Immuuntherapie bij longkanker Robin Cornelissen Longarts Erasmus MC Rotterdam Week van de Pathologie 29 maart 2017 Ede
Disclosure belangen spreker (potentiële) belangenverstrengeling Voor bijeenkomst mogelijk relevante relaties met bedrijven Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Roche en BMS Zie hieronder Bedrijfsnamen
afweer respons tegen de tumor Adapted from: Chen et al. Immunity, 2013
Checkmate 017; Nivolumab squamous 2nd line Brahmer et al, NEJM 2015
Checkmate 057; nivolumab nonsquamous 2nd line Borghaei et al, NEJM 2015
Nivolumab nonsquamous 2nd line Luis Paz-Arez at ASCO 2015, CheckMate 057
Nivolumab nonsquamous 2nd line Luis Paz-Arez at ASCO 2015, CheckMate 057
Atezolizumab 2nd line Fehrenbacher, The Lancet 2016
Atezolizumab based on PD-L1 positivity
Pembrolizumab PD-L1 >50% PD-L1>1%
Anti-PD1 Standaardbehandeling in 2 e lijn bij NSCLC van alle histologiën 3 middelen geregistreerd: Nivolumab, zonder PD-L1 expressie, verkrijgbaar Pembrolizumab, >1% PD-L1 expressie, in sluis Atezolizumab (FDA only), zonder PD-L1 expressie, gaat in sluis
Response Rate for Patients with PD-L1 Negative NSCLC Drug (Trial) Histology Testing Cut-off for PDL1<0 ORR Nivolumab (Checkmate 017) Squamous Dako 28.8 <1% 17% Nivolumab (Checkmate 057) Non-squamous Dako 28.8 <1% 9% Atezolizumab (OAK) All histologies Ventana SP142 TC0 + IC0 8% Atezolizumab (Poplar) All histologies Ventana SP142 TC0 + IC0 7.8% Durvalumab (phase I) All histologies Ventana SP263 <25% 5% Pembrolizumab (phase I) All histologies Dako 22C3 <1% 8.1% Avelumab (phase Ib) All histologies Not specified <1% 10% Brahmer, NEJM 2015; Borghaei H et al. N Engl J Med 2015;373:1627-39; Fehrenbacher; Lancet 2016; Garon, NEJM 2015; Rebelatto, ASCO 2015; Herbst, Lancet 2015; Barlesi ESMO 2016.
PD-L1 Screening 1934 patients entered screening 1729 submitted samples for PD-L1 assessment 1653 samples evaluable for PD-L1 500 TPS 50% (30%) 1153 TPS <50%
Disposition of Study Treatment 305 patients randomly allocated a 154 allocated 154 treated Pembrolizumab 151 allocated 150 treated Chemotherapy 74 ongoing 80 discontinued 51 progressive disease 17 AEs 6 deaths 4 patient withdrawal 1 physician decision 1 complete response 66/151 (44%) crossed over to pembrolizumab in study b 15 ongoing 106 discontinued 69 progressive disease 16 AEs 9 deaths 5 patient withdrawal 7 physician decision 29 completed treatment
Reasons for screen failure were untreated brain metastases (n = 59), EGFR or ALK aberration (n = 30), ECOG PS 2 or 3 (n = 27), inadequate organ function (n = 19), prohibited intercurrent condition (n = 16), NSCLC not confirmed (n = 13), informed consent not provided (n = 11) other (n = 21).
PFS,% 100 90 80 70 60 50 Assessed per RECIST v1.1 by blinded, independent central review. Data cut-off: May 9, 2016. Progression-Free Survival 62% 50% Events, n Median, mo HR (95% CI) Pembro 73 10.3 0.50 Chemo 116 6.0 (0.37-0.68) 40 30 20 10 0 0 3 6 9 12 15 18 Time, months No. at risk 48% 15% 154 104 89 44 22 3 1 151 99 70 18 9 1 0 P <0.001
Nivolumab 1st line Socinski at ESMO 2016, CheckMate 026
Nivolumab 1st line Socinski at ESMO 2016, CheckMate 026
Socinski at ESMO 2016, CheckMate 026
Socinski at ESMO 2016, CheckMate 026
Anti-PD1 gerichte therapie 1 e lijns met pemboluzumab behandeling bij geselecteerde groep superieur PD-L1>50
Kan dat beter?
Checkmate 057; nivolumab nonsquamous 2nd line Borghaei et al, NEJM 2015
Chen et al. Immunity, 2013
Mutational load Lordick, Nature, 2016
Tumor micro-omgeving M2 M2 M2 Pro-tumor Anti-tumor Cornelissen, Clinical and Developmental Immunology, 2012
Dendritic cell immunotherapy in mesothelioma
Patient 5 CR >7 yrs after DC treatment Cornelissen, The American Journal of Respiratory and Critical Care Medicine, 2016 may 2016
T cell activatie/inhibitie
T cell trafficking
Multiple checkpoints Ott, ccr 2013
TIM 3 Jan von der Thüsen, Erasmus MC
Fase I klinische studie MBG453 (TIM3 antibody) PDR001 (Anti-PD1 antibody) responsevaluatie 10 april
Kim, annals onco 2016
Erasmus MC Thoracale Oncologie Kliniek Prof J Aerts Dr R Cornelissen J van Dijke Dr W Dinjens Drs D Dumoulin Dr M de Jonge B van de Kolck B Koning Drs A Maat Dr A Odink Drs R Peric Dr M van der Pol Drs J Praag Drs M Rossius Drs C Steendam E Stuyts Dr J von der Thüsen Dr R Valkema Klinische research L Cavazza A Geel M Gerrits A van der Giessen E van Helden L van Hove T Winter Preklinische research K Bezemer F Dammeijer P de Goeie Prof R Hendriks M Kaijen Dr(s)S Lievense L Noordam M Poncin S Sittig
Zaretsky et al., 2016, NEJM
Tumorcel ongevoelig voor interferon gamma Jak2 mutatie maakt ongevoelig voor interferon gamma
Tran et al., 2016, NEJM
HLA downregulatie