, and P could be discontinued independently prior to progression, leading to varying platinum-free intervals at the time of progression. After progression, pts in the PL + CP arm could receive open-label Cx V monotherapy (300–400 mg BID continuous), beginning within 60 d of progression and continuing to second progression. Adverse events (AEs) and activity during Cx V were assessed. Exploratory analysis of BRCA reversion mutations restoring BRCA1/2 protein function that emerged during PL + CP treatment was performed on plasma circulating tumor DNA using targeted-amplicon next generation sequencing. Results: At data cutoff, 75 pts initially randomized to PL + CP had ≥1 dose of Cx V. Mean (range) duration of Cx V was 154 d (2–966). Activity during Cx V is in the Table. Mean (range) platinum-free interval at time of first dose of Cx V was 3.1 mos (0.4–10.9) vs 8.1 mos (1.0–34.9) in pts who had progressed vs had not progressed by 24 wks after first dose of Cx V. BRCA reversion analysis was completed for 18 Cx pts. Reversion mutations were identified in 1/18 pts (5.6%). This patient had Cx V duration of 19 d and had progressed by 24 wks. BRCA reversion analysis on additional Cx pts will be presented. Most common AEs during Cx V were nausea (61%), vomiting (29%), fatigue (24%), and diarrhea (21%). Any grade anemia, neutropenia, and thrombocytopenia occurred in 7%, 15%, and 7% of pts. Three pts (4%) experienced a convulsion event. Conclusions: Platinum-free interval may influence efficacy of subsequent PARPi. Impact of BRCA reversion mutations warrants further evaluation. Cross-resistance may limit PARPi efficacy after platinum failure. Clinical trial information: NCT02163694 . [Table: see text]

2527 Background: Isolated central nervous system (CNS) progression on first-line systemic therapy with Trastuzumab (T) and Pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) is a therapeutic challenge. Our aim was to describe the clinical outcome and current treatment strategies for such patients in a large retrospective cohort. Methods: Patients (pts) were selected among all MBC pts included in the French Epidemiological Strategy and Medical Economics (ESME) database involving 18 specialized cancer centers (NCT03275311). CNS progression-free survival (CNS-PFS), progression-free survival (PFS) and overall survival (OS) from diagnostic of brain metastases (BM) were estimated using the Kaplan-Meier method. Results: Between January 2008 and December 2016, 995 pts were treated with first-line T and P for their HER2-positive MBC. They were 55 years old in median, with tumors expressing hormone-receptors in 62%. A total of 132 pts (13%) experienced isolated CNS progression on T and P, with a median time from metastatic diagnosis to CNS progression of 12 months. It was the first CNS progression for 108 pts (82%) while 24 (18%) already had BM at time of metastatic relapse. After CNS progression, T and P were continued for 58% of pts (n = 73). The remaining 47 pts were switched to another HER2-directed therapy (T-DM1 for 57%, T alone or combined with chemotherapy for 36% and lapatinib for 21%). Among those 132 pts, 37% received whole-brain radiotherapy, 18% stereotactic radiation therapy, and 11% surgery. Systemic treatment was combined with CNS-directed therapy for 50% of pts. Median follow-up is 21 months (95%CI: 14.9-25.5) from the diagnosis of CNS metastases. Median OS (mOS) of the 132 pts is 35 months (95%CI: 29.2-53,6), and median PFS 7 months (95%CI: 6.3- 9.2). A total of 77 pts (58.3%) experienced a new CNS progression with a median CNS-PFS of 9 months (95%CI: 7.6-12,0). Patient who stayed on T and P had a significantly better OS in comparison to pts who were switched to another systemic HER2-directed therapy (mOS not evaluable vs23 months), whereas PFS and CNS-PFS were similar between groups. Conclusions: In this real life setting, isolated CNS progression occurred among 13% of pts with HER2+ MBC on first-line treatment with T and P, after a median time of 12 months. Following current ASCO recommendations, continuation of T and P after CNS-directed therapy, seemed to be adequate. Nevertheless, time to subsequent progression is short and better therapeutic options are needed.

1091 Background: In BROCADE3 (NCT02163694), addition of PARP inhibitor V to CP resulted in improved progression-free survival (PFS) (HR 0.71 [95% CI 0.57−0.88], p=0.002) in patients (pts) with advanced HER2-negative breast cancer and g BRCA1/2 mutation. A subset of pts transitioned to V/placebo (PL) monoTx at an intensified dose/schedule after CP discontinuation prior to progression (investigator discretion). Here, we evaluate the impact of this transition on efficacy and safety. Methods: Pts were randomized 2:1 to CP with V (n=337) or PL (n=172). V (120 mg po BID) or PL was given on Days (D) −2 to 5, C (AUC 6) on D1, and P (80 mg/m2) on D1, 8, and 15 (21-day cycles). Pts who transitioned to monoTx received V/PL 300-400mg BID daily until progression. A Cox model with a time varying covariate indicating transition from V/PL with CP to V/PL monoTx was fit to estimate treatment effect during combination and monoTx phases. PFS by cycles of CP prior to monoTx and AEs during monoTx are summarized. Results: A subgroup of 136 (40%) and 58 (34%) pts on the V and PL arms, respectively, received monoTx. When a Cox model with a time-varying covariate was fit for PFS (per investigator), the nominal P-value for treatment by covariate interaction was 0.038. The HRs (95% CI) for V vs PL during combination therapy and monoTx were 0.81 (0.62–1.06) and 0.49 (0.33–0.73). The Table summarizes PFS by cycles of C and/or P prior to monoTx. Common AEs (>20% of pts) during V or PL monoTx were nausea (52%/10%), fatigue (23%/12%), headache (21%/17%), and diarrhea (21%/9%). Seizures (2.2%/0%) were reported during monoTx. Rates of cytopenias for V or PL monoTx were: anemia 12%/14%; neutropenia 13%/12%; and thrombocytopenia 10%/5%. Conclusions: These analyses suggest that pts treated with V + CP derive benefit from both combination therapy as well as V monoTx after CP discontinuation. Pts receiving V monoTx after ≤ 6 cycles of VCP experienced a similar benefit to those who transitioned to monoTx after 7–12 cycles of VCP, suggesting that V maintenance therapy may be suitable following a limited duration of combination therapy. Clinical trial information: NCT02163694 . [Table: see text]

