Clinique spécialisée Menara Intégrations des Inhibiteurs de cycline dépendantes kinases CDK 4/6 dans le traitement de mBC ER+/HER2- Pr TAHRI Ali Clinique spécialisée Menara Marrakech

Kinases Dépendantes de Cyclines Début 1970: identification des gènes impliqués dans la division cellulaire et concept «  checkpoint » (Lee Hartwell ) Fin 1970/début 1980: identification des CDC2 et rôle dans cycle cellulaire (Paul Nurse) Début 1980s: identification des cyclines et de leur variation pendant le cycle cellulaire (Tim Hunt) 2001 Prix Nobel de Médecine (Hartwell, Nurse et Hunt)

Kinases Dépendantes de Cyclines (CDKs) Groupe de protéines kinases impliquées dans le contrôle du cycle cellulaire Activité dépendante de leur association avec les cyclines Activation de l’activité catalytique / Cyclines CDK 4 et 6 sont associées à la cycline D CDK2 cyclines E et A

Regulation of the G1/S Checkpoint in Breast Cancer Pl3K/Akt STATs MAPKs ER/PR/AR Wnt/β-catenin NF-κB D-type cyclins regulated in response to mitogenic stimuli, including activation of RTKs and steroid hormone receptors p16 p21 p53 CDK4/6 Cyclin D Active tumour suppressor G2 S M G1 G0 RB E2F R Mitogenic signals converge at the level of cyclin D1 upregulation and CDK4/6 association, localization, and kinase activity. CDK4/6 phosphorylates and inactivates RB tumor suppressor proteins, leading to dissociation of E2F transcription factors and transcriptional regulation of genes important for G1/S transition and cell cycle progression through the restriction point. Phosphorylation of the Rb protein early in G1 by CDK4 or CDK6 is central to the regulation of the G1 to S transition and cellular commitment to division Aberrations of the G1S checkpoint are involved in the pathogenesis of many human cancers E2F Gene transcription CDK4/6 control cell cycle progression from G1 to S Phase P P P RB P Inactive Lange CA, Yee D. Endocr Rel Cancer. 2011;18:C19-C24; Caldon CE, et al. J Cell Biochem. 2006;97:261-274. 5

La voie CyclinD-CDK4/6-Rb régule la progression du cycle cellulaire et présente fréquemment des anomalies dans les cancers Une activité augmentée du complexe cycline D-CDK4/6 survient dans les cancers Surexpression/amplification de la cycline D Mutations et amplifications de CDK4/6 Perte des inhibiteurs de CDK4/6: p16 (INK4A/CDKN2A), KIP Protéine/gène RB est fréquemment maintenue dans les RH+ Association avec la résistance à l’hormonothérapie dans les cancers luminaux Buckley MF, et al. Oncogene. 1993;8:2127-2133; Dickson C, et al. Cancer Lett. 1995;90:43-50. 6

La voie CyclinD-CDK4/6-Rb régule la progression du cycle cellulaire et présente fréquemment des anomalies dans les cancers Une activité augmentée du complexe cycline D-CDK4/6 survient dans les cancers Surexpression/amplification de la cycline D Mutations et amplifications de CDK4/6 Perte des inhibiteurs de CDK4/6: p16 (INK4A/CDKN2A), KIP Protéine/gène RB est fréquemment maintenue dans les RH+ Association avec la résistance à l’hormonothérapie dans les cancers luminaux CDK4/6 représentent une cible dans les cancers du sein luminaux Buckley MF, et al. Oncogene. 1993;8:2127-2133; Dickson C, et al. Cancer Lett. 1995;90:43-50. 7

Mécanisme d’action des inhibiteurs de CDK4/6 Target of CDK 4/6 inhibitors CDK4/6 Cyclin D Active tumour suppressor G2 S M G1 G0 RB E2F X X X R E2F P P Gene transcription P RB P Inactive Fry DW, et al. Mol Cancer Ther. 2004;3:1427; Carnero A. Br J Cancer. 2002;87:129. 8

Palbociclib (PD0332991) CDK (cyclin partner) IC50 (µM) Inhibiteur oral, hautement sélectif de CDK4/6 Bloque la progression du cycle cellulaire de la phase G1 à la phase S Activité in vitro dans les lignées cellulaires et tumeurs Rb+ Faibles concentrations nanomolaires bloquent la phosphorylation Rb, induisant un arrêt en phase G1 CDK (cyclin partner) IC50 (µM) CDK4 (cyclin D1) 0.011 CDK4 (cyclin D3) 0.009 CDK6 (cyclin D2) 0.015 CDK2 (cyclin A) >5 CDK1 (cyclin B) CDK5 (p25) PD-0332991 . Fry DW, et al. Mol Cancer Ther. 2004;3:1427-1438; Menu E, et al. Cancer Res. 2008;68:5519-5523; Sutherland RL, Musgrove EA. Breast Cancer Res. 2009;11:112. 9

