NSCLC (TEIL 1) IMMUNONKOLOGIE (I-O) MITTELS CHECKPOINT- INHIBITION: REVOLUTION DER NSCLC-THERAPIE?

NSCLC (TEIL 1) IMMUNONKOLOGIE (I-O) MITTELS CHECKPOINT- INHIBITION: REVOLUTION DER NSCLC-THERAPIE?

Wichtige Mediatoren der Immunabwehr Angeboren Antigen unabhängig Adaptiv Antigen abhängig Antigenpräsentierende Zellen Lymphokine B-Zellen T-Zellen DC natürliche Killer-Zellen Fc T TLR* PRR* NK IL e IFN e CK e... Fab Fab CTLA-4 TCR CD28 NKG2D KIR IFN-g Perforin Granzym B Adaptiert nach Woelfel et al, 2014

Wichtige Mediatoren der Immunabwehr Angeboren Antigen unabhängig Adaptiv Antigen abhängig Antigenpräsentierende Zellen Lymphokine B-Zellen T-Zellen DC natürliche Killer-Zellen Fc T TLR* PRR* NK NKG2D KIR IL e IFN e CK e... Fab Fab Anpassungsfähigkeit Spezifität Gedächtnis CTLA-4 TCR CD28 IFN-g Perforin Granzym B Adaptiert nach Woelfel et al, 2014

Die T-Zell-vermittelte antitumorale Immunantwort 2 Präsentation von Tumorantigen gegenüber der T-Zelle 1 Tumor: Freisetzung von Tumorantigenen 3 T-Zell-Aktivierung und Proliferation 4 Erkennung von Tumorantigen durch T-Zellen 5 Zerstörung des Tumors durch T-Zellen Andersen et al, J Invest Dermatol 2006, 126: 32; Pardoll DM, Nat Rev Cancer 2012, 11: 252; Mellman et al, Nature 2011, 480: 480; Heemskerk et al, EMBO J 2013, 32: 194; Boudreau et al, Mol Ther 2011, 19: 841; Janeway et al, Immunobiology: The Immune System in Health and Disease. 6th ed, 2004.

Immunsystem und Krebs: Der Prozess des Immunoediting Die drei E des Immunoediting beschreiben die Prozesse der Tumorkontrolle durch das Immunsystem und wie der Tumor dieser Kontrolle entkommt. Elimination Tumor-Immunüberwachung Equilibrium Tumor-Ruhezustand ( Survival of the fittest ) Escape Tumor-Wachstum CD8 + T-Zelle CD4 + T-Zelle NK Zelle Treg Tumorzellen Normale Zellen Vesely et al, Ann Rev Immunol 2011, 29: 235

Immune Escape-Mechanismen: Tumore nutzen komplexe Mechanismen, dem Immunsystem zu entkommen A. Ineffektive Tumor-Antigen- Präsentation (gp100, MART-1, verringerte MHC-Expression) VEGF APC B. Rekrutierung immunsuppressiver Zellen (regulatorische T-Zellen =Tregs, MDSCs, andere) CD8 + T- Zelle TCR MHC MDSC Treg CTLA-4 Tumorzellen PD-L1 PD-L1 PD-1 PD-1 D. T-Zell-Checkpoints TGF-β IDO IL-10 TGF-β IL-10 CD4 + T- Zelle TGF-β ARG1 inos CD8 + T- Zelle C. Sekretion von immunsuppressiven Signalen (z.b. PD-L1, TGF-β, IL-10, und indolamine 2,3- dioxygenase [IDO]) Vesely et al, Ann Rev Immunol 2011, 29: 235

Die Immunonkologie mittels Checkpoint-Modifikation als neues therapeutisches Behandlungskonzept 1 Die konventionellen onkologischen Ansätze sind direkt gegen den Tumor gerichtet. 2 Bei der Immunonkologie wird die natürliche Fähigkeit des eigenen Immunsystems genutzt, um den Krebs zu bekämpfen. 2 Operation Immunonkologie Strahlentherapie Chemo- & zielgerichtete Therapien 1. DeVita and Rosenberg, N Eng J Med 2012, 366: 2207; 2. Borghaei et al, Eur J Pharmacol 2009, 625: 41.

