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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.

Summary Background Aromatase inhibitors are a standard of care for hormone receptor-positive locally advanced or metastatic breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve progression-free survival compared with anastrozole in postmenopausal patients who had not received previous endocrine therapy. Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive, with WHO performance status 0–2, and at least one measurable or non-measurable lesion. Patients were randomly assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1·1, intervention by surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment (including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380. Findings Between Oct 17, 2012, and July 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0·797, 95% CI 0·637–0·999, p=0·0486). Median progression-free survival was 16·6 months (95% CI 13·83–20·99) in the fulvestrant group versus 13·8 months (11·99–16·59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs 24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in the anastrozole group discontinued because of adverse events. Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients. Funding AstraZeneca.

Background CT-P6 was approved by both US FDA and European Commission as a biosimilar to reference trastuzumab (RTZ). Here we report updated long term efficacy and safety. Methods 549 patients with HER2 positive EBC were randomized 1:1 to CT-P6 (n = 271) or RTZ (n = 278) with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin and cyclophosphamide (Cycles 5-8). After surgery, patients received CT-P6 or RTZ monotherapy to complete a total of 1 year and were followed up to 3 years from enrollment of the last patient. Stratified Cox regression and Kaplan-Meier methods were used for time to event (TTE) analyses. Results 528 patients (259 in CT-P6 and 269 in RTZ) were followed up. The median duration of follow-up was 39 months. Overall, the rates of disease-free survival (DFS) and overall survival (OS) were similar between CT-P6 and RTZ in both PPS and ITT set. The number of DFS events (42 [16.3%] in CT-P6 and 36 [13.8%] in RTZ) and OS events (18 [6.6%] in CT-P6 and 18 [6.5%] in RTZ) were comparable in ITT set. Median DFS and OS have not been reached due to an insufficient number of events. The mean LVEF was more than 60% in both groups, and no new cases of heart failure were reported during the follow-up period. Table. Summary of Long Term Efficacy Endpoints. Table . 190P PPS ITT set CT-P6 n = 248 RTZ n = 256 CT-P6 n = 258 RTZ n = 261 DFS rate 1 year (95% CI) 0.95 (0.91 – 0.97) 0.96 (0.93 – 0.98) 0.95 (0.91 – 0.97) 0.96 (0.93 – 0.98) 2 years (95% CI) 0.87 (0.81 – 0.90) 0.89 (0.85 – 0.92) 0.87 (0.82 – 0.90) 0.89 (0.85 – 0.93) 3 years (95% CI) 0.82 (0.77 – 0.87) 0.82 (0.75 – 0.88) 0.83 (0.77 – 0.87) 0.83 (0.76 – 0.88) Hazard ratio (95% CI) 1.23 (0.78 – 1.94) 1.23 (0.78 – 1.93) p-value 0.3808 0.3807 CT-P6 n = 248 RTZ n = 256 CT-P6 n = 271 RTZ n = 278 OS rate 1 year (95% CI) 1.00 (1.00 – 1.00) 1.00 (0.97 – 1.00) 0.99 (0.97 – 1.00) 0.99 (0.97 – 1.00) 2 years (95% CI) 0.98 (0.95 – 0.99) 0.98 (0.96 – 0.99) 0.97 (0.93 – 0.98) 0.98 (0.96 – 0.99) 3 years (95% CI) 0.95 (0.91 – 0.97) 0.94 (0.90 – 0.96) 0.93 (0.90 – 0.96) 0.94 (0.90 – 0.96) Hazard ratio (95% CI) 0.87 (0.42 – 1.82) 1.10 (0.57 – 2.13) p-value 0.7181 0.7710 Conclusions DFS and OS rates and cardiotoxicity at a median follow-up of 39 months support the similarity of CT-P6 and reference trastuzumab in early-stage breast cancer. Clinical trial identification NCT02162667. Legal entity responsible for the study Celltrion. Funding Celltrion. Disclosure J. Stebbing: Officer / Board of Directors, Editer-in-Chief: Oncogene; Advisory / Consultancy: Celltrion; Advisory / Consultancy: Vor Biopharma; Advisory / Consultancy: Benevolent AI; Officer / Board of Directors: BB Biotech Healthcare Trust; Officer / Board of Directors: Xerion Healthcare. Y. Baranau: Honoraria (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: Novatis. V. Moiseyenko: Speaker Bureau / Expert testimony: AstraZeneca. J. Pikiel: Travel / Accommodation / Expenses: Roche. A. Eniu: Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Celltrion; Research grant / Funding (self): Pfizer. S.J. Lee: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Stock option: Celltrion. M.J. Kim: Full / Part-time employment: Celltrion. S. Kim: Full / Part-time employment: Celltrion. S. Park: Full / Part-time employment: Celltrion. J.H. Bae: Full / Part-time employment: Celltrion. F.J. Esteva: Advisory / Consultancy: Celltrion; Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer. All other authors have declared no conflicts of interest.

