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Background Trastuzumab-dkst is a biosimilar of trastuzumab. The phase 3 HERITAGE trial demonstrated equivalent overall response rate (ORR) with trastuzumab-dkst or originator trastuzumab at 24 weeks in patients with HER2-positive metastatic breast cancer receiving chemotherapy. We now present the correlation of ORR with progression-free survival (PFS) for maintenance monotherapy with trastuzumab-dkst vs trastuzumab at 48 weeks of treatment, and the safety, tolerability, and immunogenicity. Methods HERITAGE is a multicenter, double-blind, randomized, parallel-group, phase 3 study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab in combination with taxane followed by continued monotherapy until disease progression. The analysis included PFS at 48 weeks to support the primary efficacy endpoint of ORR and safety, tolerability, and immunogenicity of trastuzumab-dkst vs trastuzumab as maintenance monotherapy. Results Of 500 randomized patients, 342 entered the monotherapy phase; 214 patients received ≥48 weeks of treatment. There were no statistically significant differences between PFS, ORR, or interim overall survival at week 48 between trastuzumab-dkst and trastuzumab. Week 24 ORR was highly correlated with week 48 PFS (rb = 0.75). Cumulative treatment-emergent adverse events (TEAEs) and serious AEs were similar in both groups, with few grade ≥3 TEAEs. Immunogenicity was low and similar in both groups at 48 weeks. Conclusion The correlation between ORR and PFS supports the design of first-line metastatic trials assessing biosimilar trastuzumab. Overall, trastuzumab-dkst and trastuzumab were well tolerated with similar efficacy, including ORR and PFS, in combination with a taxane followed by monotherapy., Highlights • Trastuzumab-dkst is a biosimilar of trastuzumab. • Trastuzumab-dkst and trastuzumab had similar PFS, ORR, and OS at week 48. • Results support therapeutic equivalence between trastuzumab-dkst and trastuzumab. • Week 24 ORR was highly correlated with week 48 PFS. • ORR and PFS correlation supports ORR as a valid endpoint in clinical trials for MBC.

Purpose The phase 3 HERITAGE trial demonstrated that the biosimilar trastuzumab-dkst is well tolerated with similar efficacy (measured by overall response rate [ORR] and progression-free survival [PFS]) compared with originator trastuzumab combined with taxane followed by monotherapy in patients with HER2-positive metastatic breast cancer (MBC). Herein, we present final overall survival (OS) from HERITAGE. Methods HERITAGE is a multicenter, double-blind, randomized, parallel-group study. Patients were randomized 1:1 to receive trastuzumab-dkst or trastuzumab plus taxane followed by continued monotherapy until disease progression. Overall survival was to be assessed at 36 months or after 240 deaths, whichever occurred first, as observed from time of randomization of last patient. Results At the final analysis (36 months), 242 patients in the intention-to-treat population had died during the study: 116 and 124 in the trastuzumab-dkst and trastuzumab groups, respectively, and 1 untreated patient from each treatment group. Median OS by Kaplan–Meier analysis was 35.0 months with trastuzumab-dkst and 30.2 months with trastuzumab. Evaluation of PFS showed a median of 11.1 months in both treatment groups. No new safety concerns were reported from week 48 until the end of the survival follow-up. Conclusion This is the first phase 3 trial of a trastuzumab biosimilar to report long-term survival data similar to originator trastuzumab in patients with MBC. The comparable long-term OS between the trastuzumab-dkst and originator trastuzumab groups further supports the similarity of trastuzumab-dkst with originator trastuzumab and establishes trastuzumab-dkst as a safe and effective treatment option for patients with HER2-positive MBC. ClinicalTrials.gov NCT02472964; 6/16/2015

Purpose Equivalent efficacy was demonstrated for the biosimilar CT-P6 and trastuzumab following neoadjuvant therapy for patients with human epidermal growth factor receptor-2 (HER2)-positive early breast cancer. Following adjuvant treatment, efficacy and safety were comparable between treatments. We report updated safety and efficacy data after up to 3 years’ follow-up. Methods Following neoadjuvant chemotherapy with CT-P6/trastuzumab, patients underwent surgery and continued receiving adjuvant CT-P6/trastuzumab. The primary endpoint (previously reported) was pathological complete response. Time-to-event analyses (disease-free survival [DFS], progression-free survival [PFS], and overall survival [OS]), study drug-related and cardiac adverse events, and immunogenicity were assessed during post-treatment follow-up. Results Most patients entered the follow-up period (CT-P6: 259 [95.6%]; trastuzumab: 269 [96.8%]). After a median follow-up of 38.7 (CT-P6) and 39.6 (trastuzumab) months, medians were not reached for time-to-event parameters; estimated hazard ratios (HRs) and 3-year survival rates were similar between groups. Estimated HRs (95% confidence intervals) for CT-P6 versus trastuzumab were 1.23 (0.78–1.93) for DFS, 1.31 (0.86–2.01) for PFS, and 1.10 (0.57–2.13) for OS (intention-to-treat population). Safety findings were comparable between groups for the overall study and follow-up period, including study drug-related cardiac disorders (CT-P6: 22 [8.1%] patients; trastuzumab: 24 [8.6%] patients [overall]) and decreases in left ventricular ejection fraction. Immunogenicity was similar between groups. Conclusion The similarity of the time-to-event analyses between CT-P6 and trastuzumab supports the equivalence in terms of efficacy established for the primary endpoint. CT-P6 was well tolerated, with comparable safety and immunogenicity to trastuzumab. ClinicalTrials.gov: NCT02162667 (registered June 13, 2014)