Regulation der T-Zell-Aktivität: Checkpoint-Moleküle Aktivierende Rezeptoren Inhibierende Rezeptoren CD28 OX40 CTLA-4 PD-1 TIM-3 CD137 LAG-3 Aktivierung Immunsystem Adapted from Mellman I, et al. Nature. 2011:480;481 489; Pardoll DM. Nat Rev Cancer. 2012;12:252 264.

Neues Therapeutisches Konzept: Blockade der CTLA-4- und PD-1-Checkpoint-Signalwege Lymphknoten Mikroumgebung des Tumors Dendritische Zelle MHC B7 TCR CD28 +++ B7 CTLA-4 - - - Anti-CTLA-4 +++ Aktivierung (Zytokine, Lyse, Proliferation, Migration zum Tumor) T-Zelle CTLA-4-Signalweg T-Zelle +++ - - - - - - TCR PD-1 MHC PD-L1 Anti-PD-1/PD-L1 PD-1 PD-L2 Anti-PD-1 PD-1-Signalweg Tumorzelle CTLA-4 reguliert die Amplitude der frühen Aktivierung von naiven und Memory T-Zellen. PD-1 begrenzt die T-Zell-Aktivierung in der Peripherie während einer Entzündungsreaktion. Wolchock et al, J Clin Oncol 2013 ASCO Annual Meeting Abstracts 31:15_suppl

Wahrscheinlichkeit Gesamtüberleben Die Immunonkologie: Proof of Concept Langzeitdaten Ipilimumab von 1.861 Melanompatienten (8 Ph. II-, 2 Ph. III-, 2 Ph. IV-Studien) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Ipilimumab Zensiert Medianes OS, Monate (95% KI): 11,4 (10,7 12,1) 3-Jahres OS-Rate, % (95% KI): 22 (20 24) 0 12 24 36 48 60 72 84 96 108 120 Monate Patienten unter Progressionsrisiko Ipilimumab 1.861 839 370 254 192 170 120 26 15 5 0 Schadendorf et al, annual presentation at ECCO/ESMO 2013, abstract # 24LBA

Die Immunonkologie und Hallmarks of Cancer Adapted from Hanahan et al, Cell 2011; 44: 646

Immuntherapeutische Ansätze am Beispiel Lungenkrebs Immuntherapie Aktiv Zielt auf das Immunsystem direkt Passiv (adoptiv) Zielt auf den Tumor; Immun-basierter Mechanismus Antigenabhängig Antigenunabhängig Antitumorale monoklonale Antikörper Adoptiv Verstärkt die Funktion der Immunzelle Therapeutische Vakzine Moduliert die T- Zell Funktion Zytokine GSK1572932A TG4010 Belagenpumatucel-L Tergenpumatucel-L Racotumomab Stimuvax CIMAvax Immun-Onkologie (I-O) CTLA-4-Inhibition PD-1-Inhibition PD-L1-Inhibition Bavituximab EGFR Inhibition Adoptiver Zelltransfer CTLA-4 = cytotoxic T-lymphocyte antigen-4; PD-1 = programmed death-1; PD-L1 = programmed death ligand-1 www.clinicaltrials.gov accessed 26 March 2014; NCCN Guidelines. NSCLC. V2.2013; Peters et al. Ann Oncol. 2012;23:vii56

Klinische Entwicklung: Immun-Checkpoint-Inhibitoren PD-1-/PD-L1-Signalweg Target Antibody a Development Stage PD-1 PD-L1 Nivolumab (BMS-936558) Pembrolizumab (MK-3475) Pidilizumab (CT-011) MEDI-4736 MPDL3280A MSB0010718C Phase 1-3: multiple tumors (melanoma, RCC, NSCLC, HNSCC, GBM, Hodgkin, others) Phase 1/2: multiple tumors Phase 3: NSCLC Approved: melanoma Phase 1/2: multiple tumors Phase 1/2: multiple tumors Phase 2: CRC, HNSCC Phase 3: NSCLC Phase 1/2: multiple tumors Phase 2: RCC, bladder Phase 3: NSCLC Phase 1/2: multiple tumors CRC = colorectal cancer; GBM = glioblastoma multiforme; HNSCC = head and neck squamous cell carcinoma; RCC = renal cell carcinoma a List incomplete www.clinicaltrials.gov. Accessed March 25, 2015.

