Marcello Tiseo
Oncologia Medica
Coordinatore PDTA Oncologia Toracica
Azienda Ospedaliero-Universitaria di Parma
Novità
nell’immunoterapia del NSCLC
Agenda
Introduzione
Anti-CTLA4: ipilimumab
Anti-PD1/Anti-PDL1:
– Evidenze di attività/efficacia – Tossicità
– Bio-marcatore (espressione di PDL1)
Strategie di combinazione
Prospettive future
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)
Immunotherapy (IT) and
Lung Cancer: background
Immunotherapy (IT) and
Lung Cancer: background
Immune Check-points Pathways
Ipilimumab nel NSCLC e SCLC
Lynch TJ et al, J Clin Oncol 2012 Reck et al, Ann Oncol 2012
Ipilimumab nel NSCLC
Lynch TJ et al, J Clin Oncol 2012
Ipilimumab nel NSCLC
Lynch TJ et al, J Clin Oncol 2012
Ipilimumab Phase III Trial on Squamous NSCLC – 1st line
Immune Check-points Pathways
Anti PD1/PD-L1 nel NSCLC
Target Agent Fase PD-1 Pembrolizumab (MK-3475, MSD) Approvato FDA 3
Nivolumab (BMS-936558, 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-935559 (MDX 1105, BMS-ONO) 1
MSB0010718C (EMD Serono, Merck kgA) 2-3
Nivolumab nel NSCLC:
Check-Mate 017 e 057 (II linea)
Brahmer et al, NEJM 2015
Nivolumab in Squamous NSCLC: Check-Mate 017
Brahmer et al, NEJM 2015
Nivolumab in Squamous NSCLC: Check-Mate 017
Brahmer et al, NEJM 2015
Nivolumab in Squamous NSCLC: Check-Mate 017
Reckamp K et al, WCLC 2015
Nivolumab in Squamous
Dati di follow-up più maturo…
Horn et al, WCLC 2015
Nivolumab in Squamous
Dati di follow-up più maturo (fase II, 063)
Borghaei et al, NEJM 2015
Nivolumab in Non-Squamous NSCLC: Check-Mate 057
Borghaei et al, NEJM 2015
Nivolumab in Non-Squamous NSCLC: Check-Mate 057
Borghaei et al, NEJM 2015
Nivolumab in Non-Squamous NSCLC: Check-Mate 057
Borghaei et al, NEJM 2015
Nivolumab in Non-Squamous NSCLC: Check-Mate 057
OS KEYNOTE 001
EGFR Status
PTS HR (95%CI)
MT 82 1.18 (0.69-2.00) WT 340 0.66 (0.51-0.89)
OS CHECKMATE 057
EGFR Status
PTS ORR
%
PFS OS
MT 77 7.8 ND ND WT 450 21.6 ND ND
Borghaei et al, NEJM 2015; Garon EB et al, NEJM 2015
Anti-PD1 e anti-PDL1:
Attività ed efficacia
Smoking History
PTS ORR
%
PFS OS
YES 369 22.5 4.2 14.3 NO 126 10.4 2.1 8.8
Smoking History
PTS HR (95%CI)
NO 118 1.02 (0.64-1.61) YES 458 0.70 (0.56-0.86)
Anti-PD1 e anti-PDL1:
Attività ed efficacia
PRIOR-TX
PRIOR NON-PRIOR
TX NIVO
squamous
NIVO adeno
ATEZO All comers
PEMBRO All comers
ORR (%) 20 19 15 19
mOS (mo) HR
9.2 0.62
12.2 0.73
12.6 0.73
12 - mPFS (mo)
HR
3.5 0.63
2.3 0.92
2.8 0.98
3.7
Borghaei et al, NEJM 2015; Brahmer et al, NEJM 2015 Alexander Spira, ASCO 2015; Garon EB et al, NEJM 2015
Nivolumab Check-mate 057:
Tossicità
Borghaei et al, NEJM 2015
Anti-PD1 e anti-PDL1 Tossicità di tutti i gradi
Borghaei et al, NEJM 2015; Brahmer et al, NEJM 2015 Alexander Spira, ASCO 2015; Garon EB et al, NEJM 2015
NIVO SQM
NIVO NON-SQM
ATEZO all comers
PEMBRO All comers
Fatigue 16 16 ~10 19.4
Rash 4 9 ND 9.7
diarrea 8 8 ~18 8.1
prurito 2 8 ND 10.7
polmonite 5 3 ~15 3.6
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
NIVO SQM
NIVO NON-SQM
ATEZO all comers
PEMBRO All comers
Any AEs 66.4 69 67 70.9
GR ≥ 3
AEs 7 10 12 9.5
GR 5
(death) 0 0 4 0.2
Anti-PD1 e anti-PDL1 Tossicità
Nivolumab:
In caso di PS 2?
Hussein et al, WCLC 2015
OR with anti-PD1 agent
according PDL-1 expression
Topalian et al, NEJM 2012
Brahmer et al, NEJM 2015
Nivolumab in Squamous
NSCLC: PDL-1 in Check-Mate 017
Borghaei et al, NEJM 2015
Nivolumab in Non-Squamous
NSCLC: PDL-1 in Check-Mate 057
Borghaei et al, NEJM 2015
Nivolumab in Non-Squamous
NSCLC: PDL-1 in Check-Mate 057
Garon, ESMO 2014
Pembrolizumab in PD-L1+
New Engl J Med 2015
1-49% ≥ 50%
N°
mOS (mesi) All 495 12 Naive 101 16.2
Prior Tx 394 (65% pts >
3° line)
9.3
<1%
FDA News Release- Oct 2 2015 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%)
POPLAR: A Randomized All-comer Phase II Study
Presented By Alexander Spira at 2015 ASCO Annual Meeting
PD-L1 Expression on TC and IC is a Potential Predictive Biomarker for Atezolizumab in NSCLC
Alla ricerca del biomarker…
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…)
Strategia di combinazione
Champiat et al, JTO 2014
Risultati preliminari di combinazione
Rizvi N et al. ORAL02.05
Risultati preliminari di combinazione
Camidge DR et al. ORAL02.07
Risultati preliminari di combinazione
Camidge DR et al. ORAL02.07
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
4 7 Phase III randomized trial of Nivo vs Nivo + Ipi vs Nivo + Ipi Nivo vs Chemo in advanced NSCLC (CheckMate 227)
Primary endpoint: OS N. pts: 1980
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)
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
