Articles. Funding Central European Cooperative Oncology Group; Roche.

Transcription

1 versus bevacizumab plus as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial Istvan Lang, Thomas Brodowicz, Larisa Ryvo, Zsuzsanna Kahan, Richard Greil, Semir Beslija, Salomon M Stemmer, Bella Kaufman, Zanete Zvirbule, Günther G Steger, Bohuslav Melichar, Tadeusz Pienkowski, Daniela Sirbu, Diethelm Messinger, Christoph Zielinski, on behalf of the Central European Cooperative Oncology Group* Summary Background Randomised phase 3 trials in metastatic breast cancer have shown that combining bevacizumab with either paclitaxel or significantly improves progression-free survival and response rate compared with chemotherapy alone but the relative efficacy of bevacizumab plus paclitaxel versus bevacizumab plus has not been investigated. We compared the efficacy of the two regimens. Methods In this open-label, non-inferiority, phase 3 trial, patients with HER2-negative metastatic breast cancer who had received no chemotherapy for advanced disease were randomised (by computer-generated sequence; 1:1 ratio; block size six; stratified by hormone receptor status, country, and menopausal status) to receive either intravenous bevacizumab (10 mg/kg on days 1 and 15) plus intravenous paclitaxel (90 mg/m² on days 1, 8, and 15) repeated every 4 weeks (paclitaxel group) or intravenous bevacizumab (15 mg/kg on day 1) plus oral (1000 mg/m² twice daily on days 1 14) repeated every 3 weeks ( group) until disease progression or unacceptable toxic effects. Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. The primary objective was to show non-inferior overall survival with bevacizumab plus versus bevacizumab plus paclitaxel. We report results of an interim overall survival analysis, which was planned for after 175 deaths in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT Findings Between Sept 10, 08, and Aug 30, 10, we randomised 564 patients (paclitaxel group n=285; group n=279) from 51 centres in 12 countries. The per-protocol population consisted of 533 patients (paclitaxel group n=268; group n=265). After median follow-up of 18 6 months (IQR ), 181 patients in the perprotocol population had died (89 [33%] in the paclitaxel group; 92 [35%] in the group). The hazard ratio [HR] for overall survival was 1 04 (97 5% repeated CI to 1 69; p=0 059); the non-inferiority criterion of the interim analysis (interim α= ) was not met. More patients who received bevacizumab plus paclitaxel had an objective response than did those who received bevacizumab plus (125 [44%] of 285 patients vs 76 [27%] of 279; p<0 0001). Similarly, progression-free survival was significantly longer in the paclitaxel group than in the group (median progression-free survival 11 0 months [95% CI ] vs 8 1 months [ ]; HR 1 36 [95% CI ], p=0 0052). The most common adverse events of grade 3 or higher were neutropenia (51 [18%]), peripheral neuropathy (39 [14%]), and leucopenia ( [7%]) in the paclitaxel group and hand-foot syndrome (44 [16%]), hypertension (16 [6%]), and diarrhoea (15 [5%]) in the group. One treatment-related death occurred in the paclitaxel group; no deaths in the group were deemed to be treatment-related. Interpretation In this planned interim analysis, the non-inferiority criterion was not met and overall survival results are inconclusive. Final results are expected in 14. Progression-free survival was better, and more patients achieved an objective response, with bevacizumab plus paclitaxel than with bevacizumab plus. Efficacy results in both groups were consistent with previous reports. Funding Central European Cooperative Oncology Group; Roche. Introduction Although several therapies are available for patients with HER2-negative locally recurrent or metastatic breast cancer, no gold standard first-line treatment option exists. 1,2 Chemotherapeutic options include anthracyclines, taxanes, and. In three randomised phase 3 trials (E2100, 3 AVADO, 4 and RIBBON-1 5 ) in this setting, combining bevacizumab with first-line taxane or non-taxane therapy (including anthracyclines or ) significantly improved progression-free Published Online January 10, 13 S (12) *Investigators listed in appendix National Institute of Oncology, Budapest, Hungary (Prof I Lang MD); Comprehensive Cancer Center Medical University Vienna General Hospital, Vienna, Austria (T Brodowicz MD, G G Steger MD, Prof C Zielinski MD); Tel Aviv Sourasky Medical Center, Tel Aviv, Israel (L Ryvo MD); University of Szeged, Szeged, Hungary (Prof Z Kahan MD); IIIrd Medical Department with Hematology and Medical Oncology, Paracelsus Medical University, Salzburg, Austria (Prof R Greil MD); Institute of Oncology, Sarajevo, Bosnia and Herzegovina (S Beslija MD); Rabin Medical Center, Petach Tikva, Israel (S M Stemmer MD); Sheba Medical Center, Tel Hashomer, Israel (B Kaufman MD); Riga Eastern Clinical University Hospital, Riga, Latvia (Z Zvirbule MD); Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic (Prof B Melichar MD); Postgraduate Medical Center, Warsaw, Poland (T Pienkowski MD); Oncomed Oncology Practice, Timisoara, Romania (D Sirbu MD); and IST GmbH, Mannheim, Germany (D Messinger MSc) Correspondence to: Prof Christoph Zielinski, Clinical Division of Oncology, Department of Medicine I and Comprehensive Cancer Center, Medical University Vienna General Hospital, 18 Waehringer Guertel, 1090 Vienna, Austria christoph.zielinski@ meduniwien.ac.at Published online January 10,