Patients with HER2-positive early breast cancer (EBC) preferred subcutaneous (s.c.) trastuzumab, delivered via single-use injection device (SID), over the intravenous (i.v.) formulation (Cohort 1 of the PrefHer study: NCT01401166). Here, we report patient preference, healthcare professional satisfaction, and safety data pooled from Cohort 1 and also Cohort 2, where s.c. trastuzumab was delivered via hand-held syringe.Patients were randomized to receive four adjuvant cycles of 600 mg fixed-dose s.c. trastuzumab followed by four cycles of standard i.v. trastuzumab, or vice versa. The primary endpoint was overall preference proportions for s.c. or i.v., assessed by patient interviews in the evaluable ITT population.A total of 245 patients were randomized to receive s.c. followed by i.v. and 243 received i.v. followed by s.c. (evaluable ITT populations: 235 and 232 patients, respectively). s.c. was preferred by 415/467 [88.9%; 95% confidence interval (CI) 85.7-91.6; P0.0001; two-sided test against null hypothesis of 65% s.c. preference]; 45/467 preferred i.v. (9.6%; 95% CI 7-13); 7/467 indicated no preference (1.5%; 95% CI 1-3). Clinician-reported adverse events occurred in 292/479 (61.0%) and 245/478 (51.3%) patients during the pooled s.c. and i.v. periods, respectively (P0.05; 2 × 2 χ(2)); 16 patients (3.3%) in each period experienced grade 3 events; none were grade 4/5.PrefHer revealed compelling and consistent patient preferences for s.c. over i.v. trastuzumab, regardless of SID or hand-held syringe delivery. s.c. was well tolerated and safety was consistent with previous reports, including the HannaH study (NCT00950300). No new safety signals were identified compared with the known i.v. profile in EBC. PrefHer and HannaH confirm that s.c. trastuzumab is a validated and preferred option over i.v. for improving patients' care in HER2-positive breast cancer.NCT01401166.

Background This retrospective analysis aimed to determine whether early dose reduction impacts the efficacy of ixabepilone plus capecitabine in women with metastatic breast cancer (MBC). Patients and Methods In 2 phase III trials, patients (N = 1973) with anthracycline/taxane–pretreated MBC were randomized to receive ixabepilone 40 mg/m 2 on day 1 plus capecitabine 1000 mg/m 2 twice daily (BID) on days 1 to 14 or single-agent capecitabine 1250 mg/m 2 BID on days 1 to 14 of a 3-week course. Because of the similar design and populations, data from trials were pooled to evaluate efficacy of the combination regimen among women who did or did not undergo ixabepilone dose reduction during the first 4 courses. To adjust for bias resulting from selecting patients with inherently better outcome based on longer treatment durations, these analyses were restricted to patients who received ≥ 4 courses of ixabepilone. Results The pooled cohort included 566 patients with measurable disease who were evaluable for efficacy. Patients who had early dose reduction showed similar objective response rates (ORRs) and progression-free survival (PFS) as did those with no/late dose reduction. ORRs were 62.6% (95% confidence interval [CI], 55.8%-69.0%) and 55.3% (95% CI, 49.9%-60.6%), respectively; median PFS was 7.2 months (95% CI, 6.6-8.0) and 7.0 months (95% CI, 6.5-7.5), respectively (hazard ratio=0.98; 95% CI, 0.83-1.17). Conclusion These data suggest that early ixabepilone dose reduction did not affect the overall efficacy of ixabepilone plus capecitabine in patients with MBC who received ≥ 4 courses of treatment. By making appropriate dose reductions, ixabepilone-related toxicities can be minimized while maintaining clinical efficacy.