Palbociclib inhibe préférentiellement la prolifération des lignées cellulaires tumeurs mammaires in vitro RH+ IC50 nM Les lignées cellulaires luminales sont les plus sensibles à l’inhibition CDK 4/6 10 Finn RS, et al. Breast Cancer Res. 2009;11(5):R77. 10

ER+/HER2− advanced breast cancer Etude PALOMA-1 Cohort 1 Cohort 2 Palbociclib 125 mg/d† + Letrozole 2.5 mg/d Palbociclib 125 mg/d† + Letrozole 2.5 mg/d RANDOMISATION* RANDOMISATION* ER+/HER2− advanced breast cancer with CCND1 amplification and/or loss of p16 ER+/HER2− advanced breast cancer 1:1 1:1 Letrozole 2.5 mg/d Letrozole 2.5 mg/d Notes PALOMA-1/TRIO-18 is an international, multicenter, open-label, randomized, phase 2 trial designed to assess the efficacy and tolerability of letrozole in combination with palbociclib versus letrozole alone in the first-line treatment of ER+/HER2- postmenopausal women with advanced breast cancer. The study consisted of 2 sequential cohorts. Cohort 1 enrolled patients selected based on classification of ER+/HER2-; Cohort 2 included additional biomarker criteria for enrollment: cyclin D1 (CCND1) gene amplification and/or loss of p16 (CDKN2A). Enrollment in Cohort 2 was halted (n=99) based on retrospective analysis of biomarkers from an unplanned interim analysis of Cohort 1 (based on 31 PFS events), which demonstrated clinically meaningful activity of the combination versus letrozole alone (HR: 0.35; 95% CI: 0.17–0.72; P=0.006). The final analysis reports results from both cohorts combined (Cohort 1, n=66; Cohort 2, n=99) and was performed when 95 PFS events accumulated. Patients were randomized 1:1 within each cohort to receive either letrozole 2.5 mg/day orally or letrozole 2.5 mg/day orally plus palbociclib 125 mg/day orally, given once daily for 3 weeks on treatment and 1 week off treatment over a 28-day cycle. Randomization was stratified by disease site (visceral, bone-only, or other) and disease-free interval (DFI>12 months from the end of adjuvant treatment to disease recurrence or ≤12 months from the end of adjuvant treatment to disease recurrence or de novo presentation with advanced disease). n = 66 n = 99 Randomised phase II open-label trial involving 50 centres in 12 countries Key eligibility criteria: inoperable ER+/HER2– locally recurrent disease, postmenopausal status, no prior therapy for advanced breast cancer, no letrozole within 12 months, ECOG performance status ≤1 Endpoints: Primary: PFS; Secondary: ORR, OS, clinical benefit response, duration of response (DOR),safety and tolerability, serum biomarker analyses *Randomisation stratified by disease site and disease-free interval. †Palbociclib schedule 3/1 (28-day cycles). Finn RS, et al. Lancet Oncol. 2015;16(1):25-35. 11

PALOMA-1: Caractéristiques patientes Characteristics PAL + LET n = 84, (%) LET n = 81, (%) Median (IQR) age, years 63 (54–71) 64 (56–70) ECOG PS 1 46 (55) 38 (45) 45 (56) 36 (44) Disease stage III IV 2 (2) 82 (98) 1 (1) 80 (99) Disease site* Visceral Bone Other (nonvisceral) 37 (44) 17 (20) 30 (36) 43 (53) 12 (15) 26 (32) Disease-free interval* >12 m from adjuvant to recurrence ≤12 m from adjuvant to recurrence or advanced disease [de novo advanced disease] 25 (30) 59 (70) [44 (52)] 30 (37) 51 (63) [37 (46)] Prior systemic therapy None Chemotherapy Hormonal Tamoxifen Anastrozole Letrozole Exemestane 44 (52) 34 (40) 27 (32) 24 (29) 8 (10) 4 (5) 37 (46) 28 (35) 24 (30) 11 (14) Notes Baseline demographic characteristics and established prognostic factors of the ITT population were generally well balanced with slight imbalances noted in disease site, disease-free interval and prior therapy. *Based on CRF data. All data were available for all patients. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35 12

PALOMA-1: Investigator-Assessed PFS (ITT Population) 100 Palbociclib + Letrozole (n = 84) Letrozole Alone (n = 81) Number of PFS events (%) 41 (48.8%) 59 (72.8%) Hazard ratio (95% CI) 0.488 (0.319–0.748) mPFS [months] (95% CI) 20.2 (13.8–27.5) 10.2 (5.7–12.6) 90 80 70 60 Palbociclib plus letrozole Letrozole Progression-Free Survival, % 50 40 30 Notes At the time of this analysis, median PFS was 20.2 months (95% CI, 13.8-27.5) for the palbociclib plus letrozole arm and 10.2 months (95% CI, 5.7-12.6) for the letrozole alone arm demonstrating a significant decrease in the risk of progression by the addition of palbociclib to letrozole (HR=0.488; 95% CI, 0.319 -0.748; 1-sided P=0.0004). 20 10 HR 0.488 (95% CI 0.319–0.748; one-sided P = .0004) 4 8 12 16 20 24 28 32 36 40 Time, months Number at risk Palbociclib plus letrozole 84 67 60 47 36 28 21 13 8 5 1 Letrozole 81 48 36 28 19 14 6 3 3 1 Finn RS, et al. Lancet Oncol. 2015;16(1):25-35. 13 13

