Locally Recurrent/metastatic Breast Cancer Research Articles

First-line bevacizumab-containing therapy for HER2-negative locally advanced/metastatic breast cancer: Real-world experience from >2000 patients treated in the multicentre AVANTI study

AimThe multicentre non-interventional AVANTI study assessed safety, effectiveness and patient-reported outcomes with approved first-line bevacizumab-containing regimens for HER2-negative locally recurrent/metastatic breast cancer (LR/MBC) in German routine oncology practice. MethodsEligible patients had HER2-negative LR/MBC, no bevacizumab contraindications and no prior chemotherapy for LR/MBC. Chemotherapy schedule, diagnostics and follow-up were at physicians’ discretion. Data were collected for 1 year after starting bevacizumab, then every 6 months for 1.5 years (maximum follow-up: 2.5 years). Patients and physicians rated treatment satisfaction. Subgroup analyses were prespecified in clinically relevant populations, including triple-negative breast cancer (TNBC). ResultsBetween November 1, 2009 and April 30, 2016, 2065 eligible patients at 346 centres received bevacizumab with paclitaxel or capecitabine. Patients receiving bevacizumab–capecitabine were less likely to have de novo disease and more likely to have TNBC, age ≥60 years and prior anthracycline/taxane and/or endocrine therapy. Median PFS was 12.6 (95% CI 11.9–13.2) months (12.8 with bevacizumab–paclitaxel, 10.5 with bevacizumab–capecitabine); median OS was 23.9 (95% CI 22.2–25.1) months. Outcomes were worse in patients with TNBC, prior anthracycline/taxane or prior endocrine therapy. Grade ≥3 adverse events occurred in 27% of patients. Treatment was discontinued for adverse events in 15%. Treatment satisfaction was rated as good or better by 304/394 responding patients (77%) at week 54 and in 1393/2065 patients (67%) by physicians overall. ConclusionsIn routine clinical practice, effectiveness and safety of first-line bevacizumab-containing therapy for LR/MBC were consistent with experience from phase III trials. Patient and physician treatment satisfaction showed high concordance.

Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication

The phase III CLinical Evaluation Of Pertuzumab And TRAstuzumab (CLEOPATRA) trial established the combination of pertuzumab, trastuzumab and docetaxel as standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive locally recurrent/metastatic breast cancer (LR/mBC). The multicentre single-arm PERtUzumab global SafEty (PERUSE) study assessed the safety and efficacy of pertuzumab and trastuzumab combined with investigator-selected taxane in this setting. Eligible patients with inoperable HER2-positive LR/mBC and no prior systemic therapy for LR/mBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab and pertuzumab until disease progression or unacceptable toxicity. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Prespecified subgroup analyses included subgroups according to taxane, hormone receptor (HR) status and prior trastuzumab. Exploratory univariable analyses identified potential prognostic factors; those that remained significant in multivariable analysis were used to analyse PFS and OS in subgroups with all, some or none of these factors. Of 1436 treated patients, 588 (41%) initially received paclitaxel and 918 (64%) had HR-positive disease. The most common grade ≥3 adverse events were neutropenia (10%, mainly with docetaxel) and diarrhoea (8%). At the final analysis (median follow-up: 5.7 years), median PFS was 20.7 [95% confidence interval (CI) 18.9-23.1] months overall and was similar irrespective of HR status or taxane. Median OS was 65.3 (95% CI 60.9-70.9) months overall. OS was similar regardless of taxane backbone but was more favourable in patients with HR-positive than HR-negative LR/mBC. In exploratory analyses, trastuzumab-pretreated patients with visceral disease had the shortest median PFS (13.1 months) and OS (46.3 months). Mature results from PERUSE show a safety and efficacy profile consistent with results from CLEOPATRA and median OS exceeding 5 years. Results suggest that paclitaxel is a valid alternative to docetaxel as backbone chemotherapy. Exploratory analyses suggest risk factors that could guide future trial design.

288P Final results from PERUSE, a global study of pertuzumab (P), trastuzumab (H) and investigator’s chosen taxane as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)

P + H + docetaxel (DOC) is the standard first-line therapy for HER2-positive LR/mBC, based on results from the phase III CLEOPATRA trial. The single-arm PERUSE study (NCT01572038) assessed the safety and efficacy of P + H with investigator-selected taxane in this setting. Preliminary results by taxane have been reported [Bachelot, Ann Oncol 2019]; we present final safety and efficacy results.

A phase III, randomized, double-blind, placebo (Pla)-controlled study of pertuzumab (P) + trastuzumab (H) + docetaxel (D) versus Pla + H+ D in previously untreated HER2-positive locally recurrent/metastatic breast cancer (LR/MBC) (PUFFIN).

1026 Background: In CLEOPATRA (NCT00567190), adding P to H + D significantly improved progression-free and overall survival (PFS/OS) v Pla + H + D in patients (pts) with previously untreated HER2-positive LR/MBC. PUFFIN (NCT02896855) is a China bridging study; the objective being to assess consistency of efficacy with CLEOPATRA. Methods: Pts with previously untreated HER2-positive LR/MBC were randomized 1:1 to P + H + D or Pla + H + D, stratified by visceral v non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR in pts with measurable baseline disease), OS, and safety. The target sample size (240) was determined based on the consistency threshold for PFS, defined as hazard ratio (HR) < 0.81, which maintains ≥ 50% of the risk reduction determined in CLEOPATRA (HR 0.62). Results: Two hundred forty-three pts were randomized. Baseline/disease characteristics and prior therapies were generally balanced between arms. For PFS, the HR was 0.69 (95% CI 0.49, 0.99) in the ITT population. No cases of heart failure or symptomatic left ventricular ejection fraction decline were reported. Efficacy/safety are shown in the table. Conclusions: PUFFIN met its primary endpoint. Overall, efficacy data were consistent with CLEOPATRA (ITT population and Asian subgroup). Safety was also consistent and in line with the known P safety profile, with no new or unexpected signals reported. PUFFIN adds to the totality of data with P in previously untreated HER2-positive LR/MBC, and supports the favorable benefit–risk profile of P in Chinese pts. Clinical trial information: NCT02896855. [Table: see text]

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer

The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. NCT01250379.