Summary Background The monoclonal antibody trastuzumab has survival benefit when given with chemotherapy to patients with early, operable, and metastatic breast cancer that has HER2 (also known as ERBB2) overexpression or amplification. We aimed to assess event-free survival in patients with HER2-positive locally advanced or inflammatory breast cancer receiving neoadjuvant chemotherapy with or without 1 year of trastuzumab. Methods We compared 1 year of treatment with trastuzumab (given as neoadjuvant and adjuvant treatment; n=117) with no trastuzumab (118), in women with HER2-positive locally advanced or inflammatory breast cancer treated with a neoadjuvant chemotherapy regimen consisting of doxorubicin, paclitaxel, cyclophosphamide, methotrexate, and fluorouracil. Randomisation was done with a computer program and minimisation technique, taking account of geographical area, disease stage, and hormone receptor status. Investigators were informed of treatment allocation. A parallel cohort of 99 patients with HER2-negative disease was included and treated with the same chemotherapy regimen. Primary endpoint was event-free survival. Analysis was by intention to treat. This study is registered, number ISRCTN86043495. Findings Trastuzumab significantly improved event-free survival in patients with HER2-positive breast cancer (3-year event-free survival, 71% [95% CI 61–78; n=36 events] with trastuzumab, vs 56% [46–65; n=51 events] without; hazard ratio 0·59 [95% CI 0·38–0·90]; p=0·013). Trastuzumab was well tolerated and, despite concurrent administration with doxorubicin, only two patients (2%) developed symptomatic cardiac failure. Both responded to cardiac drugs. Interpretation The addition of neoadjuvant and adjuvant trastuzumab to neoadjuvant chemotherapy should be considered for women with HER2-positive locally advanced or inflammatory breast cancer to improve event-free survival, survival, and clinical and pathological tumour responses. Funding F Hoffmann-La Roche.

Background: This Phase III, randomised, double-blind, multicentre trial (FALCON; NCT01602380) compared the selective estrogen receptor (ER) degrader (SERD) fulvestrant with anastrozole in patients with ER- and/or progesterone receptor-positive locally advanced or metastatic breast cancer who had not received prior hormonal therapy. Methods: Patients were randomised 1:1 to fulvestrant (500 mg IM on Days 0, 14, 28, then each 28 days) or anastrozole (1 mg daily). The primary endpoint was progression-free survival (PFS), assessed via RECIST 1.1, surgery/radiotherapy for disease worsening, or death. Secondary endpoints were: overall survival (OS); objective response rate (ORR, complete response [CR] or partial response [PR]); duration of response (DoR); expected DoR (EDoR); clinical benefit rate (CBR; CR, PR, or stable disease ≥24 weeks); duration of clinical benefit (DoCB); expected DoCB (EDoCB); health-related quality of life (HRQoL); and safety.

