Novità e sequenze terapeutiche nel carcinoma mammario HER2 positivo Terapia neoadiuvante Claudio Zamagni

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1 Novità e sequenze terapeutiche nel carcinoma mammario HER2 positivo Terapia neoadiuvante Claudio Zamagni Direttore SSD Oncologia Medica Addarii Policlinico S.Orsola-Malpighi Bologna

2 Open questions in HER2+ ebc Anthra/taxane vs taxane alone Dual blockade vs single Long vs short pcr vs no pcr ER+ vs ER-

3 Open questions in HER2+ ebc pcr as a surrogate endpoint

4 Cortazar P et al, Lancet 2014

5 NSABP B-41 RFI by Breast pcr and Hormone Receptor Status Presented By Andre Robidoux at 2016 ASCO Annual Meeting

6 Cortazar P et al, Lancet 2014

7 Open questions in HER2+ ebc De-escalating treatment

8 APT Trial Disease-Free Survival 3-year DFS 98.7% (95% CI ) 3-y failure rate 1.3% (95% CI ) Sequential Poisson test p<0.001 Median follow-up 4.0 y (max 6.2 y) Tolaney SM et al NEJM 2015

9 ADAPT HER2+/HR+ Neoadjuvant Phase 2 Trial *Standard chemo recommended after surgery Trastuzumab to be completed, for total of one year Harbeck N et al J Clin Oncol 2017

10 pcr superior in TDM1 arms Harbeck N et al J Clin Oncol 2017

11 Neoadjuvant chemo-free regimens in HER2+ BC pcr rate (breast and axilla) * Breast pcr 60 T-DM1+P HER2+/ER- HER2+/ER+ 50 T-DM1+HT T+P T-DM1 T + L + HT * T+P+HT HT+T * 0 12 wks 24 wks NeoSphere 1 Kristine 2 ADAPT 3 TBCRC TBCRC PerELISA 6 1. Gianni L, et al. Lancet Oncol 2012; 2. Hurvitz s, et al. ASCO 2016; 3. Harbeck N, et al. ASCO 2015; 4. Rimawi M, et al. J Clin Oncol 3013; 5. Rimawi M, et al. SABCS 2014; 6. Guarneri V, personal communication

12 Open questions in HER2+ ebc The unmet need for HER2+ ebc is treatment tailoring

13 HER2 Tumour Heterogeneity NeoSphere TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) Study dosing: q3w x 4 S U R G E R Y Gianni L, et al. Lancet Oncol 2012; 13:25 32

14 pcr, % 95% CI HER2 Tumour Heterogeneity NeoSphere: Study design and main results TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) S U R G TH THP HP TP HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) E R TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) Y Study dosing: q3w x 4 Gianni L, et al. Lancet Oncol 2012; 13:25 32

15 HER2 Tumour Heterogeneity pcr, % 95% CI pcr, % 95% CI NeoSphere: Study design and main results TH (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) THP (n=107) docetaxel ( mg/m 2 ) trastuzumab (8 6 mg/kg) pertuzumab ( mg) HP (n=107) trastuzumab (8 6 mg/kg) pertuzumab ( mg) TP (n=96) docetaxel ( mg/m 2 ) pertuzumab ( mg) Study dosing: q3w x 4 Gianni L, et al. Lancet Oncol 2012; 13:25 32 S U R G E R Y As in all other neoadjuvant trials, probability of pcr is significantly higher for hormone receptornegative tumours TH THP HP TP ER- or PR-positive ER- and PR-negative TH THP HP TP 6

16 HER2+ ebc is a heterogeneous disease Intrinsic subtypes in CALGB Hormone receptor-positive Pre-therapy tumours Hormone receptor-negative Carey LA, et al., J Clin Oncol 2016; 34:

17 HER2+ ebc is a heterogeneous disease: Subtypes have different pcr rates with neoadjuvant therapy Carey LA, et al., J Clin Oncol 2016; 34:

18 Intrinsic sub-types in CALGB are different after neoadjuvant therapy Pre-Treatment Claudin low Normal-like Basal like Residual Disease Luminal B HER2 enriched Normal Like HER2-E Claudin low Luminal A Basal-like Lum B Lum A Carey LA, et al., J Clin Oncol 2016; 34:

