ONCOLOGIA: esperienze cliniche a confronto. Il carcinoma mammario metastatico

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1 ONCOLOGIA: esperienze cliniche a confronto. Il carcinoma mammario metastatico Sequenza ottimale del trattamento Maria Teresa Scognamiglio U.O.C. Clinica Oncologica Chieti-Ortona Chieti 12 novembre 213

2 Chemotherapy vs EndocrineTherapy Methods Randomized trials of chemotherapy alone vs endocrine therapy alone Results 8 trials identified (N = 817) No significant difference for OS HR:.94 (95% CI: ; P =.5) Significant difference favoring chemotherapy for ORR OR: 1.25 (95% CI: ; P =.4) However the 2 largest trials demonstrated trends in opposite directions Toxicity: little information available on adverse events and QOL Increased toxicity with chemotherapy (nausea, vomiting and alopecia) 3 of 7 trials noted QOL aspects, with differing results Authors conclusions In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease Wilcken N, et al. Cochrane Database Syst Rev. 23:CD2747.

3 EFECT: Study Design 5 mg Day 1, 25 mg Days 14 & 28, and monthly thereafter Previous nonsteroidal AI failure Fulvestrant loading dose + Placebo for Exemestane (n = 351) Exemestane 25 mg/day orally + Placebo for Fulvestrant (n = 34) Progression Progression Survival Chia S, et al. J Clin Oncol. 28;26: Analysis after 58 events (progression or death) Survival

4 Proportion of Patients Progression-Free Time to Progression (ITT) Fulvestrant Exemestane Fulvestrant Exemestane Median, mos HR:.963 (95% CI: ; P =.6531).2 Days Fulvestrant at risk Exemestane at risk Days to Progression Chia S, et al. J Clin Oncol. 28;26:

5 Objective Response and Clinical Benefit Rate In population evaluable for response Response, n (%) OR rate (CR + PR) CB rate (OR + SD 24 wks) Fulvestrant (n = 27) Exemestane (n = 27) 2 (7.4) 18 (6.7) 87 (32.2) 85 (31.5) *Analyses are not adjusted for baseline covariates. OR* (95% CI) 1.12 ( ) 1.3 ( ) P Value Chia S, et al. J Clin Oncol. 28;26:

6 FIRST: Study Design Randomized, open-label phase II trial Primary endpoint: CBR, defined as CR, PR, or SD for 24 wks Postmenopausal women with previously untreated hormone receptor positive advanced breast cancer (N = 25) Fulvestrant 5 mg by intramuscular injection Days, 14, 28, and every 28 days thereafter (n = 12) Anastrozole 1 mg/day orally (n = 13) Until disease progression or other event requiring discontinuation Robertson JFR, et al. SABCS 21. Abstract S1-3.

7 Proportion of Patients Alive and Progression Free FIRST: Fulvestrant Significantly Increased TTP in Secondary Analysis 1..8 Fulvestrant Anastrozole HR:.66 (95% CI: ; P =.1) Patients at Risk, n Mos Fulvestrant Anastrozole Parameter Fulvestrant (n = 12) Anastrozole (n = 13) Patients progressing, n (%) 63 (61.8) 79 (76.7) Median TTP, mos Clinical benefit rate, % Robertson JFR, et al. SABCS 21. Abstract S

8 SWOG S226: Study Design Primary endpoint: PFS Secondary endpoints: OS, safety Stratified by previous adjuvant tamoxifen Treatment until disease progression Postmenopausal women with hormone receptor positive MBC (N = 77) Anastrozole 1 mg/day PO + Fulvestrant 5 mg on Day 1, 25 mg on Days 14 and 28, 25 mg every 28 days thereafter (n = 355) Anastrozole 1 mg/day PO (n = 352) Women with progression encouraged to cross over to receive fulvestrant Mehta RS, et al. SABCS 211. Abstract S1-1.

9 SWOG S226: PFS and OS Overall and by Previous Adjuvant Tamoxifen Endpoint Anastrozole + Fulvestrant Median PFS (n = 694), mos No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 28) Median OS (n = 694), mos No previous adjuvant tamoxifen (n = 414) Previous adjuvant tamoxifen (n = 28) Anastrozole HR (95% CI) P Value ( ) ( ) ( ) (.65-1.) ( ) ( ).59 Mehta RS, et al. SABCS 211. Abstract S1-1.

