Biomarker research in HER2 positive breast cancer : a journey into the desert

Transcription

1 WIN 9th Symposium 2017 Expediting Global Innovation in Precision Cancer Medicine Paris, June 26 & 27, 2017 Biomarker research in HER2 positive breast cancer : a journey into the desert Martine J. Piccart-Gebhart, MD, PhD Institut Jules Bordet, Brussels, Belgium Université Libre de Bruxelles Breast International Group (BIG aisbl), Chair

2 Relevant disclosures for this talk Consultant (honoraria) : Roche-Genentech Research grants to my Institute : most companies, including Roche-Genentech Speakers bureau/stock ownership : none

3 One of the greatest translational research achievements in Breast Cancer! Normal HER2 gene Amplified HER2 gene (15-20 % of B.C.) 1987 Aggressive Biology (Slamon) 1992 Humanized anti HER2 mab (Carter) Start of clinical development in breast cancer

4 Systemic therapies for HER2+ BC I. Metastatic disease : overall survival Median survival (months) Single HER2 blockade + chemo Dual HER2 blockade + chemo Swain S.M. et al, Lancet Oncol.,2013 * Docetaxel + trastuzumab + pertuzumab (CLEOPATRA)

5 BIG s involvement in adjuvant trials for HER2+ BC Activating trials across continents and recruiting at high speed Single HER2 blockade vs observation Dual HER2 blockade vs single HER2 blockade Trastuzumab Trastuzumab + Lapatinib Trastuzumab + Pertuzumab HERA ALTTO APHINITY 5102 Pts in 43 months 8381 Pts in 49 months 4805 Pts in 22 months N = women recruited ( ) Europe: 60% Australasia: 25% US: 10% South America: 5%

6 Systemic therapies for HER2+ BC II. Adjuvant setting: disease-free survival 70% 80% 90% 4 year DFS rates 72-79% 79-86% 92.3% (vs 90.6%) HERA NSABP-B31 N9831 Control arms No trastuzumab HERA NSABP-B31 N9831 Trastuzumab arms APHINITY Trastuzumab + pertuzumab Piccart M.J., Cancer Res.,2013 Von Minckwitz G. et al., NEJM, June 5, 2017

7 APHINITY: Trial Design S U R G E R Y Central confirmation of HER2 status (N = 4805) R Randomisation and treatment within 8 weeks of surgery Chemotherapy* + trastuzumab + pertuzumab Chemotherapy* + trastuzumab + placebo Anti-HER2 therapy for a total of 1 year (52 weeks) (concurrent with start of taxane) Radiotherapy and/or endocrine therapy may be started at the end of adjuvant chemotherapy F O L L O W - U P 10 Y E A R S *A number of standard anthracycline-taxane-sequences or a non-anthracycline (TCH) regimen were allowed

8 APHINITY: Intent-to-Treat Primary Endpoint Analysis Invasive Disease-free Survival 63% N+ 36% HR Number neededto treat: % A-based CT Observed HR 0.81 ( = 1%) Anticipated HR 0.75 ( = 2.6%) ASCO 2017, LBA 500

9 ! Median follow-up ( <4y) still short

10 APHINITY the last large adjuvant trial for HER2+ BC? Time to explore chemotherapy de-escalation with the use of dual HER2 blockade!

11 HER2 Have we been able to go beyond HER2 for improved treatment tailoring?

12 Translational Research efforts in HER2+ BC HER2 Copy n 0 /FISH ratio Polysomy mrna expression Protein expression P95 HER2 Serum ECD Other receptors/ ligands HER3 EGFR (HER1) IGFR ERα EGF TGFα Heregulin Transduction pathway Stroma PIK3CA/PTEN TILs Immune gene expression signatures pstat3 T U M O R H E T E R O G E N E I T Y

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14 Improved treatment tailoring in HER2+ BC? Advanced disease Early disease Our patients needs Which biomarkers might help addressing these needs? Our critical research gaps

15 Improved treatment tailoring in advanced HER2+ BC The patient s perspective Can I live many more years with the disease? Can I be sure that the chosen therapy will truly help me? Can I stay away from therapies with marked side effects for long periods of time?