Phase I-Studie Nivolumab Monotherapie: Design der NSCLC-Kohorte (CA209-003) Phase 1 study of the safety, antitumor activity, and pharmacodynamics of nivolumab in patients with advanced solid tumors 1 Nivolumab 0,1 to 10 mg/kg Q2W for a maximum of twelve 8-week treatment cycles (2 years); expansion cohorts for select tumor types 2 1 5 previous therapies 1 In the 129 patients with NSCLC 42% had squamous and 57% had non-squamous histology 54% received 3 prior therapies 2 Eligible patients with NSCLC randomized between 3 nivolumab dose levels (n=129) Nivolumab 1 mg/kg IV Q2W (n=33) Nivolumab 3 mg/kg IV Q2W (n=37) Nivolumab 10 mg/kg IV Q2W (n=59) IV = intravenous; Q2W = every 2 weeks. 1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 2. Brahmer JR, et al. Presented at ASCO 2013. Abstract 8030.

Der anti-pd-1-ak Nivolumab bei fortgeschrittenen Tumorerkrankungen: Phase I CA209-003 Tumor Type ORR n/n (%) [95% CI] Median Duration of Response, wk (range) Stable Disease, n/n (%) [95% CI] 24 wk Median PFS, mo [95% CI] NSCLC 22/129 (17,1) [11,0, 24,7] 74,0 (6,1+, 133,9+) 13/129 (10,1) [5,5, 16,6] 2,3 [1,9, 3,7] Squamous 9/54 (16,7) [17,9, 29,3] NR (16,1, 133,9+) 8/54 (14,8) [6,6, 27,1] 3,7 [1,8, 7,2] Nonsquamous 13/74 (17,6) [9,7, 28,2] 63,9 (6,1+, 74,0+) 5/74 (6,8) [2,2, 15,1] 2,0 [1,8, 3,6] MEL 33/107 (30,8) [22,3, 40,5] 104,0 (18,4, 117,0+) 7/107 (6,5) [2,7, 13,0] 3,7 [1,9, 9,1] RCC 10/34 (29,4) [15,1, 47,5] 56,1 (36,6, 126,7+) 9/34 (126,5) [12,9, 44,4] 7,3 [3,7, 12,9] Hodi et al, Poster presentation at ECC 2013:abstract 880

OS (%) Nivolumab beim fortgeschrittenen NSCLC: Überleben Phase I CA209-003 (mehrfach vorbehandelte Patienten) 100 90 80 70 60 Censored OS rate, % (95% CI) Group Died/Treated Median OS, mo (95% CI) 1 Year 2 Years 3 Years 1 mg/kg 99/129 9,9 (7,8, 12,4) 42 (33, 50) 24 (17, 33) 18 (11, 25) 3 mg/kg 23/37 14,9 (7,3,30,3) 56 (38,71) 42 (24,58) 27 (12, 43) 10 mg/kg 50/59 9,2 (5,2,12,4) 38 (26, 50) 20 (11, 31) 14 (7, 25) 50 40 30 20 10 0 2-year OS = 42% 3-year OS = 27% Pts at Risk Nivolumab 1 mg/kg Nivolumab 3 mg/kg Nivolumab 10 mg/kg 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 Months Since Initiation of Treatment 33 26 21 16 37 34 26 21 59 51 35 29 9 7 6 6 17 14 13 12 22 16 14 12 4 4 4 3 11 9 9 7 11 10 9 9 1 1 0 0 0 0 0 5 2 1 1 1 1 1 6 4 2 2 2 1 1 0 0 0 0 1 1 1 0 0 0 0 0 Gettinger et al, CMSTO 2014

