Nieuwe ontwikkelingen in de oncologie
Transcript of Nieuwe ontwikkelingen in de oncologie
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).