1542P - Exploratory analyses of candidate predictive and prognostic tissue biomarkers (BMs) in the open-label randomised phase III TANIA trial of bevacizumab (BEV) in HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

In the TANIA trial (NCT01250379), adding BEV to 2nd-line chemotherapy (CT) significantly improved 2nd-line progression-free survival (PFS, primary endpoint; hazard ratio [HR] 0.75, 95% CI 0.61–0.93; p = 0.0068) in BEV-pretreated LR/mBC. No difference in 3rd-line PFS or overall survival (OS) was observed. Post hoc analyses explored potential associations between 6 candidate BMs (based on previous results/biological hypotheses) and 2nd-line PFS and OS. Patients (pts) with BEV-pretreated HER2-negative LR/mBC were randomised to receive 2nd-line CT ± BEV until disease progression (PD), unacceptable toxicity or withdrawal. At 2nd PD, 3rd-line CT was given without BEV in the CT arm and with BEV in the BEV + CT arm. Archival primary or metastatic tumour samples collected before 2nd-line BEV from pts consenting to optional translational research were analysed by immunohistochemistry using median expression levels for each BM as the cut-off for high vs low BM subgroups. Samples (mainly primary tumour) were available from 210 (43%) of 494 randomised pts. Baseline characteristics and efficacy in these pts were broadly representative of the ITT population. High CA9 and CD31 were associated with worse prognosis but larger BEV benefit, although neither was consistently predictive across endpoints (table). Pts with high CA9 had median PFS of 4.6 vs 1.9 mo with BEV + CT vs CT, respectively; pts with high CD31 had median OS of 19.3 vs 13.0 mo, respectively. No BM was associated with a detrimental BEV effect.Tabled 1BM2nd-line PFS HR (95% CI)Interaction p-valueaOS HR (95% CI)Interaction p-valuea≤Median>Median≤Median>MedianCD31 No. of vessels1.02 (0.68–1.55)0.60 (0.39–0.93)0.1101.42 (0.88–2.27)0.60 (0.37–0.99)0.016CD31 volume fraction0.85 (0.57–1.29)0.74 (0.48–1.15)0.5851.20 (0.74–1.95)0.75 (0.47–1.22)0.179tVEGF-A1.10 (0.73–1.65)0.63 (0.41–0.95)0.0910.99 (0.63–1.55)0.86 (0.53–1.38)0.626CA9 cytoplasm H-score0.92 (0.64–1.30)0.49 (0.30–0.81)0.0640.93 (0.62–1.39)0.93 (0.54–1.60)0.878CA9 membrane H-score0.90 (0.65–1.27)0.41 (0.23–0.74)0.0170.99 (0.67–1.47)0.70 (0.38–1.27)0.258PD-L1 immune cell0.84 (0.59–1.19)0.61 (0.36–1.04)0.3571.01 (0.68–1.51)0.68 (0.37–1.26)0.196PD-L1 tumour cell0.79 (0.58–1.06)0.96 (0.17–5.38)0.7950.92 (0.65–1.29)0.36 (0.04–3.16)0.469CD8 invasive margin0.77 (0.44–1.33)1.07 (0.63–1.83)0.3570.87 (0.46–1.65)1.35 (0.73–2.48)0.313CD8 tumour centre0.61 (0.40–0.93)0.97 (0.63–1.49)0.1550.87 (0.55–1.37)1.00 (0.62–1.63)0.711CD163 invasive margin1.00 (0.55–1.80)0.96 (0.56–1.64)0.8910.76 (0.40–1.44)1.65 (0.87–3.14)0.094CD163 tumour centre1.09 (0.71–1.67)0.71 (0.47–1.06)0.2620.91 (0.57–1.45)0.93 (0.58–1.48)0.886aNot adjusted for multiplicity. CA9 = carbonic anhydrase 9; PD-L1 = programmed cell death 1 ligand 1; tVEGF-A = tumour vascular endothelial growth factor-A. Open table in a new tab aNot adjusted for multiplicity. CA9 = carbonic anhydrase 9; PD-L1 = programmed cell death 1 ligand 1; tVEGF-A = tumour vascular endothelial growth factor-A. Continued BEV significantly improved 2nd-line PFS irrespective of BM levels in LR/mBC. Exploratory analyses suggested potential predictive effects of CA9 (PFS) and CD31 (OS), suggesting involvement of tumour and endothelium characteristics in the therapeutic concept of anti-angiogenesis.