10 The PI3K/AKT/mTOR Pathway Oxygen, energy, and nutrients Ras/Raf pathway kinases S6 Cell growth and proliferation Growth factors including IGF-1, VEGF, ErbB TSC2 S6K1 PTEN TSC1 PI3K AKT mtor Protein production Nutrient uptake and metabolism Estrogen receptor 4E-BP1 elf-4e Angiogenesis mtor signaling plays a key role in Cell growth Cell proliferation Regulation of Apoptosis Angiogenesis Lymphocytes Homeostasis Metabolism

11 BOLERO-2: Study Design Primary endpoint: PFS (investigator assessment) Secondary endpoints: OS, ORR, clinical benefit rate, safety Randomized 2:1; stratified by sensitivity to previous hormonal therapy, presence of visceral metastases Treatment until disease progression or unacceptable toxicity Postmenopausal women with ER-positive advanced breast cancer who progressed on previous nonsteroidal AI therapy* (N = 724) Exemestane 25 mg/day + Everolimus 1 mg/day (n = 485) Exemestane 25 mg/day + Placebo (n = 239) *> 5% of patients in each arm with 3 previous therapies Hortobagyi GN, et al. SABCS 211. Abstract S3-7.

12 Probability of Event (%) BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC Patients at Risk, n Everolimus 485 Placebo 239 HR:.36 (95% CI: ; log-rank P <.1) Central Assessment Wks Everolimus + exemestane (median PFS: 1.6 mos) Placebo + exemestane (median PFS: 4.1 mos) Baselga J, et al. N Engl J Med. 212;366:

13 BOLERO-2: Final PFS Analysis (18-Mo Follow-up) PFS, Mos EVE + EXE PBO + EXE HR (95% CI) P Value Local review ( ) Central review ( ) With visceral mets (.37-.6) Without visceral mets ( ) Bone-only mets ( ) Progression after neo/adj therapy ( ) <.1 <.1 OS data still not mature (HR:.77; 95% CI: ) Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia (5%), fatigue (4%) Piccart, M, et al. SABCS 212. Abstract P6-4-2.

14 BOLERO-2 (12-Mo Follow-up): Safety Adverse Events, % Exemestane + Everolimus (n = 482) Exemestane + Placebo (n = 238) All Grades Grade 3/4 All Grades Grade 3/4 Stomatitis Rash Fatigue Diarrhea < 1 Appetite decreased < 1 Nausea Noninfectious pneumonitis 15 3 Hyperglycemia < 1 Hortobagyi GN, et al. SABCS 211. Abstract S3-7.

15 PFS Probability Aromatase Inhibitor + CDK4/6 Inhibitor Improves PFS in ER+ MBC Pts at Risk, n PD LET LET Mos Finn RS, et al. SABCS 212. Abstract S Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value 18 6 PD LET (n = 84) 21 (25) 26.1 ( ) ( ) < LET (n = 81) 4 (49) 7.5 ( )

16 Qual è la sequenza ottimale di trattamento? Prima linea: AI o fulvestrant ; fulvestrant + AI proponibile in pazienti therapy naïve -quale intervallo dalla terapia adiuvante? -associazione o sequenza programmata? Proseguire la terapia endocrina fino alla comparsa di resistenza

17 Qual è la sequenza ottimale di trattamento? Seconda linea: everolimus + exemestane a progressione da AI non steroideo (se non mts viscerali sintomatiche) Dopo everolimus: monoterapia ormonale o blocco del pathway di PI3K L associazione dell inibitore delle CDK4/6 palbociclib con letrozole in prima linea appare molto promettente; sono in corso studi di fase III

18 Qual è la sequenza ottimale di trattamento? Seconda linea: everolimus + exemestane a progressione da AI non steroideo (se non mts viscerali sintomatiche) Dopo everolimus: monoterapia ormonale o blocco del pathway di PI3K L associazione dell inibitore delle CDK4/6 palbociclib con letrozole in prima linea appare molto promettente; sono in corso studi di fase III