Purpose Our phase IIa study characterized the safety and efficacy of two human epidermal growth factor receptor 2 (HER2) –targeted agents, trastuzumab emtansine (T-DM1) and pertuzumab, in patients with HER2-positive metastatic breast cancer (MBC). Patients and Methods Patients with HER2-positive locally advanced breast cancer or MBC were treated with 3.6 mg/kg T-DM1 plus pertuzumab (840-mg loading dose, then 420 mg subsequently) once every 3 weeks. The primary efficacy end point was investigator-assessed objective response rate (ORR). Results Sixty-four patients (43 patients in the second-line or greater setting [advanced MBC]; 21 patients in the first-line setting [first-line MBC]) were enrolled. Patients with advanced MBC had received trastuzumab and a median of six prior nonhormonal treatments for MBC; 86% of first-line MBC patients had received trastuzumab in the (neo)adjuvant setting. The ORR was 41% overall, 33% in patients with advanced MBC, and 57% in first-line patients. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively. The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most frequent grade ≥ 3 adverse events were thrombocytopenia (13%), fatigue (11%), and liver enzyme elevations (increased ALT: 9%; increased AST: 9%). One patient had left ventricular ejection fraction of less than 40% after study drug discontinuation. Exploratory biomarker analyses demonstrated that patients with above-median tumor HER2 mRNA levels had a numerically higher ORR than patients with below-median levels (44% v 33%, respectively). Conclusion T-DM1 and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced MBC settings warrants further investigation.

1068 Background: IMpassion130 showed PFS benefit with A + nP vs placebo (P) + nP as 1L tx for mTNBC in the ITT and PD-L1 IC+ pts. We report expanded safety data with 4.5-mo longer follow-up (FU), focusing on adverse events of special interest (AESI), potentially immune related. Methods: Pts with unresectable locally advanced or mTNBC received nP 100 mg/m2 IV (d1, 8 and 15 of a 28-d cycle) + A 840 mg IV q2w or P until PD or toxicity. Safety was a secondary endpoint. Results: With 15.6 mo of median FU, of 453 pts with A+nP and 437 pts with P+nP, 49% and 43% had Gr 3/4, 1% and

1067 Background: In the IMpassion130 study in 1L mTNBC (N = 902), PFS with atezo + nP was significantly better than with placebo (P) + nP in ITT (HR, 0.80) and PD-L1 IC+ (HR, 0.62) patients (pts). Clinically meaningful OS improvement (HR, 0.62) was also seen in PD-L1+ pts. PROs were used to document pt perspectives on overall clinical benefit of atezo + nP. Methods: Pts received either atezo 840 mg or P q2w + nP 100 mg/m2 on days 1, 8 and 15 of each 28-day cycle until disease progression or intolerance. Pts completed the EORTC QLC-C30 and breast cancer module (QLQ-BR23) on day 1 of each cycle, at end of treatment (Tx) and q4w during follow-up for 1 y. Time to deterioration (TTD; first ≥ 10-point decrease from baseline [BL] held for 2 cycles) in HRQoL was a pre-defined secondary endpoint. Exploratory endpoints included TTD in function, and mean and mean change from BL scores (changes ≥ 10 considered clinically meaningful) in HRQoL, function and disease/Tx-related symptoms. Results: BL completion was 92% (QLQ-C30) and 89% (QLQ-BR23) and remained > 80% through Cycle 20 in both ITT and PD-L1 IC+ pts. No differences in median TTD in HRQoL (ITT: HR, 0.97 [95% CI: 0.80, 1.18]; PD-L1 IC+: HR, 0.94 [95% CI: 0.69, 1.28]), physical function (ITT: HR, 1.04 [95% CI: 0.86, 1.26]; PD-L1 IC+: HR, 1.02 [95% CI: 0.76, 1.37]) or role function (ITT: HR, 1.01 [95% CI: 0.83, 1.22]; PD-L1 IC+: HR, 0.77 [95% CI: 0.57, 1.04]) were observed between arms in either population. Mean scores at BL for HRQoL (ITT: 66.0 [atezo + nP] vs 64.3 [P + nP]; PD-L1 IC+: 67.5 vs 65.0), physical function (ITT: 80.4 vs 79.2; PD-L1 IC+: 82.8 vs 79.4) and role function (ITT: 72.7 vs 71.0; PD-L1 IC+: 73.7 vs 71.7) were similar between arms and throughout the course of Tx. In both arms, HRQoL, physical and role function, and Tx symptoms (fatigue, diarrhea, nausea, vomiting) were stable during Tx, with no clinically meaningful changes seen until pts discontinued Tx. Conclusions: PRO data suggest that atezo + nP was tolerable and similar to nP alone in maintaining HRQoL and day-to-day function relative to BL. This confirms atezo + nP had clinical benefit without compromising HRQoL, physical and role function, or worsening Tx symptoms vs P + nP in 1L mTNBC. Clinical trial information: NCT02425891.

1003 Background: IMpassion130 evaluated atezo (anti–PD-L1) + nP vs placebo + nP in 1L mTNBC. The primary PFS analysis found that atezo + nP significantly improved PFS in intent-to-treat (ITT) and PD-L1+ pts vs placebo + nP, with efficacy driven by the PD-L1+ population. At that time, the 1st interim OS analysis was conducted (Schmid, NEJM 2018). Here we report the 2nd interim OS analysis. Methods: Eligible pts had histologically documented locally advanced or mTNBC, ECOG PS 0-1 and tumor tissue for PD-L1 testing. Pts were randomized 1:1 to IV atezo 840 mg or placebo on d1 and d15 + nP 100 mg/m2 on d1, d8 and d15 of each 28-d cycle until progression (stratification factors: prior taxanes, liver metastases, PD-L1 on tumor-infiltrating immune cells [IC]). RECIST 1.1 PFS (in ITT and PD-L1+ pts) and OS (tested in ITT and, if significant, PD-L1+ pts) were co-primary endpoints. Results: OS data are shown (Table). As of data cutoff (Jan 2, 2019), 9% of pts in the atezo + nP arm and 3% in the placebo + nP arm were still on treatment. Statistical significance was not demonstrated in ITT pts, but a 7.0-month improvement in median OS was observed in PD-L1+ pts with atezo + nP (25.0 mo) vs placebo + nP (18.0 mo; HR, 0.71 [95% CI: 0.54, 0.93]). A 4.5-mo safety update (Schneeweiss, ASCO 2019, submitted) showed that atezo + nP remained tolerable. Conclusions: The 2nd IMpassion130 interim OS analysis was consistent with the 1st analysis, confirming clinically meaningful OS benefit with atezo + nP in previously untreated PD-L1+ mTNBC. Clinical trial information: NCT02425891. [Table: see text]

TPS1107 Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and Q3W dosing regimen; no observed hypersensitivity reactions; preclinical evidence of CNS penetration; and improved activity against chemotherapy-resistant tumors. Over 600 pts have been treated with T in clinical studies. T had robust monotherapy activity in a Phase 2 study in 38 pts with HER2-, HR+ MBC who received T Q3W, with a confirmed ORR per RECIST 1.1 of 45% and median PFS of 5.4 mo. The confirmed ORR in taxane-pretreated pts was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine (C) in combination with a taxane may result in reduced toxicity without reduction in efficacy. Preclinical data also suggest that T may penetrate the brain at clinically relevant concentrations. CONTESSA investigates T plus a reduced dose of C as an all-oral regimen in HER2-, HR+ LA/MBC, with revised eligibility criteria to allow inclusion of pts with CNS metastases. Methods: CONTESSA is a 600-pt, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing T (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of C (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of C alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in pts with HER2-, HR+ LA/MBC previously treated with a taxane in the (neo)adjuvant setting. The protocol was newly amended to allow pts with known CNS metastases. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are OS, ORR, and disease control rate. Enrollment began in Dec 2017. Following review in Jan 2019, the Independent Data Monitoring Committee recommended that the Study continue as planned. Clinical trial information: NCT03326674.

