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

Transcription

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

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

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

5 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)

6 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 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)

7 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

8 Slide 15 Presented By Paul Goss at 2016 ASCO Annual Meeting

9 Slide 18 Presented By Paul Goss at 2016 ASCO Annual Meeting

10 Slide 16 Presented By Paul Goss at 2016 ASCO Annual Meeting

11 Slide 21 Presented By Paul Goss at 2016 ASCO Annual Meeting

12 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?

13 Metanalysis: TAM > 5y vs < 5y

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

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18 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 years No PBI planned Sparano J A, and Paik S JCO 2008;26:

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

20 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

21 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 ( ) P: 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 ( ) Fulvestrant +/- palbociclib (Turner, NEJM, 2015) meta Resistant to AI Registration trial 521 PFS: 9.2 versus 3.8 months PFS: HR: 0.42 ( ) <0.001

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

23 Variation par rapport à l inclusion (%) MONARCH 1: essai de phase II Abemaciclib Évaluation de la réponse 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 % 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 D après Dickler MN et al., abstr. 510, actualisé

24 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 PFS months Visceral crisis / early relapse Fulvestrant + Palbo nsai + everolimus PFS3?months chemo OS 36 months

25 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

26 Predictive biomarkers: POP study Biomarker Rb prb p16 pakt (Ser 473 ) per Interaction test 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

27 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

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

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

30 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

31 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 Fulvestrant Median PFS, 5.7 months (95% CI, ) Exemestane Median PFS, 2.6 months (95% CI, ) Fulvestrant Median PFS, 8.0 months (95% CI, ) Exemestane Median PFS, 5.4 months (95% CI, ) HR = 0.52 (95% CI, ); P = 0.02 HR = 1.07 (95% CI, ); P = 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:

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

33 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

34 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

35 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 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 ( ) vs 4.6 ( ) months Chan A, et al. Lancet Oncol. 2016;17(3):

36 Disease-free survival (%) 100 Primary Endpoint: Invasive DFS % 95.6% (ITT) 93.9% 91.6% 2.3% 2.3% absolute difference No. at risk Neratinib 1420 Placebo 1420 P-value = HR (95% CI) = 0.67 ( ) Hormone receptor-positive tumors (n=1631; HR=0.51, 95% CI ; P =.001) Hormone receptor-negative Neratinib tumors Placebo (n=1209; HR=0.93, 95% CI ; P =.735) Months after randomization % 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):

37 Disease-free survival (%) 3-year idfs Analysis: Hormone receptor-positive & centrally confirmed HER2+ No. at risk Neratinib Placebo % 94.7% Two-sided *P-value <0.001 HR (95% CI) = 0.43 ( ) Months after randomization % 89.9% % 88.0% Neratinib Placebo % 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.

38 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

39 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

40 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: Nanda et al. SABCS 2014; Abs S1-09.

41 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: Nanda et al. SABCS 2014; Abs S1-09.

42 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: Nanda et al. SABCS 2014; Abs S Time (weeks) On treatment Discontinued treatment

43 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

44 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 % PR 57.1% 77.8% 62.5% SD 42.9% 22.2% 0 PD % Adams S et al. SABCS 2015; Abs

45 Anti PDL-1 : Atezolizumab + Nabpaclitaxel Etude IMpassion130 (NCT ) : 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)

46 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

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