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Immuno-checkpoints: pitfalls and promises
Perspectives in Lung Cancer: 16th European Congress March 6-7, 2015 Turin - Italy Immuno-checkpoints: pitfalls and promises Michele Maio Medical Oncology and Immunotherapy University Hospital of Siena Istituto Toscano Tumori SIENA, ITALY 1
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T-cell costimulatory receptors
D E C E M B E R | VO L | N AT U R E | 4 8 1
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Melanoma as a tool for cancer research
Tissue samples readily accessible Adaptable to tissue culture Amenable to testing of novel therapies
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Lawrence et al, Nature 2013
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Chemotherapy/Targeted Agents and
Immuno-therapy Differ in Action and Outcome Chemotherapy and Targeted Therapies IMMUNOTHERAPY Response 6 12 Time (months) Maio M. et al, unpublished 6
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Anti-CTLA4 antibodies Tremelimumab (CP675,206) IgG2 isotype antibody half-life time: 22 days Ipilimumab (MDX-010) IgG1 isotype antibody half-life time: 12.5 days T-cell potentiation T cell CTLA-4 TCR CTLA-4 mAb MHC B7 APC
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Kaplan-Meier Plot of Overall Survival CA184024
Maio M et al., J Clin Oncol, in press
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Presented By Mario Sznol at 2014 ASCO Annual Meeting
Slide 13 Presented By Mario Sznol at 2014 ASCO Annual Meeting
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Clin Cancer Res 2009
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ir-PFS RESULTS Phased Schedule (NSCLC) Phased Schedule (SCLC) R
A Randomized, double-blind, parallel, three arm, phase II trial evaluating the efficacy and safety of Ipilimumab in combination with Taxol/Paraplatin compared to Taxol/Paraplatin alone, in previously untreated subjects with lung cancer (CA ) Stage IIIb/IV NSCL Extended SCLC R *CT + PBO *CT + IPI concomitant *CT + IPI phased *CT= CBCDA/Taxol ir-PFS RESULTS Phased Schedule (NSCLC) Phased Schedule (SCLC) Study met primary end-point Phased schedule significantly improved irPFS No significant improvement for concurrent schedule Lynch T, JCO 2012 Reck M, Ann Oncol 2013
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CA : Phase III double blind study in Squamous Non Small Cell Lung Cancer Subjects Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin CA : Phase III double blind study in Extensive-Disease Small Cell Lung Cancer (ED-SCLC) Subjects Comparing Ipilimumab Plus Etoposide and Platinum Therapy to Etoposide and Platinum Therapy Alone
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[TITLE]
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PD1/PD-L1 Inhibitors in clinical developments
Target Agent Class Phase PD-1 Nivolumab (MDX 1106, BMS , BMS-ONO) IgG4 3 Pembrolizumab (MK-3475, Merck&Co) IgG4 engineered humanized Pidilizumab (CureTech-Teva) IgG1 humanized 2 AMP-514 (AstraZeneca/MedImmune) IgG 1 AMP-224 (AstraZeneca/MedImmune) PD-1/B7 Fc fusion protein Novartis (Co-stim) PD-L1 MPDL3280A (Bavituximab, Genetech/Roche) IgG1; Fc engineered MEDI4776 (AstraZeneca/MedImmune) IgG1-k 1/2 BMS (MDX 1105, BMS-ONO) MSB C (EMD Serono, Merck kgA)
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Upcoming trials of anti-PD-1/PD-L1 therapy in advanced NSCLC
Population/setting Treatment arms Phase Clinicaltrial.gov Monotherapy NSCLC PDL1+ 1st line NSCLC 2nd/3rd line squamous NSCLC 2nd/3rd line non squamous NSCLC pretreated NSCLC 2nd line Nivolumab vs Chemotherapy (investigator choice) Pembrolizumab in NSCLC versus CT (platinum-based) Nivolumab vs Docetaxel (BMS017) Nivolumab vs Docetaxel (BMS057) Nivolumab (BMS153) Pembrolizumab versus Docetaxel III II/III NCT NCT NCT NCT NCT NCT Combination with CT NSCLC multi-arm, 1st line NSCLC first line NSCLC+solid tumors Nivolumab + Cisplatin/Gemcitabine or Cisplatin/Pemetrexed, or Carboplatin/Paclitaxel, or Bevacizumab maintenance Pembrolizumab with CT (platinum based) MPDL3280A with Beva+/-CT I I/II II NCT NCT NCT Combination with target therapy NSCLC EGFR mut NSCLC + solid tumors Pembrolizumab with Gefitinib or Erlotinib MEDI-4736+Gefinitib MDPL3280A with erolotinib MDPL3280A with cobimetinib (GDC-0973) NCT NCT NCT Combination with Immunotherapy NSCLC SCLC + solid tumors All NSCLC 2nd/3rd line Pembrolizumab with Ipilimumab MEDI with Tremelimumab MEDI-4736 with antiPD1 (AMP514) Nivolumab +IL-21 Anti-LAG-3+/-Nivolumab Nivolumab +anti-KIR Nivolumab +/- Ipilimumab Azacitidine oral or Azacitidine/Entinostat Nivolumab NCT NCT NCT NCT NCT NCT NCT