Abstract P6-14-01: Final results of the TANIA randomized phase III trial of bevacizumab (BEV) after progression on 1st-line BEV therapy for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

Abstract BACKGROUND: The open-label randomized phase III TANIA trial (NCT01250379) evaluated 2nd-line BEV-containing therapy in BEV-pretreated LR/mBC. The primary objective was met: 2nd-line PFS was statistically significantly improved in patients (pts) receiving further BEV (hazard ratio [HR] 0.75, 95% CI 0.61–0.93; p=0.0068) [von Minckwitz, Lancet Oncol 2014]. We report final efficacy, safety, and health-related quality of life (HRQoL) results. METHODS: Eligible pts had HER2-negative LR/mBC that had progressed on/after 1st-line BEV plus chemotherapy (CT). Pts were randomized to receive 2nd-line CT (investigator's choice) either alone or combined with BEV (15 mg/kg q3w or 10 mg/kg q2w) until disease progression (PD), unacceptable toxicity, or consent withdrawal. At 2nd PD, pts in the CT arm received 3rd-line CT without BEV (no crossover); pts initially randomized to BEV–CT received 3rd-line BEV–CT. Secondary endpoints included 3rd-line PFS, 2nd- and 3rd-line PFS (from randomization to 3rd PD/death), overall survival (OS), HRQoL, and safety. HRQoL was assessed using FACT-B at baseline, every 8/9 weeks (depending on treatment schedule) during 2nd-line therapy, and at the time of 2nd PD. Prespecified HRQoL analyses included differences between treatment arms in mean change from baseline for each FACT-B subscale. RESULTS: At the time of data cut-off for the prespecified final analysis (April 30, 2015, 24 months after the last pt was randomized), median follow-up was 32.1 vs 30.9 months in the CT vs BEV–CT arms, respectively. All pts had stopped study treatment. Of the 494 pts randomized to 2nd-line therapy, 234 began 3rd-line therapy (105 initially randomized to CT; 129 from the BEV–CT arm, of whom 17 received CT without BEV). The most commonly selected 3rd-line CT was vinorelbine (33% of CT pts vs 31% of BEV–CT pts). EndpointNo. of events/pts (%)Median, months (95% CI)Stratified HR (95% CI)p-value CTBEV–CTCTBEV–CT 3rd-line PFS99/105 (94)124/129 (96)2.9 (2.2-3.9)3.8 (2.4-5.1)0.79 (0.59-1.06)0.10802nd- and 3rd-line PFS177/247 (72)206/247 (83)10.7 (9.2-12.5)12.8 (10.7-14.5)0.85 (0.68-1.05)0.1349OS156/247 (63)163/247 (66)18.7 (15.4-21.2)19.7 (17.6-21.0)0.96 (0.76-1.21)0.7253 Subgroup analyses of 3rd-line PFS and OS according to stratification factors were consistent with the overall ITT result. Before study closure, 68% and 61% of pts in the 3rd-line ITT population CT and BEV–CT arms, respectively, received further CT. 3rd-line safety results showed no new safety signals. At week 8/9, mean change from baseline for all FACT-B subscales was <1.5 points in either direction in both treatment arms, representing no significant difference. Similarly, exploratory HRQoL analyses of the physical and functional wellbeing subscales using mixed-model repeated measures and responder analyses revealed no meaningful significant differences between treatment arms. CONCLUSIONS: Although BEV given after PD on 1st-line BEV-containing therapy showed improvement in 2nd-line PFS, no OS benefit was demonstrated. No new safety signals were observed. There were no differences in HRQoL between treatment arms, suggesting that the PFS benefit with BEV is achieved with maintained HRQoL. Citation Format: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, Gonzalez-Martin A, Ebel K, Easton V, von Minckwitz G. Final results of the TANIA randomized phase III trial of bevacizumab (BEV) after progression on 1st-line BEV therapy for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-14-01.

1800 Final results for overall survival (OS), the primary endpoint of the CECOG TURANDOT prospective randomised trial evaluating bevacizumab-paclitaxel (BEV-PAC) vs BEV-capecitabine (CAP) for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

1800 Final results for overall survival (OS), the primary endpoint of the CECOG TURANDOT prospective randomised trial evaluating bevacizumab-paclitaxel (BEV-PAC) vs BEV-capecitabine (CAP) for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

1816 Preliminary safety results from PERUSE, a study of 1436 patients (pts) treated with first-line pertuzumab (P) combined with trastuzumab (H) and taxane therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)

1816 Preliminary safety results from PERUSE, a study of 1436 patients (pts) treated with first-line pertuzumab (P) combined with trastuzumab (H) and taxane therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)

Abstract PD2-4: Subgroup efficacy analyses of the randomized phase III TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

