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Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancer

This article discusses the use of taxanes and bevacizumab as the standard first-line therapy for HER-2 metastatic breast cancer. It provides information about relevant studies and their results.

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Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancer

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  1. 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

  2. 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 D 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.

  3. E2100—Endpoints • Primary endpoint • 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.

  4. 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 cancerHER2-negative N = 722 Paclitaxel weekly Pac. + Bev. 11.4 months 1.0 Paclitaxel 6.11 months 0.8 0.6 HR = 0.51 (0.43-0.62) PFS Probability 0.4 0.2 0.0 0 6 12 18 24 30 Months Miller K, et al New England Journal of Medicine 2007. Miller K, SABCS 05

  5. E2100 response rates Investigator assessment IRF assessment p<0.0001 p<0.0001 50% 48% Patients, % Patients, % 23% 22% Paclitaxel Bevacizumab + paclitaxel Paclitaxel Bevacizumab + paclitaxel Miller K, et al New England Journal of Medicine 2007. Miller K, SABCS 05

  6. 81.4% 74.0% 55.0% p = 0.017* 50.1% p = 0.191* E2100 Overall Survival 1.0 1.0 PAC (n = 354): Median OS 24.8 mo PAC + AVA (n = 368): Median OS 26.5 mo 0.8 0.8 0.6 0.6 HR = 0.869 (0.722, 1.046) Log-rank test, p = 0.1374 Proportion surviving 0.4 0.4 0.2 0.2 * Post-hoc 0.0 0.0 0 0 6 6 12 12 18 18 24 24 30 30 36 36 42 42 48 48 54 54 60 60 Months No. of patients at risk 368 344 297 249 193 104 48 23 5 0 PAC+AVA 354 307 258 215 165 103 48 19 8 0 PAC

  7. 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) Option to receive bevacizumab with second-line chemotherapy Women with HER2-negative, untreated locally recurrent or metastatic breast cancer (N = 736) 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 2009. Abstract 41.

  8. E21001 AVADO2 aVersus placebo + DIRF, Independent Review Facility AvastinTaxanesoverallresponse rate Overallresponserate (%) 100 Placebo + D Avastin 7.5 mg/kg q3w + D Avastin 15 mg/kg q3w + D 100 P aloneAvastin 10 mg/kg q2w + P 80 80 63(n=206) Investigator assessment IRF assessment(n=472) 55(n=201) 60 60 44(n=207) 50 40 40 22 20 20 0 0 CR + PR p<0.0001 CR + PR p<0.0001 CR + PR CR + PR p=0.0295a CR + PR p=0.0001a 1Klencke et al, ASCO 2008; 2Miles et al, ASCO 2008

  9. 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.

  10. n n 489 722 488 410 555 402 167 79 86 296 297 185 185 PFS in subgroup analyses: patient characteristics E21001,2 AVADO3 Baselinerisk factor FavorsAvastin + P FavorsP FavorsAvastin + D Favorsplacebo + D All patients Age <65 years >65 years ECOG PS 0 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

  11. n n 489 722 488 349 446 348 265 137 138 188 296 161 426 301 327 264 514 263 221 208 221 PFS in subgroup analyses: disease characteristics E21001,2 AVADO3 Baselinerisk factor FavorsAvastin + P FavorsP FavorsAvastin + D Favorsplacebo + 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

  12. n n 489 722 488 318 475 323 171 247 165 73 142 77 416 580 411 364 264 269 358 225 219 PFS in subgroupanalyses: priortherapy E21001,2 AVADO3 Baselinerisk factor FavorsAvastin + P FavorsP FavorsAvastin + D Favorsplacebo + 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

  13. TURANDOT: Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine

  14. 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 indicatedfor 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

  15. FDA withdraw Progression-Free Survival in E2100, AVADO, and RIBBON1 U.S. BL 125085/191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

  16. FDA withdraw Primary Analysis of OverallSurvival in E2100, AVADO, and RIBBON1 U.S. BL 125085/191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

  17. FDA withdraw Updated Analysis of OverallSurvival in E2100, AVADO, and RIBBON1 U.S. BL 125085/191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

  18. 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 FDA withdraw

  19. 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 125085/191 and 192: AVASTIN (Bevacizumab)—Genentech, Inc. Briefing Book JUN 2010

  20. Bevacizumab: First-line trials

  21. Pooled Efficacy Analysis of Bevacizumab + Chemotherapy vs Chemotherapy Alone *Assessed in patients with measurable disease at baseline: n = 1105 for chemotherapy plus bevacizumab; n = 788 for chemotherapy alone. O’Shaughnessy et al. ASCO 2010. Abstract 1005.

  22. Meta-Analysis crossover and post-study therapies Therapies used upon progression in AVADO and RIBBON-1a aData not available from E2100 O’Shaugnessy J et al, ASCO 2010. Abstract 1005

  23. Bevacizumab: real life

  24. Finaloverallsurvivalresults and effect of prolonged (>1 year) first-line bevacizumab-containingtherapy for metastaticbreastcancer in the ATHENA trial 53% Continue Bevacizumab 2264 pts Bevacizumab +CT 47% Stop Bevacizumab Smith I Breast Cancer Res Treat (2011)

  25. ATHENA trial OS PFS Smith I Breast Cancer Res Treat (2011)

  26. Bevacizumab maintenance in first line treatment for metastaticbreastcancer 54% Continue Bevacizumab 314 pts Bevacizumab+CT 46% Stop Bevacizumab (8,3% PD) mPFS 14,6 mo L. Mentuccia, ASCO 2015 annual meeting, P549.

  27. Meta-analysis of First-line Bevacizumab Plus Chemotherapy in Triple-Negative Breast Cancer • 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 P6-12-03.

  28. First-line Bevacizumab Plus Chemotherapy in Triple-Negative Breast Cancer O’Shaughnessy et al. SABCS 2010; abstract P6-12-03, modified.

  29. HR+ Months HR -

  30. It seems to be the same curves 7,4 mo 4,6 mo

  31. Practicechanging ??? Practicechanging !!! 7,4 mo 4,6 mo

  32. 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)*

  33. Taxanes and bevacizumab are the standard first line theraphy for Her 2 – metastatic breast cancer No Yes.. Maybe

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