Search

PURPOSE APHINITY, at 45 months median follow-up, showed that pertuzumab added to adjuvant trastuzumab and chemotherapy significantly improved invasive disease–free survival (IDFS) (hazard ratio 0.81 [95% CI, 0.66 to 1.00], P = .045) for patients with early human epidermal growth factor receptor 2 (HER2)–positive breast cancer (BC), specifically those with node-positive or hormone receptor (HR)–negative disease. We now report the preplanned second interim overall survival (OS) and descriptive updated IDFS analysis with 74 months median follow-up. METHODS After surgery and central HER2-positive confirmation, 4,805 patients with node-positive or high-risk node-negative BC were randomly assigned (1:1) to either 1-year pertuzumab or placebo added to standard adjuvant chemotherapy and 1-year trastuzumab. RESULTS This interim OS analysis comparing pertuzumab versus placebo did not reach the P = .0012 level required for statistical significance ( P = .17, hazard ratio 0.85). Six-year OS were 95% versus 94% with 125 deaths (5.2%) versus 147 (6.1%), respectively. IDFS analysis based on 508 events (intent-to-treat population) showed a hazard ratio of 0.76 (95% CI, 0.64 to 0.91) and 6-year IDFS of 91% and 88% for pertuzumab and placebo groups, respectively. The node-positive cohort continues to derive clear IDFS benefit from pertuzumab (hazard ratio 0.72 [95% CI, 0.59 to 0.87]), 6-year IDFS being 88% and 83%, respectively. Benefit was not seen in the node-negative cohort. In a subset analysis, IDFS benefit from pertuzumab showed a hazard ratio of 0.73 (95% CI, 0.59 to 0.92) for HR-positive disease and a hazard ratio of 0.83 (95% CI, 0.63 to 1.10) for HR-negative disease. Primary cardiac events remain < 1% in both the treatment groups. No new safety signals were seen. CONCLUSION This analysis confirms the IDFS benefit from adding pertuzumab to standard adjuvant therapy for patients with node-positive HER2-positive early BC. Longer follow-up is needed to fully assess OS benefit.