16 Translational Research efforts in HER2+ BC I. Advanced disease Downstream signaling pathways Other membrane receptors HER2 itself & their ligands PIK3CA mutations

17 Translational Research efforts in HER2+ BC ER HER2 EGFR Trastuzumab PiK3CA mutations 20-30% PI3K AKT HER2 HER3 HER2 mtor RAS IGFR1 RAF MEK Tumor cell ERK

18 Proportion progression-free High tumor HER2 mrna means a better prognosis CLEOPATRA : docetaxel + trastuzumab + pertuzumab > docetaxel + trastuzumab EMILIA: T-DM1 > lapatinib + capecitabine PFS High HER2 mrna : better prognosis independently from treatment arm Lap + Cap ( Median) Lap + Cap (> Median) T-DM1 ( Median) T-DM1 (> Median) Time (months) Courtesy J. Baselga

19 PiK3CA mutations (32% incidence): worse prognosis but still a benefit from treatment CLEOPATRA trial EMILIA trial pik3ca stats mutant Single blockade med PFS Dual blockade med PFS H.R. Lap + Cap med PFS T-DM1 8.6 m 12.5 m m 10.9 m 0.45 Wild type 13.8 m 21.8 m m 9.8 m 0.74 Dual blockade works in both cohorts but larger magnitude of benefit in wild type cohort H.R. T-DM1 works in both cohorts but larger magnitude of benefit in mutated cohort Baselga J., J. Clin. Oncol.,2014 Baselga J., Cancer Res., 2013

20 CLEOPATRA trial : predictive biomarkers Ligands Other receptors Pik3CA pathway No predictive biomarker identified Baselga et al. JCO (2014) 20

21 Translational Research efforts in advanced HER2+ BC Tumor Microenvironment

22 Translational Research efforts in HER2+ BC Lymphocyte ER HER2 EGFR PI3K HER2 HER3 APC AKT HER2 mtor RAS IGFR1 RAF WBC Tumor cell ERK MEK HER2 Trastuzumab FcyRIII

23 TIL s are prognostic in the context of advanced HER2 positive Breast Cancer treated with anti-her2 MAbs Clinical trial = CLEOPATRA (adding pertuzumab to trastuzumab + docetaxel improves PFS by 6.3m and OS by 15.7m in the first line setting) Tissue collected from 678 out of 808 patients (N=155 fresh samples, 519 archival samples, only 20 paired samples) Stromal TILs: median = 10%, range 1-95% (significantly higher in ER negative tumors) Each 10% increase in TILs is associated with an 11% decrease in the risk of death Luen, S.J. et al, Lancet Oncology, 2017; 18:52-62

24 TIL s are prognostic in CLEOPATRA Luen, S.J. et al, Lancet Oncology, 2017, 18:52-62

25 PANACEA TRIAL: RECRUITING ABC Prior progression while on trastuzumab S. Loi Non Eligible HER2 - Central testing HER2 by IHC HER2 + * Central PD-L1 testing PD-L1 - Non Eligible PD-L1 + Enroll Phase Ib (dose finding MK-3475 in 3+3 design) /Phase II at RP2D Treatment in 3 weeks cycles * PDL1 negative cohort to be opened soon Trastuzumab 6 mg/kg q 3 w Anti PD(L)1 q 3 w PD PD

26 Translational Research efforts in HER2+ BC Tumor heterogeneity

27 HER2 imaging G. Gebhart P. Flamen Trastuzumab Zirconium 89 - positron emitting isotope PET - compatible physical characteristic (Half-life 78.4 h) E. de Vries

28 ZEPHIR TRIAL DESIGN 89 Zr-trastuzumab injection 89 Zr-trastuzumab PET/CT Screening D 0 D 4 Baseline FDG PET/CT Diagnostic CT T-DM1 T-DM1 T-DM1 D 15 D 1 D 22 J 43 D 57 D 64 FU until PD Early FDG PET/CT Late FDG PET/CT Diagnostic CT G. Gebhart et al., Annals of Oncology, published online Nov 23, 2015

29 Patterns of 89 Zr-trastuzumab PET/CT confronted with FDG-PET/CT FDG A HER2 All (A) or most (B) of the metastatic lesions are seen on the HER2 PET FDG HER2 B All lesions :high 89 Zr-T uptake HER2 IMAGING METHODOLOGY Majority of the tumour load: high 89 Zr-T FDG HER2 FDG HER2 C None (D) or very few (C) metastatic lesions are seen on the HER2 PET D Majority of the tumour load: low/no 89 Zr-T uptake G. Gebhart et al., Annals of Oncology, published online Nov 23, 2015 All lesions: low/no 89 Zr-T uptake

30 Heterogeneity in HER2 «mapping» and early FDG-PET predict time to treatment failure (TTF) under T-DM1 Therapy 2A Short TTF with HER2 PET patterns C+D Short TTF if no early FDG-PET response G. Gebhart et al., Annals of Oncology, published online Nov 23, B

31 Critical research gaps in advanced HER2+ BC HER2 TILs Immune gene signature Majority of the tumour load: high 89 Zr-T Temporal evolution? Which BMs differentiate responding lesions from non-responding lesions? Could knowledge of both help define optimal treatment sequencing?