2 See Online for appendix For the trial protocol see assigned to bevacizumab plus paclitaxel (intentionto-treat population) 284 received treatment (safety population) 268 included in per-protocol population survival (PFS) and the proportion of patients who achieved an objective response compared with chemotherapy alone. In view of tolerability, hair loss, and avoidance of weekly intravenous administration, some patients might prefer a non-taxane regimen, such as bevacizumab plus, rather than bevacizumab plus paclitaxel, providing that overall survival is not compromised. TURANDOT (capecitabine and bevacizumab Randomised Against avastin and taxol Trial) is the first head-to-head trial comparing bevacizumab plus paclitaxel versus bevacizumab plus as firstline therapy for patients with HER2-negative locally recurrent or metastatic breast cancer. TURANDOT was designed to answer three main questions: is overall survival with first-line bevacizumab plus non-inferior to that with bevacizumab plus paclitaxel? What is the efficacy of the two regimens in terms of other endpoints, including quality of life? Do toxic effects limit the use of either paclitaxel or in combination with bevacizumab? We report the first efficacy results from the planned interim efficacy analysis of this trial. 604 assessed for eligibility 564 randomised 1 excluded from safety analysis 1 consent withdrawn 16 excluded from per-protocol population 8 violated inclusion criteria* 8 met exclusion criteria* 1 did not receive allocated treatment 40 excluded 35 did not meet inclusion criteria 4 declined to participate 1 other Figure 1: Trial profile *One patient both violated inclusion criteria and met exclusion criteria. 279 assigned to bevacizumab plus (intention-to-treat population) 277 received treatment (safety population) 265 included in per-protocol population 2 excluded from safety analysis 1 consent withdrawn 1 randomisation failure 12 excluded from per-protocol population 8 violated inclusion criteria 4 met exclusion criteria Methods Study design and participants TURANDOT is a multinational, open-label, randomised phase 3 trial. Eligible patients had HER2-negative measurable or non-measurable locally recurrent or metastatic breast cancer, Eastern Cooperative Oncology Group (ECOG) performance status 0 2, were aged 18 years or older, and had received no previous chemotherapy for locally recurrent or metastatic disease. Previous neoadjuvant or adjuvant chemotherapy or adjuvant radiotherapy was permitted only when completed more than 6 months before randomisation (>12 months for taxane-based regimens). All patients were to have adequate hepatic, renal, cardiac, and haematological function. Patients with uncontrolled hypertension or clinically significant or uncontrolled cardiovascular disease were not eligible. All patients provided written informed consent before study entry, and the study protocol was approved by the institutional review boards of all participating institutions. Randomisation and masking Eligible patients were randomly assigned to treatment groups in a 1:1 ratio, with permuted blocks of size six stratified by oestrogen and progesterone receptor status (one or both positive vs both negative or unknown), country, and menopausal status (premenopausal vs postmenopausal). Treatment group assignment was allocated sequentially in the order in which the eligible patients were enrolled into the study through an interactive web-based response instrument integrated into an electronic data capture system (Amedon GmbH, Lübeck, Germany). Treatment allocation was not masked because of the differences in routes of administration and cycle lengths. Procedures Patients randomly assigned to receive bevacizumab and paclitaxel were treated with intravenous bevacizumab 10 mg/kg on days 1 and 15 plus intravenous paclitaxel 90 mg/m² on days 1, 8, and 15, repeated every 4 weeks (paclitaxel group). Those assigned to receive bevacizumab and were given intravenous bevacizumab 15 mg/kg on day 1 plus oral 1000 mg/m² twice daily on days 1 14, repeated every 3 weeks ( group). The starting dose was reduced by 25% in patients aged 65 years or older. Treatment was continued until disease progression, unacceptable toxic effects, or withdrawal of consent. If one of the drugs was discontinued because of toxic effects, the other was continued as a single agent. Endocrine therapy was not permitted during the study treatment phase. bevacizumab dose reductions for toxic effects were allowed but bevacizumab was withheld or discontinued permanently in the event of prespecified adverse events (appendix). Capecitabine and paclitaxel dose interruptions, 2 Published online January 10, 13