Abstract BACKGROUND: The open-label randomized phase III TANIA trial demonstrated statistically significantly improved progression-free survival (PFS; primary endpoint) with the addition of BEV to 2nd-line chemotherapy (CT) in patients (pts) with HER2-negative LR/mBC progressing after 1st-line BEV-containing therapy. We describe efficacy in clinically relevant subgroups to assess consistency of the BEV treatment effect. METHODS: Pts whose HER2-negative LR/mBC had progressed during/after 1st-line BEV–CT were randomized 1:1 to investigator’s chosen 2nd-line single-agent CT given either alone or with BEV (15 mg/kg q3w or 10 mg/kg q2w). 2nd-line therapy was continued until disease progression (PD), unacceptable toxicity or consent withdrawal. At PD, BEV was continued with 3rd-line CT (investigator’s choice) in pts initially randomized to BEV–CT but was not permitted in pts randomized to CT alone. The primary endpoint was PFS from randomization to 2nd-line PD/death. Sample size was calculated based on a log-rank test assuming median PFS of 7→9.3 mo with a corresponding hazard ratio (HR) of 0.75. PFS events were required in 384 of 488 pts for 80% power at 2-sided α=0.05. Subgroup analyses of the primary endpoint were prespecified and included subgroups defined by stratification factors. RESULTS: From Jan 2011 to Apr 2013, 494 pts were enrolled. The data cut-off for the primary analysis was Dec 20, 2013 (median follow-up: CT 15.9 mo; BEV–CT 16.1 mo). The PFS benefit seen in the overall population was observed consistently in most subgroups. SubgroupPts with PFS events/Total No. of pts (%)Median 2nd-line PFS, moUnstratified HR (95% CI)CTBEV–CTCTBEV–CTAll203/247 (82)204/247 (83)4.26.30.75 (0.61-0.93)aHormone receptor statusbTriple negative56/60 (93)45/56 (80)2.14.90.59 (0.40-0.88)Positive, HER2 negative147/187 (79)159/191 (83)4.76.70.84 (0.67-1.05)1st-line PFS, mob<661/69 (88)54/68 (79)3.95.10.62 (0.43-0.90)≥6142/178 (80)150/179 (84)4.66.40.82 (0.65-1.03)LDHb≤1.5×ULN167/207 (81)168/210 (80)4.46.30.77 (0.62-0.96)>1.5×ULN36/40 (90)36/37 (97)2.15.80.73 (0.46-1.16)CT choicebTaxane25/32 (78)26/32 (81)3.26.90.55 (0.31-0.98)Non-taxane non-vinorelbine156/191 (82)151/188 (80)4.46.00.84 (0.68-1.06)Vinorelbine22/24 (92)27/27 (100)2.46.50.41 (0.22-0.75)CT choice (not stratified)Capecitabine117/146 (80)125/151 (83)4.96.20.92 (0.72-1.19)Non-capecitabine86/101 (85)79/96 (82)3.26.50.55 (0.40-0.75)BEV-free interval, wk≤6138/165 (84)130/149 (87)4.25.80.82 (0.64-1.04)>665/81 (80)74/98 (76)4.47.60.72 (0.51-1.00)aStratified.bStratification factor. CONCLUSIONS: PFS was statistically significantly improved with the addition of BEV to 2nd-line CT in BEV-pretreated pts, meeting the primary objective of TANIA. This effect was seen consistently within subgroups based on stratification factors. Within the limitations of exploratory subgroup analyses with small sample sizes, further subgroup analyses may suggest some potential inconsistencies in treatment effect. These hypothesis-generating observations require further exploration of potential differences in disease and pt characteristics in TANIA, which may have influenced physicians’ CT choice. Citation Format: Fabio Puglisi, Javier Cortes, Eduard Vrdoljak, Joseph Gligorov, Norbert Marschner, Christoph Zielinski, Michele de Laurentiis, Etienne Brain, Christelle Lévy, Anja Welt, Zsuzsanna Kahan, Moshe Inbar, Sabine de Ducla, Ulrich Freudensprung, Gunter von Minckwitz. Subgroup efficacy analyses of the randomized phase III TANIA trial evaluating continued or reintroduced bevacizumab (BEV) after 1st-line BEV for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD2-4.

Abstract CT322: Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC)

Abstract BACKGROUND: Analysis of data from 2203 patients (pts) with HER2-negative LR/mBC treated in the single-arm ATHENA study suggested that overall survival (OS) expectancy of a well-defined subset of pts with hormone receptor-positive LR/mBC was similar to that of pts with triple-negative breast cancer (TNBC). We used prognostic factors from ATHENA to analyze efficacy in the CAP cohort of the RIBBON-1 trial. PATIENTS AND METHODS: In the CAP cohort of RIBBON-1, pts with LR/mBC were randomized 2:1 to receive CAP with either BEV 15 mg/kg q3w (N=409) or placebo (PLA; N=206). The primary endpoint was investigator-assessed progression-free survival (PFS). Objective response rate (ORR) and 1-year OS rate were secondary endpoints. Exploratory efficacy analyses were done in three subgroups: TNBC; high-risk hormone receptor positive (>2 risk factors); and low-risk hormone receptor positive (≤2 risk factors) using the remaining risk factors identified in ATHENA (liver metastases/≥3 involved organs; disease-free interval [DFI] ≤24 months; prior anthracycline/taxane). The data cut-off was July 31, 2008. RESULTS: In all three subgroups, PFS and ORR numerically favored BEV-CAP, consistent with the significant PFS and ORR benefit in the intent-to-treat population. Median PFS, median OS, and 1-year OS rate with PLA-CAP suggested a similarly poor prognosis in pts with TNBC and pts with high-risk hormone receptor-positive LR/mBC. CONCLUSIONS: In these exploratory analyses, median OS in pts with high-risk hormone receptor-positive LR/mBC was short and similar to that in pts with TNBC, as seen in the ATHENA exploratory analysis. OutcomePLA-CAPBEV-CAPTNBCN=50N=87PFS events, n (%)42 (84)74 (85)PFS unstratified HR (95% CI)0.72 (0.49-1.06)Median PFS, months (95% CI)4.2 (3.5-5.9)6.1 (4.3-8.2)ORR, % (95% CI)10.6 (3.5-23.1)30.3 (20.2-41.9)1-year OS rate, % (95% CI)71 (55-81)70 (59-79)Deaths, n (%)26 (52)47 (54)Median OS, months (95% CI)20.5 (15.8-NR)19.7 (14.6-23.2)Hormone receptor-positive disease with additional risk factors*N=56N=92PFS events, n (%)42 (75)72 (78)PFS unstratified HR (95% CI)0.80 (0.54-1.17)Median PFS, months (95% CI)4.4 (3.1-6.2)7.1 (4.3-8.6)ORR, % (95% CI)22.4 (11.8-36.6)27.7 (18.4-38.6)1-year OS rate, % (95% CI)66 (52-77)80 (70-87)Deaths, n (%)32 (57)52 (57)Median OS, months (95% CI)19.6 (12.9-23.4)20.8 (17.5-25.7)Hormone receptor-positive disease with limited additional risk factors**N=90N=220PFS events, n (%)68 (76)139 (63)PFS unstratified HR (95% CI)0.67 (0.50-0.89)Median PFS, months (95% CI)7.7 (6.0-8.4)10.6 (9.1-12.0)ORR, % (95% CI)36.8 (24.4-50.7)41.5 (33.8-49.6)1-year OS rate, %86 (77-92)85 (80-89)Deaths, n (%)34 (38)83 (38)Median OS, months (95% CI)28.4 (23.4-NR)29.0 (25.8-NR)*ER and/or PgR positive with >2 risk factors (liver metastases/≥3 involved organs; DFI ≤24 months; prior anthracycline/taxane); **ER and/or PgR positive with ≤2 risk factors. Citation Format: Nicholas J. Robert, Veronique Dieras, Christian Jackisch, Stefanie Srock, Ulrich Freudensprung, Leonardo Faoro, Joyce O’Shaughnessy. Efficacy of first-line capecitabine (CAP) ± bevacizumab (BEV) according to risk factors in the RIBBON-1 randomized phase III trial in locally recurrent/metastatic breast cancer (LR/mBC). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT322. doi:10.1158/1538-7445.AM2014-CT322