Background: The APHINITY trial demonstrated that pertuzumab, when added to adjuvant trastuzumab and chemotherapy, modestly but statistically significantly improved invasive disease-free survival (IDFS) among patients with HER2-positive, operable breast cancer. From November 2011 until August 2013, 2400 patients were randomly assigned to receive pertuzumab and 2405 to receive placebo. The clinical cut off-date for the primary analysis was 19 Dec 2016 after a median follow-up of 45.4 months. In the intent-to-treat (ITT) population, the estimates of the 3-year rates of IDFS were 94.1% in the pertuzumab group and 93.2% in the placebo group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The benefit appeared more pronounced in patients with node-positive disease, with a HR of 0.77 (95% CI 0.62-0.96), and in those with hormone receptor-negative disease, where the HR was 0.76 (95% CI 0.56-1.04). Based on these results, pertuzumab in combination with trastuzumab was approved for high risk early HER2-positive breast cancer patients. The first interim analysis of OS took place at that same time. A total of 169 patients had died, with no significant treatment effect with regards to mortality found at that time. Diarrhea, grade 3 or higher, was more frequent within the pertuzumab group (9.8%) compared with the placebo group (3.7%). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Results: At 74.1 months of median follow-up (clinical cut-off date June 19, 2019), we now report results of the pre-planned, calendar-driven second interim OS analysis which requires a p-value of 0.0012 to reach statistical significance. Updated descriptive analyses of IDFS and cardiac safety were also performed. Fewer deaths were observed in the pertuzumab (P) arm [125 (5.2%) vs 147 (6.1%)], however statistical significance was not reached at this interim analysis. The hazard ratio for OS is 0.85 [95% CI 0.67-1.07 (p=0.17)]; 6-year OS percents are 94.8% vs 93.9% (0.9% difference).Updated IDFS results based on 508 events in the ITT population are: hazard ratio 0.76 [95% CI 0.64-0.91]; 6-year IDFS percents are 90.6% vs 87.8% (2.8% difference). Of note, the difference was due mainly to the reduction in distant (5.9% vs 7.7%) and loco-regional (1.2% vs 2.0%) BC relapses. The node-positive cohort continues to derive clear benefit from the addition of P: hazard ratio 0.72 (95% CI 0.59-0.87). The benefit in terms of 6-year IDFS percent is 4.5% [87.9% vs 83.4%].In the node-negative cohort, the IDFS hazard ratio is 1.02 (95% CI; 0.69-1.53) with 95% of patients being event-free in both arms at 6 years.With longer follow up, a treatment benefit of P is also seen in the hormone receptor (HR) positive cohort: IDFS hazard ratio for HR positive is 0.73 (95% CI 0.59 -0.92). IDFS hazard ratio for HR negative is 0.83 (95% CI 0.63 -1.10). No new cardiac safety concerns emerged. One additional primary cardiac event (heart failure) was reported in the P arm and 1 additional patient in each arm had a secondary cardiac event resulting to 18 and 8 for primary cardiac events and 65 and 68 for secondary cardiac events in the P and placebo arms, respectively. The benefit of P in HER2+ early BC is maintained, with the greatest benefit continuing to be observed in the node positive population. With longer follow-up, the benefit of P no longer appears to depend on HR status. Continued follow up of patients is very important to determine possible benefit for OS. A calendar-driven third interim OS analysis is planned in 2.5 years, and the event-driven final OS analysis is planned when 640 deaths have occurred. Citation Format: Martine Piccart, Marion Procter, Debora Fumagalli, Evandro de Azambuja, Emma Clark, Michael S. Ewer, Eleonora Restuccia, Guy Jerusalem, Susan Dent, Linda Reaby, Hervé Bonnefoi, Ian Krop, Tsang-Wu Liu, Tadeusz Pieńkowski, Masakazu Toi, Nicolas Wilcken, Michael Andersson, Young-Hyuck Im, Ling-Ming Tseng, Hans-Joachim Lueck, Marco Colleoni, Estefania Monturus, Mihaela Sicoe, Sébastien Guillaume, José Bines, Richard Gelber, Giuseppe Viale, Christoph Thomssen. Interim overall survival analysis of APHINITY (BIG 4-11): A randomized multicenter, double-blind, placebo-controlled trial comparing chemotherapy plus trastuzumab plus pertuzumab versus chemotherapy plus trastuzumab plus placebo as adjuvant therapy in patients with operable HER2-positive early breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-04.

BACKGROUND: Angiopoietin 1 and 2 regulate angiogenesis and vascular remodelling by interacting with the tyrosine kinase receptor Tie2, and inhibition of angiogenesis has shown promise in the treatment of ovarian cancer. We aimed to assess whether trebananib, a peptibody that inhibits binding of angiopoietin 1 and 2 to Tie2, improved progression-free survival when added to carboplatin and paclitaxel as first-line therapy in advanced epithelial ovarian, primary fallopian tube, or peritoneal cancer in a phase 3 clinical trial. METHODS: TRINOVA-3, a multicentre, multinational, phase 3, double-blind study, was done at 206 investigational sites (hospitals and cancer centres) in 14 countries. Eligible patients were aged 18 years or older with biopsy-confirmed International Federation of Gynecology and Obstetrics (FIGO) stage III to IV epithelial ovarian, primary peritoneal, or fallopian tube cancers, and an ECOG performance status of 0 or 1. Eligible patients were randomly assigned (2:1) using a permuted block method (block size of six patients) to receive six cycles of paclitaxel (175 mg/m2) and carboplatin (area under the serum concentration-time curve 5 or 6) every 3 weeks, plus weekly intravenous trebananib 15 mg/kg or placebo. Maintenance therapy with trebananib or placebo continued for up to 18 additional months. The primary endpoint was progression-free survival, as assessed by the investigators, in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01493505, and is complete. FINDINGS: Between Jan 30, 2012, and Feb 25, 2014, 1164 patients were screened and 1015 eligible patients were randomly allocated to treatment (678 to trebananib and 337 to placebo). After a median follow-up of 27·4 months (IQR 17·7-34·2), 626 patients had progression-free survival events (405 [60%] of 678 in the trebananib group and 221 [66%] of 337 in the placebo group). Median progression-free survival did not differ between the trebananib group (15·9 months [15·0-17·6]) and the placebo group (15·0 months [12·6-16·1]) groups (hazard ratio 0·93 [95% CI 0·79-1·09]; p=0·36). 512 (76%) of 675 patients in the trebananib group and 237 (71%) of 336 in the placebo group had grade 3 or worse treatment-emergent adverse events; of which the most common events were neutropenia (trebananib 238 [35%] vs placebo 126 [38%]) anaemia (76 [11%] vs 40 [12%]), and leucopenia (81 [12%] vs 35 [10%]). 269 (40%) patients in the trebananib group and 104 (31%) in the placebo group had serious adverse events. Two fatal adverse events in the trebananib group were considered related to trebananib, paclitaxel, and carboplatin (lung infection and neutropenic colitis); two were considered to be related to paclitaxel and carboplatin (general physical health deterioration and platelet count decreased). No treatment-related fatal adverse events occurred in the placebo group. INTERPRETATION: Trebananib plus carboplatin and paclitaxel did not improve progression-free survival as first-line treatment for advanced ovarian cancer. The combination of trebananib plus carboplatin and paclitaxel did not produce new safety signals. These results show that trebananib in combination with carboplatin and paclitaxel is minimally effective in this patient population. FUNDING: Amgen. ispartof: LANCET ONCOLOGY vol:20 issue:6 pages:862-876 ispartof: location:England status: published

