Novità nell immunoterapia del NSCLC. Marcello Tiseo Oncologia Medica Coordinatore PDTA Oncologia Toracica Azienda Ospedaliero-Universitaria di Parma

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1 Novità nell immunoterapia del NSCLC Marcello Tiseo Oncologia Medica Coordinatore PDTA Oncologia Toracica Azienda Ospedaliero-Universitaria di Parma

2 Agenda Introduzione Anti-CTLA4: ipilimumab Anti-PD1/Anti-PDL1: Evidenze di attività/efficacia Tossicità Bio-marcatore (espressione di PDL1) Strategie di combinazione Prospettive future

3 Immunotherapy (IT) and Lung Cancer: background Historically minimal success of IT in LC LC believed to be non-immunogenic LC has the ability to evade the immune system: - Secretion of cytokines (IL10, TGFb) - Loss/reduction of MHC expression - Advanced disease associated with immunosuppression (decreased circulating lymphocytes and TILS) - Expression of membrane inhibitory ligands such as PDL-1, PDL-2, B7-H3/4 (adaptive resistance)

4 Immunotherapy (IT) and Lung Cancer: background

5 Immunotherapy (IT) and Lung Cancer: background

6 Immune Check-points Pathways

7 Ipilimumab nel NSCLC e SCLC Lynch TJ et al, J Clin Oncol 2012 Reck et al, Ann Oncol 2012

8 Ipilimumab nel NSCLC Lynch TJ et al, J Clin Oncol 2012

9 Ipilimumab nel NSCLC Lynch TJ et al, J Clin Oncol 2012

10 Ipilimumab Phase III Trial on Squamous NSCLC 1 st line

11 Immune Check-points Pathways

12 Anti PD1/PD-L1 nel NSCLC Target Agent Fase PD-1 Pembrolizumab (MK-3475, MSD) Approvato FDA 3 Nivolumab (BMS , BMS) Approvato FDA, EMA 3 Pidilizumab (CureTech-Teva) 2 AMP-514 (AstraZeneca/MedImmune) 1 AMP-224 (AstraZeneca/MedImmune) 1 Novartis (Co-stim) 1 PD-L1 Atezolizumab (Roche, Genetech) In attesa risultati 3 MEDI4776 (AstraZeneca/MedImmune) 3 BMS (MDX 1105, BMS-ONO) 1 MSB C (EMD Serono, Merck kga) 2-3

13 Nivolumab nel NSCLC: Check-Mate 017 e 057 (II linea)

14 Nivolumab in Squamous NSCLC: Check-Mate 017 Brahmer et al, NEJM 2015

15 Nivolumab in Squamous NSCLC: Check-Mate 017 Brahmer et al, NEJM 2015

16 Nivolumab in Squamous NSCLC: Check-Mate 017 Brahmer et al, NEJM 2015

17 Nivolumab in Squamous Dati di follow-up più maturo Reckamp K et al, WCLC 2015

18 Nivolumab in Squamous Dati di follow-up più maturo (fase II, 063) Horn et al, WCLC 2015

19 Nivolumab in Non-Squamous NSCLC: Check-Mate 057 Borghaei et al, NEJM 2015

20 Nivolumab in Non-Squamous NSCLC: Check-Mate 057 Borghaei et al, NEJM 2015

21 Nivolumab in Non-Squamous NSCLC: Check-Mate 057 Borghaei et al, NEJM 2015

22 Nivolumab in Non-Squamous NSCLC: Check-Mate 057 Borghaei et al, NEJM 2015

23 Anti-PD1 e anti-pdl1: Attività ed efficacia OS KEYNOTE 001 OS CHECKMATE 057 EGFR Status PTS ORR % PFS OS EGFR Status PTS HR (95%CI) MT ND ND WT ND ND MT ( ) WT ( ) Smoking History PTS ORR % PFS OS YES NO Smoking PTS HR (95%CI) History NO ( ) YES ( ) Borghaei et al, NEJM 2015; Garon EB et al, NEJM 2015

24 Anti-PD1 e anti-pdl1: Attività ed efficacia PRIOR PRIOR-TX NON-PRIOR TX NIVO NIVO ATEZO PEMBRO squamous adeno All comers All comers ORR (%) mos (mo) HR mpfs (mo) HR Borghaei et al, NEJM 2015; Brahmer et al, NEJM 2015 Alexander Spira, ASCO 2015; Garon EB et al, NEJM 2015

