CONVEGNO NAZIONALE AIOM GIOVANI
Perugia, 7 luglio 2017
Eva Blondeaux
La scelta della terapia di I linea:
ruolo degli inibitori di CDK4/6
Tutor: Dott.ssa C. Bighin
Ospedale Policlinico San Martino
Genova
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
- HR +, HER2 – aBC or mBC
Letrozole + Palbociclib
Letrozole
34 pts
32 pts
Primary endpoints: PFS
Secondary endpoints: ORR, CBR, OS, safety
Cohort 1 Cohort 2
- HR +, HER2 – aBC or mBC - amplif.
cyclin D1 or loss of p16
Letrozole + Palbociclib
Letrozole
50 pts
49 pts
Total pts = 165 pts (cohort 1 +2)
Finn Lancet 2015
fase II
PALBOCICLIB – Paloma 1 Basal characteristics
Finn Lancet 2015
PALBOCICLIB – Paloma 1 Results: PFS
Finn Lancet 2015
PFS=20.2 vs 10.2 months
(HR=0.49; p=0.0004)
Median follow up: 29.6 months
PALBOCICLIB – Paloma 1 Results: OS
Finn Lancet 2015
PALBOCICLIB – Paloma 1 Results: OS – ASCO 2017
Finn Abstract ASCO 2017
Median follow up: 64.7 months
PALBOCICLIB – Paloma 1 Results: OS – ASCO 2017
Finn Abstract ASCO 2017
PALBOCICLIB – Paloma 2
- Post-menopausal;
- HR+ HER2- mBC
- (neo)adj NSAI allowed if DFI<12 months
Letrozole + Palbociclib
Letrozole + Placebo
444 pts
222 pts
Primary endpoints: PFS
Secondary endpoints: OS, ORR, CBR, duration of response, patient-reported outcome, pharmacokinetic effects, safety and tissue biomarker assessment
2:1
Finn NEJM 2016
fase III
PALBOCICLIB – Paloma 2 Basal characteristics
Finn NEJM 2016
PALBOCICLIB – Paloma 2 Results: PFS
Finn NEJM 2016
PFS=24.8 vs 14.5 months
(HR=0.58; p<0.001) Median follow up: 23 months
PALBOCICLIB – Paloma 3
- Pre and post- menopausal;
- HR+ HER2- mBC
- Endocrine resistant BC*
- 1 previous CT for mBC allowed
Falodex+ Palbociclib
Faslodex+ Placebo
347 pts
174 pts
Primary endpoints: PFS
Secondary endpoints: ORR, CBR, OS, duration of response, patient-reported outcome, pharmacokinetic, safety and tissue biomarker assessment
2:1
Cristofanilli Lancet Oncol 2016
*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
fase III
PALBOCICLIB – Paloma 3 Basal characteristic
Cristofanilli Lancet Oncol 2016
PALBOCICLIB – Paloma 3 Results: PFS
Cristofanilli Lancet Oncol 2016
PFS= 9.5 vs 4.6 months
(HR=0.46; p<0.0001)
Median follow up: 8.9 months
RIBOCICLIB – Monaleesa 2
- Post-menopausal;
- HR+ HER2- mBC
- no prior therapy for mBC - (neo)adj NSAI allowed if
DFI>12 months
Letrozolo + Ribociclib
Letrozolo + Placebo
334 pts
334 pts
Primary endpoints: PFS
Secondary endpoints: OS, ORR, CBR, safety and QoL
1:1
Hortobagyi NEJM 2016
fase III
RIBOCICLIB – Monaleesa 2 Basal characteristic
Hortobagyi NEJM 2016
RIBOCICLIB – Monaleesa 2 Results: PFS
Median follow up: 15.3 months
Hortobagyi NEJM 2016
PFS= not reached vs 14.7
months (HR=0.56: p<0.001)
AMEBACICLIB – Monarch 2
- Pre and post- menopausal;
- HR+ HER2- mBC
- PD during (neo)adj ET,
<12 months from
(neo)adj ET or PD during 1
stline ET
Fulvestrant + Amebaciclib
Fulvestrant + Placebo
446 pts
223 pts
Primary endpoints: PFS
Secondary endpoints: ORR, duration of response, CBR, safety, tolerability, OS, QoL and pharmacokinetics
2:1
Sledge JCO 2017
fase III
no prior CT allowed
AMEBACICLIB – Monarch 2 Basal characteristics
Sledge JCO 2017
AMEBACICLIB – Monarch 2 Results: PFS
Median follow up: 19.5 months
Sledge JCO 2017
PFS= 16.4 vs 9.3 months
(HR=0.55; p<0.001)
…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)
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) OS (months) 37.5 vs 34.5
(HR=0.897;
p=0.28)
- - - -
…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) -