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

516 Background: GAIN-2 (NCT01690702) compared efficacy and safety of intense, dose-dense epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) vs dose-dense, dose-tailored epirubicin/ cyclophosphamide followed by dose-dense, dose-tailored docetaxel (dtEC-dtD) as adjuvant or neoadjuvant CT for node-positive or high risk node-negative EBC. Here, we report safety results and interim analysis (IA) of the primary endpoint iDFS. Methods: Pts (luminal A ≥N2; luminal B N+; HER2+ and TNBC) were randomized between iddEnPC (E 150 mg/m2, nP 330 mg/m2, C 2000 mg/m2, all q2w x 3) or dtEC-dtD (dtEC q2w x 4 followed after 1 week rest by dtD q2w x 4). Primary objective was to compare iDFS. 797 events are needed to detect a hazard ratio of 0.819 with a 2-sided log-rank-test with 80% power and α=0.05. The IA of iDFS was planned after 50% of the events have occurred. Safety and compliance were secondary objectives. Results: Between 10/2012 and 09/2018, 2887 pts were randomized and 2857 started treatment (iddEnPC 1429; dtEC-dtD 1428). Median age was 51 (range 18-75) years. Overall, 18.1% were luminal A, 31.5% luminal B/HER2-, 18.8% hormone-receptor (HR)+/HER2+, 8.5% HR-/HER2+ and 23.2% TNBC. Overall, 88.1% of pts completed all treatment in both arms. 66.8% with iddEnPC vs 58.8% with dtEC-dtD delayed CT dose (p

Summary Background Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer. Methods We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m2 on days 1–5) plus either oral sorafenib 400 mg or placebo twice daily on days 6–15, repeated every 21 days for six cycles, followed by daily maintenance sorafenib or placebo for up to 1 year in patients without progression. Investigators and patients were masked to allocation of sorafenib or placebo; topotecan treatment was open label. The primary endpoint was investigator-assessed progression-free survival, analysed in all patients who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov , number NCT01047891 . Findings Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43–0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8–7·6) with sorafenib versus 4·4 months (3·7–5·0) with placebo. The most common grade 3–4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]). Interpretation Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies. Funding Bayer , Amgen , and GlaxoSmithKline .

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

Purpose Patients with primary breast cancer who have extensive axillary lymph node involvement have a poor prognosis after conventional adjuvant therapy. We compared intense dose-dense (IDD) adjuvant chemotherapy with conventionally scheduled adjuvant chemotherapy in patients with high-risk primary breast cancer. Patients and Methods In this randomized, phase III trial, a total of 1,284 eligible patients with four or more involved axillary lymph nodes were randomly assigned to receive IDD sequential epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every 2 weeks or conventionally scheduled epirubicin/cyclophosphamide followed by paclitaxel every three weeks. The primary end point was event-free survival (EFS). Results At a median follow-up of 62 months, 5-year event-free survival rates were 62% in the conventional arm and 70% in the IDD-ETC arm, representing a 28% reduction of the relative risk of relapse (P < .001). This benefit was independent of menopausal, hormone receptor, or human epidermal growth factor receptor 2 status. The 5-year overall survival rates were 77% versus 82%, representing a 24% reduction of the relative risk of death (P = .0285). IDD therapy was associated with significantly more nonhematologic and hematologic toxicities, but no treatment-related death occurred. Four occurrences of acute myeloid leukemia or myelodysplastic syndrome (MDS) were observed in the IDD-ETC arm. No severe congestive heart failure was reported. Conclusion IDD-ETC was less well tolerated compared with conventional chemotherapy but significantly improved event-free and overall survivals in patients with high-risk primary breast cancer who had four or more positive axillary lymph nodes.

