Nieuwe ontwikkelingen in de

oncologie

John Haanen

My disclosures

• Adviesraad: BMS, MSD, Pfizer, Novartis, Roche, NEON Therapeutics

• Research grant: BMS, GSK, MSD

Alle neveninkomsten gaan naar NKI-AVL

Overzicht

• “Personalized” doelgerichte behandelingen

• Immuuntherapie van kanker

Overzicht

• “Personalized” doelgerichte behandelingen

• Immuuntherapie van kanker

Next Generation Sequencing (NGS)

Meyerson et al, Nat Rev Gen 2011Poymorphisms � normal control DNA

Binnenkort kennen we alle gen. informatie voor start

Whole genome

Exome

mRNA

Longkanker als kleurrijke taarten

Oncogene drivermutaties in

adenocarcinoom zijn talrijker

TCGA, Nature 2014

Oncogen-addicted NSCLC:

Moeten we ze allemaal testen?

Frontline?

Cortesy of Drs Mitsudomi and Suda

ALK-Rearranged NSCLC

Inversion Translocation

or

ALK ~4%

NSCLC

Soda et al., Nature 448: 561-7, 2007

Clinicopathologic features:• Never or light smoking history• Younger age• Adenocarcinoma histology, often with signet ring cells

ALK gedreven oncogene pathway

ALK Rearrangement Confers Sensitivity to Small

Molecule Tyrosine Kinase Inhibitors of ALK

Pre-Treatment Crizotinib x 12 weeks

Crizotinib Is Superior to Platinum Combination

Chemotherapy in First-Line ALK+ NSCLC

Data cutoff: November 30, 2013aAs-treated population: pemetrexed−cisplatin, 6.9 months (n=91; HR: 0.49; P<0.0001); pemetrexed−carboplatin, 7.0 months (n=78; HR: 0.45; P<0.0001)b2-sided stratified log-rank test

Crizotinib(N=172)

Chemotherapy(N=171)

Events, n (%) 100 (58) 137 (80)

Median, months 10.9 7.0a

HR (95% CI) 0.45 (0.35−0.60)

Pb <0.0001

PF

S p

rob

ab

ilit

y (

%)

100

80

60

40

20

0

0 5 10 15 20 25 30 35

Time (months)

172 120 65 38 19 7 1 0171 105 36 12 2 1 0 0

No. at riskCrizotinib

Chemotherapy

Solomon et al., NEJM 371(23): 2167-77, 2014

● Median duration of treatment: crizotinib, 10.9 months; chemotherapy, 4.1 months

Solomon et al. NEJM 2014

Secondary Endpoints: ORR,a,1 OS,1 and Time to

Deterioration in Lung Cancer Symptomsb

Crizotinib(N=172)

Chemotherapy(N=171)

ORR, n (%) 128 (74) 77 (45)

95% exact CI of ORR 67–81 37–53

Treatment difference, % (95% CI) 29 (20−39)

Pc <0.0001

Median time to response, weeks (range) 6.1 (2.7−41.4) 12.1 (5.1−36.7)

Median duration of response, weeks 49.0 22.9

95% CIf 35.1−60.0 18.0−25.1

aBy IRR; btime to first ≥10-point ����from baseline in patient-reported chest pain,

dyspnea, or cough; cPearson χ2 test; din patients with an objective responseeKaplan−Meier method; fBrookmeyer−Crowley method

● Objective responses with crizotinib were rapid and durable

● With 68% of patients still in follow-up, median OS was not reached in either arm

– There was a numerical improvement in OS in the crizotinib arm (HR: 0.82; 95% CI: 0.54–1.26; P=0.361)

– Analysis was not adjusted for the potentially confounding effects of crossover – 120/171 chemotherapy patients (70%) received crizotinib after progression

● Time to deterioration in lung cancer symptomsb was significantly longer with crizotinib than with chemotherapy (P=0.002)

Solomon et al., ESMO 2014

Almost All Patients Relapse on Targeted

Therapies Due to Acquired Resistance

Pre-treatment Response to crizotinib Progression on crizotinib

General Classes of Acquired Resistance

TKI

Activated TK

PI3KERKSTAT

TKI-sensitive ON-TARGET

Mutant and/or amplified TK

PI3KERKSTAT

P PP PP P RTK2

Activated TK

PI3KERKSTAT

RTK1

P

RTK2

P

OFF-TARGET

?