Purpose One year of H-based therapy, consisting of 18 q3w cycles, is standard of care for the adjuvant treatment of HER2-positive EBC. H is administered intravenously (IV) over 30–90 mins. An SC formulation of H has been developed, which is rapidly administered (up to 5 mins), potentially improving convenience for patients and clinical staff, and reducing administration costs. The Phase III HannaH study (NCT00950300) demonstrated that the pharmacokinetics and efficacy of H-SC were non-inferior to that of H-IV, meeting the co-primary endpoints. The safety profile of H-SC was comparable and consistent with the known safety profile of H-IV. SafeHer is designed to further evaluate the safety and tolerability of H-SC in a broader patient population; to allow greater understanding of a range of safety data. H-SC will be administered via one of two different routes (handheld syringe [vial formulation] or single-use injection device [SID]; which allows self-administration). Supportive data on SID safety and patient satisfaction with self-administration will be collected. Methods SafeHer is a multicentre, international, Phase III open-label trial (NCT01566721). The primary objective is the safety and tolerability of H-SC. Secondary objectives include disease-free survival, overall survival and patient satisfaction with SID administration. Immunogenicity of H and recombinant human hyaluronidase in a subset of patients using the SID at select sites is an exploratory objective. Planned enrolment is 2500 patients, assigned to one of two cohorts at the investigators' discretion ± concurrent/sequential chemotherapy. All patients will receive H-SC at a fixed dose of 600mg regardless of body weight, for a total of 18 cycles (q3w) via injection into the thigh over a period of up to 5 minutes. Patients in cohort A (n = 1800) will receive H-SC using handheld syringes. Patients in cohort B (n = 700) will receive H-SC using an SID, first via assisted administration and then self-administered (in select patients). Enrolment began in May 2012 and parallel substudies may be performed at selected centres to evaluate medical resource utilisation (“time and motion study”). Disclosure J. Gligorov: I disclose potential conflict of interest : advisory boards and speaker honoraria for Roche laboratories. H.A. Azim: I serve on the advisory board of Roche in the middle east. B. Ataseven: I am a Roche International Steering Committee member for the SafeHer trial. I have received speaker honoraria from Roche for giveing lectures. I participated in and received a travel grant from Roche for SABCS 2011. M. Delaurentiis: I am a member of a Roche Advisory Board. F. Herbst: I am an employee of, and am a stockholder in, F. Hoffmann-La Roche. A. Llombart: I am a member of a Roche Advisory Board. S. Osborne: I am an employee of Roche. X. Pivot: I am a member of Roche and GSK Advisory Boards. All other authors have declared no conflicts of interest.

Background: Oral chemotherapy (CT) is a widely recognized treatment option for hormone receptor positive, metastatic breast cancer (MBC) patients (pts) pretreated by hormone therapy (HT). In this phase II study, we evaluated the efficacy and safety of single-agent Oral Vinorelbine (OV) as first-line CT in pts presenting bone metastases without visceral involvement. Methods: Main eligibility criteria included: age ≥18 years, documented bone disease previously untreated by CT, hormone receptor positive disease previously treated by at least one HT, HER2-negative disease, Karnofsky PS ≥70 and absence of visceral metastases. All pts received a bisphosphonate during the study. Study treatment (until progression): OV 80 mg/m2 weekly (following a first cycle at 60 mg/m2 and dose escalation to 80 in the absence of grade 3 or 4 toxicity). One cycle was defined as four weeks of treatment Results: Between April 2010 and April 2012, 70 patients have been included. Main pts characteristics: median age: 60.6 years (34% ≥65 years); median Karnofsky PS 90%. Prior HT 100% (80% in adjuvant setting, 53% in advanced setting); prior (neo)adjuvant CT 63%; prior anthracyclines/taxanes 59/24%; prior palliative radiotherapy 41%. Bone involvement 100%; other metastatic sites: lymph nodes 14%, soft tissue 3%. Median duration of treatment 5.8 months (range 0.9-18.4), median number of cycles: 6 (range: 1-18); median relative dose intensity: 83.0%. Efficacy: with a median follow up of 26.1 months, median progression-free survival (primary endpoint) was 8.2 months (95% CI [5.5-10.3]). Clinical benefit was observed in 55.7% of pts. Median duration of clinical benefit was 11.1 months (95% CI [8.6-14.7]). Overall survival results are not mature yet, at cut off date 63% of pts being alive. Safety: grade 3/4 adverse events per pt: neutropenia 37%, anemia 4%, neutropenic infection 3%, diarrhoea 3%, nausea 3%, asthenia 1%, liver toxicity 1%, non-neutropenic infection 1%. Grade 2 alopecia was reported in 6% of pts. Conclusion: For this particular population of metastatic pts, with hormone receptor positive disease progressing to HT and bone involvement, OV is an active and safe first-line CT option. Disclosure: G.G. Steger: Honoraria and Travel Grants from Pierre Fabre Medicament; G.R. Villanova: Employee of Pierre Fabre Medicament. All other authors have declared no conflicts of interest.