Terapia Immunomodulante e Target Therapies nel Trattamento del Melanoma Metastatico

Transcription

1 Terapia Immunomodulante e Target Therapies nel Trattamento del Melanoma Metastatico Pier Francesco Ferrucci Direttore, Unità di Oncologia Medica del Melanoma Istituto Europeo di Oncologia - Milano Pisa, 13/11/2015

2 Agenda 1. IMMUNOTERAPIA: Anti-CTLA4 Anti-PD1 Combinazioni anti-ctla4 e anti-pd1 2. TERAPIA TARGET: Anti-BRAF Anti-MEK Combinazioni anti-braf e antimek

3 The T-Cell Antitumor Response 1 Tumor antigens released by tumor cells 2 Tumor antigens presented to T cells 3 T cells are activated; they proliferate and differentiate into effector and memory cells 4 Effector T cells recognize tumor antigens 5 T cells kill tumor cells

4 Tumors Use Complex, Overlapping Mechanisms to Evade and Suppress the Immune System APC 1 Inhibition of tumor antigen presentation (eg, down regulation of MHC I) Inhibition of attack by immune cells (eg, disruption of T-cell checkpoint pathways) Activated T- Tumor Cell 2 Secretion of immunosuppressive factors (eg, TGF-B) 3 cell T-reg 4 Recruitment of immunosuppressive cell types (eg, Tregs)

5 Regulation of T-Cell Activation: Balancing Activating and Inhibitory Signals Immune checkpoints limit, or check, an ongoing immune response Prevents damage to the body s healthy tissues Negative co-stimulation, also called co-inhibition, helps shut down immune responses PD-1, CTLA-4, and LAG-3 are examples of co-inhibitory checkpoint molecules Amplitude and quality of a T- cell response is regulated by a balance of activating and inhibitory signals APC/ Tumor B7-2 (CD86) PD-L1 PD-L2 MHC CD40 CD137L PD-1 B7-1 (CD80) LAG-3 CD40L CD137 T cell CD28 Activation B7-1 (CD80) CTLA-4 Inhibition TCR Inhibition Inhibition Inhibition Activation Activation CTLA-4 = cytotoxic T-lymphocyte antigen-4; LAG-3 = lymphocyte activation gene-3; PD-1 = programmed death-1; PD-L1 = programmed death-ligand 1. OX40L OX40 Activation

6 Rationale for Blockade of Immune Checkpoint Molecules CTLA-4 and PD1

7 CTLA-4 and PD-1/L1 Checkpoint Blockade Priming phase (lymph node) Effector phase (peripheral tissue) Dendritic cell T cell T-cell migration T cell Cancer cell MHC TCR TCR MHC Dendritic cell B7 CD28 CTLA-4 T cell T cell PD-1 PD-L1 Cancer cell Ribas A. N Engl J Med. 2012;366:

8 Ipilimumab: Mechanism of Action CTLA-4 T cell activation T cell inhibition T cell potentiation T cell T cell T cell APC TCR MHC CD28 B7 APC TCR MHC CD28 CTLA-4 B7 APC TCR MHC B7 CTLA-4 IPILIMUMAB blocks CTLA-4 Adapted from Weber. J Cancer Immunol Immunother 2009;58:823.

9 Study Design MDX010-20: Randomized, Double-blind, Phase III Pre-treated Metastatic Melanoma (N=676) R A N D O M I Z E Ipilimumab 3 mg/kg + gp100 Ipilimumab 3 mg/kg + placebo gp100 + placebo (N=403) (N=137) (N=136) Primary endpoint: overall survival Secondary objectives: BORR, duration of response, PFS Hodi S et al. NEJM 2010;363(8):711-23

10 Proportion of patients alive (%) Durability of Survival Benefit with Ipilimumab in Heavily Pretreated Patients: 100 lpilimumab alone 80 lpilimumab + gp100 gp100 alone Ipilimumab + gp Years mos, months 95% CI HR P value 1-year OS (%) 2-year OS (%) a 3-year OS (%) b < Ipilimumab gp a Patients randomised 2 years prior to study survival cut-off date (N = 474) b Patients randomised 3 years prior to study survival cut-off date (N = 259) Hodi FS, et al. N Engl J Med 2010;363: McDermott D, et al. Ann Oncol 2013;24:2694 8