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CA209-003 OS by Dose in NSCLC OS (%) 2-year OS = 42% 3-year OS = 27%
Pts at Risk Group Died/Treated Median OS, mo (95% CI) 1-year 2-year 3-year 9.2 (5.3, 11.1) 14.9 (7.3, 30.3) 9.2 (5.2, 12.4) Months Since Initiation of Treatment 100 90 80 70 60 50 40 30 20 10 3 6 9 12 15 18 33 27 24 21 36 39 42 45 48 51 54 66 63 57 Censored 3-year OS = 27% 2-year OS = 42% Nivolumab 1 mg/kg Nivolumab 3 mg/kg Nivolumab 10 mg/kg OS (%) 33 (17, 49) 56 (38, 71) 38 (26, 50) 15 (5, 30) 42 (24, 58) 20 (11, 31) 27 (12, 43) 14 (7, 25) 26/33 23/37 50/59 1 mg/kg 3 mg/kg 10 mg/kg 37 59 26 34 35 16 29 17 22 7 14 13 4 11 1 5 2 OS rate, % (95% CI)
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Phase 3 trials of nivolumab in NSCLC
Primary Objectives • ORR and OS Secondary Objectives • PFS • ORR and OS by PD-L1 status • Duration of OR • Time to OR • Proportion of patients exhibiting disease-related symptom progression (Lung Cancer Symptom Scale) CA NCT (Phase 3; N = 264) Patients with stage IIIb/IV squamous cell NSCLC Docetaxel Nivolumab CA NCT (Phase 3; N = 574) Patients with stage IIIb/IV non-squamous cell NSCLC Primary Objective • OS Secondary Objectives • ORR • PFS • ORR and OS by PD-L1 status • Duration of OR • Time to OR • Proportion of patients exhibiting disease-related symptom progression (Lung Cancer Symptom Scale) Docetaxel Nivolumab PFS = progression-free survival
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Sponsor
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nivolumab
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Keynote 001: Pembrolizumab in NSCLC (phase 1 dose ranging study)
Tot 21% ORR -26% in CT naive pts -20% in pre-treated pts
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PREDICTIVE MARKERS OF RESPONSE TO PD1/PD-L1 BLOCKADE
PD-L1 tumor expression Topalian S, et al., NEJM 2012
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PD-L1 expression in NSCLC lung cancer: a key driver of response in monotherapy?
Agent ORR PDL1+ ORR PDL1- Source Pembrolizumab* 25% (55/222) 13% (5/40) 2014 ESMO Nivolumab* 15% (5/33) 14% (5/35) 2014 ASCO MPDL3280A** 46% (6/13) 15% (6/40) MEDI4736** 26% (12/47) 10% (7/74) *DAKO test **VENTANA test
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PD-L1 expression : a key driver of response in combination regimen?
Agent Tumor ORR PDL1+ ORR PDL1- Source Nivo+Ipi Melanoma* 57% (8/14) 40% (17/42) 2014 ASCO Kidney - 1% - 5% 50% (8/16) 25% (1/4) 55% (11/20) 56% (18/32) Lung 19% 14% *Dako automated 5% cutoff tumor staining
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PD-L1 negative tumours: Potentially better response with anti-PDL1 + tremelimumab combination
PD-L1 negative patients in NSCLC 70% (7/10) 1 2 42% (31/74) 30% (3/10) 10% (7/74) 1Mono: ORR 10% (7/74), 95%CI (3.9%, 18.5%) SD≥12weeks 32.4% (24/74), 95%CI (22.0%, 44.3%) 2Combination: ORR 30% (3/10), 95%CI (6.7%, 65.2%) SD≥12weeks 40% (4/10), 95%CI (12.2%, 73.8%)
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Effect in the CNS?
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3-years survival update
NIBIT - M1 3-years survival update Secondary Endpoints Study population (N=86) Patients with MBM (N=20) Median OS, months (95% CI) 12.9 ( ) 12.7 ( ) 3-year survival rate, % (95% CI) 28.5 ( ) 27.8 ( ) Median ir-PFS, months (95% CI) 4.5 ( ) 3.4 ( ) Di Giacomo AM et al., Annals Oncol 2015
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Evolving Therapeutic Options for Cancer Treatment
Surgery Chemotherapy Radiotherapy
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Evolving Therapeutic Options for Cancer Treatment
Surgery Chemotherapy Radiotherapy Immunotherapy
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Science “Areas to Watch” 2015: COMBINED IMMUNOTHERAPY
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Medical Oncology and Immunotherapy, University Hospital of Siena
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