ESMO Preceptorship Breast Cancer. Giuseppe Curigliano MD, PhD Breast Cancer Program Division of Early Drug Development Istituto Europeo di Oncologia

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1 ESMO Preceptorship Breast Cancer Giuseppe Curigliano MD, PhD Breast Cancer Program Division of Early Drug Development Istituto Europeo di Oncologia

2 Outline Rational for immune-based therapy in BC How to enhance immunogenicity? Evidences from clinical data How to monitor and to predict response?

3 TILs in EBC Reference N Trial Endpoint Subtype analyzed Result Denkert (JCO, 2010) 840 GBG G-3 pcr All pcr:41% in TIL+ BC Validated in G-5 Loi (JCO, 2013) 2009 BIG 2-98 DFS Preplanned analysis of molecular subtypes Prognostic impact in TNBC (n=256): HR:0.31 ( ) Loi (AnnOnc, 2014) 935 FinHer DFS Preplanned analysis of molecular subtypes Prognostic impact in TNBC (n=134): HR:0.31 ( ) Adams (JCO, 2014) 506 ECOG 2197 ECOG 1199 DFS TNBC HR:0.84 ( ) Dieci (AnnOnc, 2014) 278 MFS OS TNBC HR:0.86 ( ) HR:0.86 ( ) Denkert (JCO 2015) 580 Gepar- Sixto trial pcr TNBC and HER2 pcr rate was 59.9% in LPBC and 33.8% for non- LPBC (P <.001)

4 Mutational load of breast cancer Budczies J eta l. The Journal of Pathology: Clinical Research, 2015, Volume 1, Issue 4, pages ,

5 Classical pathology and mutational load of breast cancer integration of two worlds Budczies J eta l. The Journal of Pathology: Clinical Research, 2015, Volume 1, Issue 4, pages ,

6 Phase I open-label dose-escalation vaccine trial of dher2 protein with AS15 adjuvant in HER2-overexpressing patients with high-risk breast cancer G. Curigliano et al. 2016

7 Endpoints Primary: Safety Secondary: Humoral immunogenicity Cell-mediated immunogenicity Impact of escalating doses of HER2 G. Curigliano et al. 2016

8 Study design Cohorts N Dose (Route: IM) Timing Cohort µg dher2/as15 D 0, 14, 28, 42 (70 & 98) Cohort µg dher2/as15 D 0, 14, 28, 42 (70 & 98) Cohort µg dher2/as15 D 0, 14, 28, 42 (70 & 98) Cohort µg W 0, 4, 14, 34, 38

9 Study design: Treatment 2 weeks 4 weeks screening week analysis PBMC Ab X X X X X X X X X X X X X X X X MUGA

10 GMT (EU/ml) Immunogenicity dher2-as anti-ecd Ab titers Cohort 1 (20mcg dher2) Cohort 2 (100mcg dher2) Cohort 3 (500mcg dher2) 1000 Cohort 3 (500 µg) 100 Cohort 2 (100 µg) Cohort 1 (20 µg) G. Curigliano et al. 2016

11 Responders anti ECD and anti ICD % anti-ecd antibody responders % anti-icd antibody responders % of responder patients % of responder patients Cohort 1 Cohort 2 Cohort 3 Cohort 4 0 Cohort 1 Cohort 2 Cohort 3 Cohort 4 G. Curigliano et al. 2016

12 d-her2 induces antibodies that specifically bind the native HER2 receptor The ECD binding ratio seems to increase with the dose of HER2 protein when assessed after the administration of four dher2 + AS15 doses. SKBR3 BT Day 0 Day 56 Day 0 Day 56 % A B C 0 Cohort 1 Cohort 2 Cohort 3 Cohort 4 G. Curigliano et al. 2016

13 How to enhance immunogenicity? DRUG Doxorubicin Cyclophosphamide EFFECT ON IMMUNE SYSTEM Induces immunogenic cell death Increases proliferation of CD8 T cells Stimulates antigen presentation by DCs Stimulates MCP1 and M6PR Induces immunogenic cell death Suppressed Treg inhibitory functions and restoration of the proliferative capacity of effector T cells and NK cell cytotoxicity. Taxanes Enhance T cell and NK cell function Increase recruitment of TIL Increase efficacy of immuno-stimulatory agents Gemcitabine Reduce the number of myeloid suppressor cells Increase the antitumor activity of CD8(+) T cells and activated NK cells Oxaliplatin Induces immunogenic cell death Increases MHC I complex Inhibits PDL2 13

14 β-catenin signalling prevents anti-tumour immunity Spranger S et al, Nature 523, (09 July 2015)doi: /nature14404

15 Evidence from clinical trials Pembrolizumab (Merck) Humanized IgG4 anti- PD-1 antibody MPDL3280 (Genentech) engineered human IgG1 anti-pd-l1 antibody

