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Introduction D-CARE, an international, phase 3, randomized, double-blind, placebo-controlled study in women with early-stage breast cancer at high risk of disease recurrence, failed to meet its primary endpoint—improvement in bone metastasis-free survival (BMFS) with adjuvant denosumab vs placebo injections. As a result of the limitations of assessing BMFS, which includes relapse in bone with and without extraskeletal recurrences and deaths from any cause, the prespecified exploratory bone endpoints’ analysis may provide a more clinically meaningful effect of denosumab in this disease setting. Methods The study enrolled women (aged ≥ 18 years) with histologically confirmed stage II/III breast cancer. Patients treated with adjuvant/neoadjuvant chemotherapy meeting inclusion criteria were randomly assigned 1:1 to receive either denosumab (120 mg) or placebo subcutaneously every 3–4 weeks for about 6 months and then every 3 months for a total treatment duration of 5 years. Five prespecified exploratory bone endpoints and post hoc subgroup analysis based on age (

Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is used for the extended adjuvant treatment of patients with early-stage HER2-positive (HER2+) breast cancer following adjuvant trastuzumab-based therapy and for patients with HER2+ metastatic breast cancer in the 3rd-line setting. Diarrhea, particularly in the first 1-2 months, is the main tolerability concern with neratinib and is common in the absence of proactive management. In the ExteNET trial, where no mandatory prophylaxis was used, the rate of grade 3 diarrhea was 40%, 34% of patients experienced at least 1 dose hold, and 17% of patients discontinued due to diarrhea. The CONTROL trial previously showed that pre-emptive antidiarrheal prophylaxis (loperamide alone or in combination with budesonide or colestipol) or dose escalation (DE) reduced the rate, severity, and duration of neratinib-associated grade ≥3 diarrhea compared with ExteNET. Currently, antidiarrheal prophylaxis is initiated with the first dose of neratinib and used during the first 2 cycles of treatment (US PI). Updated findings from two DE cohorts in CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase 2 study. Patients ≥18 years with stage I-IIIc HER2+ breast cancer were treated with neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts including 2 dose-escalation cohorts: DE1 (neratinib 120 mg/day on days 1-7, 160 mg/day on days 8-14, then 240 mg/day to day 365) + loperamide as needed (PRN); and DE2 (neratinib 160 mg/day on days 1-14, 200 mg/day on days 15-28, then 240 mg/day to day 365) + loperamide PRN. Adverse events were graded per NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: May 1, 2020. Results: Complete data for DE1 (60 patients) and interim data for the ongoing DE2 (60 patients) are presented. All patients in DE1 were off study and 40 (66.7%) of patients remained on treatment in the ongoing DE2. The median treatment duration for DE1 was 12.0 months (IQR 11.1-12.0) and for DE2 was 3.7 months (IQR 1.6-9.1). Overall, 48% and 57% of DE1 and DE2 patients, respectively, had prior pertuzumab; 0% and 3%, respectively, had prior T-DM1. The majority of patients in both DE1 and DE2 dose-escalated to 240 mg on planned schedule. The incidence of grade ≥3 diarrhea was 13.3% in DE1 and 20.0% in DE2. The median cumulative duration of grade ≥3 diarrhea over the entire 12-month treatment period was 3 days (range 1-6 days) for DE1 and 2 days (range 1-7 days) for DE2. In both DE1 and DE2, 7 patients (11.7%) had at least one dose hold while on study (none during escalation phase in DE1 and 4 during escalation phase in DE2). In both DE1 and DE2, 2 (3.3%) patients discontinued neratinib because of diarrhea (1 during escalation phase in each cohort). Updated data for the DE2 cohort will be presented. Conclusions: Adoption of neratinib DE reduced the incidence, severity, and duration of neratinib-associated diarrhea in CONTROL compared with ExteNET. DE1 was associated with low rates of dose holds and diarrhea-related discontinuations compared with all previously mandated prophylaxis strategies investigated in CONTROL and with ExteNET. Together these results show improved tolerability of neratinib with DE and suggest that DE combined with loperamide PRN may allow patients to stay on neratinib for the recommended period of time. Neratinib dose escalation scheme 1 (n=60)Neratinib dose escalation scheme 2 (n=60)On neratinib treatment, %066.7Median duration of treatment, months12.03.7Diarrhea, %Grade 140.041.7Grade 245.033.3Grade 313.320.0Grade 400Discontinuation rate due to diarrhea, %3.33.3At least one dose hold due to diarrhea, %11.711.7 Citation Format: Manuel Ruiz-Borrego, Arlene Chan, Gavin Marx, Adam Brufsky, A Jo Chien, Michael Thirlwell, Maureen Trudeau, Ron Bose, José A García-Sáenz, Daniel Egle, Daniel Hunt, Utpal Khambholja, Leanne McCulloch, Naisargee Shah, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Bringing diarrhea under CONTROL: Dose escalation reduces neratinib-associated diarrhea and improves tolerability in HER2-positive early-stage 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 PS13-20.

Background: Metastatic TNBC (mTNBC) has a poor prognosis. Preclinical data suggests benefit for combination therapy of immune checkpoint inhibitor and anti-angiogenesis. Olinvacimab (O) is a fully humanised monoclonal antibody (MAB) which binds to Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) and antiangiogenic and antitumor effects have been demonstrated. Pembrolizumab (P) is an anti-PD1 MAB. This study aimed to identify the safety and tolerability of O and P to establish a phase 2 recommended dose of O. Methods: From December 2018 to September 2020, we conducted a two-site, single arm, open-label study of O and P in pts with mTNBC. Eligible patients (pts) were >18 years, had ER, PR & HER2-negative MBC with at least one measurable lesion and adequate organ function. Pts with history of serious thromboembolism, gastrointestinal haemorrhage and prior anti-VEGF therapy were excluded. A modified Toxicity Probability Interval design was used. Pts received O 12 mg/kg q7d (dose level 1) or 16mg/kg day q7d (dose level 2) in combination with P 200mg flat dose day 1 q21d. Treatment continued until dose limiting toxicity (DLT), disease progression (PD) or treatment intolerance. Results: 11 pts, median age 62 (range 39-67) were recruited and received at least one dose of treatment. 8 (73%) had ECOG PS 1 and 3 (27%) had ECOG PS 2. 5 pts had previous chemotherapy for mTNBC (with 3 pts also having received immunotherapy), 6 pts were treated in the first-line metastatic setting (with all pts having received anthracycline and taxane in the adjuvant setting). 5 pts received O at 12mg/kg with P, completing a median of 6 cycles (range 1-18). As no DLTs were seen, 6 pts were treated with O at 16mg/kg with median of 8 cycles (range 2-21), with no DLTs being observed. Treatment was ceased due to PD in 6 pts, 3 pts are receiving treatment at data cut-off. Haemangiomas were seen in 8 pts accounting for 47 events of CTCAE grade 1 and 21 events of grade 2. Treatment emergent adverse events (TEAEs) of ≥grade 3 was seen in 6 pts (27 events), with 8 events being related to treatment. 4 pts (36%) had partial response (PR) as best overall response 5 pts (45%) had clinical benefit (PR+SD≥24weeks). Conclusions: Combination therapy of O and P was well tolerated with evidence of efficacy in mTNBC pts who had all previously received anthracycline and taxanes, with 3 pts having previously received immunotherapy. These results support the combination entering into a phase 2 study. Citation Format: Arlene Chan, Eugene Moylan, Sally Jackson, Jeannette Devoto, Nicola Jones, Silvie Radmil, Kate Wilkinson, Aflah Roohullah, Tamiem Adam, Seon Young Lee, Weon Sup Lee, Jin-San Yoo. Phase Ib trial of olinvacimab and pembrolizumab 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 PS10-18.

Summary Background Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. Methods PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II–III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1–21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). Findings Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9–29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2–90·6) for palbociclib plus endocrine therapy and 88·5% (85·8–90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76–1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3–4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. Interpretation At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. Funding Pfizer.

Purpose In the MONALEESA-3 Phase III trial of patients with hormone receptor–positive human epidermal growth factor receptor–negative advanced breast cancer, ribociclib plus fulvestrant significantly improved progression-free survival (PFS) and overall survival (OS). Here, we present patient-reported outcomes from the trial, including health-related quality of life (HRQOL). Methods Patients were randomized (2:1) to receive ribociclib plus fulvestrant or placebo plus fulvestrant. Time to definitive 10% deterioration (TTD) from baseline in HRQOL (global health status [GHS] from the EORTC QLQ-C30 questionnaire) and pain (BPI-SF questionnaire) were assessed using Kaplan-Meier estimates; a stratified Cox regression model was used to estimate the hazard ratio (HR) and 95% CIs. Results Deterioration ≥10% in the EORTC-QLQ-C30 GHS was observed in 33% of patients in the ribociclib group vs 34% of patients in the placebo (reference) group (HR for TTD ≥ 10% = 0.81 [95% CI, 0.62–1.1]). Similar findings were noted for TTD ≥5% (HR = 0.79 [95% CI, 0.61–1.0]) and TTD ≥15% (HR = 0.81 [95% CI, 0.60–1.08]). TTD ≥10% in emotional functioning (HR = 0.76 [95% CI, 0.57–1.01]) trended in favor of the ribociclib group, whereas results for fatigue and pain were similar between arms. TTD ≥10% in BPI-SF pain severity index score (HR = 0.77 [95% CI, 0.57–1.05]) and worst pain item score (HR = 0.81 [95% CI, 0.58–1.12]) trended in favor of ribociclib vs placebo. Conclusions In addition to significantly prolonging PFS and OS compared with placebo plus fulvestrant, adding ribociclib to fulvestrant maintains HRQOL., Highlights • Ribociclib + fulvestrant allowed maintenance of global health status (GHS). • Time to deterioration (TTD) by 10% can convey duration until worsening of QOL. • TTD ≥10% was delayed with ribociclib in GHS and emotional functioning. • Ribociclib also demonstrated trends toward delayed TTD vs placebo in pain outcomes.

