Cancer du sein: best of Barbara Pistilli Gustave Roussy Cancer Center

Cancer du sein: best of 2016 Barbara Pistilli Gustave Roussy Cancer Center Paris, 3 Décembre 2016

Mon Plan the best of 2016 EBC MBC ER + HER2+ TN

Long-term recurrence risks after use of endocrine therapy for only 5 years Relevance of breast tumour characteristics Hongchao Pan, Richard Gray, Christina Davies, Richard Peto, Jonas Bergh, Kathleen I Pritchard, Mitch Dowsett, Daniel F Hayes, for the Early Breast Cancer Trialists Collaborative Group (EBCTCG)

Lowest-stage (T1N0) disease: Risk of ANY breast cancer event 21% risk, years 5-20 (14% DISTANT recurrence + 7% only local or contralateral) Any breast cancer event 21% 20 %, CI 14% T1N0 10 7% ET for 5 years 0 0 5 10 15 20 years since diagnosis T1N0 (n=16k): Annual event rate (and no. of events), by 5-year time period 1.4% (807) 1.7% (309) 1.8% (54)

MA.17R Trial Design <br />AI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen Presented By Paul Goss at 2016 ASCO Annual Meeting

Presented By Paul Goss at 2016 ASCO Annual Meeting

Conclusion MA17R: extended AI Population sélectionnée Bénéfice de 4% en DFS, 0 en OS Prévention secondaire essentiellement Bénéfice sur risque de métastases: 1.1% Rapport bénéfice-risque à évaluer Option possible si cancer du sein agressif N+, et rapport bénéfice-risque acceptable?

Metanalysis: TAM > 5y vs < 5y

Mon Plan the best of 2016 EBC MBC ER + ET 10 yrs vs 5 (high risk) HER2+ TN

Methods: TAILORx Design & Rationale for RS Cutpoints Enrollment period: April 7, 2006 to October 6, 2010 (N=10,273 eligible) Key Eligibility Criteria Node-negative ER-pos, HER2-neg T1c-T2 (high-risk T1b) Age 18-75 years No PBI planned Sparano J A, and Paik S JCO 2008;26:721-728 18

Mon Plan EBC MBC ER + ET 10 yrs vs 5 (high risk) No CT in ch/gl HER2+ TN

Cyclin D1 CDK 4-6 inhibitors: rationale The CDK 4/6-Cyclin D1-E2F Pathway STATs PI3K/AKT NF-kB M G0 G2 MAPKs Cyclin D G1 (ER/PR/AR) Wnt/b-catenin p21 p53 CDK 4/6 p16 P RB RB E2F E2F (Tumor suppressor) Evidence suggests that In AI resistance models, ER drives a CDK 4/ E2F-dependent transcriptional program CDK 4/6 inhibition reduces cell proliferation in both ERdependent and ERindependent, AI-resistant breast cancer models S Gene transcription 20

Randomized trials testing CDK4 inhibitors Treatment setting Pre treatment phase n Effect on primary endpoint Palbo single agent (Arnedos, AACR, 2016) early none Window of opportunity 100 Post-tt lnki67<1 : 58% vs 12% (p<0.0001) Letrozole +/- palbociclib (Finn, Lancet Oncol, 2015) meta Endocrine sensitive 1st line Phase II randomized 165 PFS: 20 versus 10 months HR: 0.49 (0.32 0.75) P: 0.0004 Letrozole +/- palbociclib (Finn, ASCO, 2016) meta Endocrine sensitive 1st line Phase III randomized 666 PFS: 24 versus 14 months (HR=0.58) Letrozole +/- ribociclib (Hortobagyi, NEJM, 2016) meta Endocrine sensitive 1st line Phase III randomized 668 PFS: NR versus 14 0.556 (0.429 0.720) Fulvestrant +/- palbociclib (Turner, NEJM, 2015) meta Resistant to AI Registration trial 521 PFS: 9.2 versus 3.8 months PFS: HR: 0.42 (0.32 0.56) <0.001