32 Improved treatment tailoring in advanced HER2+ BC The patient s perspective Can I live many more years with the disease? YES Can I be sure that the chosen therapy will truly help me? NO Can I stay away from therapies with marked side effects for long periods of time? sometimes

33 Improved treatment tailoring in HER2+ BC Advanced disease Early disease

34 Biomarker research in neoadjuvant vs adjuvant trials Neoadjuvant setting Adjuvant setting Baseline Surgery Surgery Biomarkers pcr EFS/OS DFS/OS Biomarkers DFS/OS

35 Improved treatment tailoring in HER2+ early BC The patient s perspective Can I be sure that my long treatment will help me? Can I do as well with a simpler or a shorter treatment? Can I forego (aggressive) chemotherapy?

36 Translational Research efforts in HER2+ BC II. Early disease Tumor heterogeneity Microenvironment Downstream signaling pathways HER2 itself Other membrane receptors & their ligands

37 Translational Research efforts in early HER2+ BC Neoadjuvant setting Adjuvant setting High HER2 protein = pcr HER2 staining no impact NeoALTTO (1) HERA (7) High HER2 mrna = TRYPHAENA (2) GeparQuattro (3) pcr HER2 itself HER2 amplif/fish ratio/polysomy NOT linked to outcome HERA (7)/N9831 (8)/NSABP-B31 (9) HER2 enriched (PAM50) = NOAH (4) CALGB (5) PAMELA (6) 1. Scaltriti et al, Schneeweiss, A et al Denkert, C et al Prat, A et al Carey, L.A et al Prat, A. SABCS 2016 pcr ER 7. Dowsett, M et al Perez, E et al Paik, S et al Zalbaglo, L et al Pogue-Geile KL et al, 2015 HER2 enriched (PAM50) : no impact NSABP-B31 (10) Suggestion of lack of benefit of trast if ER+/HER2 FISH ratio low NSABP-B31 HERA

38 Some Luminal B HER2 positive BC may derive no benefit from trastuzumab!! Predictive model of response to trastuzumab according to expression of ESR1 and ERBB2 related genes High ER expression and low FISH ratio associated with no benefit from trastuzumab High ESR1 expression and intermediate ERBB2 expression associated with the lowest benefit from trastuzumab Loi S. et al, JCO 2015 under review Pogue-Geile et al. JNCI (2013)

39 Our «last chance» to validate this potentially important observation will be to re-run the analysis in the context of a meta-analysis of the 5 trials looking at shorter vs longer trastuzumab duration!

40 Trials exploring shorter durations of adjuvant Trastuzumab Trial N of pts Time needed Pt charact CTX/Trast Non inf mar-gins Results 6 months vs 12 months PHARE (+2)Y N- 55% HR+ 58% HELLENIC Y (!) N- 17% HR+ 69% A/T with trast concom or seq A/T with trast concomitant 1.15 HR 1.28 ( ) (mostly driven by ERsequential CTX group) 1.53 DFS events : 13% vs 10.4% HR 1.58 ( ) PERSEPHONE Y (!)???? 9 weeks or 3 months vs 12 months SHORT-HER Y N- 53% ER+ 68% Conv A->T+H for 12m TH->A for 3m arm 1.29 HR 1.15 ( ) SOLD Y? TH->A->Tx9m(12m) TH->A (3m) Examine the outcome of women with high ER / low FISH ratio tumors across all these trials? Superior OS by 4% Piccart M., Cancer Res., 2013 Conte F., J. Clin.Oncol Abst. 501?

41 Translational Research efforts in early HER2+ BC Downstream signaling pathways Neoadjuvant trials Adjuvant trials

42 Neoadjuvant trials testing dual HER2 blockade Trials N pts chemo Single blockade pcr (trastuzumab) Dual blockade pcr pvalue NeoSphere 417 Docetaxel 29% 46% NeoAltto 455 Paclitaxel 29% 51% CALGB Paclitaxel 46% 56% 0.12 (NS) NSABP-B AC/paclitaxel 52% 62% Gianni L., Lancet Oncol., 2012., Baselga J., Lancet, 2012., Carey L., J. Clin. Oncol., 2016., Robidoux A., Lancet, 2013

43 Neoadjuvant trials investigating single (trastuzumab or lapatinib) OR dual HER2 blockade (trastuzumab + lapatinib) GeparQuinto GeparSixto Untch et al. JCO 2010 and Lancet Oncol 2012 NeoALTTO von Minckwitz et al. Lancet Oncology CHERLOB Baselga et al. Lancet 2010 Guarneri et al. J Clin Oncol 2012 Adapted from S Loibl et al. ASCO 2015