3 delays, and reductions were implemented in the event of toxic effects of grade 2 or higher (appendix). Tumours were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) at baseline and every 12 weeks with CT, MRI, or radiograph. We monitored and recorded adverse events, graded according to Common Terminology Criteria for Adverse Events (CTCAE, version 3 0), at every cycle throughout the study and for 28 days after treatment discontinuation. All patients were to complete the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) at baseline, at each tumour assessment (every 12 weeks), and 28 days after discontinuation of study treatment. Statistical analysis The primary objective was to show that overall survival with bevacizumab plus was non-inferior to that with bevacizumab plus paclitaxel. 389 deaths in the per-protocol population would provide 80% power to reject the null hypothesis of inferiority (hazard ratio [HR] 1 33) at a one-sided significance level of 0 025, assuming a median overall survival of 24 months with bevacizumab plus paclitaxel and an HR of 1 as the alternative hypothesis (non-inferiority). Since the margin of non-inferiority could not be selected on the basis of improvement in overall survival in previous trials of bevacizumab plus paclitaxel (because no trial has shown a significant overall survival benefit), the non-inferiority margin was selected according to medical judgment of a clinically appropriate and acceptable margin. The selected margin of non-inferiority is within the range of such margins in other trials. 6 We planned to randomise 560 patients, with at least 490 eligible patients anticipated in the per-protocol population. We planned one interim analysis of overall survival using Lan-DeMets α-spending methods with O Brien-Fleming boundaries for after about 175 deaths, which was expected after roughly 18 months median follow-up. The interim analysis, reported here, was done after 181 deaths, resulting in an α level of spent for the interim analysis. Final overall survival analysis is planned after 389 deaths in the per-protocol population. We used a stratified Cox proportional hazard model to calculate the HR for overall survival and the corresponding one-sided repeated CI at the interim analysis. 7 The assumption of proportional hazards was reviewed with log( log) plots and tested with the time by treatment group interactions, which showed that the assumption was appropriate. We used the Kaplan-Meier method to visualise the overall survival curve and to calculate overall survival rates at various timepoints. Secondary objectives were comparison of the proportion of patients who achieved an objective response according to RECIST, PFS, time to response, duration of response, time to treatment failure, safety (CTCAE version 3 0), and quality of life (EORTC QLQ-C30). For the proportion of patients who achieved an objective response we compared the two treatment groups with the Cochran-Mantel-Haenszel test, stratified by country, menopausal status, and oestrogen and progesterone receptor status at randomisation. Differences in PFS, time to treatment failure, and time to response between the two treatment groups were analysed with two-sided log-rank tests, adjusted by stratification factors; Kaplan-Meier methods were applied to visualise the corresponding curves. We applied plus paclitaxel (n=285) plus (n=279) Age (years) 59 (49 64) 59 (48 65) Menopausal status Premenopausal 52 (18%) 51 (18%) Postmenopausal 232 (81%) 224 (80%) t applicable (men) 1 (<1%) 4 (1%) ECOG performance status* (68%) 179 (65%) 1 75 (26%) 91 (33%) 2 15 (5%) 7 (3%) Receptor status Oestrogen receptor positive 215 (75%) 1 (72%) Progesterone receptor positive 167 (59%) 168 (60%) Triple negative 63 (22%) 67 (24%) Metastatic at first diagnosis 59 (21%) 59 (21%) Disease-free interval 12 months 15 (5%) 10 (4%) >12 months 198 (69%) 5 (73%) Metastatic sites Visceral 186 (65%) 3 (73%) Liver 113 (40%) 126 (45%) Lung 113 (40%) 122 (44%) Bone 157 (55%) 150 (54%) Soft tissue or bone, or both 42 (15%) 23 (8%) Previous hormonal therapy Adjuvant or neoadjuvant only 113 (40%) 112 (40%) Advanced only 25 (9%) 33 (12%) Both 37 (13%) 25 (9%) ne 110 (39%) 108 (39%) Adjuvant or neoadjuvant chemotherapy Anthracycline and taxane 37 (13%) 35 (13%) Anthracycline, no taxane 110 (39%) 112 (40%) Taxane, no anthracycline 21 (7%) 16 (6%) Other (neither anthracycline nor 32 (11%) 28 (10%) taxane) ne 105 (37%) 103 (37%) Data are median (IQR) or n (%). ECOG=Eastern Cooperative Oncology Group. *Missing in three patients (one in the paclitaxel group, two in the goup). Remaining patients did not receive or did not respond to therapy for primary breast cancer. More than one answer possible if adjuvant and neoadjuvant chemotherapy differed. Table 1: Baseline characteristics (intention-to-treat population) Published online January 10,