Der anti-pd-1-ak Pembrolizumab beim fortgeschrittenen NSCLC: Phase I-Studie Wirksamkeit irrc, Investigator Review RECIST v1.1, Independent Review Subgroup n ORR, n (%) [95% CI] Median PFS, wk (95% CI) n ORR,* (%), [95% CI] Median PFS, wk (95% CI) Median OS, wk (95% CI) All 38 9 (24%) [11%, 40%] 9,1 (8,3, 17,4) 33 7 (21%) [9%, 39%] 9,7 (7,6, 17) 51 (14, NR) Non-squamous 31 7 (23%) [10%, 41%] 9,1 (8,3, 17,0) 26 4 (16%) [4%, 35%] 10,3 (7,6, 17) 35 (14, NR) Squamous 6 2 (33%) [4%, 78%] 23,5 (2,7, NR) 6 2 (33%) [4%, 78%] 15,2 (1,4, NR) NR (2,7, NR) Patients with measurable disease on baseline imaging and an evaluable tumor specimen for PD-L1 Score potential cut point 9 6 (67%) [30%, 93%] 7 4 (57%) [18%, 90%] Score < potential cut point 24 1 (4%) [0%, 21%] 22 2 (9%) [1%, 29%] Garon et al, WCLC 2013, #2416

Nonsquamous Squamous Einfluss der Histologie Wirksamkeit der Anti-PD-1-/PD-L1-Antikörper Nivolumab MPDL3280A NS S NS NS NS S Duration of response on study NS S NS On study, on treatment On study, post treatment Treatment discontinued Ongoing response Time to response Response duration after discontinuation NS NS NS Ongoing response First response First PD 0 16 32 48 64 80 96 112 128 144 160 Time (week) 0 6 12 18 24 30 36 42 48 54 60 66 72 78 Time (weeks) Adapted from Brahmer JR, et al. Mini-Oral presentation at WCLC 2013. J Thorac Oncol. 2013;8(Suppl 2):abstract: MO18.03; Horn L, et al. Mini-Oral presentation at WCLC 2013. J Thorac Oncol. 2013;8(Suppl 2):abstract: MO18.01.

KEYNOTE-001: Geschätzte Überlebenskurve (Kaplan-Meier) PFS (Recist v1.1, Central Review) OS Treatment naive Median PFS: 27 weeks (95% CI, 14 45) 24-week PFS: 51% Previously treated Median PFS: 10 weeks (9,1 15,3) 24-week PFS: 26% Treatment naive Median OS: NR (95% CI, NE-NE) 6-month OS: 86% Previously treated Median OS: 8,2 months (7,3 - NR) 6-month OS: 59% Analysis cutoff date: March 3, 2014 Garon et al, Oral presentation at ESMO 2014

Klinisches Ansprechen nach PD-L1-Immunohistochemie MK-3475 ORR n/n (%) Anti PD-1 Nivolumab ORR n/n (%) MEDI4736 ORR n/n (%) Anti PD-L1 MPDL3280A ORR n/n (%) All patients 21% 22/129 (17,1%) 9/58 (16%) 12/53 (23%) PD-L1 Status (evaluable pts.) Positive 37/159 (23%) 5/31 (16%) 5/20 (25%) 8/26 (31%) Negative 3/35 (9%) 4/32 (13%) 1/29 (3%) 4/20 (20%) Offene Fragen Unterschiedliche Gewebsentnahmezeiten Unterschiedliche Antikörper und Assays Unterschiedliche IHC-Kriterien Horn L, J Thorac Oncol 2013; 8 (Suppl 2), #MO18.01; Brahmer JR, J Thorac Oncol 2013; 8 (Suppl2), #MO1803; Antonia SJ, J Thorac Oncol 2013 (Suppl 2), #P2 11-034; Garon E, ASCO 2014; #8020; Brahmer J, ASCO 2014, #8021

Progression-Free Survival, % Overall Survival, % Pembrolizumab Phase I-Studie n at risk Strong Weak Negative PFS (Recist v1.1, Central Review) 100 90 80 70 60 50 40 30 20 10 0 0 8 16 24 32 40 48 44 53 49 28 43 30 18 17 15 Time, weeks 17 12 7 9 6 1 Strong Weak Negative 6 0 0 3 0 0 100 90 80 70 60 50 40 30 20 10 0 Strong Weak Negative OS 0 1 2 3 4 5 6 7 8 9 10 11 12 13 44 53 49 43 51 42 38 48 38 38 40 34 34 34 29 32 31 26 Time, months 30 26 21 27 22 14 21 18 8 18 11 6 9 8 4 8 7 2 5 5 0 5 5 0 14 4 4 0 PFS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/ negative tumors (HR, 0.52; 95% CI, 0.33-0.80) OS was longer in patients with PD-L1 strong-positive versus PD-L1 weak-positive/ negative tumors (HR, 0.59; 95% CI, 0.35-0.99) a Evaluable patients were those patients in the training set with evaluable tumor PD-L1 expression. Strong PD-L1 positivity defined as staining in 50% of tumor cells, and weak PD-L1 positivity as staining in 1-49% of tumor cells. Negative staining is no PD-L1 staining in tumor cells. Analysis cutoff date: March 3, 2014; Garon et al, Oral presentation at ESMO 2014