19 Less than 20% concordance between intrinsic sub-types of primary biopsy and residual disease Post-treatment pre-treat HER2-E Lum A Lum B Basal-like Claudin low Normal-like HER2-E Lum A Lum B Basal-like Claudin low Normal-like NA Carey LA, et al., J Clin Oncol 2016; 34:

20 Intrinsic sub-types in residual disease after neoadjuvant therapy the CALGB data Post-treatment pre-treat HER2-E Lum A Lum B Basal-like Claudin low Normal-like HER2-E Most residual tumours Lum A are made up of luminal subtypes Lum B Basal-like Claudin low Normal-like NA Carey LA, et al., J Clin Oncol 2016; 34:

21 Residual disease after neoadjuvant therapy = micrometastasis Micrometastasis Primary Residual tumour disease bulk Surgery Drug(s) Recurrence Courtesy of Carlos Arteaga, 2013

22 A different way to test treatment according to pcr vs not HER2-directed neoadjuvant as in the main design S U R G E pcr R control standard adjuvant HER2-therapy experimental treatment R Y RD standard adjuvant HER2-therapy

23 Slide 19

24 Open questions in HER2+ ebc New therapies

25 Murine models show CDK4/6 implicated in anti-her2 therapy resistance Following anti-her2 therapy, survival of resistant HER2+ model tumours was dependent on expression of cyclin D1 CDK4/6 inhibitors resensitised tumours to HER2-targeted agents Anti-HER2 therapy + CDK4/6 inhibition reduced tumour proliferation more than either therapy alone Goel S, et al. Cancer Cell. 2016; 29;

26 Convergence of multiple signals on Rb checkpoint in breast cancer Convergence at cyclin D to drive BC cell proliferation 1 Nuclear hormone, PI3K/AKT/mTOR, MAPK, Wnt/β-catenin, JAK- STAT, and NF-κB pathways 1,2 Mitogenic signals via ER and HER2 require Cyclin D1 Cyclin D1 direct ER-target gene required for estrogen-dependent cell proliferation 4,5 Cyclin D1-deficient mice are resistant to HER2-induced BCs 6 ER+/HER2+ cell lines are most sensitive to CDK4/6 inhibition 7 Cyclin D CDK4/6 INK4 Rb pathway also disrupted in breast cancer through: CCND1 (cyclin D1) amplification 35% 3 CDK4 amplification 16% 3 CDK6 amplification 17% 3 Loss of p16 49% 8 Inactivating alterations of TP53 (p21 activator) 84% of basal and 27% of non-basal tumours 3 Cyclin D CDK4/6 INK4 Rb pathway activation is associated with poor response of BC cells to endocrine therapy 9 1. Lange CA, et al. Endocrine-related Cancer 2011;18:C18 C24; 2. Witzel II, et al. Biochem Soc Trans 2010;38: ; 3. TCGA, Nature 2012;490:61 70; 4. Lukas J, et al. Mol Cell Biol 1996;16: ; 5. Prall OW, et al. J Steroid Biochem Mol Biol 1998;65:169-74; 6. Yu Q, et al. Nature 2001;411: ; 7. Finn RS, et al. Breast Cancer Res 2009;11:R77; 8. Geradts J, Wilson PA. Am J Pathol 1996:149:15 20; 9. Thangavel C, et al. Endocr Relat Cancer 2011;18:

27 MonarcHER: Phase Ib study of abemaciclib in combination with therapies for patients with mbc Objectives: The primary objective was to evaluate safety and tolerability of abemaciclib in combination with endocrine therapies for HR+ HER2- mbc or trastuzumab for HER2+ mbc The secondary objectives were to assess pharmacokinetics and antitumour activity HR+/HER2- mbc Part A: abemaciclib + letrozole Part B: abemaciclib + anastrozole Part C: abemaciclib + tamoxifen Part D: abemaciclib + exemestane Part E: abemaciclib + exemestane + everolimus Key eligibility criteria: HR+/HER2- mbc (Parts A-E) or HER2+ (both HR+ and HR-) mbc (Part F) Post-menopausal status (natural, surgical, or medical; Parts A-E) or any menopausal status (Part F) Parts A-E: no prior systemic chemotherapy for metastatic disease Part F: 1 chemotherapy regimen for metastatic disease Patients receiving exemestane-based therapy must have received 1 nonsteroidal aromatase inhibitor for metastatic disease HER2+ mbc Part F: abemaciclib + trastuzumab HR, hormone receptor; mbc, metastatic breast cancer Beeram M, et al. ESMO 2016; abstract LBA18