4 Overall survival (%) Number at risk Overall survival (%) A Number at risk 40 stratified Cox proportional hazard models to establish HRs, median values, and corresponding 95% CIs. For all secondary endpoints, superiority tests at a two-sided α level of 0 05 were done, with 95% CIs. Because this is a non-inferiority trial, the primary efficacy analysis was based on the per-protocol population, consisting of all randomised patients except those violating any of the inclusion criteria or meeting any exclusion criteria. To support the per-protocol analysis, major efficacy analyses were repeated with the intention-to-treat population (all randomised patients). The safety population consisted of all randomised patients who received at least one dose of study drug. We did all analyses with SAS (version 8 2) and EAST (version 5). This trial is registered with ClinicalTrials.gov, number NCT Role of the funding source The sponsor of the trial, the Central European Cooperative Oncology Group, had full responsibility for the study design and the collection, analysis, and interpretation of data. The corresponding author had final responsibility for the preparation and finalisation of this manuscript and the decision to submit it for publication. F Hoffmann- La Roche (Basel, Switzerland) had no role in the design, conduct, or analysis of the trial, nor in the interpretation of the results or final content and decision to submit the HR 1 04 (97 5% repeated CI to 1 69); p= B HR 1 03 (97 5% repeated CI to 1 60); p= Time (months) Figure 2: Kaplan-Meier estimate for overall survival (A) Per-protocol population (primary efficacy analysis). (B) Intention-to-treat population manuscript for publication. ne of the authors was paid to write the Article and the corresponding author had full access to all the data from the study. Results Between Sept 10, 08, and Aug 30, 10, we randomised 564 patients from 51 centres in Hungary, Israel, Austria, Romania, the Czech Republic, Poland, Latvia, Bosnia and Herzegovina, Slovakia, Serbia, Bulgaria, and Croatia. Three patients did not receive treatment, thus the safety population included 561 patients. The per-protocol population included 533 patients (paclitaxel group n=268; group n=265; figure 1). Data cutoff for this analysis was Sept 1, 11, when median duration of follow-up was 18 6 months (IQR ): 19 1 months ( ) in the paclitaxel group and 18 5 months ( ) in the group. Baseline characteristics were generally well balanced between the treatment groups (table 1). At the time of this analysis, 54 (10%) of 561 patients remained on therapy (28 [10%] of 284 in the paclitaxel group; 26 [9%] of 277 in the group). Median duration of bevacizumab treatment was 8 0 months (IQR ) with bevacizumab plus paclitaxel versus 6 2 months ( ) with bevacizumab plus. was continued for 1 year or more in 80 (28%) of 284 patients in the paclitaxel group and in 68 (25%) of 277 patients in the group. Median duration of chemotherapy was much the same in the two treatment groups (6 2 months [IQR ] for paclitaxel vs 6 6 months [ ] for ). Chemotherapy was continued for 1 year or more in 31 (11%) patients in the paclitaxel group and in 71 (26%) patients in the group. The main reason for discontinuation of bevacizumab was disease progression in both groups (paclitaxel group 145 [57%] of 256 withdrawals, group 176 [70%] of 251 withdrawals), whereas chemotherapy was most often discontinued because of adverse events in the paclitaxel group (96 [38%]) and disease progression in the group (175 [70%]). Chemotherapy was interrupted or delayed because of toxic effects in 154 (54%) of 284 patients receiving paclitaxel and 130 (47%) of 277 patients receiving. Mean relative dose intensity of bevacizumab was 93% in the paclitaxel group and almost 100% in the group. Mean relative dose intensity of chemotherapy was 89% in both groups. At data cutoff for this interim efficacy analysis, 96 (34%) of 285 patients in the paclitaxel group and 97 (35%) of 279 patients in the group had died (intention-to-treat population). The most common causes of death were disease progression (77 [80%] deaths in the paclitaxel group vs 81 [84%] deaths in the group) and disease-related complications (11 [11%] with paclitaxel vs nine [9%] with ). In the per-protocol population, defined in the protocol for 4 Published online January 10, 13