16 Pembrolizumab in TNBC Recurrent or metastatic ER-/PR-/HER2- breast cancer ECOG PS 0-1 PD-L1+ tumour No systemic steroid therapy Pembro 10 mg/kg Q2W CR PR/SD Discontinuation permitted Treat for 24 mo or until PD or toxicity No autoimmune disease (active or history of) No active brain metastases Confirmed PD Discontinue PD-L1 positivity: 58% of all patients screened had PD-L1-positive tumors Treatment: 10 mg/kg IV Q2W Response assessment: Performed every 8 weeks per RECIST v1.1 a PD-L1 expression was assessed in archival tumor samples using a prototype IHC assay and the 22C3 antibody. Only patients with PD-L1 staining in the stroma or in 1% of tumor cells were eligible for enrollment. b If clinically stable, patients are permitted to remain on pembrolizumab until progressive disease is confirmed on a second scan performed 4 weeks later. If progressive disease is confirmed, pembrolizumab is discontinued. An exception may be granted for patients with clinical stability or improvement after consultation with the sponsor.

17 Pembrolizumab in TNBC n =32 Confirmed complete response (nodal disease) Confirmed partial response Stable disease Progressive disease Objective response rate: 18.5% Stable disease: 25.9% Nanda, SABCS 2015

18 Pembrolizumab in TNBC Responder Nonresponder PD after CR, PR, or SD Last dose Treatment ongoing Best overall response CR PR SD PD Median follow-up duration: 9.9 months (range, ) Median time to response: 18 weeks (range, 7-32) Median duration of response a : not reached (range, 15 to 40+ weeks) PFS 1.9 ms; 6 ms PFS- 23% Time, weeks a Kaplan-Meier estimate. Analysis cut-off date: November 10, Nanda, SABCS 2014

19 Atezolizumab in ER+ BC

20 Atezolizumab in ER+ BC

21 Atezolizumab in ER+ BC

22 Atezolizumab in ER+ BC

23 Atezolizumab in ER+ BC

24 Phase Ib Study of Atezolizumab and Nab- Paclitaxel in mtnbc Best Overall Response 1L (n = 9) Confirmed ORR (95% CI) a 66.7% (29.9, 92.5) ORR (95% CI) b 88.9% (51.7, 99.7) 2L (n = 8) 25% (3.2, 65.1) 75.0% (34.9, 96.8) 3L+ (n = 7) 28.6% (3.7, 71.0) 42.9% (9.9, 81.6) All Patients N = % (22.1, 63.4) 70.8% (48.9, 87.4) CR 11.1% % PR 77.8% 75.0% 42.9% 66.7% Response rates were higher for patients who received atezolizumab/nabpaclitaxel treatment as 1L therapy compared to 2L+ SD 11.1% 25.0% 28.6% 20.8% PD % 8.3% a Confirmed ORR defined as at least 2 consecutive assessments of complete or partial response. b Including investigator-assessed unconfirmed responses. Efficacy-evaluable patients were dosed by June 1, 2015, and were evaluable for response by RECIST v1.1. Minimum efficacy follow up was 3 months. Adams S, et al. SABCS [abstract ].

25 Phase Ib Study of Atezolizumab and Nab- Paclitaxel in mtnbc Including investigator-assessed unconfirmed responses. 11 of 17 responses (65%) continued on treatment at time of data cut off Adams S, et al. SABCS [abstract ].

26 Phase Ib Study of Atezolizumab and Nab- Paclitaxel in mtnbc IC0 (n = 7) IC1/2/3 (n = 9) Unknown (n = 8) ORR (95% CI) 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 % Including investigator-assessed unconfirmed responses. Responses were observed in both IC0 and IC1/2/3 patients Adams S, et al. SABCS [abstract ].

27 Phase Ib Study of Atezolizumab and Nab- Paclitaxel in mtnbc Proliferating activated CD8+ T cells transiently peaked at the end of the first cycle of atezolizumab treatment Adams S, et al. SABCS [abstract ].

28 Phase III Study of Atezolizumab and Nab- Paclitaxel in mtnbc Randomized, double-blind, placebo-controlled Phase 3 trial of nab-paclitaxel ± atezolizumab as 1 st line therapy in mtnbc (NCT ) Study design Histologically documented locally advanced or metastatic TNBC No prior therapy for advanced disease ECOG PS 0-1 Measurable disease per RECIST v1.1 Patients with significant CV or CNS disease (except asymptomatic brain metastases), autoimmune disease or prior checkpoint inhibitor therapy are excluded Target accrual: ~350 pts Stratification factors: Presence of liver metastases Prior taxane therapy Nab-paclitaxel 100 mg/m 2 QW 3/4 + Atezolizumab 840 mg Q2W PD-L1 expression status (centrally evaluated by IHC using the SP142 assay) R 1:1 Nab-paclitaxel 100 mg/m 2 QW 3/4 + Placebo Q2W Co-primary endpoints: PFS in all patients PFS according to PD-L1 expression Secondary endpoints: OS ORR Response duration Safety/tolerability PK HR QoL Emens et al. SABCS 2015 (abstract OT )