PALOMA-1: Forest Plot for PFS All patients (intention-to-treat population) Cohort 1 2 Age group (years) <65 years ≥65 years Baseline ECOG performance status Disease site Visceral Bone Only Other Previous chemotherapy Yes No Previous antihormonal therapy Previous systemic therapy Time from end of adjuvant treatment to disease recurrence ≤12 months (including de-novo presentation) >12 months ≤12 months (excluding de-novo presentation) 84 34 50 47 37 46 38 17 30 27 57 40 44 59 25 15 41 26 24 21 20 5 12 29 31 10 7 81 32 49 42 39 45 36 43 28 53 51 14 35 18 19 PAL + LET 0.14 0.34 0.78 0.44 0.75 0.88 0.36 0.95 Interaction P value* LET Patients Events 0.488 (0.319–0.748) 0.299 (0.156–0.572) 0.508 (0.303–0.853) 0.315 (0.184–0.539) 0.505 (0.269–0.948) 0.434 (0.246–0.766) 0.398 (0.220–0.721) 0.547 (0.317–0.944) 0.294 (0.092–0.945) 0.402 (0.200–0.808) 0.479 (0.255–0.898) 0.397 (0.234–0.671) 0.460 (0.222–0.956) 0.397 (0.244–0.646) 0.539 (0.302–0.962) 0.341 (0.194–0.599) 0.418 (0.259–0.674) 0.399 (0.185–0.858) 0.765 (0.232–2.523) Hazard ratio (95% CI) Favours palbociclib plus letrozole Favours letrozole 0.062 0.250 0.125 1.000 0.500 2.000 4.000 Notes When compared to results with letrozole alone, the addition of palbociclib to letrozole consistently improved PFS across all demographic subgroups and patient baseline prognostic factors. *Two-sided P value. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35. 14

PALOMA-1/TRIO-18: Best Overall Response Combined Characteristic PAL + LET LET All randomised patients, n 84 81 Objective response rate, % (95% CI) Complete response, n (%) Partial response, n (%) 43 (32−54) 1 (1) 35 (42) 33 (23−45) 26 (32) Stable disease, n (%) 37 (44) 30 (37) Stable disease ≥24 weeks, n (%) 32 (38) 20 (25) Stable disease <24 weeks, n (%) 5 (6) 10 (12) Progressive disease, n (%) 3 (4) 18 (22) Indeterminate, n (%) 8 (10) 6 (7) Patients with measurable disease, n 65 66 55 (43−68) 1 (2) 35 (54) 39 (28−52) 26 (39) 20 (31) 22 (33) 2 (3) 15 (23) 7 (11) 3 (5) Notes The secondary endpoints of objective response, clinical benefit response, and duration of response were also consistently improved with the addition of palbociclib to letrozole. The median duration of response for patients achieving a CR or PR was 20.3 months (95% CI, 13.4-25.8) for the palbociclib plus letrozole arm and 11.1 months (95% CI, 9.3-31.6) for letrozole alone. Clinical benefit response rate was 81% (95% CI, 71−89) for patients who received palbociclib plus letrozole and 58% (95% CI, 47−69) for those who received letrozole alone. CI, confidence interval; LET, letrozole; PAL, palbociclib. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

PALOMA-1: Overall Survival (ITT population) 100 Palbociclib plus letrozole Letrozole 90 80 70 60 Overall Survival, % 50 40 30 20 10 HR 0.813 (95% CI 0.492–1.345; two-sided P = .42) Notes At the time of the final PFS analysis, an overall survival analysis was performed (median follow-up 29.6 months [95% CI, 27.9-36.0] and 27.9 months [95% CI, 25.5-31.1] between two treatment arms). With 30 events in the combination group and 31 events in the control group, median OS was 37.5 months (95% CI, 28.4-NR) in patients receiving palbociclib plus letrozole and 33.3 months (95% CI, 26.4-NR) for those receiving letrozole alone (HR=0.813; 95% CI, 0.492-1.345; 2-sided P=0.42). The study was not powered to detect an overall survival advantage and few overall survival events had occurred at the time of this analysis; however, the initial data suggest no detrimental effect on overall survival with the addition of palbociclib in the first-line setting 4 8 12 16 20 24 28 32 36 40 44 Time, months Number at risk Palbociclib plus letrozole 84 80 78 73 68 65 47 35 22 17 7 2 Letrozole 81 76 74 67 64 59 37 23 14 12 5 1 With only 30 events in the palbociclib plus letrozole arm and 31 events in the control arm, the study was not powered to demonstrate an OS advantage; initial data suggest there is no detrimental effect on OS by adding palbociclib A follow-up OS analysis will be performed after the accrual of additional events Finn RS, et al. Lancet Oncol. 2015;16(1):25-35. 16 16