Purpose This phase III study compared the efficacy and safety of bevacizumab (BV) when combined with several standard chemotherapy regimens versus those regimens alone for first-line treatment of patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. Patients and Methods Patients were randomly assigned in 2:1 ratio to chemotherapy plus BV or chemotherapy plus placebo. Before random assignment, investigators chose capecitabine (Cape; 2,000 mg/m2 for 14 days), taxane (Tax) -based (nab-paclitaxel 260 mg/m2, docetaxel 75 or 100 mg/m2), or anthracycline (Anthra) -based (doxorubicin or epirubicin combinations [doxorubicin/cyclophosphamide, epirubicin/cyclophosphamide, fluorouracil/epirubicin/cyclophosphamide, or fluorouracil/doxorubicin/cyclophosphamide]) chemotherapy administered every 3 weeks. BV or placebo was administered at 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), 1-year survival rate, objective response rate, duration of objective response, and safety. Two independently powered cohorts defined by the choice of chemotherapy (Cape patients or pooled Tax/Anthra patients) were analyzed in parallel. Results RIBBON-1 (Regimens in Bevacizumab for Breast Oncology) enrolled 1,237 patients (Cape cohort, n = 615; Tax/Anthra cohort, n = 622). Median PFS was longer for each BV combination (Cape cohort: increased from 5.7 months to 8.6 months; hazard ratio [HR], 0.69; 95% CI, 0.56 to 0.84; log-rank P < .001; and Tax/Anthra cohort: increased from 8.0 months to 9.2 months; HR, 0.64; 95% CI, 0.52 to 0.80; log-rank P < .001). No statistically significant differences in OS between the placebo- and BV-containing arms were observed. Safety was consistent with results of prior BV trials. Conclusion The combination of BV with Cape, Tax, or Anthra improves clinical benefit in terms of increased PFS in first-line treatment of metastatic breast cancer, with a safety profile comparable to prior phase III studies.

LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]

TPS1120 Background: EP is a next generation topoisomerase I inhibitor-polymer conjugate that provides continuous exposure to SN-38, the active metabolite. A BM mouse model showed high penetration and retention of SN-38 in CNS lesions, resulting in decreased size of CNS lesions and improved survival (OS) at concentrations achieved at the recommended dose in pts (Adkins BMC Cancer 2015). A Phase 3 trial (BEACON) of EP vs TPC in 852 pts with advanced BC did not meet its primary endpoint of OS (HR 0.087; p = 0.08); a subset of 67 pts with stable BM showed improved OS (HR 0.51 [95% CI 0.30-0.86]; p < 0.01) (Perez Lancet Oncol 2015). The current Phase 3 trial (ATTAIN) was designed for this subpopulation of pts having high unmet medical need. Methods: Pts with MBC with locally treated stable BM will be randomized 1:1 to EP vs TPC in an open-label, randomized Phase 3 study. Eligibility includes ECOG PS 0 or 1; adequate organ function who received prior ATC (in neo/adjuvant or locally advanced/MBC setting); pts must have had ≥1 prior cytotoxic regimen for MBC (triple negative BC); ≥2 prior cytotoxic regimens and either 1 prior hormone therapy (HR+ BC) or 1 prior HER2 targeted therapy (HER2+ BC). Pts must have undergone definitive local therapy of BM (whole brain radiation [RT]; stereotactic RT or surgical resection as single-agent or combination); signs/symptoms of BM must be stable with steroids unchanged or decreasing for ≥7 days prior to randomization. Primary endpoint is OS. Key secondary endpoints: ORR and PFS by RECIST v1.1 and RANO-BM, clinical benefit rate (ORR+SD ≥ 6 months) and QoL. Pts randomized to TPC will receive 1 of 7 IV cytotoxic agents. Pts are stratified by region, PS and receptor status. 350 pts will be randomized to obtain number of events required at 90% power to detect a statistically significant improvement in OS (hypothesizing HR = 0.67); 1 interim analysis at 50% of deaths (130 events) will be performed. PK sampling and UGT1A1 testing will be performed in the EP arm; plasma ctDNA will be assessed for potential predictive markers of efficacy. Enrollment will begin early 2017. Clinical trial information: NCT02915744.

TPS1106Background: Chemotherapy treatments that offer improved quality of life are needed. Tesetaxel (T) is a novel, oral taxane that has potential advantages over currently available taxanes, incl...

Purpose This randomized, noncomparative, parallel-group study was designed to evaluate the pathologic complete response (pCR) rate of combined doxorubicin plus paclitaxel (AP) and doxorubicin plus cyclophosphamide (AC) as neoadjuvant chemotherapy in patients with previously untreated breast cancer who were unsuitable for conservative surgery. Patients and Methods A total of 200 patients with T2-3, N0-1, M0 disease were randomly assigned in a 2:1 ratio to receive preoperative chemotherapy with either doxorubicin 60 mg/m2 plus paclitaxel 200 mg/m2 as a 3-hour infusion (AP) or doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC) every 3 weeks for 4 courses followed by surgery. Results A pCR (eradication of invasive carcinoma in tumor and in axillary lymph nodes) was found in 16% and 10% of patients in the AP and AC arms, respectively, by study center pathologists, and in 8% and 6% of patients, respectively, by independent pathologists. Patients with pCRs tended to have unifocal disease, tumors with negative hormonal receptor status, and less differentiation (Scarff, Bloom, and Richardson scale grade 3). Breast-conserving surgery was performed in 58% and 45% of patients in the AP and AC arms, respectively. An objective clinical response was achieved in 89% of patients in the AP arm and 70% in the AC arm. At a median follow-up of 31 months, disease-free survival (DFS) was higher in patients who reached pCR versus those without pCR (91% v 70%). Conclusion The encouraging pathologic and clinical responses of patients with breast cancer after neoadjuvant chemotherapy with doxorubicin plus paclitaxel warrant additional investigation of paclitaxel in the neoadjuvant setting of breast cancer management.