Safety profile (Palbociclib, PALOMA3) Turner N, NEJM, 2015

Variation par rapport à l inclusion (%) MONARCH 1: essai de phase II Abemaciclib Évaluation de la réponse 100 50 20 0 Réponse selon les investigateurs a Abémaciclib 200 mg (n = 132) Taux de réponse objective (RC + RP) 19,7 % IC 95 Réponse complète Réponse partielle 13,3-27,5 0 % 19,7 % Maladie stable > 6 mois 22,7 % Taux de bénéfice clinique (taux de réponse objective + maladie stable > 6 mois) 42,4 % 30 50 100 Taux de contrôle (RC + RP + MS) = 67,4 % Progression (n = 34) Maladie stable (n = 63) Réponse partielle (n = 26) Non évalué (n = 9) a Les évaluations selon la revue indépendante étaient comparables Durée médiane avant réponse Durée de réponse médiane Taux de réponse à 6 mois Taux de réponse à 12 mois SSP médiane SG médiane 3,7 mois 8,6 mois 70,4 % 28,2 % 6,0 mois (IC 95 : 4,2-7,5) 17,7 mois (IC 95 : 16,0-NA) ASCO 2016 - D après Dickler MN et al., abstr. 510, actualisé

7000 pts/year in France ER+ Her2- MBC: current trts AI sensitive AI-resistant PFS1 AI + palbociclib 24 months (USA, ong EU) nsai + everolimus Fulvestrant + Fulvestrant palbociclib PFS2 9-10 months Visceral crisis / early relapse Fulvestrant + Palbo nsai + everolimus PFS3?months chemo OS 36 months

Quels sont les biomarquers predictifs de la réponse au CDK4/6 inh? CCND1 amplification P16 loss (not validated in Finn et al) Cell signaling Cyclin D1 expression Cyclin D CDK 4 p21 p16 p53 G2 M G0 G1 RB E2F P RB E2F (Tumor suppressor) S Gene transcription Loss of Rb 25

Predictive biomarkers: POP study Biomarker Rb prb p16 pakt (Ser 473 ) per Interaction test 0.641 0.856 0.218 0.484 0.856 CCND1 at baseline Control N = 26 Palbociclib N = 74 Non-Amplified 16 (67) 53 (73) Amplified 8 (33) 20 (27) Interaction test p=0.388 Arnedos, AACR, 2016

lnki67<1 surgery lnki67<1 surgery Predictive biomarkers: POP study PIK3CA Contro l N = 23 Palboci clib N = 61 Non- Mutated 17 (81) 32 (58) Mutated 4 (19) 23 (42) Missing 2 6 HR+/HER2- tumors PIK3CA mutation was not significantly associated with lnki67<1 (Interaction test p=0.478) Only 2 AKT1 mutations found

PIK3CA mutations and CDK4/6 inh Paloma 3 PIK3CA mutations + 33% Turner Lancet Oncol 2016

Mon Plan EBC ER + ET 10 yrs vs 5 (high risk) No CT in ch/gl MBC CDK4/6 inh HER2+ TN

ESR1 mutations and resistance to endocrine therapy Mutatitons activatrices ont été identifiées dans les 11-55% des cancer du sein métastatique RE+ résistants à l HT Plus particulièrement chez les patientes traitées par IAs Toy, Nature Genetics