28 MonarcHER: anti-tumour activity Change in tumour size for patients with measurable disease HER2+ mbc Abemaciclib combinations show clinical activity in HR+ mbc, including HR+/HER2+ tumours Beeram M, et al. ESMO 2016; abstract LBA18

29 NA-PHER2: Phase II trial of neo-adjuvant treatment with palbociclib in HR+/HER2+ ebc Patients with early and locally advanced HER2+ and ER+ (>10%) BC; chemo-naïve *HER-2, ER, PR and Ki67 centrally confirmed HPPF x 6 4-weekly cycles Herceptin + pertuzumab + palbociclib + fulvestrant H = Trastuzumab, 8 mg/kg on first dose, 6 mg/kg thereafter x 6; P = Pertuzumab, 840 mg on first dose, 420 mg thereafter x 6; Palbociclib 125 mg orally QD. x 21 q. 4 wks. x 5 Fulvestrant will be given intra-muscle at the dose of 500 mg every 4 weeks x 5 with an additional 500 mg dose given two weeks after the initial dose The total duration of neoadjuvant palbociclib (5 cycles every 4 weeks) and fulvestrant (5 administrations every 4 weeks plus the additional dose given two weeks after the initial dose) was selected to match as closely as possible the total duration of the six planned 3-weekly administrations of trastuzumab and pertuzumab Primary endpoints Ki67 changes frombaseline before therapy, at 2 weeks, and at surgery Change in apoptosis from baseline before therapy and at surgery Secondary endpoints pcr ORR Tolerability Palbociclib is not approved for use in HER2+ disease in Europe ORR, objective response rate; pcr, pathological complete response defined as absence of invasive cells in breast and axilla (ypt0-yptis ypn0) at surgery Gianni L, et al. SABCS 2016; Poster P

30 Reduction of % Ki67+ cells % Ki67+ cells NA-PHER2: Ki67 levels decreased following treatment Geometric mean (SD) Ki67 change Baseline (n=27) Week 2 (n=25) Surgery (n=22) 31.9 (15.7) 4.3 (15.0) 12.1 (20.0) Mean change 95% CI Paired T-test P-value 24.0 ( 31.0; 7.1) 7.11 < ( 19.3; 2.6) Gianni L, et al. SABCS 2016; Poster P

31 NA-PHER2: Pathological and clinical response rate ITT population (n=30) n (%) pcr (no invasive cells in breast and axilla) pcr in breast only 8 (27%) 9 (30%) Overall clinical response Complete clinical response Partial response Stable disease 29 (97%) 15 (50%) 14 (47%) 3 (3%) Gianni L, et al. SABCS 2016; Poster P

32 HER2+ BC is immunogenic

33 FcγR mediated Antigen Presentation and CTL Response FcɣR Andre F et al. Clinical Cancer Res 2012

34 Differential Fc-receptor engagement drives an anti-tumour vaccinal effect David JD & Jeffrey RV. Cell 2015; 161:

35 Must the tumour be present for an optimal vaccine-like effect? Kroemer G. Annu Rev Immunol 2013

36 Randomized Phase II Biomarker Study of Immune-mediated Mechanism of Action of Neoadjuvant Trastuzumab (either iv or sc) in Patients with HER2- positive Breast Cancer (ImmunHER) Eligibility (n = 63) Women with histologically confirmed HER2-positive breast cancer with locally advanced, inflammatory, or early stage tumor (either greater than 2 cm in diameter or node positive) with no evidence of metastatic disease Pre-randomization phase: FEC (5FU 500; epirubicin 75; CTX 500) x 3 cycles ClinicalTrials.gov Identifier: NCT R Trastuzumab IV (8 mg/kg loading dose, followed by 6 mg/kg) plus Pertuzumab IV (840 mg loading dose, followed by 420 mg) plus Docetaxel IV ( mg/m 2 ), every 3 weeks for 4 cycles Trastuzumab SC (fixed dose of 600 mg) plus Pertuzumab IV (840 mg loading dose, followed by 420 mg) plus Docetaxel IV ( mg/m 2 ), every 3 weeks for 4 cycles Primary Objective: To evaluate variations of host immune response Primary endpoint: parameters to either trastuzumab SC or trastuzumab TIL rate on residual disease after either IV IV given in combination with pertuzumab and trastuzumab or SC trastuzumab chemotherapy.st cancer.