PURPOSE: Phase II study evaluating efficacy and safety of combined oxaliplatin/fluorouracil (5-FU) in taxane-pretreated advanced and metastatic breast cancer (ABC) patients. PATIENTS AND METHODS: Sixty-four taxane- and anthracycline-pretreated (within 6 months of study entry) women were treated with oxaliplatin 130 mg/m2 (2-hour intravenous [IV] infusion), day 1, and 5-FU 1,000 mg/m2/d (continuous IV infusion) days 1 to 4, every 3 weeks. RESULTS: Median patient age was 51 years (range, 34 to 71 years), with a median of two involved organs (range, one to six organs), and metastases in the liver (70%), bone (47%), and lung (34%). Patients had a median of two prior chemotherapy regimens (range, one to six regimens), and 78% had previous hormonal therapy, with clinical taxane and anthracycline resistance in 53% and 34%, respectively. A total of 367 cycles were administered, with a median of six cycles/patient (range, one to 15 cycles). Sixty patients were assessable for response (World Health Organization criteria): 17 partial response, 26 stable disease, and 17 disease progression, giving an overall response rate of 27% (95% confidence interval, 16.3% to 39.1%), and 26% and 36% in taxane- and anthracycline-resistant populations, respectively, all responders having metastatic liver disease. Median time to progression was 4.8 months, and median overall survival was 11.9 months. Four treatment-related serious adverse events occurred, seven patients withdrew because of treatment-related toxicity. Hematotoxicity was prevalent but rarely severe, with grade 3-4 neutropenia, leukopenia, and thrombocytopenia in 34%, 19%, and 16% of patients, respectively, and a single episode of febrile neutropenia. One third of patients developed grade 2-3 peripheral neuropathy (oxaliplatin-specific scale), with grade 3 in only 8%. CONCLUSION: This oxaliplatin/5-FU combination is effective with an excellent safety profile in anthracycline/taxane-pretreated ABC patients, showing encouraging activity in patients with anthracycline/taxane-resistance or visceral disease.

1039 Background: Hormone tx (HT) is the primary 1L tx for ER+ ABC. In the PALOMA-2 study (NCT01740427), PAL+L as 1L ABC tx prolonged progression-free survival (PFS; hazard ratio [HR] 0.58; P12 mo (40%) than ≤12 mo (22%). Median PFS (mPFS) was improved in all subgroups by adding PAL to L (Table). Adverse events were consistent across subgroups, as described for the full study population. Conclusions: PAL+L improved mPFS vs P+L with manageable toxicity across all subgroups including those with visceral disease. PAL+L provides a 1L option that should be considered for all pts with ER+/HER2- ABC. Sponsor: Pfizer Clinical trial information: NCT01740427. [Table: see text]

TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and > 300 patients have been enrolled. Clinical trial information: NCT02340221.

1078 Background: Real-life data may help checking that public investments match closely medical needs. During the last decade, several drugs have been released on the market for MBC on the basis of a potential impact on overall survival (OS). Based on the large real-life ESME cohort, we aimed to describe the time evolution of MBC OS according to main phenotypes. Methods: ESME is a unique MBC national cohort including all consecutive patients (pts) who initiated treatment for MBC between 1/01/08 and 31/12/14 in the 18 French comprehensive cancer centres. ESME collects retrospective data using clinical trial-like methodology including quality assessments. Database lock was 8/12/2016. Primary objective was the impact of year of MBC diagnosis on OS. Multivariate Cox regressions were used with adjustment for main prognostic covariates. Results: 15170 out of 16703 pts in ESME had full IHC data allowing their classification as HR+HER2- (N=9922), HER2+ (N=2863), or HR-HER2- (N=2321) cases. Median FU and OS for the whole cohort are 4.05 yrs [95 CI: 3.98-4.12], and 3.1 yrs [95 CI: 3.03-3.18] respectively. In the adjusted multivariate analysis, year of MBC diagnosis, age at MBC, subtype (using HER2+ as reference), disease-free interval (DFI), visceral involvement, and number (nbr) of metastatic sites are significant OS predictors (table) although with low effect for the first item. Age at MBC, DFI, visceral involvement, and nbr of metastatic sites remained significant prognostic variables in subtypes. Year of diagnosis was no longer significant in HR+HER2- nor HR-HER2- cases (HR=0.997, p=0.71 and HR=0.997, p=0.84), while it was highly significant in HER2+ cases (HR=0.91, p

PURPOSE: To determine the efficacy and tolerability of irinotecan (CPT-11) in advanced or recurrent cervical carcinoma. PATIENTS AND METHODS: Eligible patients had histologically confirmed, inoperable, progressive, metastatic or recurrent squamous cell cervical carcinoma and had received no radiotherapy in the preceding 3 months and had never received chemotherapy. The initial irinotecan dosage of 350 mg/m2 every 3 weeks was modifiable according to toxicity. Treatment continued for six cycles after complete response, or until disease progression or excessive toxicity after partial response, or for three additional cycles in the case of stable disease. Patients were stratified into group A (≥ one measurable lesion in a previously unirradiated area, with or without progressive disease in irradiated fields) or group B (measurable new lesion[s] in an irradiated field). RESULTS: Fifty-one of 55 enrolled patients were eligible for inclusion (median age, 47 years; range, 30 to 71 years). The response rate was 15.7% (95% confidence interval [CI], 7.0% to 28.6%) overall, 23.5% (95% CI, 10.7% to 41.2%) for group A (complete response, 2.9%), and zero for group B. The median time to progression and median survival were 4.0 and 8.2 months for group A and 2.5 and 4.2 months for group B, respectively. The major grade 3/4 toxicities for groups A and B were diarrhea (24.3% and 55.5%, respectively) and neutropenia (24.3% and 33.3%, respectively). There were four toxicity-related deaths, three in group B. Patients with no prior external pelvic irradiation experienced fewer grade 3 and 4 adverse events. CONCLUSION: Irinotecan is effective in treating cervical squamous cell carcinoma if disease is located in an unirradiated area. Because of toxicity, a reduced dose is advised for patients previously treated with external pelvic irradiation.

606Background: Blockade of PI3K/AKT/mTOR pathway by E combined with T in HER2+ BC pts shows promising results. It has also been reported that T acted differently when used in PO setting with a lowe...