To report the final results of the 5-year follow-up of the non-randomized SafeHER Phase III study (NCT01566721) describing the safety, tolerability, and efficacy of subcutaneous (SC) trastuzumab alone and in combination with concurrent or sequential chemotherapy.Patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) with no prior anti-HER2 therapy were included. SC trastuzumab was administered every 3 weeks for 18 cycles as adjuvant therapy with or without chemotherapy (concurrent or sequential). The primary objective was overall safety and tolerability of SC trastuzumab; efficacy was a secondary objective.No new safety signals were observed during the final evaluation. The majority of adverse events (AEs) were grade 1 or 2 across the chemotherapy subgroups. Treatment discontinuation due to AEs was 5.1% for the intent-to-treat (ITT) population and similar for all chemotherapy subgroups. The overall disease-free survival (DFS) 5-year event-free rate in the ITT population (n = 2573) was 86.6% (95% CI, 85.2%-87.9%) with a median follow-up of 72 months. Based on chemotherapy timing, the no (n = 235), concurrent (n = 1533), and sequential (n = 805) chemotherapy subgroups had DFS 5-year event-free rates (95% CI) of 88.5% (83.4%-92.2%), 88.4% (86.6%-89.9%), and 82.6 (79.7%-85.2%), respectively.The 5-year follow-up analysis of the SafeHER trial demonstrating that SC trastuzumab has an acceptable safety profile, including cardiac toxicity, and efficacy for the treatment of HER2-positive EBC with and without chemotherapy, corresponding with historical data with trastuzumab.

LBA511 Background: TX05 is being developed as a biosimilar to trastuzumab. We previously reported results of a Phase III study (TX05-03) comparing the efficacy and safety of TX05 to originator trastuzumab (TRA) in patients with HER2+ early breast cancer (EBC). The rate of pathologic complete response for subjects treated with TX05 compared to TRA in the TX05-03 study were within pre-defined equivalence margins, supporting the therapeutic equivalence of TX05 and TRA. This is an extension study to further assess and characterize the safety, immunogenicity, and efficacy of TX05 and TRA as single agents. Methods: TX05-03e was a randomized double-blinded, parallel group Phase III trial with patients enrolled at 82 centers in 10 countries. Adjuvant treatment included single agent trastuzumab (TX05 or TRA) for up to thirteen 3-week cycles. Subjects originally assigned to TX05 in the neoadjuvant phase of treatment received TX05, while subjects randomized to TRA in the neoadjuvant phase were randomized (1:1) to receive either TX05 or TRA. Efficacy endpoints include assessment of disease-free survival and overall survival. DFS is defined as the time from randomization in the neoadjuvant study (Protocol TX05-03) to the documentation of a first failure. OS is defined as the time from randomization in the neoadjuvant study until death from any cause. Safety parameters assessed include treatment emergent adverse events (TEAE) and serious adverse events (SAE), death, clinical laboratory parameters, vital signs, 12-Lead ECG, LVEF and Physical examination. Immunogenicity was also assessed. Results: Of the 338 subjects randomized, 256 received TX05 while 82 received TRA. 81 of the TX05 patients received TRA in the neoadjuvant treatment phase. Demographic and baseline characteristics were well balanced between the three arms (TX05/TX05, TRA/TRA, or TRA/TX05 in neoadjuvant/adjuvant treatment phases). There was one death reported (TRA/TX05 group due to disease progression). DFS events occurred in only 3.4% of the TX05/TX05 group, 6.1% of the TRA/TRA group and 3.7% of the TRA/TX05 group. The number of subjects with any AE was 53.1% in the TX05/TX05, 56.1% in the TRA/TRA group and 37% in the TRA/TX05 groups. Frequency, type and severity of adverse events related to study drug were similar between the three groups and no new safety signals were detected. Conclusions: The rates of DFS, OS, AEs and immunogenicity were comparable in subjects randomized to TX05/TX05, TRA/TRA or TRA/TX05 for neoadjuvant/adjuvant treatment and continue to support the conclusion of biosimilarity of TX05 to the reference product. The change from TRA to TX05 for adjuvant treatment has no detectable impact on safety or treatment outcome. Clinical trial information: NCT04109391.

Background Abemaciclib is a selective CDK4 & 6 inhibitor approved on a continuous dosing schedule for HR+, HER2- advanced breast cancer (ABC) as monotherapy (MONARCH 1) and in combination with endocrine therapy (ET). A previous Phase 1b (NCT01394016) cohort of HR+ ABC patients (pts) demonstrated efficacy of abemaciclib monotherapy (150mg and 200mg Q12H starting dose); given the small sample size and nonrandomized design the impact of the starting dose was unclear. nextMONARCH 1 (NCT02747004) evaluated abemaciclib in 2 monotherapy arms, in a randomized setting. Abemaciclib has been associated with dose-dependent early onset diarrhea that is well managed with antidiarrheal therapy. nextMONARCH 1 also explored the 200mg Q12H abemaciclib dose in combination with prophylactic loperamide to reduce incidence/severity of diarrhea and dose adjustments. A third arm evaluated abemaciclib + tamoxifen as a strategy to overcome endocrine resistance. Methods nextMONARCH 1 is a multicenter, randomized, open-label, Phase 2 study of abemaciclib or abemaciclib + tamoxifen in women with HR+, HER2- ABC who have progressed on or after prior ET and previously received chemotherapy. Pts were stratified by presence of liver metastases and prior use of tamoxifen in the advanced setting. Randomization was 1:1:1 to abemaciclib 150mg Q12H + daily tamoxifen 20mg (Arm A) or abemaciclib 150mg Q12H (Arm B); or abemaciclib 200mg Q12H + prophylactic loperamide (Arm C). Key eligibilities were ≥2 chemotherapy regimens (1-2 administered in metastatic setting), measurable disease and no prior treatment with CDK4 & 6 inhibitors. Primary objective was progression free survival (PFS). Key secondary objectives included objective response rate (ORR), dclinical benefit rate (CBR), and safety. PFS analysis tested superiority of Arm A to C at ∼110 events across the 2 arms assuming a hazard ratio (HR) of 0.667 to achieve ∼80% power. Arm B would be considered non-inferior to Arm C if the observed PFS HR is Results 234 pts were randomized to Arms A (n=78), B (n=79) and C (n=77). 166 PFS events have been observed (A: 57; B: 54; C: 55). Median PFS was 9.1 months in Arm A, 6.5 in Arm B and 7.4 in Arm C (A vs C: HR=.815, 95% CI, .556-1.193, p=.293; B vs C: HR=1.045, 95% CI, .711-1.535 p=.811). Investigator-assessed ORR was 34.6%, 24.1% and 32.5% (confirmed ORR: 25.6%, 19.0%, 28.6%) and CBR was 61.5%, 49.4% and 51.9% in Arms A, B and C, respectively. Prophylactic loperamide reduced the incidence and severity of diarrhea (C: 62.3%, Gr 3: 7.8%) compared to MONARCH 1 (90.2%, Gr 3: 19.7%, Dickler et al. 2017) resulting in similar rates of diarrhea with 150mg abemaciclib without prophylaxis (A: 53.8%, Gr 3: 1.3%; B: 67.1%, Gr 3: 3.8%). The adverse event profile across arms was generally consistent with other breast studies of abemaciclib. Conclusions nextMONARCH 1 confirmed single-agent activity of abemaciclib in heavily pretreated pts with HR+, HER2- ABC. Efficacy of abemaciclib monotherapy at 150mg was similar to 200mg. Combining tamoxifen with abemaciclib did not demonstrate a statistically significant improvement in PFS compared to abemaciclib monotherapy. Addition of prophylactic loperamide to abemaciclib 200mg resulted in diarrhea similar to 150mg without prophylaxis. Citation Format: Hamilton E, Cortes J, Dieras V, Ozyilkan O, Chen S-C, Petrakova K, Manikhas A, Jerusalem G, Hegg R, Lu Y, Bear MM, Johnston EL, Martin M. nextMONARCH 1: Phase 2 study of abemaciclib plus tamoxifen or abemaciclib alone in HR+, HER2- advanced breast cancer [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 PD1-11.