5 the primary efficacy analysis, 89 (33%) of 268 patients in the paclitaxel group and 92 (35%) of 265 patients in the group had died. The HR for overall survival in the per-protocol population was 1 04 with a 97 5% repeated CI from to 1 69 (interim p=0 059). Because the upper boundary was above the prespecified HR of 1 33, the criterion for noninferiority was not met (figure 2A). Median overall survival was immature with events in only a third of patients. 1-year overall survival was 81% (95% CI 77 86%) in the paclitaxel group and 79% (74 84%) in the group; 2-year overall survival was 60% (52 67%) in the paclitaxel group and 55% (47 63%) in the group. Figure 2B shows overall survival for the intention-to-treat population; the results in the perprotocol and intention-to-treat populations were much the same. All further efficacy results are reported for the intention-to-treat population to enable consideration in the context of trials reported in the scientific literature. Exploratory subgroup analyses according to baseline characteristics showed no major differences in overall survival between treatment groups. For all subgroups, the 95% CI for the HR crossed 1 (figure 3). In an exploratory Cox model-building analysis of potential prognostic factors, treatment showed no significant effect on overall survival (HR 0 95, 95% CI ) when adjusted for several prognostic characteristics (hormone receptor status, ECOG performance status, liver metastases, and number of organs with metastases). By contrast with the primary endpoint, PFS and the proportion of patients who achieved an objective response were significantly better with paclitaxel than with. In the paclitaxel group, 125 (44%, 95% CI 38 50) of 285 patients achieved a complete or partial response compared with 76 (27%, 22 33) of 279 with (Cochran-Mantel-Haenszel p<0 0001). Median PFS was 11 0 months (95% CI ) with paclitaxel versus 8 1 months ( ) with (HR 1 36, 95% CI , p=0 0052; figure 4). Consistent with the difference in objective responses, time to response was also significantly better with paclitaxel than with (HR 0 58, 95% CI ; p=0 0002). Median time to response was not reached because less than 50% of patients in either group achieved a response. Among patients achieving an objective response, the duration of response was not significantly different between those patients who received bevacizumab and paclitaxel (median 11 9 months; 95% CI ) and those who received bevacizumab and (10 2; ; HR 1 28, ; p=0 23). We identified no significant betweentreatment difference for time to treatment failure (median time to treatment failure 8 4 months [95% CI ] in the paclitaxel group vs 7 3 months in the group [ ]; HR 1 11, 95% CI ; p=0 29). PFS results and the proportion of patients who achieved an objective response, in the per-protocol analyses were much the same as those reported for the intention-totreat population (data not shown). Many patients received further lines of treatment after discontinuation of study therapy. Fewer patients in the paclitaxel group than the group received subsequent chemotherapy (1 [42%] of 285 vs 144 [52%] of 279; table 2). When the analysis was limited to patients All patients Age, years <65 65 ECOG performance status 0 1/2 Metastatic at diagnosis Metastatic organs 0/1 2 3 Liver metastases Lung metastases Bone metastases (Neo)adjuvant chemotherapy* (Neo)adjuvant hormone therapy* Hormone therapy for LR/mBC ER positive n Median overall survival (months) paclitaxel HR (95% CI) 1 06 ( ) 0 98 ( ) 1 39 ( ) 1 00 ( ) 1 04 ( ) 0 96 ( ) 1 09 ( ) 1 24 ( ) 1 15 ( ) 0 87 ( ) 0 84 ( ) 1 25 ( ) 1 18 ( ) 0 94 ( ) 0 86 ( ) 1 37 ( ) 1 11 ( ) 0 97 ( ) 0 91 ( ) 1 03 ( ) 0 70 ( ) 1 15 ( ) 0 96 ( ) 1 23 ( ) Figure 3: Subgroup analysis of overall survival according to baseline characteristics ECOG=Eastern Cooperative Oncology Group. ER=oestrogen receptor. HR=hazard ratio. LR/mBC=locally recurrent/metastatic breast cancer. =not reached. PR=progesterone receptor. *Excluding patients with metastatic breast cancer at diagnosis. ER-positive or PR-positive disease. Published online January 10,

6 Progression-free survival (%) A 100 Number at risk Time (months) Figure 4: Progression-free survival (intention-to-treat population) HR 1 36 (95% CI ); p= plus paclitaxel (n=285) whose disease had progressed (to adjust for the difference between groups in the proportion of patients with progression at the time of data cutoff), the imbalance was slightly less pronounced (96 [54%] of 177 patients vs 131 [61%] of 214 patients, respectively). Generally, the type of chemotherapy administered in subsequent lines was much the same in the two treatment groups (table 2), with the exception of and paclitaxel. In the paclitaxel group, 60 (21%) of 285 patients received secondline and seven (2%) received second-line taxane; in the group, 73 (26%) of 279 patients received second-line taxane and 11 (4%) received secondline. Thus the extent of crossover was similar in the two treatment groups. Only nine (3%) patients in the paclitaxel group and 14 (5%) in the group had received further bevacizumab-containing therapy after disease progression at the time of data cutoff (n=279) Hormonal therapy 75 (26%) 63 (23%) 9 (3%) 14 (5%) Chemotherapy Any 1 (42%) 144 (52%) Second