PALOMA-1: All-Causality AEs Occurring in ≥15% of Patients (safety population) Adverse Event, % PAL + LET (n = 83) LET (n = 77) All Grades Grade 3/4 Any adverse event 99 76 84 21 Neutropenia 75 54 5 1 Leukopenia 43 19 3 Fatigue 41 23 Anaemia 35 6 Nausea 25 2 13 Arthralgia 16 Alopecia 22 n/a Diarrhoea 20 4 10 Hot flush 12 Thrombocytopenia 17 Decreased appetite 7 Dyspnoea 8 Nasopharyngitis Back pain 11 Notes All adverse events, regardless of causality were collected and analyzed. The most common AEs reported for the combination arm were neutropenia, leukopenia, and fatigue. Despite the increase in all grades of neutropenia and leukopenia, no cases of neutropenic fever were reported. Other adverse events (all causality) that were increased in the palbociclib plus letrozole treatment arm included anemia (29 patients; 35%), nausea (21 patients; 25%), arthralgia (19 patients; 23%), and alopecia (18 patients; 22%), but these were all generally of low grade. Of these, anemia and alopecia were statistically different with 2-sided P values of P<0.0001 and P=0.0002, respectively. No cases of febrile neutropenia were reported 17 One (1%) grade 5 event occurred in the PAL + LET group (from disease progression); none occurred in the LET group. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35.

Study of Palbociclib in Endocrine-Sensitive mBC: PALOMA-2 Primary endpoint: PFS Secondary/exploratory endpoints: Response, OS, safety, biomarkers, patient-reported outcomes Stratification factors: Disease site, disease-free interval, prior hormonal therapy Palbociclib (125 mg QD, 3/1 schedule) + letrozole (2.5 mg QD) Postmenopausal HR+, HER2− MBC No prior treatment for advanced disease AI-resistant patients excluded RANDOMISATION 2:1 Placebo (3/1 schedule) + letrozole (2.5 mg QD) 18 Clinicaltrials.gov. PALOMA-2: NCT01740427.

Caractéristiques des patientes à la randomisation (ITT) Palbociclib + Létrozole n = 444 Placebo + Létrozole n = 222 Âge, années Médian (min, max) 62 (30, 89) 61 (28, 88) < 65 263 (59) 141 (64) ≥ 65 181 (41) 81 (36) Race Blanche 344 (77) 172 (77) Noire 8 (2) 3 (1) Asiatique 65 (15) 30 (14) Autre 27 (6) 17(8) Performance Status ECOG 257 (58) 102 (46) 1 178 (40) 117 (53) 2 9 (2) Site métastatiquea Viscéral 217 (49) 111 (50) Non viscéral 227 (51) Osseux uniquement 103 (23) 48 (22) Intervalle librea,b > 12 mois 207 (47) 104 (47) ≤ 12 mois 89 (20) 44 (20) Maladie métastatique d’emblée 148 (33) 74 (33) Hormonothérapie antérieurea Non 191 (43) 95 (43) Oui 253 (57) 127 (57) ECOG = Eastern Cooperative Oncology Group ; ITT = intention de traiter. a. Basé sur la randomisation. b Délai entre la fin de la thérapie (néo) adjuvante antérieure et le début de la maladie métastatique ou de la récidive.

PALOMA-2 : survie sans progression 20 PALOMA-2 : survie sans progression PAL + LET (n = 444) PCB + LET (n = 222) Nombre d’événements, n (%) 194 (44) 137 (62) SSP médiane (IC95) 24,8 (22,1-NR) 14,5 (12,9–17,1) HR (IC95) ; 1-sided p value 0,58 (0,46-0,72) ; p < 0,000001 (%) 100 80 60 40 20 3 6 9 12 15 18 21 24 27 30 33 Nombre de patients à risque Mois PAL + LET PCB + LET 444 222 395 171 360 148 328 131 295 116 263 98 238 81 154 54 69 22 29 12 10 4 2 ITT : intent-to-treat ; LET : letrozole ; NR : not reached ; PAL : palbociclib ; PCB : placebo. ASCO® 2016 - D’après Finn RS et al., abstr. 507, actualisé