Evaluation of the influence of immunohistochemically defined breast cancer (BC) subtypes and other risk factors on the development of cerebral metastases (CM).Exploratory analysis of a hospital-based prospective tumour registry including all patients with primary BC treated in our EUSOMA breast unit between 1998 and 2006.The study cohort contained 2441 patients, including 284 patients (11.6%) with triple-negative (oestrogen receptor (ER), progesterone receptor (PR) and HER2-negative) and 245 patients (10.1%) with HER2-overexpressing BC subtypes. Overall, 80 patients (3.3%) developed CM within a median follow-up period of 47 months, 19 (23.8%) of them with triple-negative and 19 (23.8%) with HER2-positive tumours. Therefore, 6.7% of all patients with triple-negative and 7.8% of patients with HER2-positive breast cancer developed CM. Multivariate analysis indicated that the highest risk for CM was triple-negative breast cancer. Further independent risk factors were: HER2-overexpression, early onset BC (age50 years), and large tumour size (pT3/4). Among those patients developing CM, triple-negative BC showed the shortest interval between primary diagnosis and occurrence of CM with a median of 22 months, compared to 30 and 63.5 months in HER2-positive and ER+/HER2- BC, respectively. Survival after occurrence of CM did not differ among the subtypes.Patients with triple-negative or HER2-positive BC have a higher risk for CM compared with patients bearing the ER+/HER2- phenotype and develop CM earlier in the course of disease. A risk profile for CM might help adjust surveillance in high risk populations and identify patients with a need for new treatment strategies.

Purpose Despite the progress that has been achieved, long-term survival rates in patients with advanced ovarian cancer are still disappointing. One attempt to improve results could be the addition of non–cross-resistant drugs to platinum-paclitaxel combination regimens. Anthracyclines were among the candidates for incorporation as a third drug into first-line regimens. Patients and Methods We performed a prospectively randomized phase III study comparing carboplatin-paclitaxel (TC; area under the curve 5/175 mg/m2, respectively) with epirubicin 60 mg/m2 added to the same combination (TEC) in previously untreated patients with advanced epithelial ovarian cancer. All drugs were administered intravenously on day 1 of a 3-week schedule for a planned minimum of six courses. Results Between November 1997 and February 2000, 1,282 patients were randomly assigned to receive either TC (635 patients) or TEC (647 patients), respectively. Grade 3/4 hematologic and some nonhematologic toxicities (nausea/emesis, mucositis, and infections) occurred significantly more frequently in the TEC arm. Accordingly, quality-of-life analysis showed inferiority of TEC versus TC. Median progression-free survival time was 18.4 months for the TEC arm and 17.9 months for the TC arm (hazard ratio [HR], 0.95; 95% CI, 0.83 to 1.07; P = .3342). Median overall survival time was 45.8 months for the TEC arm and 41.0 months for the TC arm (HR, 0.93; 95% CI, 0.81 to 1.08; P = .3652). Similar nonsignificant differences were observed when strata were analyzed separately. Conclusion Addition of epirubicin to TC did not improve survival or time to treatment failure in patients with advanced epithelial ovarian cancer; therefore, it cannot be recommended for clinical use in this population.