Purpose:The primary objective was to evaluate intracranial objective response rate (iORR) in patients receiving abemaciclib with brain or leptomeningeal metastases (LM) secondary to hormone receptor–positive (HR+) metastatic breast cancer (MBC). Secondary objectives evaluated extracranial response, abemaciclib pharmacokinetics, brain metastases tissue exposure, and safety.Patients and Methods:This nonrandomized, phase II study (NCT02308020) enrolled patients in tumor subtype–specific cohorts A–D: A (HR+, HER2− MBC), B (HR+, HER2+ MBC), C (HR+ MBC LM), and D (brain metastases surgical resection). Abemaciclib 200 mg was administered twice daily as monotherapy or with endocrine therapy, or 150 mg twice daily with trastuzumab. Cohorts A and B used a Simon two-stage design.Results:In cohort A (n = 58), 3 patients were confirmed responders resulting in an iORR of 5.2% [95% confidence interval (CI), 0.0–10.9], and the intracranial clinical benefit rate (iCBR) was 24% (95% CI, 13.1–35.2). Median overall survival (OS) was 12.5 months (95% CI, 9.3–16.4). A volumetric decrease in target intracranial lesions was experienced by 38% of patients. In cohort B (n = 27), there were no confirmed intracranial responses. An iCBR of 11% (95% CI, 0.0–23.0) was observed. Median OS was 10.1 months (95% CI, 4.2–14.3). A volumetric decrease in target intracranial lesions was experienced by 22% of patients. In cohort C (n = 10), one confirmed complete parenchymal response was observed. In cohort D (n = 9), unbound brain metastases concentrations of total active abemaciclib analytes were 96- [cyclin-dependent kinase 4 (CDK4)] and 19-fold (CDK6) above in vitro IC50. Safety was consistent with prior studies.Conclusions:This study did not meet its primary endpoint. Abemaciclib was associated with an iCBR of 24% in patients with heavily pretreated HR+, HER2− MBC. Abemaciclib achieved therapeutic concentrations in brain metastases tissue, far exceeding those necessary for CDK4 and CDK6 inhibition. Further studies are warranted, including assessing novel abemaciclib-based combinations.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. CONTESSA TRIO investigates tesetaxel plus 3 different PD-(L)1 inhibitors in patients with TNBC and tesetaxel monotherapy in elderly patients with HER2- MBC. Trial design: CONTESSA TRIO is a 2-cohort, multinational, multicenter, Phase 2 study. In Cohort 1, 90 patients (with potential expansion to up to 150 patients) with metastatic TNBC who have not received prior chemotherapy for advanced disease will be randomized 1:1:1 to receive tesetaxel at 27 mg/m2 Q3W plus either: (1) nivolumab at 360 mg Q3W; (2) pembrolizumab at 200 mg Q3W; or (3) atezolizumab at 1,200 mg Q3W. Nivolumab and pembrolizumab (PD-1 inhibitors) and atezolizumab (a PD-L1 inhibitor) are approved for the treatment of multiple types of cancer; atezolizumab, in combination with nab-paclitaxel, was recently approved in the U.S. for the treatment of metastatic TNBC. The dual primary endpoints for Cohort 1 are ORR and progression-free survival (PFS). A sample size of 30 patients in each PD-(L)1 inhibitor treatment group has approximately 70% power to detect an ORR difference of 35% or greater between the treatment group with the highest ORR and the treatment group with the lowest ORR. An increase in the sample size to 50 patients in each treatment group will increase the power to approximately 85%. Secondary endpoints include duration of response (DoR) and overall survival (OS). Efficacy results for each of the 3 PD-(L)1 inhibitor combinations will be assessed for correlation with the results of each of the 3 approved PD-L1 diagnostic assays. CONTESSA TRIO is the first randomized clinical study to compare 3 approved PD-(L)1 inhibitors. In Cohort 2, 40 elderly patients (with potential expansion to up to 60 patients) with HER2- MBC who have not received prior chemotherapy for advanced disease will receive tesetaxel monotherapy at 27 mg/m2 Q3W. The primary endpoint for Cohort 2 is ORR. A sample size of 40 will allow the ORR to be estimated with a maximum standard error of < 8%. An increase in the sample size to 60 patients will decrease the maximum standard error to < 6.5%. Secondary endpoints include PFS, DoR and OS. Patients with CNS metastases are eligible for both cohorts. The Study was initiated in March 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03952325). Citation Format: Sara Tolaney, Joanne Blum, Igor Bondarenko, Arlene Chan, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Sung-Bae Kim, Mei-Ching Liu, Maria Eva Peréz Lopéz, Mafalda Oliveira, Samuel Guan Wei Ow, Michel Pavic, Hope Rugo, Lee Schwartzberg, Agostina Stradella, Stew Kroll, Joseph O'Connell, Thomas Wei, Elizabeth Mittendorf. CONTESSA TRIO: A multinational, multicenter, phase 2 study of tesetaxel plus 3 different PD-(L)1 inhibitors in patients with metastatic triple-negative breast cancer (TNBC) and tesetaxel monotherapy in elderly patients with 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 OT1-08-08.

Background: Neratinib (NERLYNX®), an irreversible pan-HER tyrosine kinase inhibitor, is used for the extended adjuvant treatment of patients with early-stage HER2-positive (HER2+) breast cancer following adjuvant trastuzumab-based therapy. Diarrhea is the main tolerability concern with neratinib and is common in the absence of proactive management. The CONTROL study (Clinicaltrials.gov: NCT02400476) is investigating the effectiveness of rationally structured antidiarrheal prophylaxis or neratinib dose escalation in the prevention of neratinib-associated diarrhea. CONTROL includes antidiarrheal prophylactic regimens with loperamide either alone or in combination with budesonide (locally acting corticosteroid) or colestipol (bile acid sequestrant), as well as two different neratinib dose-escalation schedules. Updated findings from CONTROL are reported. Methods: CONTROL is an international, multi-cohort, open-label, phase II study. Patients ≥18 years of age with stage I-IIIc HER2+ breast cancer were treated with oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Patients were enrolled sequentially into separate cohorts investigating: 1) mandatory loperamide prophylaxis; 2) budesonide + loperamide prophylaxis; 3) colestipol + loperamide prophylaxis; 4) colestipol + loperamide prn; 5) neratinib dose escalation + loperamide prn (two cohorts). Adverse events were graded according to NCI-CTCAE v4.0. Primary endpoint: incidence of grade ≥3 diarrhea. Data cut-off: 17 June 2019. Results: A total of 514 patients have been enrolled. At the cut-off date, study treatment had been completed by 100% of patients in all cohorts except for the two neratinib dose-escalation cohorts (the colestipol + loperamide prn cohort had just 1 patient continuing treatment as of the cut-off date). All preventive strategies reduced the incidence of grade 3 diarrhea (Table) compared with that seen in ExteNET (historical control: 39.9%). Median cumulative duration of grade 3 diarrhea across the study cohorts ranged from 2-5 days for the entire 12-month treatment period. The proportion of patients discontinuing neratinib because of diarrhea was decreased in all cohorts compared with ExteNET (16.8%), except for Cohort 1. The majority of adverse events (including diarrhea) leading to treatment discontinuation occurred early while on treatment, primarily during the first or second cycle. Table. Characteristics of treatment-emergent diarrheaLoperamide (n=137)Budesonide + loperamide (n=64)Colestipol + loperamide (n=136)Colestipol + loperamide prn (n=104)Neratinib dose escalation scheme 1 (n=60)Neratinib dose escalation scheme 2 (n=13)On neratinib treatment, %0001.0a85.084.6Diarrhea, %Grade 124.125.027.930.841.723.1Grade 224.832.834.632.738.346.2Grade 330.728.120.631.715.07.7Grade 4000000Median cumulative duration, days (range)Grade ≥25.0 (1-400)6.0 (1-117)4.0 (1-371)8.0 (1-375)5.0 (1-28)2.0 (1-6)Grade 33.0 (1-93)2.5 (1-6)3.5 (1-22)3.0 (1-55)2.0 (1-5)5.0 (5-5)Discontinuation (due to a diarrhea TEAE), %20.410.94.47.73.30Hospitalization (due to a diarrhea TEAE), %1.500000aAs of the data cut-off, the final patient in the colestipol + loperamide prn cohort had completed 1 year of neratinib treatment but had not yet had the final study visit. Conclusions: The addition of budesonide or colestipol to loperamide prophylaxis given for 1-2 cycles reduces the incidence, severity and duration of neratinib-associated diarrhea. These strategies reduce the rate of neratinib discontinuation due to diarrhea, allowing patients to receive the benefits of 1 year of extended adjuvant neratinib therapy. Early findings with escalating the dose of neratinib over the first 2-4 weeks of treatment are promising. Updated data for the two neratinib dose-escalation cohorts will be presented at the meeting. Citation Format: Arlene Chan, Sara A Hurvitz, Gavin Marx, Manuel Ruiz-Borrego, Cynthia Farrell, Daniel Hunt, Leanne McCulloch, A Jo Chien, Debu Tripathy, Carlos H Barcenas, the CONTROL Investigators. Effect of prophylaxis or neratinib dose escalation on neratinib-associated diarrhea and tolerability in patients with HER2-positive early-stage breast cancer: Phase II CONTROL trial [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 P5-14-03.

Background: Abemaciclib is an oral selective inhibitor of cyclin-dependent kinases 4 and 6 approved for hormone receptor (HR)+, human epidermal growth factor receptor 2 (HER2)- metastatic breast cancer. In the randomized, 3-arm, phase 2 study monarcHER (NCT02675231) for HR+, HER2+ advanced breast cancer (ABC), abemaciclib in combination with trastuzumab (T) and fulvestrant (F) significantly improved investigator-assessed progression-free survival (whereas abemaciclib + T did not) versus (vs) T + physician’s choice of chemotherapy and demonstrated a tolerable safety profile. Here, patient-reported HRQoL, functioning, and symptoms are reported. Methods: In monarcHER, 237 postmenopausal (surgical, natural, or chemical ovarian suppression) women with ABC and ≥2 prior HER2+ directed therapies in the advanced setting were randomized 1:1:1 to abemaciclib (150 mg PO Q12H every 21 days) + T (IV infusion on D1 every 21 days) with F (500 mg IM on Cycle 1 D1 and D15 and Cycle 2 D8, then Q4W; Arm A) or without F (Arm B) vs T + physician’s choice of chemotherapy (per label every 21 days; Arm C). Supportive measures to manage diarrhea were permitted. Patient-reported outcomes were measured at baseline and at each cycle using the modified Brief Pain Inventory-short form (mBPI-sf) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The EuroQol 5-Dimension 5 Level (EQ-5D 5L) questionnaire was also collected. Higher scores on EORTC QLQ-C30 functional and health status/QoL scales indicate improvement whereas higher scores on EORTC QLQ-C30 symptom scales and mBPI-sf indicate worsening of symptoms/pain. The EQ-5D 5L index score was calculated from a set of item weights to derive a score of 0-1, with 1 representing the best health status. Treatment arm comparisons of change from baseline (all post-baseline visits) were conducted using a mixed model repeated measure, with .05 considered statistically significant. Clinical meaningfulness was defined as a ≥10-point score change from baseline (on a 0-100 scale) for EORTC QLQ-C30 and a 2-point score change from baseline for mBPI-sf. Results: Patient-reported outcome compliance rates were ≥90% through Cycle 15; the range for median duration of each treatment component of each arm was 7.5-10.0 cycles. Overall, no statistically significant or clinically meaningful changes from baseline differences were observed between treatment arms for mBPI-sf pain scores or EORTC QLQ-C30 global health score, function scales, or for symptoms of fatigue, dyspnea, appetite loss, or financial difficulties. Least square (LS) mean change from baseline differences showed statistically significant improvements in Arm A vs C for EORTC QLQ-C30 symptoms of pain (-6.81; p=.026) and insomnia (-6.39; p=.041). Worsening for the symptom of nausea/vomiting was statistically significant but not clinically meaningful in Arm A vs C (4.08; p=.043). Diarrhea showed a statistically significant and clinically meaningful worsening in Arm A vs C (19.27; p Conclusions: Quality of life was maintained for patient-reported pain, global health, functioning, and most symptoms when abemaciclib was added to T + F compared with physician’s choice of chemotherapy in patients with HR+, HER2+ ABC. Gastrointestinal-related symptoms were transient and consistent with the manageable, reversible adverse event profile. Citation Format: Sara M Tolaney, Andrew M Wardley, Stefania Zambelli, John F. Hilton, Tiffany A Troso-Sandoval, Francesco Ricci, Seock-Ah Im, Sung-Bae Kim, Stephen RD Johnston, Arlene Chan, Shom Goel, Kristen Catron, Zhengyu Yang, M. Corona Gianford, Gregory L Price, Fabrice André. Health-related quality of life (HRQoL) in monarcHER: Abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in HR+, HER2+ advanced breast cancer [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 P3-11-10.