SSP : analyse en sous-groupes Toutes les patientes randomisées 666 (100) Âge < 65 ans 404 (60,7) > 65 ans 262 (39,3) Race Blanche 516 (77,5) Asiatique 95 (14,3) Site métastatique Viscéral 324 (48,6) Non viscéral 342 (51,4) Hormonothérapie antérieure Oui 375 (56,3) Non 291 (43,7) Durée sans maladie Métastases d’emblée 248 (37,2) ≤ 12 mois 147 (22,1) > 12 mois 271 (40,7) Région Amérique du Nord 267 (40,1) Europe 307 (46,1) Asie/Pacifique 92 (13,8) Score de performance ECOG 359 (53,9) 1-2 Maladie uniquement osseuse à l’entrée dans l’étude 151 (22,7) 515 (77,3) Maladie mesurable 509 (76,4) 157 (23,6) Chimiothérapie antérieure 322 (48,3) 344 (51,7) Thérapie la plus récente Inhibiteur de l’aromatase 135 (20,3) Antiestrogène 229 (34,4) Nombre de sites de la maladie 1 204 (30,6) 2 169 (25,4) ≥ 3 293 (44,0) Rapport de risque (IC à 95 %) 0,576 (0,463 à 0,718) 0,567 (0,434 à 0,740) 0,571 (0,386 à 0,843) 0,576 (0,450 à 0,739) 0,484 (0,269 à 0,871) 0,633 (0,472 à 0,849) 0,502 (0,360 à 0,699) 0,528 (0,400 à 0,698) 0,628 (0,439 à 0,897) 0,674 (0,457 à 0,993) 0,501 (0,329 à 0,761) 0,516 (0,365 à 0,731) 0,605 (0,431 à 0,849) 0,571 (0,410 à 0,796) 0,486 (0,270 à 0,872) 0,646 (0,466 à 0,896) 0,531 (0,393 à 0,718) 0,363 (0,221 à 0,594) 0,654 (0,512 à 0,837) 0,663 (0,517 à 0,849) 0,350 (0,215 à 0,568) 0,533 (0,395 à 0,720) 0,611 (0,443 à 0,842) 0,549 (0,341 à 0,883) 0,558 (0,390 à 0,799) 0,511 (0,339 à 0,770) 0,679 (0,421 à 1,096) 0,587 (0,430 à 0,803) 0,00 0,25 0,50 0,75 1,00 1,25 1,50 1,75 2,00 Supériorité de PAL+LET Supériorité de PCB+LET ECOG = Eastern Cooperative Oncology Group, LET = létrozole ; PAL = palbociclib, PCB = placebo

Principaux critères d’évaluation secondaires palbociclib + létrozole (n = 444) placebo + létrozole (n = 222) Odds Ratio [IC à 95 %] P unilatéral (Exact) Population en ITT 444 222 Taux de réponse objective,a n (%) [IC à 95 %] 187 (42 %) 37,5 (46,9) 77 (35 %) [28,4, 41,3] 1,40 [0,98, 2,01] 0,0310 Taux de bénéfice clinique,b n (%) [IC à 95 %] 377 (85 %) [81,2, 88,1] 156 (70 %) [63,8, 76,2] 2,39 [0,58, 3,59] < 0.0001 Durée médiane de réponse, mois [IC à 95 %] 23 [19,8, 28,0] 17c [14,2, 28,5] S/O Patientes avec une maladie mesurable 338 171 187 (55 %) [49,9, 60,7] 76 (44 %) [36,9, 52,2] 1,55 [1,05, 2,28] 0,0132 Taux de bénéfice clinique,b n (%) [IC à 95 %] 285 (84 %) [80,0, 88,0] 121 (71 %) [63,3, 77,5] 2,23 [1,39, 3,56] 0,0003 17 [15,4, 28,5] ITT = intention de traiter ; S/O = Sans Objet. Valeurs présentées par n (%) sauf indication contraire. a. Réponse complète confirmée + réponse partielle b. Réponse complète confirmée + réponse partielle + maladie stable ≥ 24 semaines. c1 patiente avec une maladie uniquement osseuse à l’entrée dans l’étude ; toutes les autres patientes avaient une maladie mesurable à l’entrée dans l’étude

Homogénéité des résultats d’efficacité dans les études PALOMA-1 et PALOMA-2 10031 (PALOMA-1) 1008 (PALOMA-2) 10232 (PALOMA-3) Conception Phase II ouverte Phase III Contrôlée vs placebo Traitement endocrinien Létrozole Fulvestrant Patientes incluses dans l’étude, n 165 666 521 Efficacité (palbociclib vs groupe témoin) Critère d’évaluation principal. SSPM HR 0,49 0,58 0,46 SSP médiane, mois 20,2 vs 10,2 (10 mois) 24,8 vs 14,5 (10,3 mois) 9,6 vs 4,6 Critères d’évaluation secondaires, % ORR (ITT, maladie mesurable) 43 vs 33, 55 vs 39 42 vs 35, 55 vs 44 19 vs 9, 25 vs 11 BC (ITT) 81 vs 58 85 vs 70 67 vs 40 BC = bénéfice clinique ; ITT = intention de traiter ; OOR= Taux de Réponse Globale (Overall Response Rate) 1. Finn et al. Lancet Oncol. 2015. 2. Cristofinalli et al. Lancet Oncol 2016.