37 Interaction of pcr with treatment for EFS in HER2+ groups Trastuzumab vs. no Trastuzumab Stratum Sample size EFS HR (95% CI) p pcr 45 vs ( ) non pcr 72 vs ( ) NS quality of pcr different with ADCC competent pcr vs. non pcr monoclonal antibodies Stratum Sample size EFS HR (95% CI) p Trastuzumab 45 vs ( ) <.0001 no Trastuzumab 23 vs ( ) NS p-value for interaction treatment*pcr effect = Gianni L et al, Lancet Oncol 2014

38 Percent survival Percent survival Neoadjuvant is more effective than adjuvant therapy with anti-pd-1+anti-cd137 NeoAdj -PD-1/ -CD137 4T1.2 orthotopic or control IgG injection Surgery NeoAdj -PD-1/ -CD137 E0771 orthotopic or control IgG injection Surgery Day: Day: Surgery Adj -PD-1/ -CD137 or control IgG 100 Surgery Adj -PD-1/ -CD137 or control IgG Days after 4T1.2 tumour injection NeoAdj control IgG Adj control IgG -PD-1/ -CD137 no surgery NeoAdj -PD-1/ -CD137 Adj -PD-1/ -CD137 p< Days after E0771 tumour injection NeoAdj control IgG Adj control IgG NeoAdj -PD-1/ -CD137 Adj -PD-1/ -CD137 p< Liu J Cancer Discovery 2016

39 # gp70 Tetramer CD8 T cells/ml (x10 2 ) # gp70 Tetramer CD8 T cells (x10 2 ) Neoadjuvant anti-pd-1+anti-cd137 leads to systemic expansion of tumor-specific CD8+ T cells 200 Blood 250 Liver p = p< Liu J Cancer Discovery 2016

40 Mean tumour size (mm 2 ) Tumour-free survivors after neoadjuvant immunotherapy have immunological memory Naive mice Tumour-free survivors p = Tumour-free survivors 50 Naive mice Days after 4T1.2 tumour injection Neoadjuvant modality is superior to adjuvant delivery of immunotherapy in model systems and may be the optimal approach to achieve vaccine-like effects and permanent tumour eradication Liu J Cancer Discovery 2016

41 Rationale exists for atezolizumab combinations in HER2+ BC There is evidence of anti-tumour immune response in HER2+ BC Immune biomarkers at baseline have similarities to TNBC Immune (Teff) signature PD-L1 expression TILs and CD8 prevalence TILs are associated with better outcomes for HER2 regimens pcr and DFS (EBC), OS (CLEO MBC) Immune effects of HER2 therapies are observed Neoadjuvant H/K increases PD-L1 and CD8+ TILS that are associated with higher pcr (ADAPT HR+) Preclinical synergistic activity is observed for checkpoint inhibitors combined with anti-her2 therapies Internal preclinical data K(A) consistent with published data A with (T)HP pending * αpd-1 ** αpd-l1 APTneo phase III trial Courtesy L. Gianni

42 Terapia neoadiuvante tumori HER2+ Take Home message pcr predittiva di prognosi (fino al 73% di pcr in ER- HER2+) Neoadiuvante fondamentale per selezionare pazienti a prognosi peggiore (no pcr) per nuovi studi (i.e. studio Katherine) Trattamento di scelta nei T2-3 e/o N+, ma proponibile anche in stadio 1 Lo standard*: CHT + trastuzumab + pertuzumab *non modificato dai dati dello studio Aphinity In attesa di CDK4-6i e anti PD1 PDL1i