Background: Recently neoadjuvant chemotherapy (NACT) is regarded as a potential standard approach whenever chemotherapy is indicated in principle and is considered as the preferred treatment approach for stage II/III triple-negative and HER2-positive BC. However, there is an urgent need to develop a more sensitive and robust test that can assess the response for NACT and guide the optimum adjuvant therapy. Aim: Our aim is to identify molecular, radiological and histopathologic criteria that could grade response to NACT and to develop a robust prognostic index that accurately predict clinical outcome of the subsequent adjuvant therapy. Method: Comprehensive histopathological and radiological assessment of consecutive series of 850 BC [T2-4, N0-3, M0] have been centrally carried out at the Nottingham University Hospital (NUH). Furthermore, the immunohistochemistry expression of Ki67 and SPAG5 proliferation biomarkers and the histological evaluation of tumour infiltration lymphocytes (TILs) had been examined in all patients while both volumetric and texture changes detected by magnetic resonance imaging (MRI) were available for 400 cases. Oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) were assessed according to the most recent American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines. The results were validated in an external cohort of 250 cases. The patient’s characteristics and treatment options are the same between the centres: (68%) has received anthracycline plus Taxane (AC+T) NACT and 32% of patients have received NACT Anthracycline only (AC). Neoadjuvant HER2 targeting agents (Trastuzumab) or (Trastuzumab + Petruzumab) had been prescribed to 16% of patients in addition to AC+T followed by adjuvant Trastuzumab (total=18 cycles). All pre-NACT ER+ patients were given at least 5 year of adjuvant endocrine therapy. The primary end point was disease free survival (DFS). The median follow up was 72 months. Results: Using multivariate Cox proportional hazards models with backward stepwise exclusion for DFS, we found the presence of TILs [(HR (95% CI): 0.68 (0.48-0.94; P=0.022], high SPAG5 expression in post-surgical tumour tissue [(HR (95% CI): 2.58 (1.19-5.63), p=0.017)], the reduction in the primary tumour volume measured by MRI (>30%) [(HR(95% CI): 0.38 (0.16-0.89), p=0.026)], presence of Lymphovascular invasion [(HR(95% CI): 2.92 (1.33-6.40), p=0.008)], presence of chemotherapy induced fibrosis [(HR(95% CI): 0.41 (0.19-0.91), p=0.029)] and the high histological grade [(HR(95% CI): 2.62 (1.19-5.74), p=0.016)] showed statistical significant association with DFS. A prognostic index was calculated using the aforementioned factors after adjusting for both NACT and adjuvant therapy. The receiver-operating characteristic (ROC) curves indicated that this model is a good prognostic test [AUC = 0.854 (95% CI) = 0.777-.0.931; p= 0.00000001] and it outperformed residual cancer burden (RCB score) [AUC = 0. 711 (95% CI) = 0.612-.0.810; P= 0.0003]; and other NACT response grading systems including Miller-Payne system, Clinical-Pathologic Scoring System (CPS) and CPS-ER histological grade (CPS-EG) systems. Conclusion: A prognostic test with high sensitivity and specificity for assessing response to Neo-ACT has been developed and applying this test could guide the choice of the optimal adjuvant therapy. Citation Format: Tarek M. a. Abdel-Fatah, Xin Chen, Ruizhe Li, Elisabetta Giannotti, Dorothee Auer, Jennifer Walker, Jun Lim, A. Graham Pockley, Graham Ball, Emad Rakhah, Ian Ellis, Arlene Chan, Stephen Chan. Developing a robust multidimensional molecular, pathological and radiological prognostic index (MPRPI) to evaluate the response to neoadjuvant chemotherapy (NACT) and predict clinical outcome of breast cancer (BC) [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 P3-07-02.

Background Talimogene laherparepvec (T-VEC) is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and to produce granulocyte-macrophage colony-stimulating factor to enhance systemic antitumor immune responses. The safety and efficacy of T-VEC in treatment of advanced melanoma has been demonstrated as monotherapy and in combination with the checkpoint inhibitors (CPI) pembrolizumab and ipilimumab. Additionally, T-VEC monotherapy has demonstrated tolerable safety for intrahepatic injection (Hecht GICS 2018). Atezolizumab (atezo) is a humanized monoclonal antibody that promotes antitumor immunity by targeting programmed cell death ligand-1 (PD-L1) and is approved for metastatic triple negative breast cancer (mTNBC). We hypothesize that T-VEC in combination with a CPI may be effective in mTNBC and CRC in addition to melanoma. This phase 1b, multicenter study (clinicaltrials.gov identifier: NCT03256344) evaluates the safety of intrahepatic injection of T-VEC in combination with intravenous (IV) atezo in patients (pts) with mTNBC or colorectal cancer (CRC) with liver metastases (LMs). Here we report early safety data in the TNBC cohort. Methods Key eligibility criteria included age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG PS 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable LM suitable for injection. T-VEC (≤ 4mL) was injected by image-guided intralesional injection: 106 PFU/mL day 1, 108 PFU/mL every 21 days thereafter; atezo 1,200 mg IV was given on day 1 and every 21 days thereafter. The primary objective of this study is to evaluate incidence of dose limiting toxicity (DLT) for safety of T-VEC injection into LMs in combination with IV atezo, by tumor type. The DLT analysis set included DLT-evaluable pts who were on treatment for at least 6 weeks from the initial dose of study treatment and received at least 2 doses of T-VEC and 2 doses of atezo in combination or have a DLT during the DLT evaluation period. Key secondary objectives include objective response rate, durable response rate, progression-free survival, and overall survival of the combination therapy, by tumor type. Results Thirty-two pts were enrolled in two parallel cohorts (8 TNBC, 24 CRC). Of the 8 TNBC pts, 4 were evaluable for DLT at the time of this analysis. Of the 4 pts that were not DLT-evaluable, 1 never received study drug, 1 received atezo monotherapy, and 2 received intrahepatic T-VEC and IV atezo but stopped study drugs for unconfirmed progression before the DLT evaluation period was completed. No DLTs were reported in the TNBC cohort. In the 7 TNBC pts who received at least one dose of the study drug, the most common treatment-emergent adverse events (TEAEs) in terms of the subject incidence were pyrexia (71.4%), chills (42.9%), and rash (42.9%). In the 7 TNBC pts who received at least one dose of study drug, T-VEC related AEs in more than one pt were pyrexia (n=3) and chills (n=2). Atezo related AEs in more than one pt were pyrexia (n=5), chills and rash (n=3 each), and fatigue, arthralgia, pain, and pruritus (n=2 each). Study drug-related serious adverse events (SAEs) occurred in 3 (42.9%) pts, including Grade (G) 3 hypersensitivity related to atezo, G3 orthostatic hypotension related to T-VEC and atezo, and G1 pyrexia related to T-VEC and atezo. Procedure-related SAEs occurred in 1 (14.3%) pt, of G3 hepatic hematoma and G3 abdominal infection, but these were not related to the study drugs. One confirmed partial response in the TNBC cohort has been seen thus far. Conclusion T-VEC intrahepatic injection in combination with IV atezo at standard doses has thus far been demonstrated as feasible and tolerable with no DLTs observed in the TNBC cohort to date. Citation Format: Joel Randolph Hecht, Arlene Chan, Jean-Francois Baurain, Miguel Martin, Federico Longo-Munoz, Kevin Kalinsky, Steven Raman, Chunxu Liu, Edward Cha, Emily Chan. Preliminary safety data of intrahepatic talimogene laherparepvec and intravenous atezolizumab in patients with triple negative breast cancer [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 P3-09-19.

Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer.In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154.Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness.Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer.Amgen.

Purpose: This phase II study determined the efficacy of lacnotuzumab added to gemcitabine plus carboplatin (gem-carbo) in patients with advanced triple-negative breast cancer (TNBC). Patients and Methods: Female patients with advanced TNBC, with high levels of tumor-associated macrophages not amenable to curative treatment by surgery or radiotherapy were enrolled. Lacnotuzumab was dosed at 10 mg/kg every 3 weeks, ± a dose on cycle 1, day 8. Gemcitabine (1,000 mg/m2) and carboplatin (dose in mg calculated by area under the curve [mg/mL/min] × (glomerular filtration rate [mL/min] + 25 [mL/min]) were dosed every 3 weeks. Treatment continued until unacceptable toxicity, disease progression, or discontinuation by physician/patient. Results: Patients received lacnotuzumab + gem-carbo (n = 34) or gem-carbo (n = 15). Enrollment was halted due to recruitment challenges owing to rapid evolution of the therapeutic landscape; formal hypothesis testing of the primary endpoint was therefore not performed. Median progression-free survival was 5.6 months [90% confidence interval (CI), 4.47–8.64] in the lacnotuzumab + gem-carbo arm and 5.5 months (90% CI, 3.45–7.46) in the gem-carbo arm. Hematologic adverse events were common in both treatment arms; however, patients treated with lacnotuzumab experienced more frequent aspartate aminotransferase, alanine aminotransferase, and creatine kinase elevations. Pharmacokinetic results showed that free lacnotuzumab at 10 mg/kg exhibited a typical IgG pharmacokinetic profile and target engagement of circulating colony-stimulating factor 1 ligand. Conclusions: Despite successful target engagement and anticipated pharmacokinetic profile, lacnotuzumab + gem-carbo showed comparable antitumor activity to gem-carbo alone, with slightly poorer tolerability. However, the data presented in this article would be informative for future studies testing agents targeting the CSF1–CSF1 receptor pathway in TNBC.

