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Azienda Ospedaliero Universitaria Policlinico Modena
Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancer Chieti, 27 Giugno 2016 Luca Moscetti DH Oncologia Dipartimento di Oncologia, Ematologia e Malattie dell’Apparato Respiratorio Azienda Ospedaliero Universitaria Policlinico Modena Chieti, 27 Giugno 2016
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E2100—Study Design Paclitaxel: 90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest Avastin: 10 mg/kg following paclitaxel treatment on Wk 1 and 3 of every cycle MBC not previously treated with chemotherapy (N = 685) Stratification - Disease-free interval - Adjuvant therapy - ER+, ER–, unknown - Number of metastatic sites R A N D O M I Z E Paclitaxel: 90 mg/m2 IV infusion over 1 hr every wk for 3 wk followed by 1 wk of rest Miller K, et al New England Journal of Medicine 2007.
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E2100—Endpoints Primary endpoint Secondary endpoints
Progression-free survival (PFS) Secondary endpoints Objective response rate (ORR) Overall survival (OS) Quality of life (QoL) Safety Miller K, et al New England Journal of Medicine 2007.
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Paclitaxel weekly + bevacizumab St III-IV breast cancer HER2-negative
ECOG 2100: Randomized Phase III Trial of Bevacizumab Added to Paclitaxel in Stage IV Breast Cancer Paclitaxel weekly + bevacizumab ECOG 2100 St III-IV breast cancer HER2-negative N = 722 Paclitaxel weekly 1.0 Pac. + Bev months 0.8 Paclitaxel months 0.6 HR = 0.51 ( ) PFS Probability 0.4 0.2 0.0 6 12 18 24 30 Months Miller K, et al New England Journal of Medicine 2007. Miller K, SABCS 05
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E2100 response rates Investigator assessment IRF assessment
48% 50% Patients, % Patients, % 23% 22% Paclitaxel Bevacizumab + paclitaxel Paclitaxel Bevacizumab + paclitaxel Miller K, et al New England Journal of Medicine 2007. Miller K, SABCS 05
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E2100 Overall Survival 81.4% 74.0% 55.0% 50.1% 1.0 1.0 p = 0.017*
PAC (n = 354): Median OS 24.8 mo PAC + AVA (n = 368): Median OS 26.5 mo 0.8 0.8 50.1% 55.0% p = 0.191* 0.6 0.6 HR = (0.722, 1.046) Log-rank test, p = Proportion surviving 0.4 0.4 0.2 0.2 * Post-hoc 0.0 0.0 6 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 54 54 60 60 No. of patients at risk Months PAC+AVA 368 344 297 249 193 104 48 23 5 PAC 354 307 258 215 165 103 48 19 8
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Option to receive bevacizumab with second-line chemotherapy
AVADO: Bevacizumab + Docetaxel in First- line Treatment of Advanced Breast Cancer Stratified by region previous taxane therapy, disease-free internal, measurable disease, hormone receptor status Docetaxel* 100 mg/m2 + Placebo† (n = 241) Women with HER2-negative, untreated locally recurrent or metastatic breast cancer (N = 736) Option to receive bevacizumab with second-line chemotherapy Docetaxel* 100 mg/m2 + Bevacizumab† 7.5 mg/kg (n = 248) Docetaxel* 100 mg/m2 + Bevacizumab† 15.0 mg/kg (n = 247) *Docetaxel given every 3 wks up to 9 cycles. †Bevacizumab or placebo given until unacceptable toxicity or disease progression. Miles DW, et al. SABCS Abstract 41.
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Avastin Taxanes overall response rate Investigator assessment
AVADO2 Overall response rate (%) 100 P alone Avastin 10 mg/kg q2w + P 100 Placebo + D Avastin 7.5 mg/kg q3w + D Avastin 15 mg/kg q3w + D 80 80 IRF assessment (n=472) Investigator assessment 63 (n=206) 55 (n=201) 60 60 50 44 (n=207) 40 40 22 20 20 CR + PR p<0.0001 CR + PR p<0.0001 CR + PR CR + PR p=0.0295a CR + PR p=0.0001a aVersus placebo + D IRF, Independent Review Facility 1Klencke et al, ASCO 2008; 2Miles et al, ASCO 2008 8
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AVADO: PFS by BEV doses The trial was not designed to detect a statistically significant difference between bevacizumab doses Miles DW, et al Journal Clinical Oncology 2010.