TPS1104Background: Treatment for mTNBC is limited, with chemotherapy the mainstay (bevacizumab is approved in > 80 countries). Atezolizumab (atezo; MPDL3280A), a humanized anti-PDL1 antibody, inhibits PD-L1 binding to PD-1 and B7.1 but leaves PD-L2/PD-1 binding intact. mTNBC has high levels of tumor-infiltrating immune cells, increased PD-L1 expression and high mutation rates that may generate immunogenic neoantigens, making it a good candidate for PD-L1–targeted therapy. It is hypothesized that atezo’s single-agent activity in TNBC could be enhanced with chemotherapy by exposing the immune system to high levels of tumor antigens and modulating T-cell and NK cell functions. Nab-paclitaxel (pac) has high antitumor activity that may favorably alter the immune microenvironment, and atezo + nab-pac resulted in promising activity and tolerable safety. A Phase III multicenter, randomized, double-blind, placebo-controlled trial (IMpassion130) has been initiated to evaluate atezo + nab-pac in first-line mTNBC. Me...

1013Background: In 2014, UNICANCER (composed of 18 French Comprehensive Cancer Centers) launched the Epidemiological Strategy and Medical Economics (ESME) program to centralize real-world data in oncology. Metastatic breast cancer (mBC) was first selected to address the value of bevacizumab (B) added to paclitaxel (P) as first-line chemotherapy (CT) for HER2-negative tumours, while randomized trials have led to mixed results on outcome. Methods: The ESME-mBC database was built from information systems, treatment databases and patients’ electronic files including quality control processes. All patients who started a first-line anti-cancer treatment for mBC between 01-Jan-2008 and 31-Dec-2013 were selected. The primary objective of the present study was to assess overall survival (OS) in patients with HER2-mBC treated with a first-line P-based CT ± B. Cox regression with adjustment for the main prognostic covariates was used to estimate the hazard ratio (HR) for OS and progression-free survival (PFS). To ad...

510Background: Abemaciclib is an oral, selective inhibitor of CDK4 and CDK6 dosed on a continuous schedule. In a phase 1 trial, abemaciclib demonstrated single-agent activity in refractory HR+ meta...

TPS617Background: PIK3CA mutations are one of the most frequent genomic alterations in BC, being present in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations promote growth and proliferation of tumors and can mediate resistance to endocrine therapies in BC. Taselisib is a potent and selective PI3K inhibitor that displays greater selectivity for mutant PI3Kα than wild-type PI3Kα. Taselisib has enhanced activity against PIK3CA-mutant BC cell lines, and clinical data include confirmed partial responses in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. SANDPIPER, a double-blind, placebo-controlled, randomized, phase III study, is designed to evaluate efficacy and safety of taselisib plus fulvestrant in postmenopausal pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Methods: Pts with disease recurrence or progression during or after aromatase inhibitor treatment will be randomized 2:1 to receive...

155 Background: BRCA-mutated tumors are more susceptible to platinum therapy and PARP inhibitors due to underlying defects in homologous recombination repair of DNA damage. In preclinical models the potent oral PARP1/2 inhibitor veliparib was shown to enhance sensitivity to C and to have single-agent activity in BRCA+ cell lines. Phase 1 trials suggest promising antitumor activity and acceptable toxicity of veliparib plus C/P in triple-negative BC (Puhalla et al. Cancer Res 2012;72:PD09-06) and single-agent activity of veliparib in BRCA+ BC (Somlo et al. J Clin Oncol 2014;32:abstr. 1021). This phase III trial assesses efficacy and toxicity of veliparib plus C/P vs C/P alone in patients with HER2− BRCA-associated locally advanced or metastatic BC (NCT02163694). Methods: Phase III randomized, double-blind, placebo-controlled, multicenter trial. Eligible patients (female or male; ≥ 18 years) have HER2−metastatic/locally advanced unresectable BC with (suspected) deleterious BRCA1/2 germline mutations and received 2 or fewer prior lines of DNA-damaging chemotherapy for metastatic BC. In addition, patients must have received ≤ 1 prior line of platinum therapy (any setting) without progression within 12 months of completing treatment. Patients are randomized 2:1 to C/P with veliparib or C/P with placebo, stratified by estrogen and/or progesterone receptor expression, prior platinum therapy, and central nervous system metastases. Veliparib (120 mg p.o. BID) or placebo will be given on Days −2 to 5, C (AUC 6 mg/mL/min i.v.) on Day 1, and P (80 mg/m2i.v.) on Days 1, 8, and 15 (21-day cycles). Treatment continues until unacceptable toxicity or progressive disease (PD). Patients in the placebo arm who discontinue due to PD are eligible for crossover to veliparib monotherapy. The primary objective is to assess if the addition of veliparib to C/P increases progression-free survival; additional objectives include evaluation of overall survival, clinical benefit rate, objective response rate, quality of life, and safety. Enrollment began in July 2014 with a planned sample size of 270 patients. Clinical trial information: NCT02163694.

606 Background: T-DM1, an antibody–drug conjugate composed of trastuzumab, the microtubule inhibitor DM1, and a stable linker, is a newly approved therapy for HER2-positive MBC. Two phase 3 studies...

TPS2643 Background: ONA is a type I PR antagonist, which prevents PR-induced DNA transcription. Presence of transcriptionally activated PR (APR), could indicate potential for ONA anticancer activit...

501 Background: Combination of P+BEV significantly improves progression-free survival (PFS) in MBC pts, but is associated with adverse events (AEs), mainly neuropathy and fatigue worsening over tim...

511 Background: The aim of the present study was to profile the metastatic lesion of pts using high throughput technologies, and to treat them accordingly. Methods: SAFIR01 trial aimed to include 400 pts with MBC, selected for not presenting a progressive disease at the time of biopsy. A biopsy was done in a metastatic site. DNA was extracted if the tumor contained >50% cancer cells, and sent to one of the 5 genomic centers who performed array CGH (copy number changes) and sanger sequencing on PIK3CA (exon 10/21) and AKT1 (exon 3). A targeted therapy matched to the genomic alteration was expected to be proposed at the time of progressive disease. The primary endpoint was the % of pts who received a targeted therapy according to the genomic alteration. Results: A biopsy of metastatic site was done successfully in 408 out of the 423 included pts. Biopsy was complicated by a serious adverse event in 9 pts. A discrepancy between primary and metastatic lesion was observed in 8% and 19% of pts for Her2 and HR. Array CGH and sequencing were successfully obtained in 277 (68%) and 295 (72%) pts. The main reason for failure of genomic test was the low cellularity (n=93). A targetable genomic alteration was identified in 204 pts. The most frequent genomic alterations were PIK3CA mutations, CCND1, FGF4 and FGFR1 amplifications. 76 pts presented a rare targetable genomic alteration (