25 Nivolumab Check-mate 057: Tossicità Borghaei et al, NEJM 2015

26 Anti-PD1 e anti-pdl1 Tossicità di tutti i gradi NIVO NIVO ATEZO PEMBRO SQM NON-SQM all comers All comers Fatigue ~ Rash 4 9 ND 9.7 diarrea 8 8 ~ prurito 2 8 ND 10.7 polmonite 5 3 ~ ipotiroidismo 4 7 ~5 6.9 Borghaei et al, NEJM 2015; Brahmer et al, NEJM 2015 Alexander Spira, ASCO 2015; Garon EB et al, NEJM 2015

27 Anti-PD1 e anti-pdl1 Tossicità NIVO NIVO ATEZO PEMBRO SQM NON-SQM all comers All comers Any AEs GR 3 AEs GR 5 (death) Borghaei et al, NEJM 2015; Brahmer et al, NEJM 2015 Alexander Spira, ASCO 2015; Garon EB et al, NEJM 2015

28 Nivolumab: In caso di PS 2? Hussein et al, WCLC 2015

29 OR with anti-pd1 agent according PDL-1 expression Topalian et al, NEJM 2012

30 Nivolumab in Squamous NSCLC: PDL-1 in Check-Mate 017 Brahmer et al, NEJM 2015

31 Nivolumab in Non-Squamous NSCLC: PDL-1 in Check-Mate 057 Borghaei et al, NEJM 2015

32 Nivolumab in Non-Squamous NSCLC: PDL-1 in Check-Mate 057 Borghaei et al, NEJM 2015

33 Pembrolizumab in PD-L1+ Garon, ESMO 2014

34 New Engl J Med 2015 N mos (mesi) All Naive Prior Tx 394 (65% pts > 3 line) 9.3 <1% 1-49% 50%

35 FDA News Release- Oct FDA approves Keytruda for advanced NSCLC First drug approved in lung cancer for patients whose tumors express PD-L1 Keytruda is approved for use with a companion diagnostic, the PD-L1 IHC 22C3 pharmdx test (DAKO), the first test designed to detect PD-L1 expression in non-small cell lung tumors ( 50%)

36 POPLAR: A Randomized All-comer Phase II Study Presented By Alexander Spira at 2015 ASCO Annual Meeting

37 PD-L1 Expression on TC and IC is a Potential Predictive Biomarker for Atezolizumab in NSCLC

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39 Alla ricerca del biomarker

40 PD1/PD-L1 is a reliable biomarker alone? Heterogeneity within the same tumor (cell surface/intracellular/stromal) Primary vs Metastasis Cell type expressing PD-L1 (IC-TC or IC/TC?) Intensity, percente of positive cells (cut-off 1%- 50%) Different antibodies and staining New emerging biomarkers (TIL, tumor mutation burden )

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42 Strategia di combinazione Champiat et al, JTO 2014

43 Risultati preliminari di combinazione Rizvi N et al. ORAL02.05

44 Risultati preliminari di combinazione Camidge DR et al. ORAL02.07

45 Risultati preliminari di combinazione Camidge DR et al. ORAL02.07

46 Anti-PD1 and Anti-PDL1 NSCLC: ongoing trials First-line First-line treatment strategy (single agent, combined with chemo, upfront, maintenance) Combination with targeted therapies Combination with other immunotherapy Locally advanced disease Adjuvant setting

47 Phase III randomized trial of Nivo vs Nivo + Ipi vs Nivo + Ipi in advanced NSCLC (CheckMate 227) Nivo vs Chemo Primary endpoint: OS N. pts: 1980

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50 A randomized, phase 3 trial with anti-pd-1 monoclonal antibody pembrolizumab (MK-3475) versus placebo for patients with early stage NSCLC after resection and completion of standard adjuvant therapy (PEARLS)

51 Conclusioni IT sta portando ad una rivoluzione nel NSCLC Anti-PD1/PDL-1 attivi in NSCLC con benefici durevoli (20-30% di lungo sopravviventi), indipendentemente dall istologia Maggiore attività PDL-1 + e Fumatori Nivolumab nuovo standard in pazienti pre-trattati La gestione della tossicità richiede una curva di apprendimento Ruolo dell espressione PDL-1? Come selezionare i pazienti (farmaci ad alto costo)? Studi in corso in vari setting di malattia: adiuvante; dopo CT- RT; mantenimento; I linea; combinazione con CT o con TK1

52 Grazie per l attenzione mtiseo@ao.pr.it