44 Lower likelihood of pcr with dual HER2 blockade if tumors are ER+/PiK3CA mutated S. Loibl and worse DFS!! Adapted from S Loibl et al. ASCO 2015

45 Magnitude of trastuzumab benefit independent from pik3ca/pten status in the adjuvant setting FINHER NSABP-B31 Loi et al. JNCI 2013 Pogue-Geile et al. JCO 2015 PTEN negative N9831 PTEN positive (1, 2, or 3+) Perez E et al. JCO 2013

46 Whole exome sequencing of pretreatment biopsies in NeoALTTO and correlation with pcr/os (n = 203 out of 455 patient) Mutations in PIK3CA (wt RhoA) Mutations in PIK3CA network and RhoA wild type: overall survival by treatment arm pcr rate 2% Trast 43% Trast + Lap pcr rate Mutations in RhoA (wt PIK3CA) 20% Trast 70% NEED DUAL BLOCKADE Trast + Lap Wt PIK3CA and wt RhoA pcr 43% 52% Trast rate 43% Trast + Lap DO NOT NEED DUAL BLOCKADE L. Pusztai, SABCS 2015, Dec 11 GS5: S5-01

47 Translational Research efforts in early HER2+ BC Tumor Microenvironment 1. TILs measurement 2. Immune geneexpression profiling Neoadjuvant setting Adjuvant setting

48 The association between TILs and pcr/efs in NeoALTTO (n = 387/455 patients) NeoALTTO Virtually no events if baseline TILs 40%!!! Independent Validation ALTTO APHINITY Potential treatment de-escalation?

49 NeoALTTO: effect of gene expression signatures on pcr treatment interaction tests dual blockade vs monotherapy C. Sotiriou ESR1 ERBB2 Her2 enriched (PAM50) Immune1 Immune2 Immune3 GGI aurka AKTmTOR Stroma1 Stroma2 AR OR inter CI inter 0.57 to to to to to to to to to to to to 2 p inter FDR OR Significant interaction p value Sotiriou et al., ECC 2015 Low pcr High pcr

50 Immune function genes predict trastuzumab benefit in N9831 (n = 1282 patients) Immune-response enriched Non immune-response enriched Perez et al, J Clin Oncol, 2015

51 Who does very well on CTX + Trastuzumab? ALTTO APHINITY CTX + Trastuzumab + Lapatinib + Trastuzumab then Lapatinib + Trastuzumab and Lapatinib combined CTX + Trastuzumab + Trastuzumab and Pertuzumab (95% DMFS at 5y) Investigate in ALTTO (N=2000) Validate in APHINITY (N=2400)

52 Translational Research efforts in early HER2+ BC Tumor heterogeneity

53 Intratumor heterogeneity for HER2+ Two Segments with Distinctly Different HER2 Status HER2+/ER- and Triple Negative Four blocks of primary tumor Lymph node metastasis Courtesy of Susan Lester, MD, PhD and Andrea Richardson, MD, PhD Obtained from E. Winer, with permission

54 Exploring heterogeneity with in situ single-cell analysis STAR-FISH 5 color detection Courtesy of K. Polyak H1047H WT H1047R MUT CEP17 HER2 Nuclei Combined detection of single nucleotide and copy number alterations in single cells!

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56 Summary of biological and genomic features of the 64 sequenced HER2+ tumours Ferrari A. et al, Nature Communications, 2016

57 Improved treatment tailoring in HER2+ early BC The patient s perspective Can I be sure that my long treatment will help me? NO Can I do as well with a simpler or a shorter treatment? NOT SURE Can I forego (aggressive) chemotherapy? maybe

58 BIG & NABCG are working together on one or two chemotherapy de-escalation protocols using dual HER2 blockade Focus : HER2+ HR disease

59 Nature Reviews Clinical Oncology Advance Online Publication, 2017

60 San Antonio Breast Cancer Symposium, December 8-12, 2015 A simple path to Precision Medicine does not exist We now need to boost a multidimensional approach and international collaboration in patient-centered biomarker research!

61 BREAST Data Center Team BIG HeadquartersTeam Institut Jules Bordet Team BIG Executive Board

62 BACK UP 62

63 Lessons learned from an expedition into the world of HER2+ BC: Conclusions HER2+ BC population : Huge therapeutic advances Will do well without chemotherapy Will do well with light chemotherapy Will do well with short trastuzumab therapy Will need dual HER2 blockade Will need newer therapies Steep learning curve in dissecting the biological complexity of HER2+ BC but Yet a long way to go in order to address our patients needs!