TPS652 Background: Palbociclib (PD-0332991) is an orally bioavailable selective inhibitor of CDK4/6 that prevents DNA synthesis by prohibiting progression of the cell cycle from G1 to S phase. In a randomized phase II trial comparing palbociclib (PD-0332991) plus letrozole (P + L) to letrozole (L) in postmenopausal women with ER(+), HER2(–) advanced breast cancer (ABC) who had not received any prior systemic anticancer therapy for their advanced disease, P + L demonstrated significantly longer progression-free survival (PFS) vs L (26.1 vs 7.5 mo; HR = 0.37, P < .001) and was generally well tolerated, with uncomplicated neutropenia as the most frequent adverse event (Finn et al SABCS 2012). Methods: Based on phase II data, a global, randomized, double-blind, phase III clinical trial was designed to demonstrate that P + L provides superior clinical benefit compared with L + placebo in postmenopausal women with ER(+), HER2(–) ABC who have not received any prior systemic therapy for their advanced disease. The study aims to assess whether P + L improves median PFS over L at HR of at least 0.7. Approximately 450 eligible patients with locoregionally recurrent or metastatic, pathologically confirmed ABC who are candidates to receive L as first-line treatment for their advanced disease will be randomized 2:1 to receive either P (125 mg QD 3 wk on, 1 wk off) + L (2.5 mg QD) or L (2.5 mg QD) + placebo. Patients who received anastrozole or letrozole as part of their (neo)adjuvant regimen are eligible if their disease progressed more than 12 months from completion of adjuvant therapy. Tumor tissue is required for participation. Secondary endpoints include overall survival, objective response, duration of response, clinical benefit, safety and tolerability, and patient-reported outcomes of health-related quality of life and disease- or treatment-related symptoms. Clinical trial information: NCT01740427.

TPS662 Background: Leptomeningeal metastases (LM) are commonly associated with breast cancer (BC), announcing short term prognosis that intrathecal (IT) chemotherapy poorly modifies. Incidence is particularly marked in HER2+ tumours. With the better control of extra-cerebral disease and prolonged survival yielded by intra-venous (IV) trastuzumab (T), the main hypothesis is that intra-cerebral recurrences are not reached by this high molecular weight (148 kD) monoclonal antibody. Analyses performed in cerebrospinal fluid (CSF) following IV T have shown low T levels, suggesting that LM of HER2+ BC would remain potentially sensitive to anti-HER2 agents as long as they could by-pass the meningeal blood brain barrier. Intraventricular (via Ommaya port) or IT administration of T would allow keeping control on LM progression through high T therapeutic concentrations in CSF. This prospective trial is the first phase I-II study sponsored by Institut Curie to investigate the safety and efficacy of the IT administration of T for HER2+ LM BC. Methods: Eligible patients must be 18+, have a diagnosis of LM either on CSF with HER2+ cytology or on clinical/MRI pictures of meningitis, and normal end-organ functions. The phase I cohort investigates the maximum tolerated dose (MTD) and recommended dose of T given weekly IT (or via Ommaya port) + hemisuccinate hydrocortisone 25 mg, while aiming at yielding a T target-concentration in CSF close to the plasma one (30 µg/mL) obtained with standard IV schedule. The MTD is defined as the highest dose level (DL) tested with ≥2 dose-limiting toxicity (DLT, any grade ≥3 NCI CTCAE v4.0 attributed to T) observed in ≤6 patients (3+3 Fibonacci dose escalation design, 4 DL 30-150 mg) with a maximum of 24 patients. The phase II cohort will investigate the efficacy of the recommended dose (DLMTD-1) defined in cohort I on neurological progression-free survival at 2 months, in ≤19 patients. Secondary endpoints include CSF and MRI response, quality of life, FCGR3A influence, and comparative CSF/plasma pharmacokinetics. Since study activation in May 2011, 5 patients have been included at DL1, 3 being evaluable for DLT. DL2 is now open for accrual.

LBA1 Background: T-DM1 is an antibody-drug conjugate comprising T, a stable linker, and the potent cytotoxic agent DM1; it incorporates the antitumor activities of T and the HER2-targeted delivery of DM1. Methods: EMILIA is a randomized study of T-DM1 vs XL, the only approved combination for T-refractory HER2+ MBC. Patients (pts) received T-DM1 (3.6 mg/kg IV q3w) or X (1000 mg/m2 PO bid, days 1–14 q3w) + L (1,250 mg PO daily) until progressive disease (PD) or unmanageable toxicity. Pts had confirmed HER2+ MBC (IHC3+ and/or FISH+), and prior therapy with T and a taxane. Primary end points were PFS by independent review, OS and safety. An interim OS analysis (efficacy boundary: HR= 0.617; p=0.0003) was planned at the time of the final PFS analysis. Results: 991 pts were enrolled; 978 received treatment. Median (med) durations of follow-up were 12.9 (T-DM1) and 12.4 (XL) months (mo). Baseline demographics, prior therapy and disease characteristics were balanced. There was a significant improvement in PFS favoring T-DM1 (med 9.6 vs 6.4 mo; HR=0.650 [95% CI, 0.549–0.771]; p

509 Background: With an incidence of 30%-40%, BM are common complications of HER2+ MBC. Their therapeutic management remains a challenge. As responses on central nervous system (CNS) localization have been reported with L+C combination after WBR, we sought to evaluate the clinical interest of this combination as 1st line treatment for BM in HER2+ MBC patients (pts) with the aim to avoid or to delay WBR. Methods: Eligible pts had HER2+ MBC with BM not previously treated with WBR, C or L. Pts received L1250 mg/day and C2000 mg/m2/day, days 1-14, every 21 days. The primary endpoint was a centrally assessed CNS objective response (CNS-OR) defined as a ≥50% volumetric reduction of CNS lesions in the absence of increasing steroid use, progressive neurologic symptoms, or progressive extra-CNS disease. Using a Simon’s optimal two-stage design with a minimum interesting CNS-OR rate of 20%, 41 evaluable patients were needed. Secondary endpoints included: time to progression (TTP) for both CNS and extra CNS disease;...

3017 Background: Mutations of Ras/Raf lead to a sustained and constitutive activation of ERK pathway. MEK1/2 is the only enzyme that activates ERK1/2; consequently MEK1/2 is a potential target to inhibit in cancers with an activated ERK pathway. RO4987655, a potent, highly selective ATP non-competitive MEK1i with an excellent selectivity profile, was tested in a 3+3 Ph1 study design. Objectives were determination of maximum tolerated dose (MTD), recommended Ph2 dose (RP2D), dose limiting toxicities (DLTs), safety/tolerability, PK/ PD and clinical activity. Methods: Patients (pts) with advanced/metastatic solid tumors received oral RO4987655 administered on a continuous daily dosing (QD) from 1-2.5 mg then twice daily (BID) from 3-21 mg total daily dose in 28 days (D) cycles. Blood PK samples were collected on cycle 1 (C1) [D 1, 8, 15 and 22]. Molecular target suppression was measured by pERKi in PBMC on C1 (D1, D15). Paired skin and tumor biopsies (optional) (baseline, C1D15) and sequential FDG-PET scans ...

