Immuuntherapie bij longkanker

Robin Cornelissen

Longarts

Erasmus MC

Rotterdam

Week van de Pathologie

29 maart 2017 Ede

(potentiële) belangenverstrengeling Zie hieronder

Voor bijeenkomst mogelijk relevante relaties

met bedrijvenBedrijfsnamen

Sponsoring of onderzoeksgeld

Honorarium of andere (financiële)

vergoeding

Aandeelhouder

Andere relatie, namelijk …

Roche en BMS

Disclosure belangen spreker

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 2e 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 histologiesVentana

SP142TC0 + 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 allocateda

Pembrolizumab

• 154 allocated

• 154 treated

Chemotherapy

• 151 allocated

• 150 treated

• 74 ongoing

• 80 discontinued

– 51 progressive disease

– 17 AEs

– 6 deaths

– 4 patient withdrawal

– 1 physician decision

– 1 complete response

• 15 ongoing

• 106 discontinued

– 69 progressive disease

– 16 AEs

– 9 deaths

– 5 patient withdrawal

– 7 physician decision

• 29 completed treatment

66/151 (44%) crossed over to

pembrolizumab in studyb

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).

Progression-Free Survival

Assessed per RECIST v1.1 by blinded, independent central review.Data cut-off: May 9, 2016.

Events, n Median,

mo

HR

(95% CI)

P

Pembro 73 10.3 0.50

(0.37-0.68)<0.001

Chemo 116 6.0

62%

50%

0 3 6 9 12 15 180

102030405060708090

100

Time, months

PFS

,%

No. at risk

154 104 89 44 22 3 1151 99 70 18 9 1 0

48%

15%

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

1e 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

Cornelissen, Clinical and Developmental Immunology, 2012

Tumor micro-omgeving

Pro-tumor Anti-tumor

M2

M2M2

Dendritic cell immunotherapy in mesothelioma

Patient 5

CR >7 yrs after DC treatment

may 2016Cornelissen, The American Journal of Respiratory and Critical Care Medicine , 2016

T cell activatie/inhibitie

T cell trafficking

Ott, ccr 2013

Multiple checkpoints

Jan von der Thüsen, Erasmus MC

TIM 3

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

Preklinische research

K Bezemer

F Dammeijer

P de Goeie

Prof R Hendriks

M Kaijen

Dr(s)S Lievense

L Noordam

M Poncin

S Sittig

Klinische research

L Cavazza

A Geel

M Gerrits

A van der Giessen

E van Helden

L van Hove

T Winter

Zaretsky et al., 2016, NEJM

Jak2 mutatie maakt ongevoelig voor interferon gamma

Tumorcel ongevoelig voor interferon gamma

Tran et al., 2016, NEJM

HLA downregulatie