Relevance. Breast cancer is the leading oncological disease among female population. In some cases, clinical stage T2N0M0 is contraindication to breast-concerving surgery due to a big size of the primary tumor. Mastectomy is an optimal surgery in this situation. However, removal of the breast is a serious psychological trauma for the patient, causing quality of life decrease. Attempting to perform breast-conserving surgery is quite logical. Due to this we investigated a method of complex treatment of breast cancer using intraoperative radiation therapy, sentinel lymph node biopsy and neoadjuvant systemic drug therapy. Goal: the main goal is to improve the results of early breast cancer treatment, through the introduction into clinical practice of the original method of complex treatment. Materials and methods. 101 patients treated in the State clinical oncology department of St. Petersburg in the period from 2014 to 2016 were included in the study. The main inclusion criteria was a clinical stage T2N0M0. All the patients are not the candidates for breast - conserving surgery. In the experience group were patients (n=51) who received treatment on the method studied. 50 patients were randomized to the control group, where the mastectomy was performed. In the experience group late toxicity was evaluated after radiosurgery using modified LENT-SOMA scale. Quality of life was assessed by questionnaire QLQ-C30 in both groups. Results. 49 (96%) patients of the experience group were treated by breast-conserving surgery (lumpectomy with intraoperative radiation) due to clinical and radiological tumor response to neoadjuvant therapy. After systemic therapy 10 (20%) women were performed axillary lymph node dissection. Quality of life in the experience group was significantly higher. Late toxicity was not significant after application of intraoperative and whole breast radiotherapy. Conclusion. The investigated method of a complex treatment of early breast cancer is safe and effective and is able to provide the same control of locoregional recurrence as modified radical mastectomy. However, the proposed method provides a statistically significant better quality of life.

Purpose Neoadjuvant CT-P6, a trastuzumab biosimilar, demonstrated equivalent efficacy to reference trastuzumab in a phase 3 trial of HER2-positive early-stage breast cancer (EBC) (NCT02162667). We report post hoc analyses evaluating pathological complete response (pCR) and breast pCR alongside additional efficacy and safety measures. Methods Following neoadjuvant treatment and surgery, patients received adjuvant CT-P6 or trastuzumab (6 mg/kg) every 3 weeks for ≤ 1 year. Results In total, 271 and 278 patients received CT-P6 and trastuzumab, respectively. pCR and breast pCR rates were comparable between treatment groups regardless of age, region, or clinical stage. Overall, 47.6% (CT-P6) and 52.2% (trastuzumab) of patients experienced study drug-related treatment-emergent adverse events (TEAEs), including 17 patients reporting heart failure (CT-P6: 10; trastuzumab: 7). Two CT-P6 and three trastuzumab patients discontinued adjuvant treatment due to TEAEs. Conclusion Adjuvant CT-P6 demonstrated comparable efficacy and safety to trastuzumab at 1 year in patients with HER2-positive EBC, supporting CT-P6 and trastuzumab comparability. Electronic supplementary material The online version of this article (10.1007/s00280-019-03920-4) contains supplementary material, which is available to authorized users.

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.