Traitement administré Palbociclib + Létrozole (n = 444) Placebo + Létrozole (n = 222) Palbociclib Létrozole Placebo Durée médiane de traitement, jours 603 (1 - 1 037) 617 413 (10 - 1 071) 420 (10 -1 075) Dose-intensité médiane, % 93,0 (40,3 - 109,5) 99,9 (73,4 - 100,2) 99,6 (56,1 - 104,5) 100,0 (79,0 - 100,0) Patients avec interruptions de dose, n (%) 310 (70) 237 (53) 94 (42) 99 (45) Patientes avec décalage de cycle, n (%) 303 (68) S/O 60 (27) NA Patientes avec ≥ 1 réduction de dose, n (%) 160 (36) 3 (1) NA : non applicable

palbociclib + létrozole (n = 444) placebo + létrozole (n = 222) E.I. toutes causes associés au traitement & survenant chez ≥ 15 % des patientes palbociclib + létrozole (n = 444) placebo + létrozole (n = 222) Tous grades Grade 3 Grade 4 Tout événement indésirable, n (%) 439 (99) 276 (62) 60 (14) 212 (95) 49 (22) 5 (2) Neutropéniea 353 (80) 249 (56) 46 (10) 14 (6) 2 (1) 1 (<1) Leucopéniea 173 (39) 107 (24) 3 (1) Fatigue 166 (37) 8 (2) 61 (28) Nausées 156 (35) 58 (26) 4 (2) Arthralgie 148 (33) 75 (34) Alopécie 146 (33) 35 (16) Diarrhée 116 (26) 6 (1) 43 (19) Toux 111 (25) 42 (19) Anémiea 23 (5) 20 (9) Dorsalgie 96 (22) 48 (22) Céphalée 95 (21) Bouffées de chaleur 93 (21) 68 (31) Constipation 86 (19) 2 (<1) 34 (15) Rasha 79 (18) 4 (1) 26 (12) Asthénie 75 (17) 10 (2) Thrombocytopéniea 69 (16) Vomissement 37 (17) Douleur des extrémités 68 (15) 39 (18) Stomatite 13 (6) Perte d’appétit 66 (15) Dyspnée 5 (1) 30 (14) Insomnie EI = Evénement Indésirable. a. Inclut les termes préférés regroupés du Medical Dictionary for Regulatory Activity (MedDRA).

Conclusions L’association du palbociclib et du létrozole a amélioré de manière significative la SSP médiane par rapport à l’association placebo plus létrozole dans le traitement de première ligne des patientes atteintes d’un cancer du sein ER+/HER2- au stade avancé Amélioration > 10 mois de la SSP médiane : 24,8 mois vs 14,5 mois HR = 0,58 (IC à 95 % : 0,46-0,72 ; P < 0,0001) Le bénéfice du palbociclib a été démontré pour tous les sous-groupes de patientes et confirmé par une revue indépendante en aveugle Le palbociclib a été bien toléré ; les événements indésirables les plus fréquents étant la neutropénie et la leucopénie. Cependant, l’incidence globale de neutropénie fébrile a été faible (1,8 %) Ces données confirment les résultats de l’étude ouverte PALOMA-1. Ils représentent à ce jour l’amélioration significative de la SSP la plus longue jamais démontrée en traitement de première ligne

PALOMA-3: Study Design Palbociclib (125 mg QD; 3 wks on/1 wk off) Placebo (3 wks on/1 wk off) + Fulvestrantd (500 mg IM q4w) Palbociclib (125 mg QD; 3 wks on/1 wk off) + Fulvestrantd (500 mg IM q4w) Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs post-menopausal 2:1 Randomization n=521c Stratification: HR+, HER2– ABC Pre-/peri-a or postmenopausalb Progressed on prior endocrine therapy: On or within 12 mo adjuvant On therapy for ABC ≤1 prior chemotherapy regimen for advanced cancer n=347 n=174 aAll received goserelin. bMust have progressed on prior endocrine therapy (pre-/perimenopausal) or aromatase inhibitor therapy (postmenopausal). cPatients randomized. dAdministered on Days 1 and 15 of Cycle 1, then every 28 d. Phase 3, double-blind study involving 144 centers in 17 countries (NCT01942135) Turner NC, et al. N Engl J Med 2015;373:209-219 Turner NC, et al. ASCO 2015 (Abstract LBA502)

Demographics and Baseline Tumor Characteristics Palbociclib + Fulvestrant n=347 Placebo + Fulvestrant n= 174 Median age (range) years 57 (30-88) 56 (29-80) Receptor status % ER+ PR+ ER+ PR- 69 26 64 28 Menopausal status % Pre-/peri Post 21 79 Visceral % 59 60 Number of disease sites 1 2 ≥ 3 32 29 39 35 36 Turner N et al NEJM 2015

Tumor Characteristics and Prior Treatment Palbociclib + Fulvestrant n=347 Placecebo + Fulvestrant n= 174 Documented sensitivity to prior hormonal therapy Yes No 79 21 78 22 Prior aromatase inhibitor +/- GnRH % 85 87 Prior tamoxifen +/- GnRH % 61 60 Prior chemotherapy in advanced setting 31 36 Prior lines of therapy in advanced setting 1 2 ≥ 3 24 38 26 12 40 25 9 Turner N et al NEJM 2015