Korrelation zwischen PD-L1-Status und klinischem Outcome: Ein potentieller prädiktiver Biomarker? Daten mit PD-1-Checkpoint-Inhibitoren weisen darauf hin, dass die PD-L1- Expression im Tumor signifikant mit einem verbesserten Ansprechen und Überleben assoziiert ist 1.. ABER Patienten mit PD-L1-negativen Tumoren sprechen auch auf die Therapie an 2,3 1. Garon EB, et al. Presented at ESMO 2014. Abstract LBA 43. 2. Gettinger SN, et al. Presented at CMSTO 2014. Poster 170. 3. Ramalingam S, et al. Presented at CMSTO 2014. Abstract 3462

NSCLC Zulassungsrelevante Studien mit Nivolumab STUDY PHASE POPULATION LINE ALLCOMER PD-L1+ DESIGN PRIMARY ENDPOINT STATUS PUBLICATION CA209-063 2 NSCLC squamous 3L+ Allcomer Nivolumab ORR ongoing not recruiting Rizvi N.A,, Wolf J., Grohé C., Huber R.M., et al. The Lancet Oncology 16.3 (2015): 257-265. CA209-017 3 NSCLC squamous 2L Allcomer Nivolumab vs. Docetaxel OS ongoing not recruiting CA209-057 3 NSCLC non-squamous 2L+ Allcomer Nivolumab vs. Docetaxel OS ongoing not recruiting CA209-026 3 NSCLC squamous non-squamous 1L PD-L1+ Nivolumab vs. ICC PFS ongoing not recruiting ORR = Objective Response Rate, OS = Overall Survival, PFS= Progression Free Survival, ICC = Investigator's Choice Chemotherapy www.clinicaltrials.gov

ORR = Objective Response Rate, IRRC = Independent Radiology Review Committee OS = Overall Survival, PFS= Progression Free Survival * until disease progression, discontinuation due to toxicity, withdrawal of consent or the study ends www.clinicaltrials.gov Nivolumab Phase II CA209-063: Studiendesign Population Treatment Endpoints Stage IIIB/IV NSCLC squamous 2 prior systemic therapies ECOG 0 1 Nivolumab 3 mg/kg IV Q2W* n=117 Primary: Confirmed ORR (IRC assessed) Secondary: Confirmed ORR (investigator assessed) Exploratory: Safety and tolerability PFS/OS PD-L1 expression and efficacy Title: Study of Nivolumab (BMS-936558) in Subjects With Advanced or Metastatic Squamous Cell Non-Small Cell Lung Cancer Who Have Received At Least Two Prior Systemic Regimens (CheckMate 063)

Best Reduction from Baseline in Target Lesion (%) CA209-063: Ansprechen und Überleben (Größte Reduktion der Targetläsion) a 100 75 50 Alive Expired Confirmed responders 25 0-25 -50-75 n=95 response-evaluable -100 Patient 8 confirmed PRs in patients with rapid progression on prior therapy Among all treated patients; 13% continuing treatment and 24% received subsequent therapy Most frequent therapies were gemcitabine (10%), docetaxel (4%), and vinorelbine (4%) No patients received subsequent immunotherapy a Based on July 2014 DBL; 22/117 treated patients are not displayed due to lack of evaluable on-study assessments; 18/22 expired; Dashed horizontal reference line indicates the 30% reduction consistent with a RECIST v1.1 response; Ramalingam et al. CMSTO 2014