29 Immunotherapy in TNBC Nivolumab (BMS) Human IgG4 anti-pd-1 antibody Pembrolizumab (Merck) Humanized IgG4 anti- PD-1 antibody MPDL3280 (Genentech) engineered human IgG1 anti-pd-l1 antibody MEDI4736 (AZ) Human IgG1 anti-pd-l1 antibody Tremelimumab (AZ) Human IgG2 Anti-CTLA-4 antibody

30 Immunotherapy in TNBC Phase Setting Subtype PD-L1 expression as inclusion criteria Combination/comparator Nivolumab II Metastatic TN No Monotherapy after induction with RT and CT Primary EP Pembrolizumab II Metastatic IBC HER2- No monotherapy Disease control rate Ib/II Metastatic TN No + eribulin DLT/ORR II Metastatic TN Cohort B (positive) Cohort C (strong) Ib/II Metastatic/ LABC HER2+ Presence of PD-L1 expression monotherapy PFS ORR/Safety + trastuzumab Safety/ORR II Metastatic HR+ No + Tamoxifen + Vorinostat Safety/ORR Atezolizumab III Metastatic TN No + nabpaclitaxel vs nabpaclitaxel Durvalumab II Metastatic HER2- No + tremelimumab (AZ) ORR PFS

31 Immunotherapy in TNBC: neoadjuvant setting Neoadjuvant setting NCT PD-1 blockade plus chemotherapy as Neoadjuvant treatment for TNBC Not yet opened Pembrolizumab Nab-paclitaxel Anthracycline Cyclophosphamide Carboplatin Merck Sharp & Dohme Corp. NCT /2 Anti PD-L1 therapy plus Nab-Paclitaxel and dosedense AC as Neoadjuvant treatment for Stage I-III Triple Negative Breast Cancer Recruiting MEDI4736 Nab-Paclitaxel Doxorubicin Cyclophosphamide Yale University

32 Immunotherapy in TNBC: neoadjuvant setting N=272 Primary endpoint: EFS Secondary endpoint: pcr (ypt0-yptis ypn0) surgery R +/-ATEZOLIZUMAB 1200 mg Nab-Paclitaxel 125 mg/m 2 + CBDCA AUC2

33 Immunotherapy in TNBC: neoadjuvant setting N=174 Primary endpoint: pcr (ypt0 ypn0) Nab-Paclitaxel EC surgery R MEDI 4736/Durvalumab Placebo Window of opportunity 2weeks Nab-P 125 mg/m 2 Epirubicin 90 mg/m 2 + Cyclophosphamide 600 mg/m 2 MEDI 4736/Durvalumab 2g total q4w

34 Adaptive Phase II Randomized Non-comparative Trial of Nivolumab After Induction Treatment in Triple-negative Breast Cancer (TNBC) Patients: TONIC-trial (The Netherlands Cancer Institute) Treatment Arm Assigned intervention Active Comparator: Radiation therapy Radiotherapy on metastatic lesion Active Comparator: Low dose doxorubicin 15 mg flat dose, once weekly for 2 weeks Active Comparator: Cyclophosphamide metronomic schedule, 50 mg daily orally for 2 weeks Active Comparator: Cisplatin 40 mg/m2, weekly for 2 weeks Active Comparator: No induction treatment Nivolumab 3 mg/kg, every 2 weeks after induction treatment Radiation: Radiation therapy 20 Gy to metastatic lesion Nivolumab 3 mg/kg, every 2 weeks after induction treatment Low dose doxorubicn Nivolumab 3 mg/kg, every 2 weeks after induction treatment Metronomics CTX Nivolumab 3 mg/kg, every 2 weeks after induction treatment Weekly cisplatin Nivolumab 3 mg/kg, every 2 weeks after induction treatment

35 Targeting stroma and inflammation Recurrent or metastatic LBC or IBC ECOG PS 0-1 No systemic steroid therapy No autoimmune disease (active or history of) No active brain metastases Pembro 200 mg Q3W + CTX 50 mg/die Complete Response Partial Response or Stable Disease Confirmed Progressive Disease b Discontinuation Permitted Treat for 24 months or until progression or intolerable toxicity Discontinue PD-L1 positivity: Stratification factor Treatment: metronomic CT plus pembrolizumab Response assessment: Performed every 8 weeks per RECIST v1.1 PI G. Curigliano et al.

36 Predicting immune-response Herbst RS et al Nature 515, , 2014

37 Predicting response Immune cells function in an interacting hierarchy that coordinates the activities of various cell types according to genetic and environmental contexts. Development of a graphical approaches to construct an extensible immune reference map from mass cytometry data of cells from different organs. The maps recapitulated canonical cellular phenotypes and revealed reproducible, tissue-specific deviations.

38 Democratizing systems immunology with modular transcriptional repertoire analyses Chaussabel D et al. Nature Reviews Immunology 14, (2014)

39 Conclusions Is there a rational for immune-based therapy in BC? YES Evidences from clinical data? LIMITED Can you enhance immunogenicity? MAY BE Can we monitor and to predict response? NO, BUT

40 Challenges Predicting responsive patients by modular transcriptional repertoire analysis Tissue and blood biomarkers for combination immunotherapies Role of microbioma and modulation of microbioma Managing combination-associated toxicity

41 Thank you