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Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial Gunter von Minckwitz, Fabio Puglisi, Javier Cortes, Eduard Vrdoljak, Norbert Marschner, Christoph Zielinski, Cristian Villanueva, Gilles Romieu, István Lang, Eva Ciruelos, Michele De Laurentiis, Corinne Veyret, Sabine de Ducla, Ulrich Freudensprung, Stefanie Srock, Joseph Gligorov
Summary Background Combining bevacizumab with first-line or second-line chemotherapy improves progression-free survival in HER2-negative locally recurrent or metastatic breast cancer. We assessed the efficacy and safety of further bevacizumab therapy in patients with locally recurrent or metastatic breast cancer whose disease had progressed after treatment with bevacizumab plus chemotherapy.
Lancet Oncol 2014; 15: 1269–78
Methods In this open-label, randomised, phase 3 trial, we recruited patients who had HER2-negative locally recurrent or metastatic breast cancer that had progressed after receiving 12 weeks or more of first-line bevacizumab plus chemotherapy from 118 centres in 12 countries. Patients were randomly assigned (1:1) by use of a central interactive voice response system using a block randomisation schedule (block size four) stratified by hormone receptor status, first-line progression-free survival, selected chemotherapy, and lactate dehydrogenase concentration, to receive second-line single-agent chemotherapy either alone or with bevacizumab (15 mg/kg every 3 weeks or 10 mg/kg every 2 weeks). Second-line therapy was continued until disease progression, unacceptable toxicity, or consent withdrawal. At progression, patients randomly assigned to chemotherapy alone received third-line chemotherapy without bevacizumab; those randomly assigned to bevacizumab continued bevacizumab with third-line chemotherapy. The primary endpoint was progression-free survival from randomisation to second-line progression or death in the intention-to-treat population. This trial is ongoing, and registered with ClinicalTrials.gov, number NCT01250379.
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Findings Between Feb 17, 2011, and April 3, 2013, 494 patients were randomly assigned to treatment (247 in each group). The median duration of follow-up at the time of this prespecified primary progression-free survival analysis was 15·9 months (IQR 9·1–21·7) in the chemotherapy-alone group and 16·1 months (10·6–22·7) in the combination group. Progression-free survival was significantly longer for those patients treated with bevacizumab plus chemotherapy than for those with chemotherapy alone (median: 6·3 months [95% CI 5·4–7·2] vs 4·2 months [3·9–4·7], respectively, stratified hazard ratio [HR] 0·75 [95% CI 0·61–0·93], two-sided stratified log-rank p=0·0068). The most common grade 3 or more adverse events were hypertension (33 [13%] of 245 patients receiving bevacizumab plus chemotherapy vs 17 [7%] of 238 patients receiving chemotherapy alone), neutropenia (29 [12%] vs 20 [8%]), and hand-foot syndrome (27 [11%] vs 25 [11%]). Grade 3 proteinuria occurred in 17 (7%) of 245 patients receiving combination therapy and one (5 × ULN in patients with known liver involvement, alkaline phosphatase >2 × ULN, or >5 × ULN in patients with known liver involvement, or >7 × ULN in patients with known bone involvement), or renal function (creatinine clearance 2+ unless 24 h protein was ≤1 g). Patients were also ineligible if they were participating, or had recently participated (within 4 weeks or two half-lives of the investigational drug, whichever was greater), or were planning to participate in, an experimental drug study other than previous participation in a study of bevacizumab for breast cancer. All patients provided written informed consent. The study was done in full accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The protocol and all modifications were approved by independent ethics committees at all participating sites. An independent data monitoring committee undertook ongoing review of all safety data and efficacy of the bevacizumab plus vinorelbine combination in view of exploratory analyses of RIBBON-2, in which the progression-free survival hazard ratio (HR) was less favourable for the subgroup of 76 patients receiving this combination (HR 1·42, 95% CI 0·78–2·59) compared with the overall HR (0·78, 0·64–0·93).