line 101 (35%) 129 (46%) Taxane 7 (2%) 73 (26%) Capecitabine 60 (21%) 11 (4%) Anthracycline 23 (8%) 26 (9%) Gemcitabine 10 (4%) 12 (4%) Vinorelbine 6 (2%) (7%) Platinum 10 (4%) 26 (9%) Third line 55 (19%) 61 (22%) Fourth line 17 (6%) 22 (8%) More than four lines 10 (4%) 15 (5%) Capecitabine in any line 73 (26%) 12 (4%) Taxane in any line 19 (7%) 99 (35%) Table 2: Treatment administered after discontinuation of study therapy (intention-to-treat population) 4 11 Overall, safety findings in the present dataset were much the same as those reported in detail previously 8 and as anticipated from the safety profiles of the chemotherapy agents (myelosuppression, alopecia, nail disorders, and neuropathy with paclitaxel; hand-foot syndrome and diarrhoea with ; table 3). The most common adverse events of grade 3 or higher were neutropenia, peripheral neuropathy, and leucopenia for bevacizumab plus paclitaxel and hand-foot syndrome, hypertension, and diarrhoea for bevacizumab plus. 15% of patients in both groups had adverse events that led to bevacizumab discontinuation (42 of 284 in the paclitaxel group vs 42 of 277 in the group). However, chemotherapy was discontinued because of adverse events more frequently in the paclitaxel group (109 [38%]) than the group (53 [19%]). In the paclitaxel group, one patient died from an adverse event deemed by the investigator to be treatment related (haemorrhage). treatment-related deaths occurred in the group. Baseline quality-of-life questionnaires were available from all patients in the safety population in both groups. End-of-treatment quality-of-life questionnaires were available from 138 (49%) of 284 patients in the paclitaxel group versus 141 (51%) of 277 patients in the group. Analysis of mean global health status showed no major difference between the treatment groups and little change from baseline over time (figure 5). Overall, the data suggested that the burden of symptoms was generally low and remained low throughout treatment. The highest mean baseline symptom scores in both treatment groups were for fatigue (34 1 [SD 26 9] with paclitaxel vs 38 8 [26 1] with ), pain (30 4 [29 7] vs 34 3 [29 6], respectively), and insomnia (29 3 [30 3] vs 32 4 [30 6], respectively). Mean scores for these symptom scales showed no meaningful increase (representing deterioration in quality of life) over time. Mean scores for appetite loss, dyspnoea, and financial difficulties varied slightly over time, with little difference between treatment groups (data not shown). Mean scores for physical, role, emotional, cognitive, and social functioning showed slight or no changes over time and were much the same between treatment regimens (data not shown). Discussion In this planned interim efficacy analysis of TURANDOT, the predefined criterion for non-inferiority of overall survival with bevacizumab plus compared with bevacizumab plus paclitaxel was not met. The overall survival curves and 1-year and 2-year overall survival rates seem much the same, but no conclusion about overall survival can be drawn from these results. Final overall survival analysis is planned after 389 deaths (expected in 14) and at the time of the present analysis, fewer than half of these events had been recorded. 6 Published online January 10, 13

7 Any grade Grade 3/4 Grade 5 plus paclitaxel (n=284) (n=277) paclitaxel (n=284) (n=277) plus paclitaxel (n=284) All 273 (96%) 258 (93%) 166 (58%) 125 (45%) 9 (3%)* 8 (3%) Hypertension 95 (33%) 80 (29%) 12 (4%) 16 (6%) 0 0 Fatigue 97 (34%) 74 (27%) 10 (4%) 4 (1%) 0 0 Hand-foot syndrome 8 (3%) 154 (56%) 1 (<1%) 44 (16%) 0 0 Epistaxis 87 (31%) 38 (14%) 3 (1%) 1 (<1%) 0 0 Nausea 56 (%) 66 (24%) 3 (1%) 2 (1%) 0 0 Diarrhoea 55 (19%) 60 (22%) 8 (3%) 15 (5%) 0 0 Neutropenia 85 (30%) 13 (5%) 51 (18%) 5 (2%) 0 0 Alopecia 86 (30%) 5 (2%) 4 (1%) Peripheral neuropathy 83 (29%) 8 (3%) 39 (14%) 1 (<1%) 0 0 Asthenia 41 (14%) 31 (11%) 7 (2%) 5 (2%) 0 0 Bone pain 30 (11%) 35 (13%) 4 (1%) 9 (3%) 0 0 Decreased appetite 33 (12%) 31 (11%) 1 (<1%) Headache 36 (13%) 27 (10%) 1 (<1%) 1 (<1%) 0 0 Vomiting 28 (10%) 33 (12%) 4 (1%) 2 (1%) 0 0 Dyspnoea 33 (12%) 26 (9%) 4 (1%) 6 (2%) 1 (<1%) 1 (<1%) Nail disorder 47 (17%) 9 (3%) 8 (3%) Anaemia 33 (12%) (7%) 3 (1%) 8 (3%) 0 0 Leucopenia 45 (16%) 6 (2%) (7%) 1 (<1%) 0 0 Dizziness 32 (11%) 16 (6%) 2 (1%) Dysphonia 33 (12%) 10 (4%) Polyneuropathy 27 (10%) 5 (2%) 12 (4%) Peripheral sensory neuropathy 24 (8%) 5 (2%) 7 (2%) (n=277) *Cardiopulmonary failure, acute hepatic failure, lung infection, sepsis, electrolyte imbalance, dyspnoea, pulmonary emobolism, haemorrhage, hypovolaemic shock. Cardiorespiratory arrest, disease progression, generalised oedema, abnormal hepatic function, metastases to CNS, brain hypoxia, dyspnoea, hydropneumothorax. Table 3: Adverse events of any grade in 10% of patients, or grade 3 in 2% in either group, irrespective of relation to study treatment (safety population) Both PFS and the proportion of patients who had an objective response were significantly better with bevacizumab plus paclitaxel than with bevacizumab plus. The prolongation of PFS cannot be explained by the difference in cycle duration (28 days for the paclitaxel group vs 21 days for the group) because tumour assessments were done every 12 weeks in both groups. tably, the PFS and objective response rate results in this study are much the same as data reported for each of the two regimens in previous randomised phase 3 trials versus chemotherapy alone (E2100 and RIBBON-1). 