Objectives: The key objectives of CONTESSA are to evaluate the efficacy and safety of tesetaxel plus a reduced dose of capecitabine as an all-oral regimen versus capecitabine alone in patients with HER2-, HR+ MBC previously treated with a taxane. Rationale: Tesetaxel is a novel, oral taxane with several properties that make it unique, including: oral administration with a low pill burden; a long (8-day) terminal plasma half-life in humans, enabling infrequent, once-every-3 weeks (Q3W) dosing; no observed hypersensitivity reactions; and significant activity against chemotherapy-resistant breast cancer cell lines. More than 1,000 patients have been treated with tesetaxel in clinical studies. Tesetaxel had encouraging 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% and median progression-free survival (PFS) of 5.4 months (Seidman et al, 2018 ASCO Annual Meeting). Methodology: CONTESSA is a multinational, multicenter, randomized (1:1), Phase 3 registration study comparing tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have received a taxane in the (neo)adjuvant setting. There was no restriction on the disease-free interval following taxane therapy. The primary endpoint is PFS assessed by an Independent Radiologic Review Committee (IRC). CONTESSA was designed with 90% power to detect a 2.5-month improvement in median PFS (HR=0.71). Secondary endpoints are overall survival (OS), ORR and disease control rate. Results: CONTESSA, which enrolled 685 patients, met the primary endpoint of improved PFS as assessed by the IRC. Median PFS was 9.8 months for tesetaxel plus a reduced dose of capecitabine versus 6.9 months for capecitabine alone, an improvement of 2.9 months [HR=0.716 (95% CI: 0.573-0.895); p=0.003]. ORR was 57% for tesetaxel plus a reduced dose of capecitabine versus 41% for capecitabine alone (p=0.0002). OS data are immature. Tesetaxel plus capecitabine was associated with a manageable side effect profile consistent with previous clinical studies. Grade ≥3 treatment-emergent adverse events (TEAEs) that occurred in ≥5% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia (71.2% vs. 8.3%); diarrhea (13.4% vs. 8.9%); hand-foot syndrome (6.8% vs. 12.2%); febrile neutropenia (12.8% vs. 1.2%); fatigue (8.6% vs. 4.5%); hypokalemia (8.6% vs. 2.7%); leukopenia (10.1% vs. 0.9%); and anemia (8.0% vs. 2.1%). TEAEs resulting in treatment discontinuation in ≥1% of patients (tesetaxel plus capecitabine vs. capecitabine alone) were: neutropenia or febrile neutropenia (4.2% vs. 1.5%); neuropathy (3.6% vs. 0.3%); diarrhea (0.9% vs. 1.5%); and hand-foot syndrome (0.6% vs. 2.1%). Treatment discontinuation due to any adverse event occurred in 23.1% of patients treated with tesetaxel plus capecitabine versus 11.9% of patients treated with capecitabine alone. Grade 2 alopecia occurred in 8.0% of patients treated with tesetaxel plus capecitabine versus 0.3% of patients treated with capecitabine alone. Grade ≥3 neuropathy occurred in 5.9% of patients treated with tesetaxel plus capecitabine versus 0.9% of patients treated with capecitabine alone. Conclusion: An all-oral regimen of tesetaxel plus a reduced dose of capecitabine significantly improved PFS versus capecitabine alone. Neutropenia was the most frequent Grade ≥3 TEAE. Rates of clinically significant alopecia and neuropathy were low. Citation Format: Joyce O'Shaughnessy, Lee Schwartzberg, Martine Piccart, Hope S. Rugo, Denise A Yardley, Javier Cortes, Michael Untch, Nadia Harbeck, Gail S. Wright, Igor Bondarenko, John Glaspy, Zbigniew Nowecki, Fadi Kayali, Arlene Chan, Christelle Levy, Mei-Ching Liu, Sung-Bae Kim, Julie Lemieux, Alexey Manikhas, Sara Tolaney, Elaine Lim, Andrea Gombos, Agostina Stradella, Mark Pegram, Peter Fasching, Laszlo Mangel, Vladimir Semiglazov, Veronique Dieras, Luca Gianni, Michael A Danso, Jeff Vacirca, Stew Kroll, Joseph O'Connell, Kevin Tang, Thomas Wei, Andrew Seidman. Results from CONTESSA: A phase 3 study of tesetaxel plus a reduced dose of capecitabine versus capecitabine alone in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane [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 GS4-01.

Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer.Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS).One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms.The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials.NCT00294996.

Trastuzumab is a key drug in the neoadjuvant treatment of breast cancers that overexpress the human epidermal growth factor receptor 2 (HER2). Pathological complete response (pCR) is commonly used as an endpoint in neoadjuvant clinical trials of trastuzumab as evidence suggests it may be a surrogate for long-term survival. Several biosimilar candidates of originator or 'reference' trastuzumab are in development and have used pCR as a primary endpoint to assess therapeutic equivalence between treatments. The exact definition of pCR has varied across studies. Areas covered: Here we look at the clinical relevance of pCR and compare rates of total pCR (defined as ypT0/is ypN0) and breast pCR (defined as ypT0/is) in clinical trials of reference and biosimilar trastuzumab. Expert commentary: In order to evaluate the efficacy of neoadjuvant systemic therapies in a uniform way, standardization of trial endpoints is necessary. Future studies in HER2-positive breast cancer should include full assessment of the breast and lymph node basin before and after neoadjuvant systemic therapy, and the use of total pCR as the primary outcome.

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.

Purpose CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. Patients and Methods Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m2 per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m2 per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). Results The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, −1.6%; 95% CI, −2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. Conclusion CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Purpose The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) –positive metastatic breast cancer (BC) is unknown. Patients and Methods The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. Results From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). Conclusion As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

Summary Background CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer. Methods In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I–IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2–8) in conjunction with neoadjuvant docetaxel (75 mg/m 2 on day 1 of cycles 1–4) and FEC (fluorouracil [500 mg/m 2 ], epirubicin [75 mg/m 2 ], and cyclophosphamide [500 mg/m 2 ]; day 1 of cycles 5–8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3–6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was −0·15 to 0·15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting. Findings Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46·8%; 95% CI 40·4–53·2] of 248 patients) and reference trastuzumab (129 [50·4%; 44·1–56·7] of 256 patients). The 95% CI of the estimated treatment outcome difference (−0·04 [95% CI −0·12 to 0·05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [ vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%). Interpretation CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer. Funding Celltrion Inc.