Objectives The objective of this study was to evaluate patient compliance with management recommendations given by a breast cancer multidisciplinary team (MDT), assess for reasons for noncompliance, and perform an exploratory assessment on breast cancer outcomes in noncompliant patients. Materials and methods A retrospective analysis of prospectively collected data was undertaken for patients selected by their primary clinician to be discussed at the MDT of Breast Cancer Research Centre-WA in Perth between 1st March 2011 and the 28th February 2016. The primary objective was the rate of compliance with MDT management recommendations. Secondary objectives included factors associated with noncompliance, rate of clinical trial uptake, and impact of treatment noncompliance on breast cancer events in a subgroup of early breast cancer (EBC) patients. Results and conclusion A total of 2614 MDT management recommendations were made for 925 patients. Overall, 92% were compliant with all recommendations given. Clinical trial recruitment was successful in 84.1%. The reasons given for treatment noncompliance were fear of toxicity, choosing an alternative treatment, and treatment inconvenience. In a subset of 337 EBC patients, there was a significantly higher rate of contralateral breast cancer, distant recurrence, and breast cancer-specific death, P = .0016, in those who were noncompliant. Our study demonstrates a high rate of MDT treatment recommendation compliance and clinical trial recruitment. In a subgroup of EBC patients, noncompliance was associated with significantly worse outcomes. Attention to educating patients to minimize their fear of treatment toxicity and ensuring their understanding of evidence-based treatment may lead to lower rates of noncompliance.

Aim: To evaluate the efficacy and safety of neratinib as extended adjuvant therapy in patients from Asia based on exploratory analyses of the Phase III ExteNET trial. Patients & methods: A total of 2840 women with early stage HER2-positive breast cancer were randomly assigned to neratinib 240 mg/day or placebo for 1 year after trastuzumab-based adjuvant therapy. Results: A total of 341 patients were from Asia (neratinib, n = 165; placebo, n = 176). 2-year invasive disease-free survival rates were 92.8 and 90.8% with neratinib and placebo, respectively (HR: 0.70; 95% CI: 0.31–1.55), and 5-year rates were 91.9 and 87.2%, respectively (HR: 0.57; 95% CI: 0.27–1.13). Diarrhea was the most common adverse event with neratinib. Conclusion: Extended adjuvant therapy with neratinib reduces disease recurrences in Asian women with HER2-positive breast cancer. Trial registration: Clinicaltrials.gov NCT00878709.

Background: Neratinib is an irreversible pan-HER tyrosine kinase inhibitor that inhibits PI3K/Akt and MAPK signaling pathways after HER2 receptor activation. The ExteNET study showed that neratinib significantly improved 5-year invasive disease-free survival (iDFS) in women who completed trastuzumab-based adjuvant therapy for early breast cancer (EBC). We assessed the prognostic and predictive significance of PIK3CA alterations in patients in ExteNET. Methods: Participants were women aged ≥ 18 years (≥ 20 years in Japan) with stage 1–3c (modified to stage 2–3c in February 2010) operable breast cancer, who had completed (neo)adjuvant chemotherapy plus trastuzumab ≤ 2 years before randomization, with no evidence of disease recurrence or metastatic disease at study entry. Patients were randomized to oral neratinib 240 mg/day or placebo for 1 year. Formalin-fixed, paraffin-embedded primary tumor specimens underwent polymerase chain reaction (PCR) PIK3CA testing for two hotspot mutations in exon 9, one hot-spot mutation in exon 20, and fluorescence in situ hybridization (FISH) analysis for PIK3CA amplification. The primary endpoint (iDFS) was tested with log-rank test and hazard ratios (HRs) estimated using Cox proportional-hazards models. Results: Among the intent-to-treat population (n = 2840), tumor specimens were available for PCR testing (991 patients) and PIK3CA FISH (702 patients). Overall, 262 samples were PIK3CA altered: 201 were mutated (77%), 52 (20%) were amplified, and 9 (3%) were mutated and amplified. iDFS was non-significantly worse in placebo-treated patients with altered vs wild-type PIK3CA (HR 1.34; 95% CI 0.72–2.50; P = 0.357). Neratinib’s effect over placebo was significant in patients with PIK3CA-altered tumors (HR 0.41; 95% CI 0.17–0.90, P = 0.028) but not PIK3CA wild-type tumors (HR 0.72; 95% CI 0.36–1.41; P = 0.34). The interaction test was non-significant (P = 0.309). Conclusions: Although there was a greater absolute risk reduction associated with neratinib treatment of patients with PIK3CA-altered tumors in ExteNET, current data do not support PIK3CA alteration as a predictive biomarker of response to neratinib in HER2-positive EBC. Trial registration: ClinicalTrials.gov , NCT00878709 . Trial registered April 9, 2009.

Background: Previously we found that SPAG5 gene was amplified/gained in 20-35% of HER2+BC. Herein, we investigated the prognostic and predictive significance of SPAG5 (mRNA, protein) expression in 1726 HER+BC patients with median follow-up >5 years. Methods: Analysis of SPAG5 mRNA (cDNA array expression) and protein (immunohistochemistry) and their association with distant relapse risk (DRR) were determined in 446 and 642 cases of HER+2 early stage BC in which 36% and 40% of them had received adjuvant Herceptin (H) + Anthracycline based (AC) + Taxane (T); respectively. In 33% and 31% of SPAG5 mRNA cohort and 21% and 38% of SPAG5 protein cohort had received adjuvant (Adj) AC+T or chemotherapy (CT) naïve; respectively. The association between SPAG5 expression (mRNA, protein) and both pCR and DRR after receiving neoadjuvant chemotherapy (Neo-Adj-CT) were evaluated in 476 and 162 patients with HER2+ locally advanced BC; respectively. Neo-Adj AC+T+HER2 targeting (Herceptin, Herceptin+ Lapatinib or Lapatinib) and AC+/-T has been prescribed to 51% and 49% of mRNA cohort whereas the 45% and 55% of the protein expression cohort has received Neo-Adj AC+T+H and AC+/-T; respectively. Findings: In patients with SPAG5 mRNA overexpression (+;> median), those who had received AC+/-T Neo-Adj-CT alone achieved similar pCR to those who had received AC+T+HER2 targeting Neo-Adj (38% vs., 37%; OR (95% CI): 1.0 (0.6–1.6), p=0.923) in either ER- (46% vs., 52%; OR (95% CI): 1.3 (0.5–3.0), p=0.58) or ER+ subgroups (25% vs., 26%; OR (95% CI): 1.1 (0.4–3.4), p=0.88). Whereas in patients with low SPAG5 mRNA (-), those who had received AC+T+HER2 targeting Neo-Adj had achieved 2.5 fold increased in pCR compared to those who received AC+/-T alone (47% vs., 26%; OR (95% CI): 2.5 (1.4–4.4), p=0.001) in either ER- (60% vs., 31%; OR (95% CI): 3.4 (1.7–6.7), p Conclusion: SPAG5 expression could help in selecting patients who would benefit from both HER2-targeting agents and or AC-CT. Therefore patients with SPAG5- expression could avoid unnecessary AC-CT whereas those with SPAG5+ could receive a shorter Herceptin course. Citation Format: Abdel-Fatah TM, Ball GR, Ellis IO, Chan A, Chan SY. Sperm associated antigen 5 (SPAG5) predicts pathological complete response (pCR) and distant relapse risk to HER2 targeting agents and anthracycline based chemotherapy in HER2 positive (HER2+) breast cancer (BC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-11-08.

AIMS Male breast cancer is rare and treatment recommendations are based on female breast cancer guidelines. We analyzed an Australian dataset of patients with early breast cancer (including ductal carcinoma in situ, DCIS) for demographic, pathological and treatment information. The primary objective was to compare treatment delivery for males versus females. METHODS Australian data from the BreastSurgANZ Quality Audit (BQA) from 1 October 2006 and 30 September 2016 were analyzed. Demographic and pathological information was obtained and compared between males and females. Treatment recommendations were compared to BreastSurgANZ Key Performance Indicators (KPIs) and National Comprehensive Cancer Network (NCCN) guidelines to assess for adherence to national and international guidelines, respectively. RESULTS A total of 99,768 breast cancer episodes were analyzed, comprising 585 males (544 invasive; 41 DCIS) and 99 183 (99.4%) females (85 596 invasive; 13 525 DCIS; 62 unknown). Compared with females, males were older at diagnosis, more likely to be hormone receptor-positive and lymph node-positive disease, and more likely to have mastectomy. The proportion of males undergoing breast conserving surgery receiving radiotherapy was the only BreastSurgANZ KPI that was not met. Males were less likely to receive adjuvant chemotherapy than females using NCCN guidelines. CONCLUSION Australian males with breast cancer account for 0.6% of breast cancer incidence and have similar clinico-pathological features as reported internationally. Overall, there is good compliance with the surgical KPIs, and adherence to NCCN guidelines for adjuvant systemic treatment is similar to previous international studies.

