Longkanker: Immuun voor therapie? Els De Droogh, longarts, ZNA Middelheim, Antwerpen LOK, huisartsen Hoboken, 14/03/2019
Immunotherapie voor de long Hype? Werkingsmechanisme In praktijk Voordelen Nevenwerkingen
Nobelprijs 2018 Tasuku Honjo, Universiteit Kyoto, Japan James P. Allison Universiteit Texas, USA
Waarom herkent ons lichaam geen kankercellen?
Wetenschap
Checkpoints
Antitumor Immune Response T-cell mediated immune response 1,2 Tumor-specific antigens Antitumor effector mechanisms Dendritic cell Tumor cell Naïve cytotoxic T cell Activated cytotoxic T cell Tumor cell The body s immune response can detect and destroy tumor cells through activated T cells and other mechanisms 1 Tumor cells express multiple antigens that are not expressed in normal tissue 2 Image adapted from Chen DS et al. Immunity. 2013;39(1):1 10. Reprinted with permission from Elsevier. May KF Jr et al. In: Prendergast GC et al. Cancer Immunotherapy. 2nd ed. Philadelphia, PA: Elsevier; 2013:101 113. Chen DS et al. Immunity. 2013;39(1):1 10. 7
In Advanced tumors, the PD-1 Pathway May Be Exploited to Evade the Immune Response Antigen Antigen TCR MHC TCR MHC PD-1 PD-L1 PD-1 PD-L1 PD-L2 PD-L2 Activated cytotoxic T cell Tumor cell/apc Inactivated cytotoxic T cell Tumor cell/apc Emerging research has identified PD-1 as a key immune checkpoint pathway involved in inhibiting the T-cell mediated immune response Tumor cells can downregulate T-cell activity by exploiting the PD-1 checkpoint pathway through expression of the PD-1 ligands, PD L1 and PD L2 PD-L1 and PD-L2 engage the PD-1 receptor on T cells to inactivate them, which may allow tumor cells to evade the immune response APC = antigen-presenting cell; MHC = major histocompatibility complex; NSCLC = non small cell lung cancer; PD-1 = programmed death receptor- 1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252 264. SPC Keytruda, 09/2018 Pardoll DM. Nat Rev Cancer. 2012;12(4):252 264. 8
PD-1 Receptor Blockade With Pembrolizumab By inhibiting the PD-1 receptor from binding to its ligands, pembrolizumab reactivates tumor-specific cytotoxic T lymphocytes in the tumor microenvironment and reactivates antitumor immunity 1 Antigen Antigen TCR MHC TCR MHC KEYTRUDA PD-1 PD-L1 PD-1 PD-L1 PD-L2 KEYTRUDA PD-L2 Inactivated cytotoxic T cell Tumor cell/apc Activated cytotoxic T cell Tumor cell/apc APC = antigen-presenting cell; MHC = major histocompatibility complex; PD-1 = programmed death receptor-1; PD-L1 = programmed death ligand 1; PD-L2 = programmed death ligand 2; TCR = T-cell receptor. Image adapted with permission from Pardoll DM. Nat Rev Cancer. 2012;12(4):252 264. SPC Keytruda, 09/2018 2. Pardoll DM. Nat Rev Cancer. 2012;12(4):252 264. 9
Checkpoint controle
Beelden zeggen meer dan woorden
Werking immunotherapie
Bijwerking immunotherapie Te weinig Infectie Kanker Te veel Inflammatie Auto-immune pathologie
Xxxxxxx-MAB Monoclonale antilichamen Programmed death-ligand 1 PD-1 T-cel PDL-1 Tumor-cel
Antilichamen als therapie
Check point stofnaam merknaam firma Immunotherapie gevorderd longcarcinoma Anti-PD-1 nivolumab opdivo Merck&co Anti-PD-1 pembrolizumab keytruda Bristol-myers squibb Anti-PD-L1 atezolizumab tecentriq Roche Anti-PD-L1 durvalumab imfinzy Astra zeneca Anti-CTLA-4 ipilimumab yervoy Anti-CTLA-4 tremelimumab
Longcarcinoma SCLC Limited Extensive NSCLC Adenocarcinoma Squameus (spino) carcinoma Grootcellig (neuro endocrien ) carcinoma stadium I, II, III, IV
Doelgroep Stadium III ( inoperabel) Stadium IV NSCLC In eerste lijn In tweede lijn
In tweede lijn CheckMate 017 NSCLC Nivolumab Squameus Carcinoma Adenocarcinoma Alle waarden PDL-1 (0%-100%)
Check Mate 017 Overal survival Nivolumab
Check Mate 017 Toxiciteit
Versus docetaxel Response rate Mediane 1-j OS ratio HR voor OS Immuno overal versus Docetaxel survival (m) tweede lijn Check Mate 017 20% versus 9% 9,2 vs 6,0 42% vs 24% 0,59 CheckMate 057 19% versus 12% 12,2 vs 9,4 51% vs 39% 0,74 Keynote 010 (2 mg/kg) 18% versus 9% 18 vs 8,5 43% vs 35% 0,71 Oak bijwerking chemo vs Atezo 18 versus 16% 13,8 vs 9,6 55 vs 41% 0,74
In eerste lijn KEYNOTE- 024 Pembroluzimab NSCLC Adenocarcinoma PDL-1 >50%
Keynote024
Globale overleving
Keynote -024 bij PDL1>50% Pembroluzimab Grotere kans op effect Hoe hoger expressie van PD-L1 op de tumorcel Hoge mutational burden (roker) KRAS-mutatie tumorcel Minder kans op effect Nooit-roker EGFR- of ALK-mutatie in tumorcel