TKI-resistant

TKI

TKI

ALK-dependent ALK-independent

Overview of Crizotinib Resistance

ON-TARGET:

Amplification

L1196M

G1269A/P

S1206Y

C1156Y

G1202R

I1171T

Multiple ALK mutations

ALK mutation of unknownsignificance

No ALK mutations or amplification

N=51

First and Next Generation ALK Inhibitors

Marsilje et al., J Med Chem 56:5675-90, 2013; Johnson et al., J Med Chem 57:4720-44, 201

Crizotinib Ceritinib

Alectinib

Brigatinib

Lorlatinib

Next Generation ALK Inhibitors Can Induce Rapid

Responses in Crizotinib-Resistant Patients

After 3.5 weeks

of ceritinib

Baseline

Shaw et al., NEJM 370(13): 1189-97, 2014

Activity of Alectinib in Crizotinib-Resistant, ALK+ NSCLC

Ou et al., ASCO 2015

*

* *

Su

m o

f lo

ng

est

dia

me

ter,

ma

xim

um

de

cre

ase

fro

m b

ase

lin

e (

%)

140

120

40

0

–20

–100

100

80

60

20

–40

–60

–80

*

* *

* ***

* *

* ***

*

***

***

***

PD (n=22) SD (n=35) PR (n=61)Systemic BOR:

Global Phase 2 Study

Baseline After 8 weeks of crizotinib

WT EML4-ALK

After 34 months of crizotinib

After 12 weeks of ceritinib

After 15 months of ceritinib

Friboulet et al., Cancer Discov 4(6): 662-73, 2014

Acquired Resistance to Next Generation ALK Inhibitors

ALK S1206Y

(sensitive to

ceritinib)

ALK G1202R

(resistant to

ceritinib)

Shifting Profile of ALK Resistance Mutations Depending on the ALK Inhibitor

Post-ceritinib

(N=21)

Post-crizotinib

(N=51)

L1196M

G1202R

F1174C

Multiple ALK

mutations

No ALK

mutations

G1202R

+EMT

F1174C

Lorlatinib (PF-06463922) Is Effective Against ALK

G1202R

Patient 1: ALK+ NSCLCPreviously treated with crizotinib and ceritinibLocal molecular testing after ceritinib with ALK G1202RStarted lorlatinib at 75 mg QDDose reduced to 50 mg QDOngoing at >16 months

Patient 2: ALK+ NSCLCPreviously treated with crizotinib and brigatinibLocal molecular testing after brigatinib with ALK G1202RStarted lorlatinib at 200 mg QDDose reduced to 100 mg QDOngoing at >12 months

Shaw et al., ASCO 2015

Conclusies

• Doelgerichte behandeling (targeted therapy) is vaak zeer

effectief bij patienten met oncogene ‘driver’ mutaties

• Behandeling kan aanleiding geven tot zeer significante

verbetering in PFS en OS van patienten

• Grootste probleem is het ontstaan van resistentie, vaak

ivv nieuwe mutaties in zelfde gen

• Soms te overkomen met nieuwe drugs specifiek voor

deze nieuwe mutaties

• Deze behandelingen leiden zelden tot nooit tot genezing

Overzicht

• “Personalized” doelgerichte behandelingen

• Immuuntherapie van kanker

Immuuntherapie in wetenschappelijke bladen

2013 2014 2015

Immuuntherapie in lekenpers

“The cancer-immunity cycle”

Modified from Chen and Mellman. Immunity 2013

Toenadering tot

de tumor

Actieve T cel

TUMOR MICROENVIRONMENT

3 ‘Priming’ en activatie

2 Antigeen

presentatie

1 Vrijkomen van kankercel

antigenen7 Doden van kanker cellen

6 Herkenning

van

kankercellen

door T cellen

5 Infiltratie van

T cellen in de

tumor

4 ‘Trafficking’ van T cellen

naar tumoren

Apoptotische tumorcel

kankercel herkenning

en start cytotoxiciteit

Antigenen

Initieren en propageren

anti-cancer immuniteit

Dendritische

cel

Actieve T cel

Tumorcel

Tumor Infiltrerende Lymfocyten (TIL) (HNSCC)