Summary Background Patients with HER2-positive breast cancer who have received two or more previous therapies for advanced disease have few effective treatment options. The monarcHER trial aimed to compare the efficacy of abemaciclib plus trastuzumab with or without fulvestrant with standard-of-care chemotherapy of physician's choice plus trastuzumab in women with advanced breast cancer. Methods This phase 2, three-group, open-label trial was done across 75 hospitals, clinics, and medical centres in 14 countries. Eligible patients were women aged 18 years or older, who had hormone receptor-positive, HER2-positive advanced breast cancer with unresectable, locally advanced, recurrent or metastatic disease, Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received at least two HER2-targeted therapies for advanced disease. Patients were randomly assigned 1:1:1 to the abemaciclib, trastuzumab, and fulvestrant (group A), abemaciclib and trastuzumab (group B), or standard-of-care chemotherapy and trastuzumab (group C). Oral abemaciclib 150 mg 12 hourly was administered on days 1–21 of a 21-day cycle, intravenous trastuzumab 8 mg/kg on cycle 1 day 1, followed by 6 mg/kg on day 1 of each subsequent 21-day cycle, and intramuscular fulvestrant 500 mg on days 1, 15, and 29 and once every 4 weeks thereafter. Standard-of-care chemotherapy was administered as specified by the product label. Randomisation was by a computer-generated random sequence by means of an interactive web-response system and stratified by number of previous systemic therapies for advanced breast cancer and measurable versus non-measurable disease. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population, first testing group A versus group C and, if this result was significant, then group B versus group C. Safety was assessed in all patients who had received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov ( NCT02675231 ) and is ongoing for long-term survival follow-up. Findings Between May 31, 2016, and Feb 28, 2018, 325 patients were screened, of whom 237 eligible patients were enrolled and randomly assigned to groups A (n=79), B (n=79), and C (n=79). Median follow-up was 19·0 months (IQR 14·7–25·1). The study met its primary endpoint, showing a significant difference at the prespecified two-sided α of 0·2 in median progression-free survival between group A (8·3 months, 95% CI 5·9–12·6) and group C (5·7 months, 5·4–7·0; HR 0·67 [95% CI 0·45–1·00]; p=0·051). No difference was observed between median progression-free survival in group B (5·7 months, 95% CI 4·2–7·2) and group C (HR 0·94 [0·64–1·38]; p=0·77). The most common grade 3–4 treatment-emergent adverse event in groups A, B, and C was neutropenia (21 [27%] of 78 patients, 17 [22%] of 77, and 19 [26%] of 72). The most common serious adverse events were: in group A, pyrexia (three [4%]), diarrhoea (two [3%]), urinary tract infection (two [3%]), and acute kidney injury (two [3%]); in group B, diarrhoea (two [3%]) and pneumonitis (two [3%]); and in group C, neutropenia (four [6%]) and pleural effusion (two [3%]). Two deaths were attributed to treatment: one due to pulmonary fibrosis in group B and one due to febrile neutropenia in group C. Interpretation The combination of abemaciclib, fulvestrant, and trastuzumab significantly improved progression-free survival versus standard-of-care chemotherapy plus trastuzumab while showing a tolerable safety profile. Our results suggest that a chemotherapy-free regimen might potentially be an alternative treatment option for patients with hormone receptor-positive, HER2-positive advanced breast cancer. Funding Eli Lilly and Company.

We sought to uncover genetic drivers of hormone receptor–positive (HR+) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identified intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR+ breast cancer. FISH confirmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in three-dimensional culture, whereas expression in HR+ breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon ( Significance: By using a powerful clinical molecular diagnostic assay, we identified expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR+ breast cancer. The prevalence and biological and prognostic significance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities. Cancer Discov; 8(3); 336–53. ©2017 AACR. See related commentary by Natrajan et al., p. 272. See related article by Liu et al., p. 354. This article is highlighted in the In This Issue feature, p. 253

This randomized, open‐label, active‐controlled study investigated the safety and efficacy of three doses of Rolontis (eflapegrastim), a novel, long‐acting myeloid growth factor, versus pegfilgrastim in breast cancer patients being treated with docetaxel and cyclophosphamide (TC). The primary efficacy endpoint was duration of severe neutropenia (DSN) during the first cycle of treatment. Patients who were candidates for adjuvant/neoadjuvant TC chemotherapy were eligible for participation. TC was administered on Day 1, followed by 45, 135, or 270 μg/kg Rolontis or 6 mg pegfilgrastim on Day 2. Complete blood counts were monitored daily when the absolute neutrophil count (ANC) fell to

Breast cancer is the most common cancer affecting women in Australia, and second overall for all Australians. Molecular targets have been developed in the management of breast cancer to allow directed therapy. Complications such as nausea and vomiting can be common as well as less common such as osteonecrosis of the jaw (ONJ). While previously thought to be attributable only to bisphosphonate medications, there has been an increase in recognition of other medications that may also cause this complication. This case report demonstrates a first instance of osteonecrosis of the jaw attributable to pertuzumab and trastuzumab, indicated in the management of HER2-positive metastatic breast cancer, in a patient naive to ONJ-associated anti-resorptive medications. Following sequestrectomy, the patient had an uncomplicated postoperative healing 5 months following intervention. With increasing medications being used for a number of malignant conditions such as this, an awareness of less common complications such as ONJ among dental and medical specialties is highlighted in this case report.

536 Background: The primary tolerability concern with neratinib (NERLYNX®; N), an irreversible pan-HER tyrosine kinase inhibitor, is diarrhea. Data from the multi-cohort, open-label, phase 2 CONTROL trial [Barcenas et al. Ann Oncol 2020] demonstrated significant improvement in grade 3 diarrhea and diarrhea-related discontinuations vs the ExteNET trial, which did not mandate anti-diarrheal prophylaxis. We report a systematic analysis of tolerability in CONTROL and ExteNET. Methods: Patients (pts) ≥18y with stage I–IIIc HER2+ breast cancer received N (240 mg/d po for 1y) after trastuzumab-based adjuvant therapy and were enrolled sequentially into cohorts assessing different modalities to mitigate diarrhea. Cohorts with complete data were included: loperamide (L); L+budesonide (BL); L+colestipol (CL); CL as needed (CL-PRN); and N dose escalation (DE; 120 mg/d on d1–7, 160 mg/d on d8–14, and 240 mg/d thereafter). Integrated ranking (IR) analysis was performed on 13 endpoints in 4 domains (exposure, diarrhea, adverse events [AEs], quality of life [QoL]) identified with input from clinicians; cohorts were ranked from 1 (best) to 5 (worst). Index scores (IS) based on individual pt data from CONTROL were calculated as supportive analysis to confirm selection of the regimen with best overall tolerability, which was then compared with ExteNET. Results: Of the 5 CONTROL cohorts evaluated, DE ranked best for most endpoints. Average ranks per IR method: L 3.4; BL 3.2; CL 3.0; CL-PRN 3.3; DE 2.0. The IS analysis supported DE as the cohort with best overall tolerability. Comparison of CONTROL DE vs ExteNET showed improvement in tolerability in all domains (table). Conclusions: These analyses suggest superiority of weekly DE vs other anti-diarrheal strategies. A lower rate of grade 3 diarrhea was observed with CONTROL DE vs ExteNET (13.3 vs 39.9%, respectively), as well as a comparable or improved AE profile. The data also reveal greater compliance with N (fewer early discontinuations, longer treatment duration, higher cumulative dose) and reduced impact on QoL with DE, suggesting improved tolerability. Clinical trial information: NCT02400476. [Table: see text]

540 Background: Completion of planned treatment has been shown to improve clinical outcomes. In the ExteNET trial (NCT00878709), where diarrhea prophylaxis was not mandated, 17% of patients (pts) discontinued neratinib early due to diarrhea. This compares with 3.3% of pts from the CONTROL trial (NCT02400476) who used a neratinib dose-escalation strategy. Prior analyses have shown improved invasive disease-free survival (iDFS) in pts who completed planned duration of neratinib therapy in ExteNET (Table). Here we assess outcomes, including overall survival (OS), for pts who completed planned therapy in 3 groups from ExteNET: intent-to-treat (ITT) population; pts with hormone receptor-positive (HR+) disease who initiated neratinib within 1y after prior trastuzumab (HR+/≤1y, the population neratinib is approved for in the EU); and HR+/≤1y with residual disease post-neoadjuvant therapy (no pathologic complete response [pCR]). Methods: Pts with early-stage HER2+ breast cancer received oral neratinib 240 mg/d or placebo after trastuzumab-based (neo)adjuvant therapy. Pts who completed neratinib therapy (defined as ≥11m or cessation of neratinib if recurrence occurred prior to 11m) were compared with placebo (all randomized pts). iDFS and OS were analyzed using Kaplan-Meier methods; hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional-hazards models. Data cutoff: July 2019. Results: There were 2840 pts in the ITT population. The table shows iDFS and OS in the overall population and in pts who completed planned duration of neratinib therapy. Completion of planned neratinib was associated with improvements in iDFS and OS in all groups evaluated. Conclusions: These descriptive findings suggest that pts who receive the recommended duration of treatment of 1y with neratinib may have improved outcomes. Clinical trial information: NCT00878709. [Table: see text]

Background: Patients with ABC who present with visceral metastases have a worse outcome than patients with non-visceral disease, while patients with bone-only disease tend to have a better prognosis. Ribociclib (LEE011) is an oral, selective inhibitor of cyclin-dependent kinase (CDK) 4/6. In a Phase 3, placebo-controlled, randomized trial (MONALEESA-2; NCT01958021), first-line ribociclib (R) + letrozole (L) significantly prolonged progression-free survival (PFS) vs placebo (P) + L in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC, with a hazard ratio of 0.556 (95% confidence interval [CI]: 0.429–0.720; p=0.00000329) at the interim analysis cut-off date (Jan 29, 2016). Here, we present subgroup analyses in patients with visceral metastases, and those with bone-only disease. Methods: Postmenopausal women with HR+, HER2– ABC were randomized 1:1 to receive R (600 mg/day; 3-weeks-on/1-week-off) + L (2.5 mg/day; continuous) or P+L, stratified by the presence of liver and/or lung metastases. No prior CDK4/6 inhibitors or systemic therapy for ABC were allowed. Eligible patients had Eastern Cooperative Oncology Group performance status ≤1, baseline alanine/aspartate aminotransferase levels Results: Overall, 668 patients were randomized; 393 had visceral metastases and 147 had bone-only disease. Visceral metastasesBone-only disease n=393n=147 R+LP+LR+LP+L n=197n=196n=69n=78Median age, years (range)63 (23–91)63 (29–88)65 (37–85)63 (37–84)De novo metastatic disease, n (%)53 (27)55 (28)28 (41)24 (31)Non-de novo disease-free interval, n (%)≤24 months12 (6)15 (8)5 (7)6 (8)>24 months132 (67)126 (64)36 (52)48 (62)Discontinued treatment, n (%)83 (42)111 (57)29 (42)40 (51)Reason for discontinuation, n (%)Disease progression56 (28)93 (47)17 (25)31 (40)Patient/physician decision10 (5)15 (8)7 (10)6 (8)Adverse events16 (8)3 (2)4 (6)2 (3)Protocol deviation001 (1)1 (1)Death1 ( In patients with visceral metastases: Median PFS was not reached in the R+L arm (95% CI: 19.3–not estimable [NE]) vs 13.0 months (95% CI: 12.6 –16.5) in the P+L arm, with hazard ratio 0.535 (95% CI: 0.385–0.742). Median duration of exposure was 12.0 and 13.0 months (R and L, respectively) in the R+L arm, and 12.1 and 12.2 months (P and L, respectively) in the P+L arm. In patients with bone-only disease: Median PFS was not reached in the R+L arm (95% CI: NE–NE) vs 15.3 months (95% CI: 13.8–NE) in the P+L arm, with hazard ratio 0.690 (95% CI: 0.381–1.249). Median duration of exposure was 12.1 and 12.6 months (R and L, respectively) in the R+L arm, and 12.7 and 12.9 months (P and L, respectively) in the P+L arm. Conclusions: First-line R+L was well tolerated and significantly prolonged PFS vs P+L in postmenopausal women with HR+, HER2– ABC, both in patients with visceral metastases and those with bone-only disease. Keywords: Advanced breast cancer; CDK4/6 inhibitor; Letrozole; Ribociclib Citation Format: Burris HA, Chan A, Campone M, Blackwell KL, Winer EP, Janni W, Verma S, Burdaeva O, Alba E, Favret AM, Mondal S, Miller M, Germa C, Hirawat S, Yap YS. First-line ribociclib + letrozole in patients with HR+, HER2– advanced breast cancer (ABC) presenting with visceral metastases or bone-only disease: A subgroup analysis of the MONALEESA-2 trial [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-22-16.