In adjuvante therapie Pacific trial Durvalumab Stadium III (lokaal gevorderd) Na eerste lijn met concomitante chemo- en radiotherapie
Pacific trial
Eerste lijn chemo + immunotherapie(pembroluzimab) KEYNOTE -189 NSCLC Doublet chemotherapie Doublet chemotherapie + immunotherapie
KEYNOTE-189: Study design Analysis cut-off date: 08 November 2017. Ghandi L, et al. KN-189: Randomized Double-Blind, Phase 3 Study of Pembrolizumab or Placebo plus Pemetrexed and Platinum as First-Line Therapy for Metastatic NSCLC, presented at AACR 2018 30
KEYNOTE-189: Overall Survival ITT population Pembrolizumab in combination with pemetrexed and platinum significantly prolonged overall survival compared to placebo plus pemetrexed and platinum. (HR 0.49) Analysis cut-off date: 08 November 2017. CI: confidence interval; HR: hazard ratio; ITT: intention-to-treat; NR: not reached; OS: overall survival. Ghandi L, et al. KN-189: Randomized Double-Blind, Phase 3 Study of Pembrolizumab or Placebo plus Pemetrexed and Platinum as First-Line Therapy for Metastatic NSCLC, presented at AACR 2018 31
KEYNOTE-189: Overall Survival by PD-L1 TPS Superior OS observed irrespective of PD-L1 TPS Analysis cut-off date: 08 November 2017. CI: confidence interval; HR: hazard ratio; ITT: intention-to-treat; NR: not reached; OS: overall survival; TPS: tumor proportion score Ghandi L, et al. KN-189: Randomized Double-Blind, Phase 3 Study of Pembrolizumab or Placebo plus Pemetrexed and Platinum as First-Line Therapy for Metastatic NSCLC, presented at AACR 2018 32
Naar de praktijk
Flowchart diagnose 1.Histologische diagnose ( biopten ) NSCLC 2. Type Adeono, spino, NE 3. Staging 4. Genetisch profiel (Histogenex PD-L1 ( 7 wd), mutaties >14wd) EGFR of AKL mutaties : TKI PD-L1 expressie : Hoog> 50% Immuno (Pembrolizumab) bij progressie chemo >1-5%-50% Pembrolizumab +/-Chemo
Precision cancer treatment - a new paradigma
Genetic testing - Key to precision cancer medicine
Next Generation Sequencing
Mutaties
Molecular Advice Board
Algoritme R/in NSCLC III/IV
Nevenwerkingen
Checkpoint inhibitor therapy: a new spectrum of adverse events Champiat et al. Annals of Oncology, 2016;27:559-74. 43
Immune related adverse events (iraes)
Inschatten ernst nevenwerking
Incidentie van iraes
Nivolumab all ireas s (%)
Nivolumab grade ¾ irae (%)
Pembroluzimab irea (%)
Van dag 1 tot x-tijd na stop
Hoe herkennen en aanpakken
Start- Monitor -Manage Bilan voor start Anamnese :auto-immune aandoeningen patiënt/familie Beroepsanamnese: silicose, minerale stoffen Doorgemaakte infecties: hepatitis, HIV, tbc, Medicatiegebruik: interferentie corticoïden, NSAID, allopurinol, salicylaten, metformine Bloedname: hemato, leverset, nierfunctie, TSH,T3, T4, ACTH, hepatitis serologie, HIV Urine sediment : eiwitten EKG+ echocardio Longfunctie Rx thorax/ct thorax
Start-Monitor -Manage Informatie patiënt en familie Eerste weken extra klinische controle Telefoonnummer/bereikbaarheid Info spoed /cardiologen Info specialisten Orgaan specifieke verantwoordelijke Guidelines ESMO en ASCO
Algemene bijwerkingen
Hepatitis
Colitis
Endocriene bijwerkingen
Pneumonitis
Pneumonitis
Behandeling pneumonitis
Huidtoxiciteit
Zeldzame bijwerkingen
Bij twijfel
Algemene behandelrichtlijnen
Start-Monitor- Manage Corticoïden 1-2 mg prednison/kg/d Afbouw over minstens 1 maand Preventie Eusaprim (PCP), Nicotibine 300 mg (TBC) Opvolgen graad van nevenwerkingen tijdens afbouw STOP graad 4 graad 3 met recidief graad 2 na 3 maanden therapie Herstart als prednison <=10 mg/d
Casuistiek
1. Man, 47j Roker Stadium IV Adeonocarcinoma hersenmetastase Eerste lijn Chemotherapie /HK/RT PDL1 90% Tweede lijn Nivolumab 2. Man 69j Roker Stadium IV adenocarcinoma PDL1 60% Eerste lijn Pembroluzimab 200 mg, na C3 groei ct (flair?), nog 2C Tweede lijn chemotherapie; partiele respons 3. Man 49j Roker Stadium IV adenocarcinoma PDL1 80% Eerste lijn Pembroluzimab
Pseudoprogression
Hyperprogression
4. Man 73j Spinocellulair carcinoma stadium IIA Chemo/RT TKI Nivolumab 240 mg Sepsis? ACTH, substitutie hydrocortisone Hepatitis graad III Verdere partiele respons 5. Vrouw 68j Stadium IV adenocarcinoma-botmetastasen Chemo/RT Tweede lijn Nivolumab Hepatitis graad 3 Tijdens afbouw medrol tot 8 mg Hypoxie, pneumonitis