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PFS in subgroup analyses: patient characteristics
AVADO3 Baseline risk factor n 555 722 167 Favors Avastin + P Favors P n 488 489 402 410 86 79 296 297 185 Favors Avastin + D Favors placebo + D All patients Age <65 years >65 years ECOG PS Not analyzed 1 0.25 0.5 1 2 4 0.25 0.5 1 2 4 Avastin 10 mg/kg q2w + P Avastin 7.5 mg/kg q3w + D 1Klencke et al, ASCO 2008; 2Schneeweiss et al, ESMO 2008; 3Miles et al, ASCO 2008 Avastin 15 mg/kg q3w + D 10
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PFS in subgroup analyses: disease characteristics
AVADO3 Baseline risk factor n 722 446 265 296 426 514 208 Favors Avastin + P Favors P n 488 489 348 349 138 137 161 188 327 301 263 264 221 Favors Avastin + D Favors placebo + D All patients ER status positive negative Disease-free interval =24 months >24 months No. metastatic sites <3 =3 0.25 0.5 1 2 4 0.25 0.5 1 2 4 Avastin 10 mg/kg q2w + P Avastin 7.5 mg/kg q3w + D 1Klencke et al, ASCO 2008; 2Schneeweiss et al, ESMO 2008; 3Miles et al, ASCO 2008 Avastin 15 mg/kg q3w + D 11
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PFS in subgroup analyses: prior therapy
AVADO3 Baseline risk factor n 475 247 142 580 364 358 722 Favors Avastin + P Favors P n 323 318 165 171 77 73 411 416 269 264 219 225 488 489 Favors Avastin + D Favors placebo + D All patients Prior adjuvant chemo Yes No Prior taxane Yes No Prior anthracycline Yes No 0.25 0.5 1 2 4 0.25 0.5 1 2 4 Avastin 10 mg/kg q2w + P Avastin 7.5 mg/kg q3w + D 1Klencke et al, ASCO 2008; 2Schneeweiss et al, ESMO 2008; 3Miles et al, ASCO 2008 Avastin 15 mg/kg q3w + D 12
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TURANDOT: Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine
Phase III Pts 564 BEVA PAC vs BEVA CAPE mPFS 11 mo vs 8,1 mo 1,28 p=0.0052 HR 1.04
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FDA withdraw EMA approval November 18, 2011
Withdraw approval of bevacizumab for breast cancer Initial benefits in PFS not confirmed from two additional studies AVADO and RIBBON1 did not confirmed the clinical benefit showed in ECOG2100 Avastin (bevacizumab) in combination with paclitaxel is indicated for first-line treatment of patients with locally recurrent or metastatic breast cancer Avastin in combination with capecitabine is indicated for first-line treatment of patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline-containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Avastin in combination with capecitabine
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Progression-Free Survival in E2100, AVADO, and RIBBON1
FDA withdraw Progression-Free Survival in E2100, AVADO, and RIBBON1 U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010
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Primary Analysis of Overall Survival in E2100, AVADO, and RIBBON1
FDA withdraw Primary Analysis of Overall Survival in E2100, AVADO, and RIBBON1 U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010
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Updated Analysis of Overall Survival in E2100, AVADO, and RIBBON1
FDA withdraw Updated Analysis of Overall Survival in E2100, AVADO, and RIBBON1 U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010
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Only ECOG 2100 used weekly paclitaxel
FDA withdraw Only ECOG 2100 used weekly paclitaxel Is effect drug or schedule related? No reason to believe that the effect should be the same Effect of capecitabine in combination diluted by taxane and anthracycline arms 51% of patients in the non-bev arm received bevacizumab post-progression compared to 40% who continued bev after first-line 42% vs 35% (non bev vs bev) received 3 or more subsequent lines of therapy following progression
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FDA withdraw This extensive use of subsequent therapy at investigator discretion may have affected later survival, making it more difficult to assess the effect of Avastin on overall survival in the first-line HER2-negative MBC setting U.S. BL /191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010
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Bevacizumab: First-line trials
Efficacy E-2100 AVADO Ribbon-1 Capecitabine Ribbon-1 A/T Control arm Beva Arm Placebo arm Beva arm PFS months 5.9 11.8 8.2 9/10.1 5.7 8.6 8.0 9.2 HR 0.60 P<.0001 0.86 P=.12 (7.5 mg) 0.77 P=.006 (15 mg) 0.69 P=.0002 0.64 OS months 25.2 26.7 31.9 30.8/30.3 21.2 29 23.8 0.88 P=.16 1.05/1.03 P=.72/.85 0.85 P=.27 1.03 P=.83 SPP months 19.3 14.9 23.7 21.8/20.2 15.5 20.4 15.8 16
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Chemotherapy + Bevacizumab
Pooled Efficacy Analysis of Bevacizumab + Chemotherapy vs Chemotherapy Alone Outcome Chemotherapy + Bevacizumab (n = 1439) Chemotherapy Alone (n = 1008) Median PFS, mos 9.2 6.7 HR (95% CI) 0.64 ( ) ORR,* % 49 32 Median OS, mos 26.7 26.4 0.97 ( ) 1-yr OS, % 82 77 *Assessed in patients with measurable disease at baseline: n = 1105 for chemotherapy plus bevacizumab; n = 788 for chemotherapy alone. O’Shaughnessy et al. ASCO Abstract 1005.