Background Phosphatidylinositol 3-kinase (PI3K) pathway activation in preclinical models of breast cancer is associated with tumor growth and resistance to anticancer therapies, including paclitaxel. Effects of the pan-Class I PI3K inhibitor buparlisib (BKM120) appear synergistic with paclitaxel in preclinical and clinical models. Patients and methods BELLE-4 was a 1:1 randomized, double-blind, placebo-controlled, adaptive phase II/III study investigating the combination of buparlisib or placebo with paclitaxel in women with human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer with no prior chemotherapy for advanced disease. Patients were stratified by PI3K pathway activation and hormone receptor status. The primary endpoint was progression-free survival (PFS) in the full and PI3K pathway-activated populations. An adaptive interim analysis was planned following the phase II part of the study, after ≥125 PFS events had occurred in the full population, to decide whether the study would enter phase III (in the full or PI3K pathway-activated population) or be stopped for futility. Results As of August 2014, 416 patients were randomized to receive buparlisib (207) or placebo (209) with paclitaxel. At adaptive interim analysis, there was no improvement in PFS with buparlisib versus placebo in the full (median PFS 8.0 versus 9.2 months, hazard ratio [HR] 1.18), or PI3K pathway-activated population (median PFS 9.1 versus 9.2 months, HR 1.17). The study met protocol-specified criteria for futility in both populations, and phase III was not initiated. Median duration of study treatment exposure was 3.5 months in the buparlisib arm versus 4.6 months in the placebo arm. The most frequent adverse events with buparlisib plus paclitaxel (≥40% of patients) were diarrhea, alopecia, rash, nausea, and hyperglycemia. Conclusions Addition of buparlisib to paclitaxel did not improve PFS in the full or PI3K pathway-activated study population. Consequently, the trial was stopped for futility at the end of phase II.

Background: NACT is a standard option for BC (T2-4, N0-3, M0) and certain BC phenotypes. The choice of AT based on the pre-NACT biomarkers status may not be optimum for individual patient because dynamic phenotypic changes induced by NACT may alter the response to treatment. Aim: The aim of this study is to determine the incidence of changes in the receptor status (ER, PR and HER2) and other proliferation biomarkers (Ki67 and SPAG5) before and after NACT and to assess the clinical significance of such changes. Methods Immunohistochemistry staining of ER, PR, HER2, Ki67 and SPAG5 in pre and post NACT tumors tissues from a consecutive series of 850 of BC (T2-4, N0-3, M0) treated at the Nottingham University Hospital (NUH) from 2000 to 2018, have been centrally evaluated according to ASCO guidelines. All cases with conversion in HER2 status had also been retested by HER2-FISH. The results were validated in an external cohort of 250 cases. Treatment options and patients characteristics are the same between the centres: (68%) received anthracycline plus Taxane (AC+T) NACT and 32% of patients have received NACT Anthracycline only (AC). Neoadjuvant HER2 targeting agents (Trastuzumab) or (Trastuzumab + Petruzumab) had been prescribed to 16% of patients in addition to AC+T followed by adjuvant Trastuzumab (total=18 cycles). All pre-NACT ER+ patients were given at least 5 year of adjuvant endocrine therapy (ET). In 2013 NUH started a prospective audit of retesting of receptor status in all post NACT surgical tumour samples. The results of the tests were presented to the weekly tumour board meeting and any change in the receptor status (ER and HER2) from negative (in the pre NACT core biopsies) to positive (in the post NACT surgical specimen) being considered for additional AT (ET for ER+ and Trastuzumab for HER2+ cases).The primary end points for this study are the % changes of biomarker changes and the disease free survival (DFS). The median follow up was 72 months. Results In pre NACT core biopsies 32% and 68% were HER2+ and HER2-; respectively. Twelve percent (12%) of the pre NACT HER2- tumours had a conversion to HER2+ in the post NACT surgical specimens. In this group of patients who subsequently received adjuvant Trastuzumab, 95% 3-year DFS was reported; which was similar to those patients who achieved pCR (3-year DFS; 90%) and was superior to cases which remained HER- in post NACT specimens (3-year DFS; 41%); (p Citation Format: Tarek M. a. Abdel-Fatah, Rebekah Webb, Jennifer Walker, Jun Lim, A. Graham Pockley, Graham Ball, Matthew Griffiths, Ian Ellis, Emad Rakhah, Zsolt Hodi, Andrew Lee, Arlene Chan, Stephen Chan. Clinically significant changes of receptors status (ER, PR and HER2) after receiving neoadjuvant chemotherapy (NACT) in breast cancer (BC) predicts the prognosis and guides the choice of the optimal adjuvant therapy (AT): Retesting of the receptor status should be mandatory [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 P5-06-06.

Background. Although long considered a tumor suppressor gene, PML (promyelocytic leukemia) also plays tumor-promoting functions in specific contexts. In vitro and in vivo studies have demonstrated that PML is upregulated by HIF-1α transcriptional activation in triple-negative breast cancer (TNBC) cells and it is implicated in promoting metastasis downstream of HIF-1α. This pro-metastatic function of PML is inhibited by arsenic trioxide, a pharmacological compound currently in use in acute promyelocytic leukemia. However, the clinical relevance of PML expression in BC has not been extensively investigated. In this study, we evaluated the association of PML expression with clinic-pathological factors and outcome (pathological complete response -pCR- and risk of recurrence) in the ETNA trial, and risk of recurrence in the TCGA. Methods. In the ETNA study (NCT01822314) 695 patients with HER2-negative breast cancer (BC) were randomized to receive neoadjuvant paclitaxel or nab-paclitaxel followed by 4 cycles of an anthracycline regimen. In the ITT study population, the two treatments did not show significantly different rates of pCR nor different Event-Free Survival (EFS) (Gianni JAMA Oncol 2018, Gianni ASCO 2019). A central histologic assessment of ER, PgR, HER2 status and Ki67 was mandatory. We evaluated PML expression by immunohistochemistry using the continuous histoscore (H-score) on pre-treatment core biopsies. The H-score is generated from the estimation of the percentage of cells with no (0), light (1+), moderate (2+) and strong (3+) intensity staining, and the corresponding score is generated with the following algorithm: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)]. We evaluated the association of PML with clinic-pathological features and clinical outcomes (pCR and EFS) in triple negative (TN) and in LuminalB-like (ER+ and/or PgR+, Ki67≥14%) groups. We also investigated the association between PML mRNA expression (RNA-seq) and DFS in HER2-negative BC (TN, n=192; ER+/HER2-, n=702) in the TCGA dataset. Results. In the ETNA study, PML was successfully assessed and valuable in 491 pts (70.6%). The average PML expression was 126.3 (median 120, range 0-295). In the ETNA trial, TNBC showed the highest expression of PML (p20%, LumB-high) (p=0.0005). However, within the LumB-high group, higher proliferation (Ki67>40%) showed a higher expression of PML (p=0.025), suggesting a non-linear relationship between PML and proliferation in luminal tumors. In LumB-high, PML was higher in PgR-negative tumors (p=1.0E-5). Finally, PML showed a positive association with higher stromal tumor-infiltrating lymphocytes (sTILs) both in LumB-like and TN group (p=0.019 and p=0.001, respectively). PML expression was not significantly associated with pCR and risk of recurrence in LumB-like nor in TN BC.In the TCGA dataset also PML expression was highest in the TN group (p Citation Format: Stefania Zambelli, Chanel Smart, Giampaolo Bianchini, Isabella Sassi, Mauro Mansutti, Antonio Anton, Lourdes Calvo, Giancarlo Bisagni, Begona Bermejo, Martina Uggè, Barbara Galbardi, Vladimir Semiglazov, Marc Thill, Jose Ignacio Chacon, Arlene Chan, Serafin Morales Murillo, Isabel Alvarez, Ainhara Lahuerta, Patrizia Zucchinelli, Claudio Doglioni, Pinuccia Valagussa, Ignasi Tusquets, Luca Gianni, Rosa Bernardi. Prognostic and predictive value of PML in the ETNA study and the TCGA [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 P5-06-21.

OBJECTIVE Breast cancer (BC) accounts for 24% of female cancers, with approximately one quarter of women likely to have offspring aged less than 25 years. Recent publications demonstrate negative psychosocial well-being in these offspring. We prospectively assessed for psychological distress and unmet needs in offspring of BC patients. METHODS Eligible offspring aged 14 to 24 years were consented and completed the Kessler-10 Questionnaire and Offspring Cancer Needs Instrument. Demographic and BC details were obtained. RESULTS Over a 7-month period, 120 offspring from 74 BC patients were included. Fifty-nine mothers had nonmetastatic BC (nMBC), and 27 had metastatic BC (MBC) with median time from diagnosis of 27.6 and 36.1 months, respectively. The prevalence of high/very high distress was 31%, with significantly higher scores reported by female offspring (P = .017). Unmet needs were reported by more than 50% of offspring with the majority of needs relating to information about their mother's cancer. Greater unmet needs were seen in female offspring and offspring with none or one sibling for several domains (practical assistance, time-out, dealing with feelings, and support from friends; P < .05). Greater unmet needs were seen in regard to feelings for MBC patients' offspring compared with nMBC but were similar for other unmet needs. CONCLUSIONS Our study confirms high levels of psychological distress in offspring of BC patients, with female offspring reporting significantly higher emotional distress and unmet needs. More than 50% of respondents reported unmet needs in areas that can potentially be supported, including greater information provision, improving practical issues, and enabling sufficient recreational time.