Keck et al., Clin Canc Res 2014

Diffuse infiltration with CD8+ TILs in HNSCC Absence of TILs in HNSCC

Rol voor T cellen bij kanker

T cell activation requires at least 2 signals

www.immunooncologyhcp.bmsinformation.com

CTLA4 ligation dampens an induced T

cell response

www.immunooncologyhcp.bmsinformation.com

CTLA4 blockade renders T cells in an

active state

Ribas. NEJM 2012

Ipilimumab

Hodi et al 2010 NEJM

1 Year 2 Year

Ipi + gp100 N=403 44% 22%

Ipi + pbo N=137 46% 24%

gp100 + pboN=136 25% 14%

1 Year 2 Year 3 Year

Ipilimumab+ DTIC

N=25047.3 28.5 20.8

Placebo+ DTIC

N=252

36.3 17.9 12.2

Pre-treated-pts+/- gp100HLA-A23mg/kg

Re-induction possible

Robert et al NEJM 2011

naive-pts+ DTIC

10 mg/kgMaintenance possible

Pooled OS Analysis of ipilimumab treated 4846

patients (incl EAP)

Mediane OS (95% CI): 9.5 (9.0–10.0)

3-year OS rate (95% CI): 21% (20–22%)

Schadendorf et al., J Clin Oncol 2015

Immune related adverse events upon anti-

CTLA-4 mAb treatmentcolitis hypophysitis

vitiligo dermatitis

thyroiditis

hepatitis

meningitis

etc.

Immune checkpoints PD1/PDL1

www.immunooncologyhcp.bmsinformation.com

PD1/PDL1 blockade reinvigorates

inactivated T cells at the tumor site

Ribas. NEJM 2012

Updated OS results from CheckMate 066 trial in BRAF wt advanced melanoma

Atkinson et al. abstract 3774 SMR 2015

Nivolumab: Overall survival in NSCLC (>1st line therapy with cisplatin doublet)

Nivolumab

http://packageinserts.bms.com/pi/pi_opdivo.pdf

Activity of anti-PD1/PDL1 over many tumor

types

Courtesy of J Eid

Combinatie van anti-CLTA4 en anti-

PD1/PDL1

Zeer snelle complete remissie na combinatie

immuuntherapie met anti-CTLA4 en anti-PD1

CheckMate 067: Study Design

Randomized, double-blind, phase III studyto compare NIVO + IPI or NIVO alone to IPI alone

Unresectable or

Metatastic Melanoma

• Previously untreated

• 945 patients

Treat until progression**

orunacceptable

toxicity

NIVO 3 mg/kg Q2W +IPI-matched placebo

NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then

NIVO 3 mg/kg Q2W

IPI 3 mg/kg Q3W for 4 doses +

NIVO-matched placebo

Randomize

1:1:1

Stratify by:

• PD-L1 expression*

• BRAF status

• AJCC M stage

N=314

N=316

N=315

*Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses.

**Patients could have been treated beyond progression under protocol-defined circumstances.

Co-primary endpoints:PFS and OS (intent-to-treat population)

Secondary and other endpoints:

ORR by RECIST v1.1Predefined tumour PD-L1 expression level as a predictive biomarker of efficacySafety profile (in patients who received ≥1 dose of study drug)

1. Larkin et al. N Engl J Med 2015; 373:23-34. 2. Oral presentation by Dr. Jedd Wolchok at the ASCO 2015 Annual Meeting.

Progression-Free Survival (Intent-to-Treat Population)

49%

42%

18%

46%

39%

14%

Perc

en

tag

e o

f P

FS

PFS per Investigator (months)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 272421

314

316

315

174

148

78

133

114

46

103

94

25

8

8

3

219

177

137

156

127

58

126

104

40

48

46

15

0

0

0

Number of patients at risk:

Nivolumab + Ipilimumab

Nivolumab

Ipilimumab

NIVO+IPI

NIVO

IPI

NIVO + IPI (N=314) NIVO (N=316) IPI (N=315)

Median PFS, months (95% CI)

11.5 (8.9–16.7)

6.9 (4.3–9.5) 2.9 (2.8–3.4)

HR (99.5% CI) vs. IPI0.42 (0.31–

0.57)*0.55 (0.43–

0.76)*--

HR (95% CI) vs. NIVO0.76 (0.60–

0.92)**-- --*Stratified log-rank P<0.00001 vs. IPI

**Exploratory endpoint

Pro

gre

ssio

n-f

ree S

urv

ival (%

)

Database lock Nov 2015

1. Larkin et al. N Engl J Med 2015; 373:23-34. 2. Oral presentation by Dr. Jedd Wolchok at the ASCO 2016 Annual Meeting.

Safety Summary by Key Subgroups

Patients Reporting Event, %

NIVO + IPI (N=313)

NIVO (N=313)

Any GradeGrade

3–4 Any GradeGrade

3–4

Treatment-related AE 96 55 82 16

Age ≥65 and <75 years 95 50 81 22

Age ≥75 and <85 years 97 48 83 21

M1c disease 94 54 79 14

PD-L1 expression ≥5% 97 53 85 16

Patients with complete response 100 58 93 32

Treatment-related AE leading to discontinuation 36 29 8 5

Treatment-related death* 0 <1

*One death in the NIVO group was reported as neutropaenia.