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Meta-Analysis crossover and post-study therapies
Therapies used upon progression in AVADO and RIBBON-1a Therapy, % CT + Beva (n=1071) CT (n=654) Chemotherapy 65 71 Bevacizumab 40 51 Hormonal therapy 23 25 Number of subsequent agents 1 2 3 ≥ 4 15 26 12 10 27 aData not available from E2100 O’Shaugnessy J et al, ASCO Abstract 1005
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Beva Pac/Cape/other CTs
Bevacizumab: real life ATHENA obs AVAREG AVANTI ML21165 # pts 2251 220 1807 865 Tx Beva Taxs/ other CTs Beva Taxs Beva Pac/Cape/other CTs Beva Pac B cont / B stop PFS months 9.7 11,6 Beva cont 6,7 Beva stop 9,3 9.5 9,6 18,4 Beva cont HR - OS months 25 30 Beva cont 18 Beva stop 21,6 35,7 Beva cont
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53% Continue Bevacizumab
Final overall survival results and effect of prolonged (>1 year) first-line bevacizumab-containing therapy for metastatic breast cancer in the ATHENA trial 53% Continue Bevacizumab 2264 pts Bevacizumab +CT 47% Stop Bevacizumab Smith I Breast Cancer Res Treat (2011)
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OS PFS ATHENA trial mOS Cont’d Stop’d 25,2 mo 30 18,4 mPFS Cont’d
9.7 mo 11,7 6,7 Smith I Breast Cancer Res Treat (2011)
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Bevacizumab maintenance in first line treatment for metastatic breast cancer
54% Continue Bevacizumab 314 pts Bevacizumab+CT 46% Stop Bevacizumab (8,3% PD) mPFS 14,6 mo L. Mentuccia, ASCO 2015 annual meeting, P549.
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Meta-analysis of First-line Bevacizumab Plus Chemotherapy in Triple-Negative Breast Cancer
Bevacizumab/ Chemo (n = 363) Chemo (n = 258) HR (95% CI) P Value Median Progression-Free Survival 8.1 months 5.4 months 0.649 ( ) < .0001 Overall Response Rate 42% 23% NR Median Overall Survival 18.9 months 17.5 months 0.959 ( ) .6732 1-Year Overall Survival Rate 71% 65% .1140 This meta-analysis represents the largest reported population of patients randomized to treatment for metastatic TNBC. The addition of bevacizumab significantly improved PFS but not OS. O’Shaughnessy et al. SABCS 2010; abstract P
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First-line Bevacizumab Plus Chemotherapy in Triple-Negative Breast Cancer
Trial Chemo Partner Number of Patients With TNBC (%) Median PFS Bev/Chemo Chemo HR E2100 Weekly paclitaxel 122 (33%) 110 (31%) 10.6 mo. 5.3 mo. 0.49 AVADO Docetaxel q 3 weeks 58 (23%) 52 (22%) 8.1 mo. 6.1 mo. 0.68 RIBBON-1 (Taxane/ Anthracycline) Docetaxel/nab paclitaxel or anthracycline combination 96 (23%) 46 (22%) 6.5 mo. 6.2 mo. 0.78 RIBBON-1 (Capecitabine) Capecitabine 87 (21%) 50 (24%) 4.2 mo. 0.72 8,1 mo 5.4 mo ATHENA Taxanes 68% 585 (25%) - 7,2 mo. AVAREG Paclitaxel 106 (48%) 8,3 mo. TURANDOT Cape or Pac 130 (23%) 9/5.6 mo. O’Shaughnessy et al. SABCS 2010; abstract P , modified.
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HR+ Months HR -
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Capecitabine docetaxel Gemcitabine paclitaxel Paclitaxel Bevacizumab
Outcome Anthra Paclitaxel Docetaxel Capecitabine docetaxel Gemcitabine paclitaxel Paclitaxel Bevacizumab Nabholtz 2003 Jones 2005 O’shaugnessy 2002 Melemed 2008 Miles 2007 Number of pts 213 211 256 266 368 Median PFS, mos 6,2 5,7 6 11.4 Median OS, mos 22,5 16 14 18,6 26.7 ORR% 59 32 42 41,4 50
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It seems to be the same curves
7,4 mo 4,6 mo
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Practice changing ??? Practice changing !!! 7,4 mo 4,6 mo
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Bevacizumab combined with a chemotherapy as 1st or 2nd line therapy for MBC provides only a moderate benefit in PFS and no benefit in OS. The absence of known predictive factors for bevacizumab efficacy renders recommendations on its use difficult. Bevacizumab can only therefore be considered as an option in selected cases in these settings and is not recommended after 1°/ 2nd line. ESO-ESMO 2nd international consensus guidelines for advanced breast cancer (ABC2)*
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Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancer
No Yes.. Maybe
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