11 Specific Patterns of Response Ipilimumab monotherapy resulted in four distinct response patterns, 2 captured with conventional RECIST/WHO criteria and 2 by new irrc: 1. shrinkage in baseline lesions, without new lesions; 2. durable stable disease (in some patients followed by a slow, steady decline in total tumor burden); 3. response after an increase in total tumor burden; 4. response in the presence of new lesions. All these patterns were associated with favorable survival.

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13 Specific Patterns of Toxicities

14 SKIN: Immune-related dermatitis Back: confluent red rash Back: close up of papular lesions Right upper arm: vacuolar changes Anti-CD8 staining: extensive epidermal exocytosis Jaber SH, et al. Arch Dermatol 2006;142:

15 GASTROINTESTINAL: Immune-related Enterocolitis

16 ENDOCRINE: Immune-related Endocrinopathies 6/30/04 baseline (4.5 mm) 12/3/04 headache and fatigue after 5 doses (10.8 mm) Ipilimumab-related pituitary swelling and dysfunction Resolution of symptoms with hormone replacement therapy, with slow return of some endocrine function Blansfield JA, et al. J Immunother 2005;28:

17 LIVER: Immune-related Hepatitis Monitor liver function tests (LFTs): increases in AST and ALT or total bilirubin should be evaluated to exclude other causes of hepatic injury and monitored until resolution Withold ipilimumab dosing in patients with moderate aspartate AST or ALT elevations of > 5 to 8 times ULN, or moderate total bilirubin elevation of > 3 to 5.1 Permanently discontinue ipilimumab for any of the following: Severe AST or ALT elevations of > 8 times ULN; Total bilirubin elevations of > 5 times ULN; Symptoms of hepatotoxicity. Systemic high-dose corticosteroids may be required

18 PD1 Pathway As a Key Checkpoint in Cancer

19 Effects of PD1 Signalling on T-cell Function Normal function: attenuate immune responses to avoid immune system attack of self Direct effects on activated CD4+/CD8+ T cells PD1: PD-L1/L2 = proliferation PD1: PD-L1 = IL-2 PD1: PD-L1 = CD8+ T-cell anergy Indirect effects via Treg cells PD1: PD-L1 = naïve CD4+ cell conversion Treg PD1: PD-L1 = Treg function (inhibition of CD8+ T-cell responses) Blank C, et al. Cancer Immunol Immunother. 2007;56: Carter LL, et al. Eur J Immunol 2002;32: Chikuma S, et al. J Immunol 2009;182:

20 Anti-PD1 Mechanism of Action Recognition of tumour by T cell through MHC/antigen interaction mediates IFNγ release and PD-L1/2 upregulation on tumour Priming and activation of T cells through MHC/antigen and CD28/B7 interactions with antigen-presenting cells IFNγR IFNγ MHC T cell receptor T-cell receptor MHC Tumour cell PD-L1 PD-L2 PD-1 Shp-2 PI3K NFκB Other T cell Shp-2 CD28 PD-1 B7 PD-L1 Dendritic cell PD-1 PD-1 PD-L2 PD1 Receptor Blocking Ab

21 Activity of Anti-PD-1/PD-L1 in Patients With Advanced Melanoma Agent Pts, n ORR (at Optimal Dose), % Grades 3/4 Tx-Related AEs, % 6-Mo PFS, % 12-Mo PFS, % Median PFS, Mos 1-Yr OS, % 2-Yr OS, % Nivolumab (anti-pd-1) [1-3] (41) Pembrolizumab (anti-pd-1) [4,5] (52) NA NA > BMS NA NA NA NA NA (anti-pd-l1) [6] MPDL3280A 44 29* NA NA NA NA (anti-pd-l1) [7] *Includes 4 patients with UM without a response. 1. Topalian SL, et al. J Clin Oncol. 2014;32: Sznol M, et al. ASCO Abstract Topalian SL, et al. N Engl J Med. 2012;366: Ribas A, et al. ASCO Abstract Hamid O, et al. N Engl J Med. 2013;369: Brahmer JR, et al. N Eng J Med : Hamid O, et al. ASCO Abstract 9010.