Stig Larsen,1 Kritiya Butthongkomvong,2 Alexey Manikhas,3 Ekaterina Trishkina,4 Elena Poddubuskaya,5 Marina Matrosova,6 Vichien Srimuninnimit,7 Steen Lindkær-Jensen81Department of Controlled Clinical Trials and Biostatistics, Centre for Epidemiology and Biostatistics, University of Life Science, Oslo, Norway; 2Udonthani Cancer Hospital, Udonthani, Thailand; 3Department of Oncology, City Clinical Oncology, Dispensary, St Petersburg, Russia; 4Department of Oncology, Leningrad Regional Oncology Centre, St Petersburg, Russia; 5Department of Oncology, Unit of Russian Academy of Medical Science, Moscow, Russia; 6Department of Oncology, N Novgorod Regional Oncology Dispensary, Novgorod, Russia; 7Division of Medical Oncology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 8Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, UKAbstract: The aims were to compare the efficacy and tolerability of a new benzene-poly-carboxylic acids complex with cis-diammineplatinum (II) dichloride (BP-C1) versus placebo and to investigate the long-term tolerability of BP-C1 in the treatment of patients with metastatic breast cancer.Material and methods: A randomized, double-blind, placebo-controlled multicenter study was performed with a semi-crossover design. Patients allocated to placebo switched to BP-C1 after 32 days of treatment. Patients who completed 32 days of BP-C1 treatment were offered the opportunity to continue on BP-C1 for an additional 32 days in an open-label extension. Patients were then followed up for another 28 days. Thirty patients were given daily intramuscular injections of 0.035 mg/kg of body weight BP-C1 or placebo for 32 days. Biochemistry, hematology, National Cancer Institute Common Terminology Criteria for Adverse Events (CTC-NCI), European Organisation for Research and Treatment of Cancer quality of life questionnaire (QOL-C30 and the breast-cancer–specific BR23) data were recorded at screening and after every 16 days of treatment. Computed tomography was performed at screening and every 32 days.Results: The sum of target lesions increased 2.4% in the BP-C1 group and 14.3% in the placebo group. Only the increase in the placebo group was significant (P=0.013). The difference between the groups was significant in favor of BP-C1 (P=0.04). There was a significant difference (P=0.026) in favor of BP-C1 regarding Response Evaluation Criteria In Solid Tumors (RECIST) classification. The sum of lesions increased slightly in the patients receiving 64 days of continuous BP-C1 treatment, of whom 68.4% were classified as responders. The sum CTC-NCI toxicity score increased nonsignificantly in the BP-C1 group but significantly in the placebo group (P=0.05). The difference in increase between groups did not meet the level of significance (P=0.12). The sum toxicity score was reduced in the patients receiving 64 days of BP-C1 from 9.2 at screening to 8.9 at Day 48, but it increased again to 10.1 by Day 64 and 10.6 during the 28-day follow-up. "Breast cancer-related pain and discomfort" and "Breast cancer treatment problem last week" were significantly reduced (P=0.02) in the BP-C1 group but increased slightly in the placebo group; between-group differences were significant in favor of BP-C1 (P=0.05). "Breast cancer related pain and discomfort", "Breast cancer treatment problem last week," and "Physical activity problem" were significantly reduced during the 64 days of BP-C1 treatment (P≤0.05).Conclusion: For patients suffering from stage IV metastatic breast cancer, treatment with BP-C1 reduces cancer growth, is well tolerated, improves quality of life, and produces few adverse events, which were mainly mild and manageable.Keywords: tumor growth reduction, improved Quality of Life, safe, few transient adverse effectsCorrigendumfor this paper has been published

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.

12 Background: To compare the effect of BP-C1 versus equal looking placebo in heavily pre-treated metastatic breast cancer (MBC) patients and to evaluate the efficacy of BP-C1 according to number of negative receptors. Methods: The study sample consisted of 61 patients from two randomized, double blinded and placebo controlled multicentre studies with semi-cross-over design. By randomization, 31 patients were allocated to BP-C1 and 30 to equal looking placebo treatment for 32 days. Twenty-five of the 30 patient allocated to placebo were switched to BP-C1 after finalizing the placebo period. A joint sample of 56 patients received one daily intramuscular injection of 0.07 ml/kg BW of BP-C1 for at least one cycle of 32 days. Receptor status including Estrogen, Progesterone and Human epidermal growth factor receptor was analysed prior to entering the study and available in 54 of the 56 patients. CT scans were performed at screening and after every 32-days of treatment, and were blindly analysed by one independent radiologist. The sum of target lesion diameters (SLD), RECIST classification and disease control rate (DCR) defined as patients obtaining at least stabile disease (SD) at the end of treatment was the main variables. Results: The SLD increased non-significantly by 1.5mm (5.7%) in the BP-C1 group and significantly (p < 0.001) by 13.6 mm (26.2%) in the placebo group during the 32 days of treatment. The difference between groups with respect to SLD and DCR was significant in favour of BP-C1 (p < 0.001). The tumour growth in the joint BP-C1 group was 2.5mm (5.9%) and DCR was 89.1% [95% CI: 38.1 – 96.0]. Nine of the 56 patients reported 26 Adverse Events (AE) related to BP-C1; all of mild to moderate degree. SLD increased 16.2% (p = 0.03) in patients with three positive receptors, 7.5% (p = 0.02) in the group with one negative receptor, 2.5% in the group of two negative receptors and 0.8% in triple negative patients. The tumor growth declined with increasing number of negative receptors (r = -0.26; p = 0.05). Conclusions: BP-C1 treatment of pre-treated MBC patients controlled the cancer growth with few mainly mild AE’s. The BP-C1 efficacy increased with the number of negative receptors. Clinical trial information: NCT03603197. Clinical trial information: NCT02783794.

Aim To assess the safety and tolerability of adjuvant subcutaneous trastuzumab (Herceptin ® SC, H SC), delivered from an H SC Vial via hand-held syringe (Cohort A) or single-use injection device (Cohort B), with or without chemotherapy, for human epidermal growth factor receptor 2 (HER2)-positive stage I to IIIC early breast cancer (EBC) in the phase III SafeHer study (NCT01566721). Methods Patients received 600 mg fixed-dose H SC every 3 weeks for 18 cycles. The chemotherapy partner was at the investigators' discretion (H SC monotherapy was limited to ≤10% of the population). Data from the first H SC dose until 28 days (plus a 5-day window) after the last dose are presented. Results are descriptive. Results In the overall population, 2282/2573 patients (88.7%) experienced adverse events (AEs). Of the above, 128 (5.0%) patients experienced AEs leading to study drug discontinuation; 596 (23.2%) experienced grade ≥ 3 AEs and 326 (12.7%) experienced serious AEs. Grade ≥ 3 cardiac disorders were reported in 24 patients (0.9%), including congestive heart failure in eight (0.3%). As expected, the AE rates varied according to the timing of chemotherapy in both cohorts, with higher rates in concurrent versus sequential chemotherapy subgroups. In the concurrent chemotherapy subgroup, AEs were more common during the actual period of concurrent chemotherapy compared with the period when patients did not receive concurrent chemotherapy. Conclusion SafeHer confirms the safety and tolerability of the H SC 600 mg fixed dose for 1 year (every 3 weeks for 18 cycles) as adjuvant therapy with concurrent or sequential chemotherapy for HER2-positive EBC. These primary analysis results are consistent with the known safety profile for intravenous H and H SC.