Background Endocrine therapy (ET) targeting ER signaling is the mainstay of care for ER+ metastatic BC. There remains an unmet need in patients whose tumors become resistant to currently available ET. Selective ER degraders (SERDs) were developed to overcome resistance to existing ER-directed therapies by both competitively antagonizing and degrading ERs, while exploiting continued dependence of the tumor on ER signaling. SAR439859 is a potent SERD with robust preclinical ER degrading activity. In AMEERA-1, a Phase 1 dose escalation trial, SAR439859, had a favorable safety profile with no dose-limiting toxicities across all doses (20-600 mg once per day; QD). ER occupancy generally exceeded > 87% with plasma concentrations > 100 ng/mL. Overall response rate was 6.3% and the recommended Phase 2 monotherapy dose was 400 mg QD. Methods AMEERA-3 is an international, prospective, open-label, randomized Phase 2 study (NCT04059484; ACT16105) designed to assess safety and efficacy of SAR439859 in pts with ER+ (>1%)/HER2− metastatic or locally advanced BC progressing on ≥ 6 months of continuous ET (0-2 lines in the metastatic setting). Prior cyclin-dependent kinase (CDK) inhibitors are allowed. Exclusion criteria include: Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2, life expectancy < 3 months, > 1 chemotherapy or targeted therapy in the metastatic setting, concomitant illness and factors potentially affecting SAR439859 absorption. Patients are randomized 1:1 to SAR439859 400 mg QD orally or physician’s choice of endocrine monotherapy (fulvestrant, tamoxifen, aromatase inhibitor). Patients receive 28-day cycles until unacceptable toxicity, progression, death, investigator decision, or patient request. Stratification factors include visceral metastases, prior CDK4/6 inhibitors, and ECOG PS. The primary endpoint is progression-free survival (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints include overall survival, response rate, duration of response, clinical benefit, pharmacokinetics, quality of life and safety. Target enrollment: n = 282; current enrollment: n = 9. Funding: Sanofi. © 2020 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2020 ASCO Annual Meeting. All rights reserved. Citation Format: Sara Tolaney, Irfan Cicin, Rafael Betancourt, Arlene Chan, Diego Kaen, Peter Kaufman, Suzette Delaloge, Qianying Liu, Sylvaine Cartot-Cotton, Amele Amrate, Vasiliki Pelekanou, Katharine Cuff. AMEERA-3, a phase 2 trial of SAR439859 vs endocrine monotherapy in pre- and post-menopausal, estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (her2−), locally advanced or metastatic breast cancer (BC) with prior exposure to hormonal therapies [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 OT-09-09.

Background: Neratinib (NERLYNX®) is an irreversible pan-HER inhibitor that significantly improves invasive disease-free survival (iDFS) compared with placebo when given as extended adjuvant therapy in patients with HER2-positive (HER2+) early breast cancer after trastuzumab-based adjuvant therapy. In the phase 3 ExteNET trial, an absolute iDFS benefit of 2.5% and distant disease-free survival (DDFS) benefit of 1.7% were observed with neratinib after 5 years’ follow-up. As reflected in the approved indication by the European Medicines Agency (EMA), patients with hormone receptor-positive (HR+) disease who initiated neratinib treatment within 1 year of completing trastuzumab (HR+/≤1 year) experienced an absolute iDFS benefit of 5.1% and DDFS benefit of 4.7% at 5 years. In HR+/≤1 year patients with residual disease after neoadjuvant therapy, absolute 5-year iDFS and DDFS benefits of 7.4% and 7.0%, respectively, were observed. Here we report the final protocol-defined, event-driven analysis of overall survival (OS) from ExteNET, and provide descriptive analyses of subgroups of primary interest according to the EU label and current clinical practice in early-stage HER2+ disease. Methods: ExteNET was a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of women with early-stage HER2+ breast cancer who had completed neoadjuvant or adjuvant trastuzumab plus chemotherapy (NCT00878709). Patients were randomly assigned to oral neratinib 240 mg/day or placebo for 1 year. Hazard ratios (HR) for OS were estimated from Cox proportional hazards models, and survival rates by the Kaplan-Meier method. The OS analysis was event-driven and powered for the intention-to-treat (ITT) population with a target of 248 events. Descriptive analyses were performed in the HR+/≤1 year subgroup per the approved indication in the EU, and in higher-risk patients, i.e. HR+/≤1 year who have residual disease after neoadjuvant therapy [i.e. those who did not achieve a pathologic complete response (pCR)]. Cut-off date: July 2019. Results: 2840 patients were randomized to study treatment (1420 per group). After a median follow-up of 8.1 years, 127 (8.9%) and 137 (9.6%) patients in the neratinib and placebo ITT groups had died, respectively. The 8-year OS rates were 90.1% (95% CI, 88.3–91.6) in the neratinib group and 90.2% (95% CI, 88.4–91.7) in the placebo group (absolute difference at 8 years -0.1%; stratified HR=0.95; 95% CI, 0.75–1.21; p=0.6914). A positive trend was seen in the prespecified HR+ subgroup (n=1631; absolute difference at 8 years 1.5%; HR=0.80; 95% CI, 0.58–1.12), and within this population, descriptive analyses suggested greater benefits with neratinib in the HR+/≤1 year subgroup (n=1334; absolute difference at 8 years 2.1%; HR=0.79; 95% CI, 0.55–1.13) and in the HR+/≤1 year subset with no pCR after neoadjuvant therapy (n=295; absolute difference at 8 years 9.1%; HR=0.47; 95% CI, 0.23–0.92). No new safety signals were reported with this long-term follow-up to 8 years. Conclusions: In this final OS analysis of ExteNET, there were fewer deaths with neratinib than placebo in the ITT population, but the results did not reach statistical significance. Analyses showed greater OS improvements with neratinib in subgroups including HR+/≤1 year, and HR+/≤1 year with residual disease after neoadjuvant therapy. These findings are consistent with the results based on the primary endpoint of iDFS, and support the use of neratinib in clinical practice in these patients. Citation Format: Frankie Ann Holmes, Beverly Moy, Suzette Delaloge, Stephen Chia, Bent Ejlertsen, Janine Mansi, Hiroji Iwata, Michael Gnant, Mark Buyse, Carlos Barrios, Tajana Silovski, Robert Separovic, Anna Bashford, Angel Guerrero-Zotano, Neelima Denduluri, Debra Patt, Erhan Gokmen, Ira Gore, John Smith, Richard Bryce, Feng Xu, Alvin Wong, Miguel Martin, Arlene Chan. Continued efficacy of neratinib in patients with HER2-positive early-stage breast cancer: Final overall survival analysis from the randomized phase 3 ExteNET trial [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 PD3-03.

Background. We investigated the association between TILs assessed by different metrics and clinical outcome (pathological complete response -pCR- and risk of recurrence) in the ETNA trial. Methods. In the ETNA study (NCT01822314) 695 patients with HER2-negative breast cancer (BC) were randomized to receive neoadjuvant paclitaxel or nab-paclitaxel followed by 4 cycles of an anthracycline regimen. In the ITT study population, the two treatments did not show significantly different rates of pCR nor different Event-Free Survival (EFS) (Gianni JAMA Oncol 2018, Gianni ASCO 2019). We measured TILs by optical evaluation on pre-treatment core biopsies using three different metrics: stromal and intratumoral TILs (sTILs, iTILs), and hotspot TILs (hTILs)ie. the field of highest TILs density, in order to capture some of the spatial heterogeneity of TILs reported as more informative in ER+ BCs (Heindl JNCI 2018). We then investigated the association of TILs with pCR and EFS separately in TN and in LuminalB-like (ER+ and/or PgR+, Ki67≥14%) groups, as well as possible treatment-biomarker interactions. Results. TILs could be assessed in 589 pts (85%). The three TILs metrics were significantly correlated (p20%, n=126) TILs. In the low hTILs group, abraxane was significantly more effective than paclitaxel (HR 0.64 [0.26-0.89], p=0.02). In the high hTILs group, paclitaxel was associated with better long-term outcome (HR 3.79 [1.33-10.8], p=0.01). If the same cut-off was applied in TN BC, abraxane had a numerical trend for superiority compared to paclitaxel in the low hTILs tumors (HR 0.64 [0.34-1.20]). No differences were observed in the high TIL group. Conclusions. Pre-treatment assessment of TILs in the ETNA trial was predictive of the likelihood of pCR regardless of the tumor subtype, and was prognostic in the TN subgroup. The assessment of hotspot TILs seems to be more informative than average stromal TILs in LumB-like tumors. Finally, different levels of hTILs at baseline were associated with different benefit from abraxane compared to paclitaxel. This finding warrants independent confirmation, and the mechanism for the association is being investigated. Supported in part by an unrestricted grant from Celgene Sarl, Swizerland Citation Format: Giampaolo Bianchini, Chanel Smart, Mauro Mansutti, Antonio Anton, Luca Licata, Isabella Sassi, Lourdes Calvo, Giancarlo Bisagni, Begona Bermejo, Vladimir Semiglazov, Marc Thill, Jose Ignacio Chacon, Arlene Chan, Serafin Morales Murillo, Isabel Alvarez, Ainhara Lahuerta, Patrizia Zucchinelli, Claudio Doglioni, Giuseppe Viale, Pinuccia Valagussa, Ignasi Tusquet, Luca Gianni. Clinical implication of tumor infiltrating lymphocytes (TILs) in the ETNA study [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 PD5-05.

Introduction Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. Patients and Methods A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. Results Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). Conclusion The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Aim: To evaluate the efficacy and tolerability of lapatinib (L) and intravenous vinorelbine (V) in patients with metastatic HER2-positive breast cancer who have previously received two lines of anti-HER2 therapy (i.e. trastuzumab [T] with chemotherapy and lapatinib with capecitabine [LC]). Method: Consenting patients with measurable or evaluable disease and normal cardiac function who had progressed were recruited. Patients received LV (lapatinib 1250mg orally daily, vinorelbine 20mg/m intravenously on days 1 and 8 every 3 weeks) until progressive disease, intolerable toxicity or patient request. Results: The trial was closed early following inclusion of 19 patients due to slow accrual. Ten, five and four patients had received two, three andmore thanfour lines of chemotherapy with T and LC, respectively, prior to study entry. Patients received a median of 5 cycles (range 1-18) of LV. Confirmed partial response was seen in 2 of 16 patients with measurable disease (12.5%); stable disease>24 weeks was seen in two patients (10.5%) with a clinical benefit rate of 20%. Fatigue and any grade neutropenia occurred commonly, but grade 4 severity occurred in only 5 and 11%, respectively. There were no episodes of cardiac dysfunction and no treatment-related deaths. The median progression-free survival was 3.9 months and overall survival (OS) was 9.1 months. Conclusion: The combination of LV demonstrated modest efficacy but was well tolerated. This combination may be of benefit to those patients who are unable to access the newer anti-HER2 agents and the low rate of treatment-emergent adverse effects will enable patients' symptoms, such as pain, to be minimized.