PALOMA-3: Treatment Summary Treatment Summary (AT population) Palbociclib + fulvestrant (n=345) Placebo + fulvestrant (n=172) Relative fulvestrant dose intensity (%), median 99.7 100 Relative palbociclib/placebo dose intensity (%), median 91.7 Dose reductions, n (%) 109 (32) 3 (2) Discontinuation due to AEs, n (%) 9 (3) Disease progression was the most common reason for discontinuation in both the palbociclib + fulvestrant (25%, n=85) and placebo + fulvestrant (50%; n=87) arms. Turner NC, et al. N Engl J Med 2015;373:209-219 Turner NC, et al. ASCO 2015 (Abstract LBA502)

Palbociclib + fulvestrant PALOMA-3: Primary Endpoint of Investigator-Assessed PFS (ITT Population) 100 90 Palbociclib + fulvestrant n=347 Placebo + fulvestrant n=174 Median PFS, months (95% CI) 9.2 (7.5, NE) 3.8 (3.5, 5.5) HR (95% CI) 0.42 (0.32, 0.56) 2-sided P value <0.001 80 70 60 Progression-free survival probability (%) 50 40 30 20 Palbociclib plus fulvestrant 10 Placebo + fulvestrant 2 4 6 8 10 12 Time (months) Number of patients at risk PAL+FUL 347 279 132 59 16 6 PBO+FUL 174 109 42 16 6 1 CI=confidence interval; HR=hazard ratio; ITT=intent-to-treat; NE=not estimable; PFS=progression-free survival Turner NC, et al. N Engl J Med 2015;373:209-219 Turner NC, et al. ASCO 2015 (Abstract LBA502)

PALOMA-3: Analysis of PFS by Patient Subgroup Hazard ratio and 95% CI P value for interaction All randomized patients (ITT) 521 (100) Age <65 years ≥65 years 392 (75.2) 129 (24.8) 0.480 Racea White Asian Black and other 385 (73.9) 105 (20.2) 29 (5.6) 0.412 Menopausal status at study entry Pre/peri Post 108 (20.7) 413 (79.3) 0.940 Site of metastatic disease Visceral Non visceral 311 (59.7) 210 (40.3) 0.624 Sensitivity to prior hormonal therapy Yes No 410 (78.7) 111 (21.3) 0.302 Receptor status ER+/PgR+ ER+/PgR– 349 (67.0) 139 (26.7) 0.883 Disease-free interval ≤24 months >24 months 65 (1.5) 281 (53.9) 0.149 Prior chemotherapy (Neo)adjuvant only Metastatic +/– (neo)adjuvant No prior chemotherapy 219 (42.0) 170 (32.6) 132 (25.3) 0.427 Prior lines of therapy in advanced setting 0 1 2 3+ 129 (24.8) 202 (38.8) 133 (25.5) 57 (10.9) 0.684 0.125 0.25 0.5 1 2 8 In favor of palbociclib + fulvestrant In favor of placebo + fulvestrant ER=estrogen receptor; PgR= progesterone receptor aRace was unspecified in 2 patients (1 in each group) Turner NC, et al. N Engl J Med 2015;373:209-219 Turner NC, et al. ASCO 2015 (Abstract LBA502)

PALOMA-3: Summary of Key Secondary Efficacy Endpoints Patients, % P=0.16 36% of palbociclib and 24% of placebo patients remain on study treatment with <24 wk of follow up At the time of the interim analysis, OS data were immature with 28 deaths 19 (5.5%) of palbociclib + fulvestrant patients and 9 (5.2%) of placebo + fulvestrant patients died *CBR is underestimated CBR=clinical benefit rate (CR+PR+SD ≥24 wk); CI=confidence interval; CR=complete response; OR=odds ratio; ORR=objective response (CR+PR); OS=overall survival; PR=partial response; SD=stable disease. Turner NC, et al. N Engl J Med 2015;373:209-219 Turner NC, et al. ASCO 2015 (Abstract LBA502)

PALOMA-3: Patient-Reported Outcomes* Global QoL Emotional Functioning Mean Change From Baseline P=0.03 P=0.002 *Evaluated based on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Core Module (QLQ-C30). QoL=quality of life. Turner NC, et al. N Engl J Med 2015;373:209-219

CDK4/6 Inhibitors Currently in Development Agent Company Development Status Trials Brand Name Palbociclib (PD0332991) Pfizer Phase III PALOMA LEE011 Novartis MONALEESA Abemaciclib (LY28335219) Lilly MONARCH There are pros and cons to having a greater or lesser degree of specificity – flavopiridol, which is quite non-specific lacked potency in shrinking tumors, yet was quite toxic. Pfizer's initial ACDK 1, 2 and 4 inhibitor compound was also excessively toxic. So, rather than shutting down the checkpoint altogether, it may be necessary to identify specific alterations target those. We’ve focused on PD0332991 as a very specific cdk 4/6 inhibitor Note: All are investigational compounds. 35 Clinicaltrials.gov. Palbociclib: NCT01740427; LEE011: NCT01958021; Abemaciclib: NCT02057133.