544 Background: AMG 386 is an investigational peptide-Fc fusion protein that inhibits angiogenesis by neutralizing the interaction between the Tie2 receptor and angiopoietin-1 and -2. We assessed t...

TPS116 Background: Despite advances in the treatment of HER2 overexpressed MBC, nearly all patients develop progressive disease and innovative well-tolerated HER2-directed therapies are needed. T-DM1 is a unique antibody-drug conjugate that combines the antitumor activities of trastuzumab with intracellular delivery of the highly potent cytotoxic agent, DM1 (derivative of maytansine). In two phase II studies (TDM4258g; TDM4374g) single-agent T-DM1 3.6 mg/kg IV q3w showed substantial efficacy in patients with HER2-positive MBC who had received prior chemotherapy and ≥1 HER2-directed therapy for MBC (Burris JCO 2010; Krop ESMO 2010) providing strong rationale to assess T-DM1 in the phase III setting. In addition, comparable response rates and improved safety relative to trastuzumab and docetaxel were reported in a randomized phase II study of T-DM1 in first-line MBC (Perez ESMO 2010). Methods: EMILIA (TDM4370g, registry #NCT00829166) is an international, phase III study evaluating the safety and efficacy of...

LBA1011 Background: Recent trials support combining an antiangiogenic agent with chemotherapy (CT) in pretreated patients (pts) with metastatic BC (MBC). SU, an oral multitargeted tyrosine kinase inhibitor demonstrated single-agent activity (11% ORR) in heavily pretreated pts with MBC. Antitumor activity with SU+C was reported in pts with advanced solid tumors. This multicenter, randomized, phase III trial (SUN 1099) compared the efficacy and safety of SU + C vs. C in pts with ABC. Methods: Eligibility criteria were: age ≥18 yrs, ECOG PS ≤1, measurable HER2-positive (FISH+, CISH+ or IHC3+) or -negative ABC, no brain metastases, prior treatment (tx) with an anthracycline and taxane in the (neo)adjuvant or metastatic setting, and ≤2 prior CT regimens for advanced disease. Prior C tx was not permitted. Pts were randomized (1:1) to combination tx with C 2,000 mg/m2/d po days 1–14 every q3w + SU 37.5 mg/d po daily, or to C 2,500 mg/m2/d days 1–14 q3w. Pts with progressive disease per RECIST on the C arm were offered single-agent SU (37.5 mg/d). Endpoints included PFS (primary), ORR, OS, QoL, and safety. Stratified and unstratified log-rank tests compared PFS between arms. Results: At the data cutoff (December 15, 2009), the ITT population comprised 442 pts: 221 in each arm with baseline characteristics well balanced between arms. The trial did not meet its primary endpoint of prolonging PFS based on the independent radiologic assessment nor secondary endpoint of longer OS (final analysis March 10, 2010). Median PFS was 5.5 mos (95% CI 4.5–6.0) in the SU+C arm vs. 5.9 mos (95% CI 5.4–7.6) in the C arm (HR 1.224). Median OS was 16.4 mos (95% CI 13.6–18.4) for the SU+C arm and 16.5 mos (95% CI 14.2–18.6) for the C arm (HR 0.995). ORR was 18.6% for the SU+C arm and 16.3% for the C arm. The most common all causality grade 3/4 AEs (≥10%) were neutropenia (32%), hand–foot syndrome (HFS; 16%), thrombocytopenia (17%), asthenia (12%), fatigue (10%) in the SU+C arm and HFS (24%) and diarrhea (10%) in the C arm. Intended drug delivery for each arm was >80%. Discontinuations due to an AE were more frequent in the SU+C arm vs. the C arm. Discontinuations by drug in the SU+C arm: SU 39%, C 42%, SU and C 33%; in the C arm: 18%. Conclusions: Data from this randomized phase III trial do not support use of SU+C for therapy of patients with ABC. [Table: see text]

3023 Background: Ob is a tubulin binding vascular disrupting agent, derivative of combretastatin A4. In preclinical studies synergistic activity between Ob and D has been observed. Methods: Study objectives were to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic (PK) profile, preliminary antitumor activity, and to assess potential predictive biomarkers of the combination of Ob (day 1) followed by D (day 2) once every 3 weeks. Results: Forty-eight pts (M/F 17/31), median age 53 (range 28-71), were treated in 2 cohorts: D 75 mg/m2 with Ob 11.5, 15.5, 20, 25, 30, 35, or 42 mg/m2 and D 100 mg/m2 with Ob 30 or 35 mg/m2. Median number of cycles per pt was 3.5 (range 1-22). The most common tumor types were breast (n=18, including 6 triple negative pts) and oesophagus (n=9). First cohort MTD was 35/75 mg/m2 with 2 DLTs (grade 3 headache and asthenia) reported at 42/75 mg/m2. Second cohort MTD was 30/100 mg/m2 with grade 3 asthenia and deep vein thrombosis reported at 35/10...

1005 Background: E2100, AVADO, and RIBBON-1, three randomized trials in patients with MBC evaluating BV plus first-line chemotherapy regimens (taxane-, anthracycline-, or capecitabine-based), each demonstrated improvement in the primary endpoint of progression-free survival (PFS). Although the trials were not designed to show an overall survival (OS) benefit, it was a secondary endpoint in all trials. We present a meta-analysis of OS in 2,447 patients from these trials using complete survival data for each study. Methods: Kaplan—Meier methodology was used to estimate the median duration of PFS and OS. Stratified log-rank test was used to assess the difference in PFS and OS between treatment arms (control vs. BV+chemo). Stratified hazard ratio (HR) was estimated using the Cox regression model. Each individual study was included as a stratification factor in the stratified analysis. 1-year survival rate was compared using normal approximation method. All p-values were two-sided and tested at the type I erro...

651 Background: Concurrent radiotherapy (RT) and chemotherapy (CT), two effective treatments for breast cancers (BC), has seldom been reported in the preoperative setting. This phase II trial was d...