22 CTL Infiltrates in Regressing Metastatic Melanoma Lesion After MK-3475 Treatment Baseline: February 29, 2012 August 20, 2012 CD8+ IHC CD8+ IHC Ribas A, et al. ASCO Abstract 9009.

23 AEs in > 5% of Patients Adverse Event (N = 135) All Grades, n (%) Grades 3/4, n (%) Any 107 (79.3) 17 (12.6) Fatigue 41 (30.4) 2 (1.5) Rash 28 (20.7) 3 (2.2) Pruritus 28 (20.7) 1 (0.7) Diarrhea 27 (20.0) 1 (0.7) Myalgia 16 (11.9) 0 Headache 14 (10.4) 0 Increased AST 13 (9.6) 2 (1.5) Asthenia 13 (9.6) 0 Nausea 13 (9.6) 0 Vitiligo 12 (8.9) 0 Hypothyroidism 11 (8.1) 1 (0.7) Increased ALT 11 (8.1) 0 Cough 11 (8.1) 0 Pyrexia 10 (7.4) 0 Chills 9 (6.7) 0 Abdominal pain 7 (5.2) 1 (0.7)

24 Anti-PD1 in Advanced Melanoma: Expert Perspective Excellent toxicity profile (Grade 3/4 iraes: 13% Pembro, 22% Nivo) Response rates in Ipi-naive pts 41% (Nivo), 52% (Pembro) - Lower response rates in patients who progressed after Ipi, BRAF inhibitor, or LDH >ULN Response duration (even when stopped): 81% at 1y (Pembro), 64% beyond 24 wks (Nivo) Median DoR of 22.9 mos (Nivo) Survival outcomes: Extimated median OS is >24 mo (Pembro) 2-yr OS: 48%; 3-yr OS: 41% (Nivo)

25 Rationale for concurrent Blockade of Immune Checkpoint Molecules CTLA-4 and PD1

26 Blocking CTLA-4 and PD1 Perifery Tumour microenvironment Activation (cytokines, lysis, proliferation, migration to tumour) Dendritic cell MHC B7 TCR CD B7 CTLA anti-ctla T cell T cell TCR MHC PD1 PD-L1 anti-pd1 PD1 PD-L2 anti-pd1 Tumour cell CTLA-4 blockade (ipilimumab) PD1 blockade (nivolumab) Ribas A. N Engl J Med 2012;366(26):

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28 CA : Study Design Study design: Randomized, double-blind, phase III study to compare NIVO alone or NIVO + IPI to IPI alone NIVO 3 mg/kg Q2W + IPI-matched placebo Unresectable or Metatastic Melanoma Previously untreated Tissue available for PD-L1 testing Randomize 1:1:1 Stratify by: PD-L1 status* BRAF status AJCC M stage NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W + NIVOmatched placebo Treat until progression** or unacceptable toxicity IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo *Verfied PD-L1 assay using 5% cutoff, was used for the stratification of patients; validated PD-L1 assay was used for the results of the study. **Patients could have been treated beyond progression under protocol-defined circumstances. 28

29 Proportion alive and progression-free Co-primary Endpoint: PFS (Intent-to-Treat) NIVO (N=316) NIVO + IPI (N=314) IPI (N=315) Median PFS, months (95% CI) 6.9 ( ) 11.5 ( ) 2.9 ( ) 0.8 HR (95% CI) vs. IPI 0.57 ( )* 0.42 ( )* HR (95% CI) vs. NIVO ( )** *Stratified log-rank P< vs. IPI **Exploratory endpoint NIVO NIVO + IPI IPI 0.0 Number at Risk NIVO NIVO + IPI IPI Months