Randomisation and masking Patients were randomly assigned (1:1) to receive secondline chemotherapy either alone or with bevacizumab by investigators using a central interactive voice response system with an allocation sequence generated by Parexel Informatics (Nottingham, UK). Randomisation was by stratified blocks (block size of four) within the following strata: hormone receptor status (triple negative vs oestrogen receptor [ER] or progesterone receptor [PR] or both positive); first-line progression-free survival from the time of diagnosis of locally recurrent or metastatic breast cancer (1·5 × ULN). Neither the patients nor the investigators were masked to treatment assignment, but the steering committee and all representatives of the funder (including the lead biostatistician) only had access to data pooled from across both treatment groups until the database was locked and the treatment code was revealed. www.thelancet.com/oncology Vol 15 October 2014
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Procedures Before randomisation, investigators selected the singleagent chemotherapy for each patient from prespecified standard options: intravenous paclitaxel (80–90 mg/m² weekly), intravenous nanoparticle albumin-bound paclitaxel (260 mg/m² every 3 weeks, or 100 mg/m² weekly), intravenous docetaxel (75–100 mg/m², or 60 mg/m² for Japanese patients, every 3 weeks), oral capecitabine (1000 mg/m² twice daily for 14 days followed by a 7-day rest period), intravenous gemcitabine (1000 mg/m² on days 1, 8, and 15 every 4 weeks), intravenous pegylated liposomal doxorubicin (40–50 mg/m² every 4 weeks), intravenous non-pegylated liposomal doxorubicin (60 mg/m² every 3 weeks), intravenous doxorubicin (60–75 mg/m² every 3 weeks, or 20–25 mg/m² weekly), intravenous epirubicin (75–90 mg/m² every 3 weeks, or 25–30 mg/m² weekly), vinorelbine (weekly 30 mg/m² administered intravenously, or weekly 80 mg/m² administered orally), cyclophosphamide (500–700 mg/m² administered intravenously every 3 weeks, or 50 mg/m² administered orally every day), or intravenous ixabepilone (40 mg/m² administered every 3 weeks). Patients assigned to bevacizumab received 15 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, depending on the chosen chemotherapy regimen. Second-line therapy was continued until disease progression, unacceptable toxicity, or patient withdrawal. If patients allocated to combination therapy discontinued bevacizumab or chemotherapy for any reason before disease progression, the other treatment was continued as monotherapy until disease progression, unacceptable toxicity, or patient withdrawal. If chemotherapy-related toxicity necessitated chemotherapy discontinuation before disease progression, patients received standard of care (potentially switching to another chemotherapy drug) until disease progression. Maintenance endocrine therapy was allowed in both groups (with bevacizumab in the combination arm). In the event of toxicity, dose reduction or modification of bevacizumab was not allowed, but bevacizumab was to be interrupted or permanently discontinued for hypertension, proteinuria, thrombosis, embolism, haemorrhage, congestive heart failure, or wound-healing complications (appendix). After disease progression on second-line therapy, patients initially assigned to chemotherapy alone received third-line chemotherapy without bevacizumab (no crossover), whereas those assigned to combination therapy continued to receive bevacizumab with third-line chemotherapy (unless prevented by unacceptable toxicity). Investigators chose the third-line chemotherapy for each patient from the prespecified standard options listed above, or intravenous eribulin (1·23 mg/m² on days 1 and 8 every 3 weeks) as an additional option following a protocol amendment in September, 2013. After third-line disease progression, fourth-line treatment (with or without bevacizumab) was at the investigator’s discretion in all patients. www.thelancet.com/oncology Vol 15 October 2014
Tumour assessment was based on limited Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with CT, MRI, bone scans, and x-rays done at baseline and at 8-week or 9-week intervals, depending on the chosen chemotherapy. No independent review of tumour assessment was done; clinical examinations were done as clinically indicated before starting every cycle. Safety was assessed using Common Terminology Criteria for Adverse Events (version 4.0). All grade 3–5 adverse events, serious adverse events (any grade), and adverse events of special interest for bevacizumab (any grade) were recorded at every study visit. All laboratory assessments were done locally according to local standards. Unless a patient withdrew consent, was lost to follow-up, or the investigator withdrew the patient—eg, because of another illness, adverse event, treatment failure after a prescribed procedure, protocol violation, cure, or administrative reason—all patients remained in the study with continued follow-up for overall survival. Patient-reported outcomes were assessed with the Functional Assessment of Cancer Therapy–Breast questionnaire (FACT-B).
Outcomes The primary endpoint was second-line progression-free survival, defined as the time from randomisation to disease progression or death on second-line treatment.
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556 screened
62 not randomised
494 randomised
247 assigned to chemotherapy group
Second-line efficacy population
9 received no treatment
238 patients included in second-line safety analysis 18 still on second-line therapy 31 in second-line follow-up
90 still on study
247 assigned to chemotherapy plus bevacizumab group
2 received no treatment
245 patients included in second-line safety analysis 17 still on second-line therapy 28 in second-line follow-up
91 withdrawn from second-line 38 premature study withdrawal 53 died
84 withdrawn from second-line 31 premature study withdrawal 53 died
57 withdrawn from third-line 8 premature study withdrawal 49 died
51 withdrawn from third-line 6 premature study withdrawal 45 died
110 still on study
Figure 1: Trial profile
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Chemotherapy alone (n=247) Age (years)
Chemotherapy plus bevacizumab (n=247)
54 (30–77)
56 (24–81)
≥65
51 (21%)
64 (26%)
≥70
21 (9%)
28 (11%)
Hormone receptor status Triple negative
57 (23%)
49 (20%)
188 (76%)
198 (80%)
49 (20%)
37 (15%)
≤12 months
24 (10%)
18 (7%)
≤24 months
58 (23%)
53 (21%)
97 (39%)
100 (40%)
ER or PgR positive or both positive Locally recurrent or metastatic disease at first diagnosis Disease-free interval*
Previous (neo)adjuvant chemotherapy† Taxane Anthracycline
139 (56%)
155 (63%)
Other
144 (58%)
162 (66%)
Previous (neo)adjuvant bevacizumab Previous endocrine therapy for locally recurrent/metastatic breast cancer
3 (1%)
4 (2%)
112 (45%)
125 (51%)
Timing of first-line progression in relation to first-line chemotherapy plus bevacizumab During bevacizumab After bevacizumab Unknown/missing/other
48 (19%)
45 (18%)
198 (80%)
196 (79%)
1 (