Importance Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)–positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. Objective To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Interventions Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. Main Outcomes and Measures The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. Results Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). Conclusions and Relevance Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome. Trial Registration clinicaltrials.gov Identifier:NCT02472964; EudraCT Identifier: 2011-001965-42

This multi-center Phase II study evaluated lapatinib, pazopanib, and the combination in patients with relapsed HER2+ inflammatory breast cancer. In Cohort 1, 76 patients were randomized 1:1 to receive lapatinib 1,500 mg + placebo or lapatinib 1,500 mg + pazopanib 800 mg (double-blind) once daily until disease progression, unacceptable toxicity, or death. Due to high-grade diarrhea observed with this dose combination in another study (VEG20007), Cohort 1 was closed. The protocol was amended such that an additional 88 patients (Cohort 2) were randomized in a 5:5:2 ratio to receive daily monotherapy lapatinib 1,500 mg, lapatinib 1,000 mg + pazopanib 400 mg, or monotherapy pazopanib 800 mg, respectively. The primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival, and safety. In Cohort 1, ORR for the lapatinib (n = 38) and combination (n = 38) arms was 29 and 45 %, respectively; median PFS was 16.1 and 14.3 weeks, respectively. Grade ≥3 adverse events (AEs) were more frequent in the combination arm (71 %) than in the lapatinib arm (24 %). Dose reductions and interruptions due to AEs were also more frequent in the combination arm (45 and 53 %, respectively) than in the lapatinib monotherapy arm (0 and 11 %, respectively). In Cohort 2, ORR for patients treated with lapatinib (n = 36), lapatinib + pazopanib (n = 38), and pazopanib (n = 13) was 47, 58, and 31 %, respectively; median PFS was 16.0, 16.0, and 11.4 weeks, respectively. In the lapatinib, combination, and pazopanib therapy arms, grade ≥3 AEs were reported for 17, 50, and 46 % of patients, respectively, and the incidence of discontinuations due to AEs was 0, 24, and 23 %, respectively. The lapatinib–pazopanib combination was associated with a numerically higher ORR but no increase in PFS compared to lapatinib alone. The combination also had increased toxicity resulting in more dose reductions, modifications, and treatment delays. Activity with single-agent lapatinib was confirmed in this population.

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.

Pemetrexed/cyclophosphamide was evaluated as first-line treatment for patients with locally advanced/metastatic breast cancer. In this randomized phase II study (NCT00190671), therapy consisted of either 600 mg/m(2) (P600) or 1,800 mg/m(2) (P1800) pemetrexed, followed by 600 mg/m(2) cyclophosphamide, every 21 days; 103 females (42 P600; 61 P1800) were enrolled. P600 was discontinued, as response rate (19.1%) was lower than targeted. In the P1800 arm, 20 patients had partial response (32.8%; 95% CI: 21.0-44.6) and 26 (42.6%) had stable disease. Median progression-free survival was 6.3 months (range: 0.3-31.1). P1800 plus cyclophosphamide 600 represents a regimen of reasonable efficacy and acceptable tolerability.

BACKGROUND Brain metastases constitute a major clinical concern occurring in 28–43% of women treated for HER2+ metastatic breast cancer (MBC). The initial diagnosis of Central Nervous System (CNS) lesion is commonly based upon development of neurological symptoms. Data to address incidence of CNS lesions in asymptomatic patients are rare and not generally reported. EGF111438/CEREBEL study requires systematic screening for brain metastases by brain MRI and the ineligible patients due to detection of asymptomatic brain metastases are reported here. METHODS The patients screened for CEREBEL have consented to a multi-centre, open-label Phase III study in subjects with HER2+ metastatic breast cancer who received prior treatment with anthracyclines or taxanes and trastuzumab in the adjuvant or metastatic setting. Eligible subjects must not have any history of CNS metastases (including leptomeningeal involvement) or have evidence of benign or malignant brain tumours and/or clinical evidence of spinal cord metastases at baseline. In order to confirm this, subjects must have negative brain MRI at baseline as confirmed by independent review (IR). All MRI scans of the brain had to be acquired with gadolinium contrast agent (T1 only) and 3mm slice thickness without gaps. The primary endpoint of CEREBEL is the incidence of CNS lesions as first site of relapse. A total of 650 subjects (325 per group) are expected to be randomized between capecitabine + trastuzumab versus capecitabine + lapatinib. RESULTS The study is currently recruiting with 322 patients enrolled as of 15.06.2011. At this date, the total number of patients screened were 492 and 170 of these patients were screen failures. There are 15 patients in screening. The percentage of screen failures due to asymptomatic brain metastases assessed by investigators was 13.5% (23/170). The overall incidence of clinically asymptomatic brain metastases assessed by investigators for this study is 4.7% (23/492). CONCLUSIONS Around 5% of all screened patients (14% of screen failures) in this study who were clinically thought to be free of brain lesions actually had brain metastases verified by brain MRI. We therefore conclude that screening for occult brain metastases by MRI is important for trials with defined CNS endpoints. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-17-03.