Treatment-related AEs reported with IPI were consistent with prior experience

Combinatie immuuntherapie

• Klinische trials bij

– NSCLC

– Uitgezaaide nierkanker

– Uitgezaaide blaaskanker

– Uitgezaaide HH kanker

– Etcetera.

Potentiele biomarkers voor respons op immuuntherapie

• CD8 T cel infiltraten

• Expressie van PDL1 op:

– Tumorcellen

– Immuuncellen

• Tumor mutational burden

CD8 T cellen in ‘invasive tumor margins’ correleert met respons op anti-PD1

Tumeh et al. Nature 2014

Potentiele biomarkers voor respons op immuuntherapie

• CD8 T cel infiltraten

• Expressie van PDL1 op:

– Tumorcellen

– Immuuncellen

• Tumor mutational burden

OS in Checkmate-066 naar PDL1 expressie

Atkinson et al. abstract 3774 SMR 2015

(MSD) PD-L1 NSCLC IHC kleuring

Negatief Zwak Positief(1%-49%)

PD-L1 = 0% positief PD-L1 = 2% positief PD-L1 = 100% positief

Sterk Positief(50%-100%)

PD-L1 en respons in Melanoom en NSCLC

Pembrolizumab

ORR – “PDL1+”1% cut-off: 49%

10% cut-off: 52%

ORR – PDL1-1% cut-off: 13%

10% cut-off: 23%

Pembrolizumab

ORR – “PDL1+”1% cut-off: 25%

50% cut-off: 37%

ORR – PDL1-1% cut-off: 7%

50% cut-off: 11%

Melanoom NSCLCs

Daud, AACR 2014

Garon, WCLC 2013, #2416

Ghandi, AACR 2014

Potentiele biomarkers voor respons op immuuntherapie

• CD8 T cel infiltraten

• Expressie van PDL1 op:

– Tumorcellen

– Immuuncellen

• Tumor mutational burden

Correleert de mate van DNA schade

met klinische effecten van immuuntherapie van kanker?

Alexandrov et al, Nature 2013

Snyder et al. NEJM 2014

Mutational load en uitkomst na ipilimumab

Tobacco expositie en anti-PD-1 respons bijNSCLC

Govindan et al., Cell 2012

Never

smokers

Smokers or

Ex-smokers

Pembrolizumab 5/60 (8%) 33/129 (26%) Garon et al, ASCO 2014

MPDL3280A 1/10 (10%) 11/43 (26%) Soria et al, WCLC 2013

Nivolumab 0/13 (0%) 20/75 (25%) Hellmann et al, ESMO 2014

Courtesy of Dr Rizvi

p = 0.04

Validation cohort

p = 0.02

# n

on

syn

on

ym

ou

sm

uta

tio

ns/t

um

or

Discovery cohort

Durable clinical

benefitNon-durable

benefit

Durable clinical

benefitNon-durable

benefit

Rizvi et al, Science 2015

Mutational load correleert met klinische uitkomst op anti-PD-1 in NSCLC

Respons op anti-PD1 bij mismatch repair deficiente

tumoren

Le et al., NEJM 2015

De kans op respons op immuuntherapie is correleert met mutational burden

Schumacher & Schreiber. Science 2015

Conclusies

• Immuuntherapie van kanker is een revolutie in de

behandeling van deze aandoening

• Immuunstimulatie door inhibitie van immunologische

checkpoint eiwitten zorgt voor klinische effecten en soms

langdurige remissies (wellicht soms curatie) bij vele soorten

van kanker

• Behandeling kan gepaard gaan met auto-immuunachtige

bijwerkingen (tgv onderdrukking van perifere tolerantie)

• Vele nieuwe combinatiebehandelingen zijn in ontwikkeling

• Behandeling met adoptieve celtherapie ivv genetisch

veranderde T cellen is eveneens een doorbraak bij vnl

hematologische maligniteiten (zogenaamde CAR-T cellen).