First-line pertuzumab (P), trastuzumab (H), and taxane therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC): Interim safety results (N=704) from PERUSE.

548^ Background: Combining P with 1st-line H + docetaxel (DOC) in pts with HER2-positive mBC significantly improved progression-free survival (PFS) and overall survival (OS) in the randomized phase...

Abstract P6-06-40: Analysis of outcome according to risk factors in the randomized phase III TURANDOT trial evaluating first-line bevacizumab-containing therapy for HER2-negative locally recurrent/metastatic breast cancer (LR/mBC)

Abstract Background: The randomized phase III TURANDOT trial compared first-line bevacizumab (BEV) + paclitaxel (PAC) vs BEV + capecitabine (CAP) in HER2-negative LR/mBC [Lang, Lancet Oncol 2013]. At the prespecified interim analysis there was no detectable difference in overall survival (OS; primary endpoint) between treatment groups, but the secondary endpoints of progression-free survival (PFS) and objective response rate (ORR) favored BEV-PAC. We sought to identify patient populations defined by risk factors that may be most appropriately treated with one or other of the regimens. Methods: Patients with HER2-negative LR/mBC who had received no prior chemotherapy for LR/mBC were randomized to either BEV-PAC (BEV 10 mg/kg d1 & 15 + PAC 90 mg/m2 d1, 8, & 15 q4w) or BEV-CAP (BEV 15 mg/kg d1 + CAP 1000 mg/m2 bid d1-14 q3w). The study population was categorized into three cohorts: triple-negative (TNBC), high-risk hormone receptor-positive (HR+) and low-risk HR+. High-risk and low-risk HR+ were defined, respectively, as having ≥2 vs ≤1 of the following four risk factors: disease-free interval ≤24 months; visceral metastases; prior (neo)adjuvant anthracycline and/or taxane; ≥3 metastatic sites. Results: Baseline characteristics, efficacy, and safety by treatment arm are summarized below for the three cohorts. Although PFS results in all cohorts favored BEV-PAC, interim OS results showed a trend in favor of BEV-PAC in TNBC patients and in favor of BEV-CAP in low-risk HR+ patients. Grade ≥3 adverse events were less common with BEV-CAP than BEV-PAC in all three cohorts. TNBCHigh-risk HR+Low-risk HR+ BEV-PAC (n = 63)BEV-CAP (n = 67)BEV-PAC (n = 146)BEV-CAP (n = 162)BEV-PAC (n = 75)BEV-CAP (n = 50)Median age, years545658576161ECOG PS 0,%756068666366PFS Events, n (%)50 (79)54 (81)93 (64)125 (77)33 (44)35 (70)Median, months (95% CI)9.0 (7.8-10.7)5.6 (4.9-8.0)11.1 (10.4-13.4)8.3 (7.1-10.7)14.4 (10.4-20.5)11.5 (8.1-16.3)HR (95% CI)a1.37 (0.93-2.02)1.29 (0.98-1.69)1.39 (0.86-2.25)OS Events, n (%)28 (44)34 (51)50 (34)52 (32)18 (24)11 (22)1-year OS rate,%786380828590HR (95% CI)a1.33 (0.80-2.19)0.97 (0.66-1.43)0.80 (0.38-1.69)Grade ≥3 AEs,%634261516148aBEV-CAP vs BEV-PAC Conclusion: The simple risk factor index is prognostic for both PFS and OS and may be used to guide treatment choice when selecting BEV-containing therapy, balancing outcome with safety profile and patient preference. Final analysis of OS is expected in 2014. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-06-40.

Abstract P4-12-08: Final efficacy results from a single-arm multicenter phase II study evaluating first-line trastuzumab, bevacizumab, and capecitabine (HAX) therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC)