5517 Background: Therapeutic paradigms for recurrent OC vary by geography. Maintenance following response to platinum-based chemotherapy (Plat) is standard in Europe, whereas in the US maintenance is considered following complete response (CR) vs treatment for partial response (PR). Niraparib is a highly selective PARP 1/2 inhibitor (PARPi). In preclinical studies it concentrates in the tumor relative to plasma, delivering > 90% durable PARP inhibition and antitumor effects. Niraparib demonstrated significantly longer PFS vs placebo (P) in pts with recurrent OC following a CR or PR to Plat in the randomized, controlled, double-blind phase 3 ENGOT-OV16/NOVA trial. Methods: Pts with recurrent OC, no prior PARPi use, ≥2 prior courses of Plat, and response to most recent Plat were eligible. Pts were assigned to 1 of 2 cohorts on the basis of g BRCA testing (g BRCAmut or non-g BRCAmut) and randomized 2:1 within each cohort to niraparib 300 mg or P qd until progressive disease (PD). Randomization occurred up to 8 weeks after last dose of the most recent Plat. Pts were stratified by time to progression after penultimate Plat (6 to < 12 months or ≥12 months), prior use of bevacizumab (yes/no), and response to most recent Plat (CR or PR). PFS was measured from time of randomization to death or earliest PD as assessed by independent review committee. Results: 49% of pts (niraparib: 67/138; P: 32/65) in the g BRCAmut and ~49% of pts (niraparib: 117/234 [50%]; P: 56/116 [48%]) in the non-g BRCAmut cohorts entered NOVA with a PR following their most recent Plat. At time of unblinding, 30 (45%) niraparib and 23 (72%) P pts in the g BRCAmut and 65 (56%) niraparib and 45 (80%) P pts in the non-g BRCAmut cohorts had PFS events. PFS hazard ratios (95% CI) were 0.24 (0.131–0.441) in g BRCAmut and 0.35 (0.230–0.532) in non-g BRCAmut cohorts for pts who had a PR to their most recent platinum regimen. This compared favorably to the overall NOVA study results, where PFS hazard ratios (95% CI) were 0.27 (0.173–0.410) in g BRCAmut and 0.45 (0.338–0.607) in non-g BRCAmut cohorts. Conclusions: Niraparib treatment provided significant benefit to pts with recurrent OC who achieved a PR following Plat. Clinical trial information: NCT01847274.

Background The presence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients is associated with reduced clinical outcome. Bisphosphonate treatment was shown to eradicate DTC from BM in several studies. This controlled randomized open-label multi-center study aimed to investigate the influence of zoledronic acid (ZOL) on DTC and survival of breast cancer patients (Clinical Trial Registration Number: NCT00172068). Methods Patients with primary breast cancer and DTC-positive bone marrow were randomized to treatment with ZOL plus adjuvant systemic therapy (n = 40) or adjuvant systemic therapy alone (n = 46) between 03/2002 and 12/2004. DTC were identified by immunocytochemistry using the pancytokeratin antibody A45B/B3 and by cytomorphology. The change in DTC numbers at 12 months and 24 months versus baseline, as well as patient outcomes were evaluated. Results 86 patients could be included into survival analysis (median follow-up: 88 months, range: 8–108 mths). Patients in the control group were more likely to die during follow-up than those in the ZOL-group (11% vs. 2%, p = 0.106). 15% of patients in the control group presented with relapse whereas only 8% of ZOL group patients developed metastatic or recurrent disease during follow-up (p = 0.205). At 24 months, 16% of patients from the control group were still DTC positive, whereas all patients treated with ZOL became DTC negative (p = 0.032). Patients presenting with persistent DTC 12 months after diagnosis had significantly shorter overall survival (p = 0.011). Conclusions Bisphosphonate therapy contributes to eradication of disseminated tumor cells. The positive influence of bisphosphonates on survival in the adjuvant setting may be due to their effects on DTC. Trial registration ClinicalTrials.gov Identifier: NCT00172068 [Zoledronic Acid in the Treatment of Breast Cancer With Minimal Residual Disease in the Bone Marrow (MRD-1)].

5522Background: Sorafenib (S), a multi TK-inhibitor in combination with topotecan (T), a topoisomerase inhibitor showed preclinical synergistic effects in ovarian cancer but critical toxicity. To a...

1036 Background: Information on deaths occurring during oncological clinical trials has never been systematically assessed to describe patient, tumor, and treatment characteristics. Methods: Inform...