CA209-063: Klinische Aktivität von Nivolumab Nivolumab 3 mg/kg IRC Assessed (per RECIST v1.1) a ORR, % (n) [95% CI] 15 (17) [9, 22] Disease control rate, % (n) 40 (47) Median DOR, months (range) NR (2+, 12+) Ongoing responders, % (n) 76 (13) Median time to response, months (range) 3 (2, 9) PFS rate at 1-year, % (95% CI) 20 (13, 29) Median PFS, months (95% CI) 2 (2, 3) Investigator-assessed ORR was 13% (95% CI, 7, 20) Concordance between IRC and investigator assessed responders was 92% (based on March 2014 DBL) a July 2014 DBL NR = not reached; DOR = duration of response; ORR = objective response rate; PFS = progression free survival Ramalingam et al. CMSTO 2014

Percent Change in Baseline (%) CA209-063: Ansprechmuster a 100 75 50 1 st Occurrence of new lesion PR Patients still on treatment 25 0-25 -50-75 -100 0 6 12 18 25 30 36 42 48 54 60 66 Time Since First Treatment (Weeks) 4 patients with non-conventional responses not reported as IRC-assessed responders 3 alive (OS: 12+, 13+, 14+ months) a Based on July 2014 DBL Ramalingam et al. CMSTO 2014

Overall Survival (%) CA209-063: Gesamtüberleben (OS): Alle behandelten Patienten a 100 90 80 70 60 50 40 Median OS, months (95% CI) 8,2 (6, 11) 1-year OS rate, % (95% CI) 41 (32, 50) Number of events 72/117 Median OS = 8,2 months 1-year OS = 41% 30 20 10 0 0 3 6 9 12 15 18 Overall Survival (Months) Number of Patients at Risk Nivolumab 117 93 68 51 28 5 0 3mg/kg Median follow-up for survival: 8 months (range 0 17 months) a Based on July 2014 DBL; Symbols represent censored observations Ramalingam et al. CMSTO 2014

CA209-063: Therapiebedingte unerwünschte Ereignisse in 10% der Patienten a Nivolumab 3 mg/kg (n = 117) Any Grade Grade 3 4 Total patients with an event, b % 74 17 Fatigue 33 4 Decreased appetite 19 0 Nausea 15 0 Asthenia 12 0 Rash 11 1 Diarrhea 10 3 85% of patients received at least 90% of their planned dose intensity 12% discontinued treatment due to study drug toxicity (4% pneumonitis) Grade 3 treatment-related pneumonitis was reported in 4 patients (3%); one additional grade 3 case occurred between 30 100 days after last nivolumab dose 62% had expired at time of analysis (54% PD and 2% study drug toxicity) Two treatment-related deaths (1 hypoxic pneumonia and 1 ischemic stroke) occurred in patients with multiple comorbidities and concurrent PD a July 2014 DBL; b Includes events reported between first dose and 30 days after last dose of study therapy. Of the adverse events included in the table, no events were grade 5 Ramalingam et al. CMSTO 2014

Studiendesign: CA209-017 und CA209-057 CA209-017 Phase 3 Stage IIIb/IV squamous cell NSCLC 2L Nivolumab 3 mg/kg IV q2w Docetaxel 75 mg/m 2 IV q3w OS OS CA209-057 Phase 3 Stage IIIb/IV nonsquamous cell NSCLC 2/3L Nivolumab 3 mg/kg IV q2w Docetaxel 75 mg/m 2 IV q3w OS OS www.clinicaltrials.gov

http://www.bms.com/news/press_releases/pages/default.aspx

Fazit: PD-1-Inhibition beim NSCLC Immun-Checkpoint-Inhibitoren zeigen ermutigende Ergebnisse in klinischen Studien (Phase 1-3) Eindrucksvolles Ansprechen und Überleben bei vorbehandelten Patienten mit Adeno- und Plattenepithelkarzinomen Ein Teil der Patienten zeigt möglicherweise ein Langzeitüberleben Toxizität mäßig und beherrschbar Mehrere Substanzen in klinischer Entwicklung PD-L1 erster prädiktiver Biomarker, aber auch PD-L1-negative Patienten profitieren Ausblick: Optimierung durch Kombinationstherapien

Die Immunonkologie als fest verankertes Behandlungskonzept in der Onkologie Operation Strahlentherapie Immunonkologie Chemo- & zielgerichtete Therapien DeVita et al, N Eng J Med 2012; 366: 2207; Borghaei et al, Eur J Pharmacol 2009; 625: 41

Stand: April 2015 Bitte beachten Sie, dass sehr bald neue Daten und Updates der hier vorgestellten Studien folgen!