Abstract Background: After median follow-up of 8.8 months, the primary efficacy results from the HAX study [Martín et al., Oncologist 2012] demonstrated a 73% overall response rate (ORR) according to RECIST (primary endpoint), median progression-free survival (PFS) of 14.4 months and a safety profile typical of the component agents; overall survival (OS) data were immature at that time. We present final efficacy results. Methods: Patients with measurable HER2-positive LR/mBC who had received no prior chemotherapy for LR/mBC received bevacizumab 15 mg/kg day 1, trastuzumab 6 mg/kg day 1 (8 mg/kg loading dose in cycle 1), and capecitabine 1000 mg/m2 bid days 1–14, repeated every 3 weeks until progression, unacceptable toxicity, or withdrawal of consent. Results: At the time of data cut-off, median follow-up was 31.8 months (range 1.2–44.5 months). Median duration of study therapy was 9.0, 9.4, and 10.3 months for bevacizumab, capecitabine, and trastuzumab, respectively. More than 8 cycles were administered in 67%, 65%, and 70%, respectively. Efficacy results in the intent-to-treat population (n = 88) and clinically important subgroups are shown below. Patient subgroupBest ORR,% (95% CI)PFS events, n (%)Median PFS, months (95% CI)Deaths, n (%)Median OS, months (95% CI)1-year OS rate,% (95% CI)All patients (n = 88)75 (65-84)70 (80)14.2 (10.5-14.9)40 (45)31.8 (26.3-38.2)94 (86-98)ER and/or PgR positive (n = 37)73 (56-86)32 (86)14.1 (8.5-17.0)19 (51)31.8 (24.4-42.6)100 (*-*)ER and PgR negative (n = 51)77 (63-87)38 (75)14.5 (10.5-18.9)21 (41)33.1 (23.6-44.5)90 (77-96)No prior chemotherapy (n = 37)81 (65-92)27 (73)14.9 (10.5-24.8)14 (38)31.8 (26.3-44.4)94 (80-99)Prior chemotherapy (n = 51)71 (56-83)43 (84)13.6 (8.5-14.8)26 (51)30.9 (24.3-42.1)94 (82-98)Taxane pretreated (n = 28)57 (37-76)26 (93)9.5 (5.2-14.0)17 (61)27.4 (21.4-33.2)93 (74-98)Prior anti-HER2 therapy (n = 22)73 (50-89)18 (82)12.1 (5.2-17.0)11 (50)30.9 (24.3-*)95 (72-99)Age >60 years (n = 25)72 (51-88)16 (64)14.2 (10.5-21.7)11 (44)33.2 (22.0-*)100 (*-*)*Not reached The most common grade ≥3 adverse events were hand-foot syndrome (26% of patients), diarrhea (11%), and hypertension (11%). The majority of deaths (38/40) were from progressive/underlying disease. The cause of the two remaining deaths was described as unknown; one was reported at the primary analysis and the other occurred 19 months after last study drug administration, following progression. Detailed long-term safety results will be presented. Conclusion: Long-term follow-up results from the HAX study show that this is an active and tolerable first-line triplet therapy for HER2-positive mBC, demonstrating median OS of 31.8 months. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-08.

AVEREL: A Randomized Phase III Trial Evaluating Bevacizumab in Combination With Docetaxel and Trastuzumab As First-Line Therapy for HER2-Positive Locally Recurrent/Metastatic Breast Cancer

PURPOSE The AVEREL trial [A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab)/Docetaxel in Patients With HER2-Positive Metastatic Breast Cancer] evaluated first-line bevacizumab-containing therapy for human epidermal growth factor receptor 2 (HER2) -positive locally recurrent/metastatic breast cancer (LR/MBC). PATIENTS AND METHODS Patients with measurable/evaluable HER2-positive LR/MBC who had not received trastuzumab or chemotherapy for LR/MBC were stratified by prior adjuvant trastuzumab, prior (neo)adjuvant taxane, hormone receptor status, and measurable disease and were randomly assigned to receive docetaxel 100 mg/m(2) plus trastuzumab 8 mg/kg loading dose followed by 6 mg/kg either with bevacizumab 15 mg/kg or without bevacizumab, all administered every 3 weeks. The primary end point was progression-free survival (PFS). Additional end points included overall survival, response rate (RR), safety, quality of life, and translational research. Results Baseline characteristics of the 424 patients were balanced between treatment arms. Most patients had visceral metastases, 43% had a disease-free interval less than 12 months, and 85% had measurable disease. Median follow-up was 26 months. The hazard ratio for investigator-assessed PFS was 0.82 (95% CI, 0.65 to 1.02; P = .0775; median PFS, 13.7 v 16.5 months in the non-bevacizumab and bevacizumab arms, respectively; PFS events in 72%). The Independent Review Committee-assessed PFS hazard ratio was 0.72 (95% CI, 0.54 to 0.94; P = .0162; median PFS, 13.9 v 16.8 months, respectively; PFS events in 53%). The RR was 70% versus 74%, respectively (P = .3492). Grade ≥ 3 febrile neutropenia and hypertension were more common with bevacizumab-containing therapy. High baseline plasma vascular endothelial growth factor A (VEGF-A) concentrations were associated with greater bevacizumab benefit (not statistically significant). CONCLUSION Combining bevacizumab with docetaxel and trastuzumab did not significantly improve investigator-assessed PFS. The potential predictive value of plasma VEGF-A is consistent with findings in HER2-negative LR/MBC, warranting prospective evaluation.

1657P - Biomarker (BM) Results from the Phase III Averel Trial of 1st-Line Bevacizumab (BV), Trastuzumab (H) + Docetaxel (T) for HER2-Positive Locally Recurrent/Metastatic Breast Cancer (LR/MBC)

