CONVEGNO NAZIONALE AIOM GIOVANI La scelta della terapia di I linea: ruolo degli inibitori di CDK4/6 Tutor: Dott.ssa C. Bighin Ospedale Policlinico San Martino Genova Eva Blondeaux Perugia, 7 luglio 2017
Meccanismo d azione degli inibitori delle cicline Murphy The Oncol 2015
Studi clinici con inibitori delle cicline PALBOCICLIB: + letrozolo Paloma 1 1,2 + letrozolo Paloma 2 3 + fulvestrant Paloma 3 4 RIBOCICLIB + letrozolo Monaleesa-2 5 + fulvestrant Monaleesa-3 (on going) + tamoxifen o NSAI + goserelin Monaleesa-7 (on going) AMEBACICLIB + fulvestrant Monarch-2 6 + letrozolo o anastrozolo Monarch-3 (on going) 1 Finn Lancet 2015; 2 Finn ASCO Ann Meet 2017 ; 3 Finn NEJM 2016; 4 Cristofanilli Lancet Oncol 2016; 5 Hortobagyi NEJM 2016; 6 Sledge JCO 2017
PALBOCICLIB Paloma 1 fase II Cohort 1 Cohort 2 - HR +, HER2 abc or mbc Letrozole + Palbociclib 34 pts Letrozole 32 pts - HR +, HER2 abc or mbc - amplif. cyclin D1 or loss of p16 Letrozole + Palbociclib 50 pts Letrozole 49 pts Total pts = 165 pts (cohort 1 +2) Primary endpoints: PFS Secondary endpoints: ORR, CBR, OS, safety Finn Lancet 2015
PALBOCICLIB Paloma 1 Basal characteristics Finn Lancet 2015
PALBOCICLIB Paloma 1 Results: PFS PFS=20.2 vs 10.2 months (HR=0.49; p=0.0004) Median follow up: 29.6 months Finn Lancet 2015
PALBOCICLIB Paloma 1 Results: OS Finn Lancet 2015
PALBOCICLIB Paloma 1 Results: OS ASCO 2017 Median follow up: 64.7 months Finn Abstract ASCO 2017
PALBOCICLIB Paloma 1 Results: OS ASCO 2017 Finn Abstract ASCO 2017
PALBOCICLIB Paloma 2 fase III Letrozole + Palbociclib 444 pts - Post-menopausal; - HR+ HER2- mbc - (neo)adj NSAI allowed if DFI<12 months 2:1 Letrozole + Placebo 222 pts Primary endpoints: PFS Secondary endpoints: OS, ORR, CBR, duration of response, patient-reported outcome, pharmacokinetic effects, safety and tissue biomarker assessment Finn NEJM 2016
PALBOCICLIB Paloma 2 Basal characteristics Finn NEJM 2016
PALBOCICLIB Paloma 2 Results: PFS PFS=24.8 vs 14.5 months (HR=0.58; p<0.001) Median follow up: 23 months Finn NEJM 2016
PALBOCICLIB Paloma 3 fase III - Pre and postmenopausal; - HR+ HER2- mbc - Endocrine resistant BC* - 1 previous CT for mbc allowed 2:1 Falodex+ Palbociclib Faslodex+ Placebo 347 pts 174 pts *Progression after ET with IA if post-menop or Tam if pre-menop while or within 1 months after treatment in the advanced setting, or while or within 12 months from adj therapy Primary endpoints: PFS Secondary endpoints: ORR, CBR, OS, duration of response, patient-reported outcome, pharmacokinetic, safety and tissue biomarker assessment Cristofanilli Lancet Oncol 2016
PALBOCICLIB Paloma 3 Basal characteristic Cristofanilli Lancet Oncol 2016
PALBOCICLIB Paloma 3 PFS= 9.5 vs 4.6 months (HR=0.46; p<0.0001) Results: PFS Median follow up: 8.9 months Cristofanilli Lancet Oncol 2016
RIBOCICLIB Monaleesa 2 fase III - Post-menopausal; - HR+ HER2- mbc - no prior therapy for mbc - (neo)adj NSAI allowed if DFI>12 months 1:1 Letrozolo + Ribociclib Letrozolo + Placebo 334 pts 334 pts Primary endpoints: PFS Secondary endpoints: OS, ORR, CBR, safety and QoL Hortobagyi NEJM 2016
RIBOCICLIB Monaleesa 2 Basal characteristic Hortobagyi NEJM 2016
RIBOCICLIB Monaleesa 2 Results: PFS PFS= not reached vs 14.7 months (HR=0.56: p<0.001) Median follow up: 15.3 months Hortobagyi NEJM 2016