Background: Myocet™ (M) is a non-pegylated liposomal doxorubicin which exhibits reduced cardiotoxicity as compared to conventional doxorubicin. A phase 1/2 non-randomized multi-site trial combining M, trastuzumab (H) and paclitaxel (T) has resulted in high response rate, prolonged time to progression and improved overall survival, with no clinical cardiac toxicity in patients (pts) with first line metastatic breast cancer (MBC) over-expressing human epidermal growth factor-2neu (HER2+) (Cortes et al Clin Cancer res 2009:15:307). Methods: This multicenter study was designed to demonstrate the efficacy and cardiac safety of M+ H + T vs. the standard of care, H + T, in pts with HER2+ MBC with no prior chemotherapy for MBC. After stratification by hormone receptor status, prior or no prior anthracycline (A) therapy, age ≥50 or >50 y and geography, patients were randomly allocated to receive either M (50 mg/m2 q 3 wks for 6 cycles), H (4 mg/kg loading dose followed by 2 mg/kg q wk) and T (80 mg/m2 q wk) or H + T until progression or toxicity. The primary efficacy outcome is progression-free survival (PFS), as determined by a blinded independent review committee (IRC). The primary safety outcome is the incidence of NYHA class 3 or 4 heart failure or cardiac death, independently adjudicated. Secondary endpoints are overall survival and tumor response, also determined by the IRC according to RECIST. 332 pts were needed to detect a 30% difference in PFS with 80% power. Results: Between 2006 and 2009, 363 HER2+ women from 12 countries were enrolled. Median age is 53 yr (range 22-79); 80% are Caucasian; with ECOG performance status of 0 (62%) and 1 (38%); 42% are ER and/or PR positive; 40% received adjuvant chemotherapy, 24% hormone therapy, and 37% radiotherapy; 33% received prior A, median lifetime cumulativedoxorubicin and epirubicin dose (range) were 240 (45-360) mg/m2 and 360 (69-600) mg/m2, respectively. The final analysis of PFS is scheduled for 3Q10. Conclusions: The safety and efficacy data will be presented at the meeting. Clinical Trials.Gov Identifier: NCT00294996 Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-02.

Purpose A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin. Patients and Methods This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) –positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m2) and either epirubicin 60 mg/m2 (HEC-60) or 90 mg/m2 (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m2) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC). Results Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively. Conclusion The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.

Introduction: Lapatinib, an orally active tyrosine kinase inhibitor of epidermal growth factor receptor ErbB1 (EGFR) and ErbB2 (HER2), has activity as monotherapy and in combination with chemotherapy in HER2-overexpressing metastatic breast cancer (MBC). Methods: This phase II single-arm trial assessed the safety and efficacy of first-line lapatinib in combination with paclitaxel in previously untreated patients with HER2-overexpressing MBC. The primary endpoint was the overall response rate (ORR). Secondary endpoints were the duration of response (DoR), time to response, time to progression, progression-free survival (PFS), overall survival, and the incidence and severity of adverse events. All endpoints were investigator- and independent review committee (IRC)-assessed. Results: The IRC-assessed ORR was 51% (29/57 patients with complete or partial response) while the investigator-assessed ORR was 77% (44/57). As per the IRC, the median DoR was 39.7 weeks, and the median PFS was 47.9 weeks. The most common toxicities were diarrhea (56%), neutropenia (44%), rash (40%), fatigue (25%), and peripheral sensory neuropathy (25%). Conclusions: First-line lapatinib plus paclitaxel for HER2-overexpressing MBC produced an encouraging ORR with manageable toxicities. This combination may be useful in first-line treatment for patients with HER2-overexpressing MBC and supports the ongoing evaluation of this combination as first-line therapy in HER2-overexpressing MBC.

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.

Purpose Cross-talk between the estrogen receptor (ER) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathways is a mechanism of resistance to endocrine therapy, and blockade of both pathways enhances antitumor activity in preclinical models. This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor, everolimus (RAD001). Patients and Methods Two hundred seventy postmenopausal women with operable ER-positive breast cancer were randomly assigned to receive 4 months of neoadjuvant treatment with letrozole (2.5 mg/day) and either everolimus (10 mg/day) or placebo. The primary end point was clinical response by palpation. Mandatory biopsies were obtained at baseline and after 2 weeks of treatment (ie, day 15). Samples were assessed for PI3K mutation status (PIK3CA) and for pharmacodynamic changes of Ki67, phospho-S6, cyclin D1, and progesterone receptor (PgR) by immunohistochemistry. Results Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone (ie, placebo; 68.1% v 59.1%), which was statistically significant at the preplanned, one-sided, α = 0.1 level (P = .062). Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms, and dramatic downregulation of phospho-S6 occurred only in the everolimus arm. An antiproliferative response, as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15, occurred in 52 (57%) of 91 patients in the everolimus arm and in 25 (30%) of 82 patients in the placebo arm (P < .01). The safety profile was consistent with historical results of everolimus monotherapy; grades 3 to 4 adverse events occurred in 22.6% of patients who received everolimus and in 3.8% of patients who received placebo. Conclusion Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer.

Pemetrexed and carboplatin have demonstrated activity in breast cancer. Their potential synergism in experimental models and the proven efficacy of pemetrexed/platinum in other indications make pemetrexed/carboplatin an attractive combination in breast cancer. Thus, this two-stage, sequential, open-label, multicenter, phase II study assessed the efficacy and safety of pemetrexed plus carboplatin as first-line therapy in patients with locally advanced breast cancer (LABC) or metastatic breast cancer (MBC).Patientsor= 18 years with a histologic/cytologic diagnosis and no prior chemotherapy for LABC or MBC received pemetrexed 600 mg/m(2) and carboplatin AUC 5.0 on day 1 every 21 days with folic acid and vitamin B(12) supplementation.From June 2003 to April 2005, 50 patients with stage IIIB (30.0%) and stage IV (70.0%) disease were enrolled at 3 study centers. Twenty-eight percent of patients previously received adjuvant chemotherapy, 46.0% had visceral metastases, and 36.0% hador=3 organs involved. Partial responses (RECIST criteria) were achieved in 27 (54.0%) patients (ORR = 54.0%; 95% CI, 39.3-68.2%). The median response duration was 11.1 months (95% CI, 6.5-14.0 months) and the median time to disease progression was 10.3 months (95% CI, 8.3-14.6 months). CTC hematologic toxicities were grade 3/4 neutropenia (58.0%/28.0%) and grade 3 thrombocytopenia (10.0%) and anemia (18.0%). Two (4.0%) patients had febrile neutropenia, 1 of whom died. No grade 4 non-hematologic toxicities occurred. Grade 3 non-hematologic toxicities were ALT (4.0%) and AST elevation, and edema, fatigue, pruritus, rash/desquamation, and renal toxicity (2.0% each).Results of this study suggest that the combination of pemetrexed and carboplatin has promising efficacy and an acceptable safety profile. Further assessment of this combination in a randomized trial of various breast cancer patient populations is warranted.