Progression-Free Survival, % Progression-Free Survival, % SoFEA Trial: fulvestrant +/ exemestane vs exemestane in HR+ AI-resistant ABC patients ESR1-mutated ESR1wt ESR1 mutation in 39% patients 100 75 Fulvestrant Median PFS, 5.7 months (95% CI, 3.0-8.5) Exemestane Median PFS, 2.6 months (95% CI, 2.4-6.2) 100 75 Fulvestrant Median PFS, 8.0 months (95% CI, 3.0-11.5) Exemestane Median PFS, 5.4 months (95% CI, 3.7-8.1) 50 50 25 25 HR = 0.52 (95% CI, 0.30-0.92); P = 0.02 HR = 1.07 (95% CI, 0.68-1.67); P = 0.77 0 6 12 18 24 0 6 12 18 24 Time From Random Assignment, months Time From Random Assignment, months No. at risk (events) No. at risk (events) Exemestane 18 (12) 6 (4) 2 (2) 0 (0) 0 Exemestane 39 (18) 21 (9) 12 (5) 5 (0) 3 Fulvestrant-containing 45 (23) 22 (10) 12 (5) 6 (5) 1 Fulvestrant-containing 59 (31) 27 (7) 19 (8) 8 (2) 5 Reprinted from Fribbens C, et al. J Clin Oncol. 2016;34:2961-2968. 31

ER degraders: preclinical activity Weir et al, Cancer Res 2016

Mon Plan EBC ER + ET 10 yrs vs 5 (high risk) No CT in ch/gl MBC CDK4/6 inh ER degraders for ESR1 mut? HER2+ TN

Neratinib as Extended Adjuvant HER2+ breast cancer Prior adjuvant trastuzumab/ chemotherapy LN+/- or residual invasive disease after neoadjuvant rx ER/PR +/- Therapy: The ExteNET Trial R N=2840 neratinib x 1 year 240 mg/d placebo x 1 year 24% node negative, 47% 1-3+ nodes; 57% HR+ Summary of changes: 3 sponsors from 2009 to 2011 Study population decreased from 3850 to 2840 2 nd sponsor: Change to stage 2-3; LN+ and <1 year from trastuzumab, endpoint idfs 3 rd sponsor: FU truncated to 2 years for all patients Now extended to 5 years Primary endpoint: Invasive DFS (idfs) Secondary endpoints: DFS-DCIS, time to distant recurrence, distant DFS, CNS metastases, OS, safety Other: Biomarkers, QOL Stratification: Nodes 0, 1-3+, vs 4+, ER/PR status, concurrent vs sequential trastuzumab Median time from trastuzumab N vs P: 4.4 (0.2-30.9) vs 4.6 (0.3-40.6) months Chan A, et al. Lancet Oncol. 2016;17(3):367-377

Disease-free survival (%) 100 Primary Endpoint: Invasive DFS 90 97.8% 95.6% (ITT) 93.9% 91.6% 2.3% 2.3% absolute difference 80 70 60 50 0 No. at risk Neratinib 1420 Placebo 1420 P-value = 0.009 HR (95% CI) = 0.67 (0.50 0.91) 0 3 6 9 12 15 18 21 24 1291 1367 Hormone receptor-positive tumors (n=1631; HR=0.51, 95% CI 0.33 0.77; P =.001) Hormone receptor-negative Neratinib tumors Placebo (n=1209; HR=0.93, 95% CI 0.60 1.43; P =.735) 1260 1324 Months after randomization 1229 1292 1189 1243 1150 1209 1108 1163 1033 1090 662 704 2.5% 3 year difference in centrally confirmed HER2+ disease Safety 95% diarrhea 39.9% grade 3/4 Diarrhea prophylaxis Intensive loperamide prophylaxis reduced grade 3 diarrhea to 17% in one study Ongoing studies evaluating this effect Chan A, et al. Lancet Oncol. 2016;17(3):367-377

Disease-free survival (%) 3-year idfs Analysis: Hormone receptor-positive & centrally confirmed HER2+ No. at risk Neratinib Placebo 100 90 80 70 60 50 0 0 6 12 18 24 30 36 42 48 455 448 426 426 410 406 98.1% 94.7% Two-sided *P-value <0.001 HR (95% CI) = 0.43 (0.26 0.70) Months after randomization 398 385 342 336 96.1% 89.9% 258 275 252 262 94.4% 88.0% Neratinib Placebo 237 245 200 205 92.8% 86.3% Absolute difference: 6.5% Increases to 7.7% in HR+, completing adjuvant trastuzumab < one year before study * p value descriptive Chan A, et al. Cancer Res. 2016;76(4 Suppl):Abstract S5-02.