30 Response to Treatment NIVO (N=316) NIVO + IPI (N=314) IPI (N=315) 19.0 (14.9 ORR, % (95% CI) 43.7 ( ) 57.6 ( ) 23.8) Two-sided P value vs IPI < < Best overall response % Complete response Partial response Stable disease Progressive disease Unknown Duration of response (months) Median (95% CI) NR (11.7, NR) NR (13.1, NR) NR (6.9, NR) NR, not reached. 30

31 Proportion alive and progression-free Proportion alive and progression-free PFS by PD-L1 Status (5% Cutoff) 1.0 PD-L1-positive ( 5%)* PD-L1-negative (<5%)* mpfs HR mpfs HR 0.0 NIVO NIVO + IPI IPI NIVO NIVO + IPI IPI NIVO NIVO + IPI IPI Number at Risk NIVO 80 NIVO + IPI IPI Months Number at Risk Months NIVO NIVO + IPI IPI Similar results were obtained using a 1% cutoff. *Per validated PD-L1 assay. 31

32 ORR by PD-L1 Status (5% Cutoff) NIVO + IPI resulted in a higher ORR vs. NIVO alone regardless of PD-L1 status NIVO NIVO + IPI IPI PD-L1- positive ORR, % (95% CI) 57.5 (45.9, 68.5) 72.1 (59.9, 82.3) 21.3 (12.7, 32.3) PD-L1- negative ORR, % (95% CI) 41.3 (34.6, 48.4) 54.8 (47.8, 61.6) 17.8 (12.8, 23.8) PD-L1 positivity defined as 5% tumor cell surface staining. Pre-treatment tumor specimens were centrally assessed by PD-L1 immunohistochemistry (using a validated BMS/Dako assay). 32

33 Rapid and durable changes in target lesions

34 Tempo mese + 2 mesi + 5 mesi + 8 mesi + 12 mesi

35 Safety Summary Patients Reporting Event, % Treatment-related adverse event (AE) Treatment-related AE leading to discontinuation NIVO (N=313) NIVO + IPI (N=313) IPI (N=311) Any Grade Grade 3 4 Any Grade Grade 3 4 Any Grade Grade Diarrhea Colitis Treatment-related death* *One reported in the NIVO group (neutropenia) and one in the IPI group (cardiac arrest) 35

36 Concurrent Therapy With Ipilimumab and Nivolumab: Expert Perspective Up to 70% ORR with 17% CRs and 82% in remission for all patients receiving concurrent treatment Up to 50% rate of grade 3/4 iraes at optimal doses: LFTs, lipase, amylase, rash, colitis BRAF status, PD-L1 tumor staining not clearly associated with response (maybe to Nivo) Response in sequential patients associated with plasma ipilimumab levels prior to starting nivolumab Concurrent 2-yr OS of 79% = impressive!!! Benefit worth the toxicity?

37 Molecularly Targeted Therapy

38 New Targets New Drugs

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40 Rationale for Combination of BRAFi + MEKi in BRAF Mutant Tumors

41 Rationale for Combination of BRAFi + MEKi in BRAF Mutant Tumors RAS BRAF MEK perk Proliferation Survival Invasion Metastasis BRAFi : RR 77% MEKi RR 35% Goals of Combination: Improve complete response rate Decrease incidence of BRAFi-induced proliferative skin lesions Suppress MAP kinase dependent resistance mechanisms and improve duration of response

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43 COMBI-v n=495 Co-BRIM

44 COMBI-v Co-BRIM 11.3 months HR=0.60

45 COMBI-v Co-BRIM

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48 COMBI-v Co-BRIM

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50 What may the Future Hold? Evaluation earlier in disease Optimization Biomarkers Schedule/regimen Outcomes assessment Evaluation across cancer types Immune checkpoints inhibitors Evaluation in combination Chemotherapy Radiotherapy Targeted agents Other I-O therapies Novel targets

51 What may the Future Hold? Evaluation earlier in disease Optimization Biomarkers Schedule/regimen Outcomes assessment Evaluation across cancer types Immune checkpoints inhibitors Evaluation in combination Chemotherapy Radiotherapy Targeted agents Other I-O therapies Novel targets

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53 Della serie. Grazie per l attenzione