3,5 In our study, median PFS was 11 0 months (95% CI ) and 44% (95% CI 38 50) of patients achieved an objective response with bevacizumab plus paclitaxel compared with 11 4 months and 50%, respectively, in E Results from the CALGB randomised phase 3 trial 9 comparing bevacizumab combined with weekly paclitaxel (n=283), nanoparticle albumin-bound paclitaxel (n=271), or ixabepilone (n=245) as first-line therapy for locally recurrent or metastatic breast cancer showed median PFS of 10 6 months with bevacizumab plus paclitaxel. This consistency is further supported by the median PFS of 11 5 months (95% CI Number of questionnaires available Worse Better 0 Baseline EOT Follow-up Time (weeks) Mean score (points) Figure 5: Quality of life according to global health status EOT=end of treatment ) with bevacizumab plus paclitaxel in the randomised phase 2 TRIO 010 trial 10 assessing motesanib or bevacizumab in combination with first-line paclitaxel. Median PFS reported for first-line bevacizumab plus paclitaxel in the scientific literature ranges from 8 3 to Published online January 10,

8 Panel: Research in context 13 5 months, 9 15 although differences in populations of patients, duration of follow-up, and duration of therapy should be considered when doing such cross-trial comparisons (panel). The median PFS of 8 1 months (95% CI ) and proportion of patients achieving an objective response of 27% (95% CI 22 33) with bevacizumab plus in our trial is also in agreement with efficacy results reported within the bevacizumab plus cohort of RIBBON-1 (median PFS 8 6 months, 35% of patients with an objective response). 5 Although the results with bevacizumab plus for these endpoints are generally inferior to efficacy recorded with bevacizumab plus paclitaxel, the seemingly similar overall survival, differences in tolerability, and small qualitative differences in quality of life support the selection of bevacizumab plus for certain subsets of patients, depending on the relative priority of these variables for each individual patient. This view and the need to broaden treatment options were also deemed important by regulatory authorities, as shown by the European Medicines Agency approval of bevacizumab plus in 11 for the first-line treatment of patients with metastatic breast cancer in whom other chemotherapy options are not judged appropriate. Analyses of interim safety data from this study have been reported previously 8 and the results we report here, from the later data cutoff, which provide almost 9 months Systematic review The TURANDOT trial was designed taking into account results from the E trial of bevacizumab plus paclitaxel and interest in non-taxane options containing bevacizumab under assessment at the time. had shown efficacy as first-line treatment of HER2-negative patients 16 but no results from randomised trials in this setting were available. Since the trial was designed, results of phase 2 and 3 trials assessing these regimens in the first-line setting have become available, and were identified by searching PubMed and major oncology and breast cancer-specific congresses (American Society of Clinical Oncology, San Antonio Breast Cancer Symposium, and European Society for Medical Oncology) from 07, to August, 12, with the search terms bevacizumab and metastatic breast cancer (and first line for PubMed). Searches were not restricted by language. Interpretation Our results reproduce the progression-free survival (PFS) and proportion of patients achieving objective responses recorded in previous phase 3 trials 3,5 comparing bevacizumab plus paclitaxel and bevacizumab plus with chemotherapy alone. We also confirm the safety profile of bevacizumab-containing therapy defined in previous trials. 