Mon Plan EBC ER + ET 10 yrs vs 5 (high risk) No CT in ch/gl MBC CDK4/6 inh ER degraders for ESR1 mut HER2+ Extended adjuvant NERATINIB? TN

Essai KEYNOTE-012 Anti PD-1 : Pembrolizumab TN M+/Localement avancées PS 0 ou 1 > 1 lésion mesurable Pas de M+ cérébrales actives PD-L1+ Pembrolizumab 10 mg/kg i.v. toutes les 2 sem. Évaluation de la réponse /8 semaines Réponse complète ou partielle ou maladie stable Maladie progressive confirmée ou toxicité inacceptable Traitement de 24 mois ou jusqu à progression ou toxicité Arrêt du pembrolizumab *PD-L1+ = > 1% des cellules (tumorales ou stromales) sur tissu archivé ; 58% des patientes screenées étaient PD-L1 positives Nanda R et al. J Clin Oncol 2016;20:2460-7. Nanda et al. SABCS 2014; Abs S1-09.

Anti PD-1 : Pembrolizumab n =32 Confirmed complete response Confirmed partial response Stable disease Progressive disease Taux de réponse objective : 18,5% - (1RC 4 RP) Stabilité : 25,9% (7 SD) Nanda R et al. J Clin Oncol 2016;20:2460-7. Nanda et al. SABCS 2014; Abs S1-09.

Change from baseline, % Anti PD-1 : Pembrolizumab n =32 Confirmed complete response Confirmed partial response Stable disease Progressive disease Taux de réponse objective : 18.5% - (1RC 4 RP) Stabilité : 25,9% (7 SD) Réponse durable Nanda R et al. J Clin Oncol 2016;20:2460-7. Nanda et al. SABCS 2014; Abs S1-09. 10 80 60 40 20 0-20 -40-60 -80-100 0 8 16 24 32 Time (weeks) On treatment Discontinued treatment 40 48 56

Anti PDL-1 : Atezolizumab + Nabpaclitaxel Phase Ib Sécurité et tolérance TN < 2 lignes de chimiothérapie Maladie mesurable PS 0-1 Non sélectionné sur l expression de PD-L1 Nab-paclitaxel 125 mg/m 2 QW 3/4 + Atezolizumab 800mg Q2W BOR par RECIST 1.1 PK Adams S et al. SABCS 2015; Abs 850477.

Anti PDL-1 : Atezolizumab + Nabpaclitaxel PDL1- (n = 7) PDL1+ (n = 9) Unknown (n = 8) ORR (IC 95%) 57.1% (18.4, 90.1) 77.8% (40.0, 97.2) 75% (34.9, 96.8) CR 0 0 12.5% PR 57.1% 77.8% 62.5% SD 42.9% 22.2% 0 PD 0 0 25% Adams S et al. SABCS 2015; Abs 850477.

Anti PDL-1 : Atezolizumab + Nabpaclitaxel Etude IMpassion130 (NCT02425891) : Phase III, 1 ère ligne, TN TN 1 ère ligne PS 0-1 Maladie Mesurable RECIST v1.1 M+ cérébrale stable Effectif: ~350 pts R 1:1 Nab-paclitaxel 100 mg/m 2 QW 3/4 + Atezolizumab 840 mg Q2W Nab-paclitaxel 100 mg/m 2 QW 3/4 + Placebo Q2W Objectifs primaires: SSP SSP en fonction du statut PD-L1 Objectifs secondaires: SG TRG Durée réponse Tolérance Stratification: M+ hépatique PK Qualité de vie Traitement antérieur par taxane Statut PD-L1 (centralisé par IHC)

Conclusions EBC ER + ET 10 yrs vs 5 (high risk) No CT in ch/gl MBC CDK4/6 inh ER degraders for ESR1 mut we are making progress HER2+ TN Extended adjuvant NERATINIB? when escalate and de-escalate? new Immunotherapie strategies? are urgently required