Aim: In locally advanced breast cancer pts (≥pN2), adjuvant iddETC resulted in superior disease-free (DFS) and overall survival (OS) compared to conventionally dosed EC > Tq3w (AGO-ETC; Mobus JCO 2010). In the GAIN trial, iddETC was compared to a 4-drug dose-dense regimen with capecitabine (ddEC > TwX). Using the GAIN data, here we want to confirm the iddETC-results of the AGO-ETC trial with regard to DFS, OS, and toxicity. Methods: In the AGO-ETC trial (1998-2003) 681 of 1,284, and in GAIN (2004-2008) 1,498 of 3,023 pts were treated with iddETC. Pts were included in AGO-ETC if ≥pN2 and in GAIN if ≥pN1; median number of positive nodes was 8 and 5, respectively; all other inclusion criteria were comparable. Median follow-up was 62 and 74 months, respectively, in both trials primary end point was DFS. IddETC consists of a sequence of 3 x E 150mg/m2, 3 x T 225 mg/m2, and 3 x C 2,5 g/m2 q2w, with primary G-CSF support. After 40% accrual in GAIN, a reduced dose of C (2,0 g/m2) and antibiotic prophylaxis was implemented. Pts were randomly assigned to anemia prophylaxis with ESF in AGO-ETC, and to adjuvant ibandronate in GAIN (von Minckwitz JCO 2013). Results: In the iddETC-arm of AGO-ETC, 5y-DFS was 70% (95% CI 68% - 75%) and 5y-OS was 82% (95% CI, 79%to 85%). Comparing to conventional EC > Tq3w, HR for DFS was 0.69 (95% CI, 0.57 - 0.84). In GAIN, 5y-DFS was 80% (95% CI 78% - 82%) and 5y-OS was 85%. DdEC > TwX was not superior to iddETC. Evaluating GAIN pts with ≥pN2 (n = 923) separately, in order to match with the AGO-ETC inclusion criteria, results were comparable: 5yr-DFS was 75% (95% CI 72% - 78%) and 5y-OS was 85% (95% CI 83% - 88%). In AGO-ETC, 47 pts (7%) had at least one episode of febrile neutropenia during iddETC, no toxic death was observed. In GAIN, three pts (0,2%) died from therapy related septicaemia during iddETC. In both trials, paclitaxel induced neuropathy was in the expected range, and no grade 3 congestive heart failure occurred. Treatment induced MDS/AML was rare in both, AGO-ETC (0,6%) and GAIN (0,3%). Conclusions: We consistently show high efficacy of adjuvant iddETC for node-positive breast cancer pts (≥pN2) in two consecutive prospective trials: DFS and OS-results were superior to those with conventionally dosed therapy. In the reported studies, iddETC was feasible without excessive toxicity. We suggest to add iddETC to the group of preferred regimens in current guidelines. Disclosure: C. Thomssen: has received compensated honoraria for presentations and participating in advisory boards from Roche, Amgen, Pfizer; G. von Minckwitz: has received research funds from Roche, BMS, Amgen, Speaker and consultancy honoraria from Roche and Amgen; H. Tesch: has received compensated honoraria from Roche; N. Harbeck has received compensated honoraria from Roche; V. Muller: has received speaker honoraria from Amgen, Celgene, Glaxo Smith Kline, Pierre-Fabre, Roche, Jannsen-Cilag I. Bauerfeind: speakers honoraria from Amgen and Bristol Myers Squibb; S. Loibl: has received compensated honoraria for presentations and participating in advisory boards from Roche, Amgen V. Moebus: has receivedCompensated honoraria from Amgen, Jannsen-Cilag, Roche for presentations and participation in advisory boards. All other authors have declared no conflicts of interest.

1009 Background: Intense dose-dense (idd) epirubicin (E), paclitaxel (T), cyclophosphamide (C) (idd-ETC) resulted in a superior disease-free (DFS) and overall survival (OS) compared to conventional...