590 Background: We hereby evaluated the histopathological and radiological alterations of tumor characteristics after receiving NACT and the clinical significance of the changes of adjuvant therapy based on these findings. Methods: A pathological assessment of tumor features including ER, PR, HER2 and proliferation markers (Ki67 and SPAG5) status in pre and post NACT tumors tissue have been centrally evaluated in two cohorts [Nottingham University Hospital (NUH; n=850) and Australian cohort (n=250 patients)]. Since 2013 any change in the ER and HER2 status from negative (-) [in the pre NACT biopsies] to positive (+) [in the post NACT surgical specimens] received additional adjuvant therapy (Endocrine therapy (ET) for ER+ and Trastuzumab for HER2+ cases) in NUH. MRI volumetric and texture changes have been assessed in 400 cases. The primary end point was disease free survival (DFS; median follow-up = 62 months). Results: 10% of pre NACT HER2- cases had been converted to post NACT HER2+ and those cases who subsequently received adjuvant Trastuzumab had achieved 92% 5-year DFS compared to those who remained HER- in post NACT specimens (58% 5-year DFS); (HR (95% CI)= 0.25 (0.08-0.80); p=0.016). While 13% of pre NACT HER2+ tumors were converted into HER2- in post NACT surgical specimens and had similar 5-year DFS to those who remained post NACT HER2+ (5-year DFS= 94% vs., 87%; p=0.613). Loss of PR in the residual disease of pre NACT ER+ BC was associated with shorter 5-year DFS after ET compared to those who remained post NACT PR+ (HR (95% CI)=2.1 (1.25-3.46); p=0.005). After NACT, 40% of pre NACT SPAG5+ cases were converted into post NACT SPAG5- and these patients had prolonged DFS compared to those who remained SPAG5+ in post NACT specimens (27%) [5-year DFS=84% vs 49%; (HR (95% CI)= 3.8 (2.1-6.9); p

515 Background: The ETNA study showed that substituting P with nab-P did not significantly increase the overall rate of pathological complete response (pCR) (P 18.6%, nab-P 22.5%, p = 0.19). The multivariate analysis revealed that tumor subtype (triple negative vs luminal B-like) was the most significant factor (OR 4.85) influencing treatment outcome (Gianni L et al, JAMA Oncol 2018). Methods: This multicenter open label study (NCT01822314) in collaboration with GEICAM and BCRC-WA randomized 695 patients with centrally-confirmed HER2-negative breast cancer to nab-P 125 mg/m2 (346 patients) or P 90 mg/m2 (349 patients). The two drugs were given on weeks 1, 2 and 3 followed by 1-week rest for 4 cycles before 4 cycles of an anthracycline regimen as per investigator choice. The primary endpoint was pCR (absence of invasive cells in breast and nodes). A secondary endpoint is event-free survival (EFS) defined as the time from randomization to the first date of disease progression while on primary therapy or disease recurrence (local, regional, distant, invasive contralateral breast cancer) after surgery or death due to any cause. Results: The ITT analysis of the secondary endpoint EFS at 5 years is reported below: Clinical trial information: NCT01822314. Overall 5-year survival was 84.8% after P and 87.3% for nab-P. No serious adverse events were documented during the follow-up. Conclusions: The improved 5-year EFS after nab-P failed to reach statistical significance (unadjusted P = 0.245). In the analysis by subgroup the numerical improvement was almost exclusively observed in luminal B and not in TN tumors. So far the data do not support substitution of P with nab-P in the schedule and doses adopted in the ETNA trial. Additional analyses will be based on ongoing molecular studies.[Table: see text]

548 Background: CONTROL (clinicaltrials.gov: NCT02400476) is an open-label, sequential-cohort, phase II study investigating the effectiveness of prophylaxis or dose escalation in preventing diarrhea and improving tolerability of neratinib, an irreversible pan-HER tyrosine kinase inhibitor. Neratinib has demonstrated benefit as an extended adjuvant therapy for early-stage HER2+ breast cancer. Various prophylactic agents are being studied in adult patients treated with oral neratinib (240 mg/day for 1 year) after trastuzumab-based adjuvant therapy. Methods: Patients (n = 485) were enrolled into cohorts investigating antidiarrheal prophylaxis for 1–2 cycles (28 days) with the following agents: loperamide (n = 137); loperamide + budesonide (n = 64); loperamide + colestipol (n = 136); loperamide prn + colestipol (n = 104). An additional cohort assessing loperamide prn + neratinib dose escalation with no mandatory prophylaxis (n = 44) is ongoing. Adverse events were graded according to NCI-CTCAE v4.0. The primary endpoint was incidence of grade ≥3 diarrhea. Data cut-off: 14 Jan 2019. Results: As shown in the table, all prophylactic regimens reduce the incidence of Grade 3 diarrhea and drug discontinuation compared with the prior ExteNET trial [Martin et al. 2017]. The median cumulative duration of Grade 3 or higher diarrhea spanned from 2.0 to 3.5 days across regimens for the entire treatment period. No Grade 4 diarrhea was reported. Conclusions: The addition of budesonide or colestipol to loperamide prophylaxis given for 1–2 cycles reduces the severity and duration of diarrhea in patients treated with neratinib, thereby improving tolerability. Updated data for the dose-escalation cohort will be presented at the meeting. Clinical trial information: NCT02400476. [Table: see text]

Background: Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) is the most frequently activated signaling pathway in breast cancer. Activation of this pathway has been implicated in tumor growth, progression, and resistance to anticancer therapies. Buparlisib (BKM120) is an oral pan-PI3K inhibitor that targets all four isoforms of class I PI3K (α, β, γ, Δ). Preliminary clinical activity was observed with buparlisib in combination with weekly paclitaxel in patients with advanced solid tumors. The maximum tolerated dose of this combination was declared as 100 mg/day and 80 mg/m2/week for buparlisib and paclitaxel, respectively (Dirix et al. ESMO 2012). Trial design: BELLE-4 (NCT01572727) is a randomized, double-blind, placebo-controlled, Phase II trial of buparlisib or placebo plus weekly paclitaxel in adult women with chemotherapy-naïve, HER2-negative, locally advanced or metastatic breast cancer. Key inclusion criteria are: known PI3K pathway activation status (activated vs non-activated; centrally determined); ECOG performance status ≤1; and adequate bone marrow and organ function. Key exclusion criteria are: no prior treatment with a PI3K or Akt inhibitor; no prior systemic chemotherapy for advanced breast cancer (prior endocrine and adjuvant chemotherapy allowed); and no symptomatic CNS metastases. Patients are randomized 1:1 to receive oral buparlisib (100 mg once daily) or matching placebo, and IV paclitaxel (80 mg/m2 once weekly) in a 28-day treatment cycle until disease progression, unacceptable toxicity, death or discontinuation from study treatment for any other reason. Stratification at randomization is based upon PI3K pathway activation and hormone receptor status. Tumor assessments are performed locally every 8 weeks from randomization until radiologic progression (RECIST 1.1). Endpoints: The primary endpoint is progression-free survival* (PFS; per local investigator) in the full and PI3K pathway-activated populations. Secondary endpoints include overall survival (OS), overall response rate (ORR)*, duration of response (DOR)*, clinical benefit rate (CBR)*, time to response*, buparlisib pharmacokinetics, and safety† (*RECIST 1.1, †CTCAE v4.03). Statistical methods: PFS analysis will be performed in PI3K pathway-activated sub-population, PI3K non-activated sub-population, and the full population, using Bayesian methodology. A stratified Cox proportional hazard model will estimate the hazard ratio of PFS. The Kaplan–Meier method will estimate PFS, OS and DOR (if relevant) for both full and PI3K pathway-activated populations. ORR and CBR will be summarized with exact 95% confidence intervals. Target accrual: Approximately 200 patients will be randomized onto BELLE-4 at around 80 centers across 18 countries. Recruitment is ongoing across America, Europe, and Asia. Contact: For further information about the study, contact your local Novartis representative. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-07.

Background: In women with early-stage breast cancer, the skeleton represents one of the most common sites for metastases and represents approximately 40% of all first recurrences. Preclinical studies demonstrated that inhibition of RANKL significantly delays skeletal tumor formation, reduces skeletal tumor burden, and prolongs survival of tumor-bearing mice. Denosumab, a human IgG2 monoclonal antibody, binds RANKL with high specificity and affinity thus inhibiting RANKL activity. Denosumab has been approved for the prevention of skeletal-related events (SREs) in patients with established bone metastases from solid tumors. Purpose: The D-CARE trial is designed to assess if denosumab treatment prolongs bone metastasis-free survival (BMFS; primary endpoint) in the adjuvant breast cancer setting. Secondary endpoints include disease-free survival (DFS) and overall survival. Additional endpoints include safety, patient reported outcomes (pain, health utilities), as well as exploratory including breast density, time to first on-study SRE following the development of bone metastasis and biomarkers. Methods: In this global, randomized, double-blind, and placebo-controlled phase 3 trial, approximately 4500 women with stage II or III breast cancer at high risk for recurrence were randomized. High risk is defined as biopsy evidence of breast cancer in regional lymph nodes, tumor size > 5 cm (T3), or locally advanced disease (T4). Patients must be receiving or planned to receive standard-of-care adjuvant/neoadjuvant therapy (chemo-, endocrine, or HER-2 targeted), alone or in combination. Patients with a prior history of breast cancer (except DCIS or LCIS) or distant metastasis, oral bisphosphonate (BP) use within 1 year of randomization, or any intravenous BP use, were not eligible. Patients were randomized 1:1 to receive denosumab 120 mg or placebo subcutaneously monthly for 6 months, then every 3 months for a total of 5 years of treatment. Supplemental vitamin D (≥ 400 IU) and calcium (≥ 500 mg) are required. The primary efficacy and two interim efficacy analyses are planned and will be event-driven. The trial, sponsored by Amgen Inc. and registered with the ClinicalTrials.gov identifier NCT01077154, began enrolling patients in June 2010 and completed enrollment in late 2012. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-6-02.