1012 Background: The HER2-targeted antibody-drug conjugate T-DM1 has shown encouraging efficacy and safety in patients (pts) with heavily pretreated HER2-positive (HER2+) BC. P is the first HER2-directed dimerization inhibitor for treatment of HER2+ BC. T-DM1 and P bind different subdomains of HER2. Combination of P with T or T-DM1 has shown synergistic antitumor activity in HER2+ xenograft models. Methods: This international, 3+3 design, single-arm, phase 1b/2 study investigated P (840 mg cycle 1,420 mg cycle 2 and beyond) with T- DM1 (3.0 mg/kg in cohort 1 and, in the absence of dose limiting toxicity [DLT], 3.6 mg/kg in cohort 2), in pts with HER2+ locally advanced or metastatic BC. This was followed by a 60 pt expansion into phase 2 at the established dose. Primary objectives included safety and preliminary responses per RECIST. Results: As of October 1, 2009, 37 pts had enrolled; 23 safety evaluable pts (9 in phase 1b and 14 in phase 2) received ≥1 cycle of T-DM1 and P (median of 2 cycles each, range...

1049 Background: While most patients with HER+ MBC respond to treatment with D+T, the majority ultimately develop and die from progressive MBC. L produces responses in patients with T-pretreated HE...

1005 Background: B in combination with weekly paclitaxel or docetaxel (D) as 1st-line therapy for MBC has improved progression-free survival (PFS) compared with the respective taxane alone in two large Phase III trials. This study investigated the addition of B to standard 1st-line chemotherapy regimens for MBC. Methods: Patients were randomized in 2:1 ratio to receive B + chemotherapy or placebo (pl) + chemotherapy. Prior to randomization, investigators chose capecitabine (Cap) (2000 mg/m2 x 14d), taxane (T) (nab-paclitaxel [260 mg/m2] or D [75 or 100 mg/m2], q3wk), or anthracycline (Ant)-based chemotherapy (q3wk). B or pl was administered at 15 mg/kg q3wk. Key eligibility criteria included MBC or locally-recurrent disease, no prior cytotoxic treatment, ECOG PS 0 or 1, HER2-negative disease and no CNS metastases. The primary endpoint was investigator-assessed PFS. Secondary endpoints included overall survival (OS), objective response rate (ORR), independent review of PFS, and safety. At progression, all patients were eligible for B with 2nd line chemotherapy. The Cap cohort and the pooled T or Ant (T + Ant) cohort were independently powered and analyzed in parallel using two-sided stratified log-rank test (Cap: 80% power to detect HR=0.75; T + Ant: 90% power to detect HR=0.7). Results: RIBBON-1 enrolled 1237 patients (Cap, 615; T, 307; Ant, 315) from 12/05 to 8/07 in 22 countries with a median follow-up of 15.6 months in the Cap cohort and 19.2 months in the T + Ant cohort. The results are summarized below. OS data are limited with only 33% of events. Safety was consistent with results of prior B trials. Conclusions: The addition of B to Cap, T; or Ant-based chemotherapy regimens used in 1st-line treatment of MBC resulted in statistically-significant improvement in PFS with a safety profile comparable to prior Phase III studies. [Table: see text] [Table: see text]

e14554 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor. Preclinical studies have shown synergistic antitumor activity with the combination of trastuzumab plus vinorelbine in metastatic breast cancer.The recommended dose of neratinib in monotherapy is 240 mg. In this phase 1 study, a combination dose of neratinib plus vinorelbine that is tolerable was determined in patients (pts) with solid tumors. Methods: This is an open-label, 2-part study of ascending multiple daily oral doses of neratinib (160 mg, 240 mg) in combination with 25 mg/m2 IV vinorelbine (administered on days 1, 8 every 3 wks). Tumor measurements were made every 6 wks by modified RECIST criteria. Results: 6 pts have been treated at each dose level. Data for 12 pts (5 pts still ongoing) as of 30 Oct 2008 are presented (median age [range] of 53.5 [38–75] yrs; 83% female). The median duration of treatment [range] was 1.9 [1.5–2.7] m. There was only 1 dose limiting toxicity (DLT) of grade 3 neuropathy (pt had preexisting grade 1 neuropathy) at 160 mg neratinib-25 mg/m2 vinorelbine, so the dose was escalated to 240 mg neratinib- 25 mg/m2 vinorelbine. In this cohort, there were no DLTs, and since the neratinib and vinorelbine doses reached full standard doses there was no need for further dose escalation. AEs, any causality, all grades in ≥ 15% of pts included diarrhea (92%), nausea (67%), constipation (50%), fatigue (42%), vomiting and anthralgia (33% each), abdominal pain and anorexia, (25% each), anemia and neutropenia (17% each). Grade ≥3 AEs that occurred in ≥1 pt included neutropenia (2 pts), pneumonia (1 pt) and peripheral neuropathy (2 pts). Preliminary efficacy data show that 1 pt with stomach cancer had stable disease, lasting ≥21 weeks. Conclusions: The combination of 240 mg neratinib and 25 mg/m2 vinorelbine was found to be tolerable and to demonstrate early evidence of clinical benefit in pts with solid tumors, to be assessed further in pts with metastatic ErbB-2+ breast cancer in part 2. [Table: see text]

1004 Background: Neratinib (HKI-272) is an orally administered irreversible pan-ErbB receptor tyrosine kinase inhibitor. In an ongoing phase II study, the preliminary objective response rate was 26% in patients with ErbB2+ advanced breast cancer with prior trastuzumab therapy. This study assessed the safety and preliminary efficacy of the combination of neratinib plus trastuzumab. Methods: Patients with advanced ErbB2+ breast cancer that progressed following trastuzumab therapy were enrolled. The primary endpoint was 16-week progression free survival rate (PFS). In part 1 (dose escalation), patients received neratinib 160 mg or 240 mg daily plus trastuzumab 4 mg/kg IV loading dose then 2 mg/kg weekly. In part 2, patients received weekly trastuzumab with neratinib 240 mg daily. Timed blood samples were collected for PK analyses. PK analysis is ongoing. Results: 45 patients (part 1 n = 8; part 2 n = 37) were enrolled (mean age 52 yr); 9 are active. In part 1, cohorts 1 and 2 were fully enrolled with 4 patients each. No dose limiting toxicities were observed. Most common AEs, any grade, were diarrhea (91%), nausea (51%), anorexia (40%), vomiting (38%), and asthenia (27%). Grade 3/4 AEs were diarrhea (13%), nausea (4%), vomiting (4%). Two patients receiving neratinib 240 mg reported AEs leading to withdrawal. No AEs of congestive heart failure and no significant drops of left ventricular ejection fraction were reported. Among 33 patients evaluable for efficacy, objective response rate was 27% (95% CI, 13% - 46%); 16-week PFS rate (for part 2) 47% (95% CI, 29% - 63%); median PFS was 19 weeks (95% CI 15 - 32 weeks). Conclusions: Neratinib plus trastuzumab was well tolerated with no significant or unexpected toxicities, and demonstrated clinical activity. [Table: see text]