Purpose Currently, antiangiogenic strategies in metastatic breast cancer have demonstrated modest improvements in progression-free survival (PFS) but not improved quality or duration of survival, warranting evaluation of new agents in a placebo-controlled setting. Ramucirumab is a human immunoglobulin G1 antibody that binds vascular endothelial growth factor receptor-2 and blocks ligand-stimulated activation. The ROSE/TRIO-012 trial evaluated ramucirumab with docetaxel in unresectable, locally recurrent, or metastatic breast cancer. Patients and Methods In this double-blind, placebo-controlled, randomized, multinational phase III trial, 1,144 patients with human epidermal growth factor receptor 2 (HER2) –negative breast cancer who had not received cytotoxic chemotherapy in the advanced setting were randomly assigned at a two-to-one ratio to receive docetaxel 75 mg/m2 plus ramucirumab 10 mg/kg or docetaxel 75 mg/m2 plus placebo once every 3 weeks. Treatment continued until disease progression, unacceptable toxicity, or other withdrawal criteria. Patients were stratified by previous taxane therapy, visceral metastasis, hormone receptor status, and geographic region. An independent data monitoring committee oversaw the trial. The primary end point was investigator-assessed PFS. Results Median PFS in patients treated with ramucirumab plus docetaxel was 9.5 months, compared with 8.2 months in patients who received placebo plus docetaxel (hazard ratio [HR], 0.88; P = .077). Median overall survival was 27.3 months in patients who received ramucirumab plus docetaxel, compared with 27.2 months in patients who received placebo plus docetaxel (HR, 1.01; P = .915). Toxicities seen at significantly higher rates in patients receiving ramucirumab included fatigue, hypertension, febrile neutropenia, palmar-plantar erythrodysesthesia syndrome, and stomatitis. Conclusion Addition of ramucirumab to docetaxel in HER2-negative advanced breast cancer did not meaningfully improve important clinical outcomes.

e12580 Background: Eribulin demonstrates improved overall survival compared to standard treatments, Her2-negative and TNBC patients have the most survival benefit. We sought to describe treatment patterns of eribulin and clinical outcomes among TNBC patients with advanced breast cancer treated in community oncology practices across the Russian Federation. Methods: Patients treated with eribulin anytime between January 1, 2014 and January 1, 2017 with a diagnosis of MBC were identified by providers within the Russia Oncology Research Center. Providers reviewed the health records (electronic or paper-based) and abstracted selected data points into an electronic case report form for each eligible patient. Results: A total 52 TNBC patients were considered by 10 providers. A median of age at start of eribulin was 47,5 (39-55) yrs and ECOG status 0-1 were assessed. Most of the pts (92,3%) had visceral mts, a median number metastatic disease regions was 2 (1-3). Eribulin was administered as the 1st and 2nd line of BC treatment to 14 (26,9%) pts, 3rd line – to 9 (17,3%), the 4thand later lines – to 29 (55,8%) pts. Objective response occurred in 5 (9,6%) pts. Stable disease registered in 24 (46,1%) pts. Median PFS was 3,0 months (95% CI 1,9-8,55). Overall the drug was well tolerated. The most common type of toxicity was hematologic. Neutropenia gr II was observed in 8 (15,4) pts and III-IV gr in 6 (11,5%), two cases of febrile neutropenia were registered. 4 (7,7%) pts experienced fatigue gr II. Peripheral neuropathy gr II was observed in 4 (7,7%) pts. Dose reduction due to toxicity was performed in 8 (15,4%) pts. Treatment was never withdrawn due to toxicity. Conclusions: This is the first real-life study of clinical outcomes, for patients initiating eribulin therapy for TNBC in community oncology practices throughout the Russian Federation. . Our experience with Eribulin in TNBC patients confirms it efficacy and safety in all lines of treatment, including intensively pretreated patients in this hard-to-treat population.

510 Background: CT-P6 (C) is a proposed biosimilar to trastuzumab. This trial (NCT02162667) evaluated the similarity of C and trastuzumab in efficacy and safety for HER2+ EBC. Methods: 549 patients with HER2+ EBC were randomized to receive C (n=271) or trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (Cycles 5-8). C or trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. The primary endpoint was pathological complete response (pCR) rate at surgery. Secondary endpoints were overall response rate (ORR), PK, PD and safety. After surgery, patients received adjuvant C or trastuzumab to complete a total of 1-year treatment. Results: The pCR rate was 46.8% for C and 50.4% for trastuzumab. The 95% CIs for the risk ratio estimate were within the equivalence margin (0.74, 1.35) in PPS and ITT analyses. Other efficacy endpoints were similar between C and trastuzumab. The proportion of patients with at least 1 treatment-emergent SAE was 6.6% for C and 7.6% for trastuzumab. Only 1 patient in each group withdrew treatment due to significant LVEF decrease. Infusion-related reaction was reported for 8.5% of patients in C and 9.0% of patients in trastuzumab. Conclusions: This study demonstrated the similarity of efficacy in terms of pCR between CT-P6 and trastuzumab in EBC patients. Secondary efficacy endpoints also supported the similarity between CT-P6 and trastuzumab. CT-P6 was well tolerated with a similar safety profile to that of trastuzumab during the neoadjuvant period. Clinical trial information: NCT02162667. [Table: see text]