ABSTRACT Background AVEREL efficacy and safety results have been reported. We present exploratory analyses from the optional BM substudy. Methods Patients (pts) with HER2-positive LR/mBC received 1st-line T (100 mg/m2 q3w) + H (8 → 6 mg/kg q3w) ± BV (15 mg/kg q3w). The primary endpoint was investigator-assessed PFS. Baseline (BL) blood and tissue samples were collected from consenting pts. BL plasma levels of candidate BMs were measured using a novel ELISA. Median BL values for each BM were used to define high (> median; H) vs low (≤ median; L) BM cohorts and to correlate BMs with PFS using Cox regression corrected for prognostic factors. Results Plasma samples were available from 162/424 pts (38%). ICAM-1 correlated statistically significantly with PFS at α = 0.05. Table: 1657P TH BV + TH Subgroup Events/pts, n Median, mo HR (95% CI) Events/pts, n Median, mo Interaction p value a All 64/82 11.2 66/80 16.5 0.78 (0.56–1.11) E-selectin L H 31/44 32/37 16.4 8.2 30/36 35/43 16.5 16.6 1.01 (0.61–1.68) 0.57 (0.35–0.92) 0.241 IL-8 L H 35/45 28/36 13.6 8.4 28/35 37/44 16.4 17.8 0.84 (0.51–1.40) 0.74 (0.45–1.22) 0.506 ICAM-1 L H 30/45 33/36 16.4 10.3 29/35 36/44 16.5 16.2 1.13 (0.68–1.89) 0.49 (0.30–0.80) 0.017 bFGF L H 32/41 31/40 13.3 11.1 33/39 32/40 16.4 19.1 0.80 (0.49–1.30) 0.80 (0.49–1.32) 0.837 PDGF-C L H 29/40 35/42 17.1 8.5 32/41 34/39 16.5 16.6 0.87 (0.52–1.44) 0.72 (0.45–1.16) 0.342 VEGF-A L 33/45 13.6 30/36 16.5 0.83 (0.50–1.36) 0.795 H 31/37 8.5 35/43 16.6 0.70 (0.43–1.14) VEGF-C L H 35/42 29/40 13.5 9.6 32/39 34/41 14.8 19.1 0.70 (0.43–1.15) 0.92 (0.56–1.51) 0.649 VEGFR-1 L H 30/40 33/41 11.1 13.3 33/40 32/39 16.2 16.6 0.76 (0.46–1.25) 0.84 (0.52–1.37) 0.982 VEGFR-2 L H 35/44 28/37 11.2 11.0 30/36 35/43 13.7 19.2 0.95 (0.58–1.55) 0.67 (0.40–1.10) 0.174 VEGFR-3 L H 35/48 28/33 12.2 11.0 25/32 40/47 15.3 16.6 0.88 (0.52–1.47) 0.65 (0.40–1.06) 0.051 a Model includes prognostic factors. Conclusions High BL ICAM-1 correlated significantly with greater PFS benefit from BV at α = 0.05, consistent with data in lung cancer. VEGF-A, VEGFR-2 and -3 and E-selectin showed potential predictive value. VEGF-A and VEGFR-2 results are in line with data in HER2-negative mBC and pancreatic cancer. Disclosure L. Gianni: LG acts as a Consultant and has sat on Advisory Boards for Roche, Genentech, GSK, Novartis, Pfizer, Boehringer Ingelheim, Astra Zeneca, and Celgene. A. Chan: AC has acted as a Consultant, sat on Advisory Boards, and received honoraria and research funding from Roche. X. Pivot: XP has acted as a Consultant and sat on Advisory Boards for Roche, Eisai and GlaxoSmithKline, and has received honoraria from Sanofi. R. Greil: RG has acted as a Consultant for, sat on Advisory Boards for, and received honoraria and research funding from Roche. L. Provencher: LP has received a travel grant and honoraria from Roche. S. Prot: SP is an employee of F Hoffmann-La Roche Ltd. N. Moore: NM is an employee and holds stock in F Hoffmann-La Roche Ltd. S.J. Scherer: SS is an employee of Genentech. C. Pallaud: CP is an employee of F Hoffmann-La Roche Ltd. . All other authors have declared no conflicts of interest.

First-Line Bevacizumab-Containing Therapy for Triple-Negative Breast Cancer: Analysis of 585 Patients Treated in the ATHENA Study

Background: The prognosis for patients with triple-negative breast cancer (TNBC) is poor and treatment options are limited. Bevacizumab improves the efficacy of standard first-line therapy in locally recurrent/metastatic breast cancer (LR/mBC). The benefit of bevacizumab seen in patients with TNBC appears similar to that observed in the overall population. We conducted an exploratory analysis of patients with TNBC treated in the single-arm routine oncology practice ATHENA study. Methods: Patients with previously untreated LR/mBC received standard first-line chemotherapy combined with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks, until progression, unacceptable toxicity, or patient/physician decision). Results: Of 2,264 patients treated in ATHENA, 585 (26%) had TNBC. Most patients received single-agent taxane with bevacizumab. In the TNBC subgroup, the overall response rate was 49%, including complete responses in 10%; only 16% had primary resistant disease. Median time to progression was 7.2 months (95% CI 6.6–7.8) and median overall survival was 18.3 months (95% CI 16.4–19.7). The 1-year overall survival rate was 60%. The safety profile in TNBC was consistent with results in the overall population. Conclusion: This exploratory subgroup analysis suggests that first-line chemotherapy in combination with bevacizumab is an active regimen in patients with metastatic TNBC.

What Can Be Learned From Trials Running Short of Patients or Events?

chemotherapy for locally recurrent or metastatic breast cancer: Safety and efficacy in an open-label study in 2,251 patients. Ann Oncol 22:595-602, 2011 18. Miles D, Chan A, Romieu G, et al: Randomized, double-blind, placebocontrolled, phase III study of bevacizumab with docetaxel or docetaxel with placebo as first-line therapy for patients with locally recurrent or metastatic breast cancer: AVADO. J Clin Oncol 26:43s, 2008 (suppl 15; abstr 1011) 19. Brufsky A, Rivera RR, Hurvitz SA, et al: Progression-free survival (PFS) in patient subgroups in RIBBON-2, a phase III trial of chemotherapy (chemo) plus or minus bevacizumab (BV) for second-line treatment of HER2-negative, locally recurrent or metastatic breast cancer (MBC). J Clin Oncol 28:119s, 2010 (suppl 15; abstr 1021) 20. Miller KD, Chap LI, Holmes FA, et al: Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 23:792-799, 2005 21. Bear HD, Tang G, Rastogi P, et al: Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med 366:310-320, 2012 22. von Minckwitz G, Eidtmann H, Rezai M, et al: Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med 366:299-309, 2012 23. Gianni L, Romieu G, Lichinistser M, et al: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) docetaxel (DOC) as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer (LR/mBC). Cancer Res 71:S4-S8, 2011 (suppl 24) 24. An SJ, Huang YS, Chen ZH, et al: Posttreatment plasma VEGF levels may be associated with the overall survival of patients with advanced non-small cell lung cancer treated with bevacizumab plus chemotherapy. Med Oncol [epub ahead of print on April 3, 2011] 25. Peppercorn J, Shapira I, Collyar D, et al: Ethics of mandatory research biopsy for correlative end points within clinical trials in oncology. J Clin Oncol 28:2635-2640, 2010