1082 Background: Conventional chemotherapy combined with novel molecular targeted agents has been proven effective and tolerable in metastatic breast cancer (MBC). Taxanes (T) plus bevacizumab (B) and T plus capecitabine (X) showed a benefit in progression free survival (PFS) compared to T alone. Life-threatening or highly symptomatic situations require poly-chemotherapies in MBC patients; therefore a combination of all 3 drugs appears reasonable. Methods: TABEA (NCT01200212) is a prospective, randomized, open label, phase III trial comparing T plus B +/- X as 1st-line therapy in MBC. Patients with histologically confirmed HER2- locally advanced or MBC were included. All patients received T (paclitaxel 80 mg/m2 i.v. d1,8,15 q22 or docetaxel 75 mg/m2 i.v. d1 q22) and B (15 mg/kg i.v. d1 q22) (TB) and were randomized to X (1800 mg/m² daily d1-14 q22) in addition and concurrently to TB (TBX) or TB alone. Randomization was stratified by receptor status, planned taxane, and disease free interval (≤ or >12 months). Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (CR, PR, stable disease ≥ 24 weeks), 3yr overall survival, PFS in patients ≥ 65 years, toxicity, and compliance. Sample size calculation assumed a PFS of 10 and 13.3 months for TB and TBX, respectively (HR=0.75) requiring 432 patients and 386 events with 2-sided α=0.05 and β=0.2. Interim analysis was planned after 25% of required events (n=96). Results: Planned interim futility and safety analyses after 100 documented events in 202 patients have shown no efficacy benefit and higher toxicity in the TBX arm. For PFS, HR=1.061, 95% CI (0.715, 1.576) was observed, futility boundary was crossed. Overall grade 3-4 adverse events (e.g., thrombopenia, diarrhea, hand-foot-syndrome) (72.3 vs. 57.4%, p=0.039)and serious adverse events (40.6 vs. 24.8%, p=0.016) rates were higher for TBX after 16.3 months median follow up. There were 6 deaths in the TBX vs. 1 in the TB arm. Recruitment and therapy were stopped on 5th Oct 2012 following the advice from the IDMC. Conclusions: TABEA failed to show an improvement using the 3 drug regimen TBX in high-risk MBC patients. Clinical trial information: NCT 01200212.

e17544 Background: The optimal CTX regimens and their sequence is the subject of ongoing debates esp. on the use of anthracycline/taxane (AT)-based adjuvant therapy (tx). Methods: Since 2004 a biennial survey is performed to evaluate routine CTX practice in MBC A total of 1,966 German sites were contacted. From 515 (26.2%) patient data were used for evaluation in order to achieve a representative sample for a chart review between June and August 2012. The current analysis is based on data from 291 sites on characteristics and tx of 741 pts undergoing first (1L), second (2L) or third (3L) line CTX for MBC in May 2012. Results: Data from 417 pts in 1L, 203 pts in 2L, and 121 pts in 3L were evaluated. Median age was 60 years (yrs). Patient characteristics were: 74% hormone receptor positive, 24% HER2-positive at primary diagnosis, 67% premenopausal, 60% had metastases in ≥ 2 organs, 66% had visceral disease. Prior tx (excluding M1 pts) was: no systemic tx 10%, endocrine tx only 13%, adjuvant CTX 58% (40% A and 44% AT-based), neoadjuvant CTX 20% (12% A and 75% AT-based). Median time from primary diagnosis to start of any treatment for MBC was 4.5 yrs for node-negative and 2.1 yrs for node-positive disease. Median time from primary diagnosis to current CTX was 4.9 yrs in 1L, 5.1 yrs in 2L and 5.8 yrs in 3L. Combination CTX was given in 21% of 1L, 12% of 2L and 9% of 3L pts, and its use decreased with increasing age. Agents used most frequently in 1L were taxanes in 61% (paclitaxel (P) 52%, docetaxel (D) 6%, nab-paclitaxel (Nab) 3%), capecitabine (X) 21%, vinorelbin (V) 19%, Epirubicin 6%, carboplatin 5%. 1L taxane tx was given to 73% of pts with prior A-based and 46% of pts with prior AT-based (neo-)adjuvant tx. Agents used most frequently in 2L were X 31%, P 20%, V 20%, gemcitabine (G) 7%, Nab 6% and in 3L V 27%, X 22%, eribulin 15%, Nab 12% P 7%, G 5%. Targeted tx was given in 54% of pts (20% trastuzumab, 4% lapatinib, and 30% bevacizumab), additional tx were bisphosphonates in 58%, and radiotherapy in 20%. Conclusions: The survey showed a high concordance of routine treatment and the existing national guidelines regarding CTX. Taxanes still dominate CTX in MBC including a significant amount of taxane rechallenge after their use in (neo-)adjuvant tx.