SABCS 2011: Metastasierte Situation

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1 Dr. med. Johannes Ettl Interdisziplinäres Brustzentrum und Frauenklinik rechts der Isar, Technische Universität München, Direktorin: Prof. Dr. M. Kiechle SABCS 2011: Metastasierte Situation München, Projektgruppe 26.Januar 2012

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4 mtor und endokrine Resistenz Moy B et al. Clin Cancer Res. 2006;12:

5 TAMRAD (Ph II): Tamoxifen ± Everolimus in Advanced d BC 111 postmenopausal women with ER+ advanced BC previously treated with an AI were randomized in a phase II trial 1.0 Probab bility of Pr rogression HR = 0.54 Log-rank P = TAM: 4.5 mos TAM + EVE: 8.6 mos Months AI = aromatase inhibitor; BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; TAM = tamoxifen. Bourgier C et al. ECCO/ESMO 2011 (Abstract #5005) 5

6 BOLERO-2 (Ph III): Everolimus in Advanced BC N = 724 Postmenopausal ER+ Unresectable locally advanced dor metastatic BC Recurrence or progression after letrozole or anastrozole R 2:1 EVE 10 mg daily + EXE 25 mg daily (n = 485) Placebo + EXE 25 mg daily (n = 239) Endpoints Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases Primary: PFS (local assessment) Secondary: OS, ORR, QOL, safety, bone markers, PK BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; EXE = exemestane; ORR, overall response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; QOL = quality of life. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) 6

7 BOLERO-2: Prior Therapy Therapy Everolimus + Placebo + Exemestane Exemestane (N=485), % (N=239), % Sensitivity to prior hormonal therapy Last treatment: LET/ ANA Last treatment Adjuvant Metastatic Prior tamoxifen Prior fulvestrant Prior chemotherapy for metastatic BC Number of prior therapies: LET: letrozole, ANA: anastrozole Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 7

8 BOLERO-2 (12 mo f/up): PFS Local Prob bability (% %) of Even nt HR = 0.44 (95% CI: ) 053) Log rank P value: <1 x EVE + EXE: 7.4 months PBO + EXE: 3.2 months 0 EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239) Number of patients still at risk Time (weeks) Everolimus Placebo Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 8

9 BOLERO-2 (12 mo f/up): PFS Central 100 HR = 0.36 (95% CI: ) Log rank P value: <1 x Proba ability (%) of Event EVE + EXE: 11.0 months PBO + EXE: 4.1 months 0 EVE + EXE (E/N = 155/485) PBO + EXE (E/N = 127/239) Time (weeks) Number of patients still at risk Everolimus Placebo Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 9

10 BOLERO-2 (12 mo f/up): Response & Clinical Benefit 60 Everolimus + Exemestane 50 Placebo + Exemestane 50.5% Perce ent % P < % Response P < % Clinical Benefit Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 10

11 BOLERO-2 (12 mo f/up): Overall Survival As of July 8, 2011: 137 deaths 17.2% in everolimus arm 22.7% in placebo arm OS final analysis at 392 events 80% power to detect 26% reduction in risk OS = overall survival; PFS = progression-free survival. Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) 11

12 BOLERO-2 (12 mo f/up): Most Common Adverse Events Everolimus + Exemestane (n = 482), % All Grades Grade 3 Grade 4 Placebo + Exemestane (n = 238), % All Grades Grade 3 Grade 4 Stomatitistiti <1 0 Rash Fatigue 36 4 < Diarrhea 33 2 <1 19 <1 0 Appetite decreased <1 0 Nausea 29 <1 < Non-infectious Pneumonitis* Hyperglycemia* 14 5 <1 2 <1 0 *Adverse Events of clinical interest Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) 12

13 BOLERO-2: Patient t Disposition iti Disposition Everolimus + Placebo + Exemestane Exemestane (N=485), % (N=239), % Protocol therapy ongoing Discontinued Disease progression Adverse event Subject withdrew consent Death due to AE New cancer therapy Protocol deviation Administrative problems Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 13

14 BOLERO-2 (Longer Term Data): QOL QoL Scale Score: Time to 5% deterioration 100 HR = 0.81 (97.5% CI: ) Log rank p value: Probabil lity (%) of Event EVE + EXE: 7.0 months PBO + EXE: 5.6 months 0 EVE + EXE (E/N = 246/485) PBO + EXE (E/N = 106/239) Number of patients still at risk Time (weeks) Everolimus Placebo QOL evaluated using the EORTC-QLQ-30 scale Hortobagyi G. et al, SABCS 2011 (Abstract #S3-7) 14

15 Fazit BOLERO-2 Die Hinzunahme von Everolimus zu Exemestan führt zur deutlichen Verlängerung des PFS im Kollektiv der endokrinen Resistenz unter nichtsteroidalem AI (hauptsächlich über die Verlängerung der stable Disease), Fatigue und Mukositis beeinträchtigen die Verträglichkeit Nach einer negativen Studie mit Temserolimus nun zweite positive Studie mit Everolimus (unterschiedliche Kollektive!) Everolimus für Nierenzellca bereits zugelassen Fußzeile

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25 Fazit Cleopatra Verlängerung des PFS um 6 Monate durch duale Blockade in der firstline 90% der Pat. waren Trastuzumab naiv! Fast Verdoppelung der Grad ¾ febrilen Neutropenien im Pertuzumab Arm Kombination mit anderen (verträglicheren?) CTX: Vino, Cap, Pacli, TDM 1?? Kombination mit antiöstrogener Therapie bei HR pos? Effektivität ohne CTX? Fußzeile

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