Transcript BOLERO 2
2011 European Multidisciplinary Cancer Congress Stockolm, 23-27 September 2011 Everolimus in combination with exemestane for postmenopausal women with advanced breast cancer who are refractory to letrozole or anastrozole: results of the BOLERO-2 phase III trial J. Baselga, M. Campone, T. Sahmoud, M. Piccart, H. Burris, H. Rugo, S. Noguchi, M. Gnant, P. Mukhopadhyay, G. Hortobagyi On behalf of the BOLERO-2 Investigators Discussant: F. Andre (France) September 26, 2011 3 Crosstalk between ER and mTOR Signaling • mTORC1 activates ER in a ligand-independent fashion1 • Estradiol suppresses apoptosis induced by PI3K/mTOR blockade2 • Hyperactivation of the PI3K/mTOR pathway is observed in endocrineresistant breast cancer cells3 • mTOR is a rational target to enhance the efficacy of hormonal therapy 1. Yamnik, RL. J Biol Chem 2009; 284(10):6361-6369. 2. Crowder, RJ. Cancer Res 2009;69:3955-62. 3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413. 4 Ph II Neoadjuvant Letrozole ± Everolimus: Proof of Concept N= 270 Postmenopausal ER+ early breast cancer Everolimus 10 mg/day + Letrozole 2.5 mg/day ORR Surgery Placebo + Letrozole 2.5 mg/day Biomarkers: D14 and surgical specimen Results: • • Significantly higher response rate (primary endpoint) Everolimus arm 68% vs placebo arm 59% Significantly greater decrease in Ki67 proliferation index Everolimus arm 57% vs placebo arm 30% Baselga J. 2009. J Clin Oncol 2009;27:2630-7. BOLERO-2: Trial Design N = 724 Postmenopausal 2 ER+ HER2- ABC refractory to 1 letrozole or anastrozole Everolimus 10 mg/day + Exemestane 25 mg/day (N = 485) Placebo + Exemestane 25 mg/day (N = 239) PFS OS ORR Bone Markers Safety PK Stratification: 1. Sensitivity to prior hormonal therapy 2. Presence of visceral disease No cross-over ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 – negative; PFS: progression-free survival; PK: pharmacokinetics Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 6 Participating Countries 7 BOLERO-2: Baseline Characteristics Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % 62 (34, 93) 61 (28, 90) Caucasian 74 78 Asian 20 19 Performance status 0 60 59 Liver involvement 33 30 Lung involvement 29 33 Measurable diseasea 70 68 Characteristic Median age (range), years Race a All other patients had ≥ 1 bone lesion. Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 8 BOLERO-2: Prior Therapy Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Sensitivity to prior hormonal therapy 84 84 Last treatment: LET/ ANA 74 75 Adjuvant 21 16 Metastatic 79 84 Prior tamoxifen 47 49 Prior fulvestrant 17 16 Prior chemotherapy for metastatic BC 26 24 Number of prior therapies: ≥3 54 53 Therapy Last treatment LET: letrozole, ANA: anastrozole Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 9 BOLERO-2: Patient Disposition Everolimus + Exemestane (N=485), % Placebo + Exemestane (N=239), % Protocol therapy ongoing 47 29 Discontinued 53 71 Disease progression 37 66 Adverse event 6.6 2.5 Subject withdrew consent 6.8 2.1 Death due to AE 1.4 0.4 New cancer therapy 0.4 0 Protocol deviation 0.6 0 0 0.4 Disposition Abnormal laboratory value Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 10 BOLERO-2 Primary Endpoint: PFS Local Assessment HR = 0.43 (95% CI: 0.35–0.54) Log rank P value = 1.4 x 10 -15 Probability of Event (%) 100 80 EVE + EXE: 6.9 months PBO + EXE: 2.8 months 60 40 20 Everolimus + Exemestane (E/N=202/485) Placebo + Exemestane (E/N=157/239) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 51 14 34 9 18 4 8 3 3 1 3 0 0 0 Time (weeks) No. of Patients Still at Risk: Everolimus 485 398 294 Placebo 239 177 109 212 70 144 36 108 26 75 16 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 11 BOLERO-2 Primary Endpoint: PFS Central Assessment HR = 0.36 (95% CI: 0.27–0.47) Log rank P value = 3.3 x 10 -15 Probability of Event (%) 100 EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months 80 60 40 20 Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239) 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 43 11 28 6 18 3 9 3 3 1 2 0 0 0 Time (weeks) No. of Patients Still at Risk: Everolimus 485 385 281 Placebo 239 168 94 201 55 132 33 102 20 67 11 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 12 BOLERO 2: PFS Subgroup Analyses Favors EVE + EXE Favors PBO + EXE Subgroups (N) All (724) Age <65 (449) ≥65 (275) Region Asia (137) Europe (275) North America (274) Other (38) Sensitivity to prior hormonal therapy Yes (610) No (114) Visceral metastasis Yes (406) No (318) Last therapy Aromatase inhibitor (532) Antiestrogen (122) Other (70) Last therapy setting Metastatic (586) Adjuvant (138) Prior chemotherapy Adjuvant only (306) Metastatic (186) None (232) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 Hazard Ratio Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 1.4 1.5 BOLERO-2: Overall Response Rate and Clinical Benefit Rate by Local Assessment P < 0.0001 P < 0.0001 Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 14 BOLERO-2: Overall Survival As of PFS interim analysis: 83 deaths 10.6% in everolimus arm 13.0% in placebo arm OS interim analysis after 173 events OS final analysis at 392 events 80% power to detect 26% reduction in hazard ratio (0.74) Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 15 BOLERO-2: Most Common G3/4 AEs Everolimus + Exemestane (N = 482), % Placebo + Exemestane (N = 238), % All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Stomatitis 56 8 0 11 1 0 Fatigue 33 3 <1 26 1 0 Dyspnea 18 4 0 9 1 <1 Anemia 16 5 <1 4 <1 <1 Hyperglycemia 13 4 <1 2 <1 0 AST 13 3 <1 6 1 0 Pneumonitis 12 3 0 0 0 0 AE: Adverse Event; AST: Aspartate aminotransferase Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 16 BOLERO-2: Summary • Addition of everolimus to exemestane prolongs PFS in patients with ER+ HER2- breast cancer refractory to initial non-steroidal aromatase inhibitors – Local: median 6.9 vs 2.8 months, HR = 0.43, P < 0.0001 – Central: median 10.6 vs 4.1 months, HR = 0.36, P < 0.00 • Benefit is observed in all subgroups • Adverse events are consistent with previous experience with everolimus including stomatitis, fatigue and hyperglycemia Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 17 BOLERO-2: Conclusions • Everolimus is the first agent to enhance the clinical benefit of hormonal therapy in refractory ER+ patients • Our results could represent a paradigm shift in the management of patients with hormone receptor-positive breast cancer Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. 18 Conclusiones • Everolimus en combinación con Examestane aumenta significativamente la SLE y respuestas vs. Examestane en pacientes refractarias a Anastrozole – Letrozole • Puede ser otra alternativa terapéutica en pacientes con cáncer de mama avanzado 19 Muchas Gracias!