First-line bevacizumab-containing therapy for breast cancer: results in patients aged ≥70 years treated in the ATHENA study

There are limited data on treatment outcomes in the growing population of elderly patients with locally recurrent/metastatic breast cancer (LR/mBC). To gain information on first-line bevacizumab combined with chemotherapy in the elderly, we analyzed data from the ATHENA trial in routine oncology practice. Patients with human epidermal growth factor receptor-2-negative LR/mBC received first-line bevacizumab with standard chemotherapy until disease progression, unacceptable toxicity, or physician/patient decision. We carried out a subgroup analysis of safety and efficacy in patients aged≥70 years. Possible correlations between tolerability and baseline comorbidities or Eastern Cooperative Oncology Group status were explored. Bevacizumab was combined with single-agent paclitaxel in 46% of older patients. Only hypertension and proteinuria were more common in older than in younger patients (grade≥3 hypertension: 6.9% versus 4.2%, respectively; grade≥3 proteinuria: 4.0% versus 1.5%, respectively). Grade≥3 arterial/venous thromboembolism occurred in 2.9% versus 3.3%, respectively. Further analysis revealed no relationship between baseline presence and severity of hypertension and risk of developing hypertension during bevacizumab-containing therapy. Median time to progression was 10.4 months in patients aged≥70 years. These findings suggest that bevacizumab-containing therapy is tolerable and active in patients aged≥70 years. Hypertension was more common than in younger patients but was manageable. We find no evidence precluding the use of bevacizumab in older patients, including those with hypertension, although age may influence chemotherapy choice.

S4-8: First results of AVEREL, a randomized phase III trial to evaluate bevacizumab (BEV) in combination with trastuzumab (H) + docetaxel (DOC) as first-line therapy for HER2−positive locally recurrent/metastatic breast cancer (LR/mBC)

Abstract Background: H + taxane is an established and effective first-line treatment for HER2−positive LR/mBC. Preclinical data provide the rationale for combining BEV and H in HER2−positive LR/mBC but clinical data in this setting are limited to single-arm phase II studies. AVEREL is the first randomized trial of BEV in HER2−positive LR/mBC. Methods: Eligible patients had measurable or evaluable HER2−positive LR/mBC (centrally confirmed IHC 3+ or FISH/CISH +), ECOG performance status 0/1, and had received no prior chemotherapy for advanced disease. Prior adjuvant H/taxanes were permitted unless disease had recurred <6/<12 months after the last dose, respectively. Patients with CNS metastases were excluded. Patients were stratified according to adjuvant H, prior (neo)adjuvant taxane (further stratified by time to relapse since last dose of [neo] adjuvant chemotherapy/no chemotherapy), hormone receptor status, and measurable disease, and were randomized to receive either H (8 mg/kg → 6 mg/kg q3w) + DOC (100 mg/m2 q3w) or H + DOC + BEV (15 mg/kg q3w). H and BEV were given until disease progression; DOC was given for a planned minimum of 6 cycles unless progression or unacceptable toxicity mandated earlier discontinuation. The primary endpoint was progression-free survival (PFS). Additional endpoints included overall survival (OS), overall response rate (ORR; assessed by RECIST 1.0), duration of response, time to treatment failure, safety (NCI CTCAE v3.0 adverse events [AEs] and AEs of special interest for BEV), quality of life (FACT-B), and translational research. The primary analysis of PFS was prespecified after 310 investigator-assessed PFS events. The statistical design provided 90% power to detect a PFS hazard ratio (HR) of 0.69 (median PFS 11→16 months) with α=0.05. Results: Between Sep 2006 and Feb 2010, 424 patients were enrolled from 60 centers; 421 received treatment. Baseline characteristics were generally well balanced in the H + DOC and H + DOC + BEV arms: median age 55 and 53 years, respectively; visceral metastases 71% and 77%; prior adjuvant H 12% and 13%; disease-free interval <12 months 43% in both arms; measurable disease 85% in both arms. Median follow-up was 26 months in both arms. Efficacy results are summarized in the table. No new safety signals were observed. The following grade ≥3 AEs were more common in the BEV-containing arm than the H + DOC arm: congestive heart failure (5.1% vs 2.9%, respectively); febrile neutropenia (11.6% vs 8.7%); hypertension (11.6% vs 0.5%). Grade 5 AEs occurred in 1.4% of the H + DOC + BEV arm vs 1.9% of the H + DOC arm. Conclusions: The addition of BEV to H + DOC improved PFS without reaching statistical significance according to investigator assessment (unstratified HR 0.82; 95% CI 0.65−1.02). The improvement as assessed by Independent Review Committee was statistically significant. Evaluation of biomarkers is ongoing to try to identify those patients who may benefit from first-line BEV-containing therapy for HER2−positive LR/mBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-8.