Key characteristics of CDK inhibitors Drug Palbociclib (Pfizer) PD0332991 Ibrance® Ribociclib (Novartis) LEE011 Abemaciclib (Lilly) LY2835219 IC50 CDK4 (D1) 11nmol/L CDK4 (D3) 9nmol/L CDK6 (D2) 15 nmol/L CDK1 >10µmol/L CDK2 >10µmol/L CDK4 10 nmol/L CDK6 39nmol/L CDK1 > 100 µmol/L CDK2 > 50 µmol/L CDK4 (D1) 0.6-2nmol/L CDK6 (D1) 2.4-5nmol/L CDK9 57 nmol/L CDK1 >1µmol/L CDK2 > 500nmol/L PK Tmax 4.2-5.5 hr T1/2 25.9-26.7 hr Tmax 4 hr T1/2 24-36hr Tmax 4-6hr T1/2 17-38hr Cross BBB Dosing 125 mg daily (3weeks 1 week off) 600 mg daily (3weeks 1 week off) 200mg twice daily (continuous dosing) DLT Neutropenia Thrombocytopenia Fatigue Other AEs Anemia, nausea, anorexia, fatigue, diarrhea Mucositis, QTc interval, elevated creatinine ,nausea Diarrhea, neutropenia nausea Key characteristics of CDK inhibitors

Other CDK Inhibitors in Phase III Trials in ER+ Advanced Breast Cancer HN N O CH3 H3C H N Ribociclib (LEE011) MONALEESA-2 (NCT01958021) – postmenopausal – letrozole +/- ribociclib MONALEESA-3 (NCT02422615) – postmenopausal – fulvestrant +/- ribociclib MONALEESA-7 (NCT02278120) – premenopausal – endocrine Rx +/- ribociclib Abemeciclib (LY2835219) MONARCH 1 postmenopausal monotherapy MONARCH 2 (NCT02107703) – postmenopausal – fulvestrant +/- abemeciclib MONARCH 3 (NCT02246621) – postmenopausal – non-steroidal AI +/- abemeciclib IC50 CDK1: >100 µM CDK2: >50 µM CDK4: 10 nM CDK5: ND CDK6: 39 nM CDK7: ND CDK9: ND F N HN CH3 H3C IC50 CDK1: >1 µM CDK2: >500 nM CDK4: 2 nM CDK5: ND CDK6: 5 nM CDK7: 300 nM CDK9: 57 nM Presented by J. Sparano. ASCO 2015.

Conclusions (1) La voie Cycline D1-CDK4/6-Rb est critique pour la prolifération cellulaire

Conclusions (1) La voie Cycline D1-CDK4/6-Rb est critique pour la prolifération cellulaire Dysrégulation est fréquement observée dans les cancers du sein RH+ et associée à une hormonorésistance

Conclusions (1) La voie Cycline D1-CDK4/6-Rb est critique pour la prolifération cellulaire Dysrégulation est fréquement observée dans les cancers du sein RH+ et associée à une hormonorésistance Plusieurs Inhibiteurs CDK 4/6 en développement: palbociclib, ribociclib et abemaciclib

Conclusions (1) La voie Cycline D1-CDK4/6-Rb est critique pour la prolifération cellulaire Dysrégulation est fréquement observée dans les cancers du sein RH+ et associée à une hormonorésistance Plusieurs Inhibiteurs CDK 4/6 en développement: palbociclib, ribociclib et abemaciclib Inhibiteurs CDK4/6 et hormonothérapie : mode d’action complémentaire

Conclusions (2) Palbociclib, inhibiteur CDK4/6 a démontré une activité préclinique (dans les lignées cellulaires et les xénogreffes) en association avec tamoxifene et letrozole

Conclusions (2) Palbociclib, inhibiteur CDK4/6 a démontré une activité préclinique (dans les lignées cellulaires et les xénogreffes) en association avec tamoxifene et letrozole En première ligne M+, l’association palbociclib letrozole (PALOMA-1) a démontré un doublement de la SSP observée dans tous les sous-groupes (20.2 mois vs 10.2 mois) Confirmation des résultats avec Phase III PALOMA2

Conclusions (2) Palbociclib, inhibiteur CDK4/6 a démontré une activité préclinique (dans les lignées cellulaires et les xénogreffes) en association avec tamoxifene et letrozole En première ligne M+, l’association palbociclib letrozole (PALOMA-1) a démontré un doublement de la SSP observée dans tous les sous-groupes (20.2 mois vs 10.2 mois) Etude de confirmation Phase III PALOMA2 L’activité du palbociclib a été confirmée dans une population résistante à l’hormonothérapie (PALOMA3) Le profil de tolérance était acceptable avec des effets secondaires transitoires et réversibles

Palbociclib + IA Une des option préférée en 1ère ligne chez les patientes ( pré et post ménopause)

Saint Gallen/San Antonio 2017 Nadia Harbeck

Interactions médicamenteuse

Modifications posologiques: Toxicités hématologiques Bilan: Biologie mensuelle + NFS au J15 les 2 premiers mois.

Modifications posologiques: Toxicités hématologiques

Conclusion Palbociclib : nouvelle arme thérapeutique Action Complémentaire avec l’hormonothérapie Efficacité: dédoublement de la SSP observée dans tous les sous-groupes Tolérance: effets secondaires transitoires et réversibles