AMEBACICLIB Monarch 2 fase III - Pre and postmenopausal; - HR+ HER2- mbc - PD during (neo)adj ET, <12 months from (neo)adj ET or PD during 1 st line ET 2:1 Fulvestrant + Amebaciclib Fulvestrant + Placebo 446 pts 223 pts no prior CT allowed Primary endpoints: PFS Secondary endpoints: ORR, duration of response, CBR, safety, tolerability, OS, QoL and pharmacokinetics Sledge JCO 2017
AMEBACICLIB Monarch 2 Basal characteristics Sledge JCO 2017
AMEBACICLIB Monarch 2 PFS= 16.4 vs 9.3 months (HR=0.55; p<0.001) Results: PFS Median follow up: 19.5 months Sledge JCO 2017
comparing the three Results PALOMA 1 84 +81 pts (%) PALOMA 2 444+222 pts (%) PALOMA 3 347 + 174 pts (%) MONALEESA 2 334 + 334 pts (%) MONARCH 2 446 + 223 pts (%) DFI Stage IV de novo > 12 months < 12 months 44 (52) 25 (30) 15 (18) 167 (37.6) 178 (40.1) 99 (22.3) - 114 (34.1) 216 (64.7) 4 (1.2) - - (8.8) Prior Treatment Adjuvant ET AI Tam Adjuvant CT CT for MBC 27 (32) 14 (17) 24 (29) 34 (40) - 249 (56.1) 122 (27.5) 209 (47.1) 213 (48) - - - - 139 (40) 113 (33) 175 (52.4) 100 (30) 140 (41.9) 146 (43.7) - 267 (59.9) - Site of disease Visceral Non-visceral 37 (44) 47 (56) 214 (48.2) 230 (51.8) 206 (59) 168 (41) 197 (59) 137 (41) 245 (54.9) 198 (44.4) PFS (months) 20.2 vs 10.2 (HR=0.49; p=0.0004) OS (months) 37.5 vs 34.5 (HR=0.897; p=0.28) 24.8 vs 14.5 (HR=0.58; p<0.001) 9.5 vs 4.6 (HR=0.46; p<0.0001) not reached vs 14.7 (HR=0.56: p<0.001) 16.4 vs 9.3 (HR=0.55; p<0.001) - - - -
comparing the three side effects PALOMA 1 84 +81 pts (%) PALOMA 2 444+222 pts (%) PALOMA 3 347 + 174 pts (%) MONALEESA 2 334 + 334 pts (%) MONARCH 2 446 + 223 pts (%) Neutropenia (G3-4) 45 (54) vs 1 (1) 295 (66.5) vs 3 (1.4) 123 (65) vs 1 (1) 198 (59.3) vs 3 (0.9) 117 (26.5) vs 4 (1.7) Leucopenia (G3-4) 16 (19) vs 0 110 (24.8) vs 0 95 (28) vs 2 (2) 70 (21) vs 2 (0.6) 39 (8.8) vs 0 Fatigue (G1-2) 30 (36) vs 17 (22) 166 (37.4) vs 61 (27.5) 127 (37) vs 47 (27) 122 (36.5) vs 99 (30.0) 176 (39.9) vs 60 (26.9) Anemia (G1-2) 24 (29) vs 4 (5.0) 107 (24.1) vs 20 (9.0) 86 (25) vs 16 (9) 62 (18.6) vs 15 (4.5) 128 (29) vs 8 (3.6) Alopecia (G1-2) 18 (22) vs 2 (3.0) 146 (32.9) vs 35 (15.8) 58 (17) vs 11 (6) 111 (33.2) vs 51 (15.5) 69 (15.6) vs 4 (1.8) Diarrhea (G3-4) 3 (4) vs 0 6 (1.4) vs 3 (1.4) 0 vs 1 (1) 4 (1.2) vs 3 (0.9) 59 (13.4) vs 1 (0.4) AST/ALT increase (G1-2) - - 15 (4) vs 5 (3) 52 (15.6) vs 13 (3.9) 59 (13.4) vs 12 (5.4) Allungamento QTc >480 msec - - 1 (<1) 11 (3.3) -
Indicazioni attuali in Italia Palbociclib disponibile in fascia CNN. Nel nostro centro seguiamo le seguenti indicazioni: in prima linea in associazione a Letrozolo per le pazienti stadio IV de novo o per le pazienti con DFI>12 mesi in prima linea in associazione a Fulvestrant per le pazienti con DFI<12 mesi in seconda linea in associazione a Fulvestrant per le pazienti in PD dopo prima linea con IA Ribociclib e Amebaciclib ancora non disponibili Ribociclib utilizzabile dai centri che partecipano allo studio COMPLEEMENT
Domande ancora aperte Quale terapia per la paziente con solo metastasi non viscerali e/o malattia limitata? E necessario per forza utilizzare gli inibitori di cicline? Il fulvestrant in monoterapia è un alternativa? (Studio FALCON: nelle pazienti senza malattia viscerale PFS di 22.3 mesi) Le pazienti in premenopausa si considerano come quelle in postmenopausa? Quale terapia a progressione dopo inibitori di cicline? nuova terapia endocrina (everolimus?) chemioterapia? inibitori cicline «beyond progression» con cambio ormonoteraopia o eventuale cambio inibitori cicline?