3 5 These results provide insight into the relative efficacy of the two regimens, although overall survival results at this interim analysis are inconclusive because the non-inferiority criterion was not met. Treatment should be selected according to the needs and preferences of each individual patient. If PFS and objective response are the most important parameters, bevacizumab plus paclitaxel might be preferred. However, if oral dosing or adverse effects, such as hair loss, are of prime importance, bevacizumab plus is a valid and active regimen. It is not yet clear whether the bevacizumab plus regimen offers much the same overall survival as bevacizumab plus paclitaxel. additional follow-up, are much the same. The main toxic effects differed between the regimens, but were not unexpected in view of previous results in chemotherapyonly trials. The proportion of patients discontinuing chemotherapy because of adverse events was twice as high with paclitaxel compared with, which is indicative of the more tolerable safety profile of. The starting dose of was 1000 mg/m² twice daily (reduced to 750 mg/m² in patients aged 65 years or older), which might have contributed to the relatively high dose intensity and less frequent dose modification compared with trials using the registered starting dose % of patients had delayed or interrupted, which is much the same as the 54% incidence reported in the GBG39 MONICA trial 18 of first-line at a starting dose of 1000 mg/m². To the best of our knowledge, this study is the first trial of bevacizumab-containing therapy for metastatic breast cancer with comparison of overall survival as the primary objective, although at this interim analysis, overall survival results are inconclusive. There is little debate that improving overall survival is the ultimate goal of treatment. However, since the study was designed in 07, the relative benefits of overall survival and PFS as primary endpoints of clinical trials have been discussed intensely and remain controversial, particularly in settings with long post-progression survival. 19, The substantial differences in some of the secondary efficacy endpoints identified between bevacizumab plus paclitaxel and bevacizumab plus emphasise the need to consider each patient s situation and preference carefully when selecting treatment. We included extensive assessment of quality of life, results of which have been reported in detail elsewhere. 21 We acknowledge that conclusions are slightly limited by the small numbers of patients in later cycles and at the end of treatment. However, no clear difference in global health score was identified and we noted little or no difference in functioning and symptom scales between treatment regimens. The absence of deterioration in global health score in both groups is a notable finding and has important implications when considering the potential benefit of a treatment, particularly in the firstline metastatic breast-cancer setting, for which clinically meaningful endpoints continue to be debated. Our study had weaknesses deserving discussion. biomarker analyses were planned (although with bevacizumab in both groups it would be difficult to examine potential predictive factors). Substantial efforts to identify patients who derive the greatest benefit from bevacizumab continue, but currently our trial does not contribute to these efforts. Additionally, these are interim results; only the final results will provide a definitive answer for the primary objective. In conclusion, both of the bevacizumab-containing regimens assessed in this study are active first-line treatments for patients with HER2-negative locally 8 Published online January 10, 13

9 recurrent or metastatic breast cancer. Ultimately, selection of a particular regimen should be based on each individual s treatment goals (eg, response, PFS, overall survival, hair loss, and quality of life) and preferences. Contributors TB and CZ designed the trial. DM was involved in data analysis. All authors were involved in data collection, data interpretation, and revision and finalisation of the manuscript. Conflicts of interest TB and TP have received speaker honoraria from Roche. SB has received research support and honoraria from Roche. BM has received honoraria for presentations and advisory boards from Roche. GGS has received travel grants and honoraria from Bristol-Myers Squibb, Roche, and Roche Austria. DM is an employee of IST GmbH, the clinical research organisation providing consultancy and various other services to Roche and the Central European Cooperative Oncology Group. CZ has received honoraria from Roche for consultancy and advisory boards. IL, LR, ZK, RG, SMS, BK, ZZ, and DS declare that they have no conflicts of interest. Acknowledgments The study is sponsored by the Central European Cooperative Oncology Group. F Hoffmann-La Roche (Basel, Switzerland) funded the trial and third-party writing assistance for this manuscript, provided by Jennifer Kelly (Medi-Kelsey, Ashbourne, UK). References 1 Cardoso F, Costa A, rton L, et al. 1st International consensus guidelines for advanced breast cancer (ABC 1). Breast 12; 21: Cardoso F, Fallowfield L, Costa A, Castiglione M, Senkus E, ESMO Guidelines Working Group. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 11; 22 (suppl 6): vi Gray R, Bhattacharya S, Bowden C, Miller K, Comis RL. Independent review of E2100: a phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol 09; 27: Miles DW, Chan A, Dirix LY, et al. 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