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)
Binnenkort kennen we alle gen. informatie voor start
Whole genome
Exome
mRNA
Poymorphisms normal control DNA
Meyerson et al, Nat Rev Gen 2011
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
NSCLC
Inversion
Translocation
or
ALK ~4%
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
PFS probability (%)
100
Events, n (%)
Median, months
HR (95% CI)
Pb
80
60
Crizotinib
Chemotherapy
(N=172)
(N=171)
100 (58)
137 (80)
10.9
7.0a
0.45 (0.35−0.60)
<0.0001
40
20
0
No. at risk
Crizotinib
Chemotherapy
●
0
5
10
172
171
120
105
65
36
15
20
Time (months)
38
12
19
2
25
30
35
7
1
1
0
0
0
Median duration of treatment: crizotinib, 10.9 months; chemotherapy, 4.1 months
Data cutoff: November 30, 2013
aAs-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
et al.2167-77,
NEJM 2014
Solomon et al.,Solomon
NEJM 371(23):
2014
Secondary Endpoints: ORR,a,1 OS,1 and Time to
Deterioration in Lung Cancer Symptomsb
ORR, n (%)
95% exact CI of ORR
Treatment difference, % (95% CI)
Pc
Median time to response, weeks (range)
Median duration of response, weeks
95% CIf
Crizotinib
(N=172)
128 (74)
67–81
Chemotherapy
(N=171)
77 (45)
37–53
29 (20−39)
<0.0001
6.1 (2.7−41.4)
12.1 (5.1−36.7)
49.0
22.9
35.1−60.0
18.0−25.1
● 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)
a
By IRR; btime to first ≥10-point from baseline in patient-reported chest pain,
dyspnea, or cough; cPearson χ2 test; din patients with an objective response
eKaplan−Meier method; fBrookmeyer−Crowley method
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-resistant
TKI-sensitive
Activated TK
OFF-TARGET
ON-TARGET
Activated TK
Mutant and/or amplified TK
P
TKI
PP
P
P
RTK1
TKI
P
RTK2
P
TKI
?
STAT
ERK
PI3K
STAT
ERK
ALK-dependent
RTK2
PI3K
STAT
ERK
PI3K
ALK-independent
P
Overview of Crizotinib Resistance
ON-TARGET:
Amplification
L1196M
G1269A/P
S1206Y
C1156Y
G1202R
I1171T
Multiple ALK mutations
ALK mutation of unknown
significance
No ALK mutations or amplification
N=51
First and Next Generation ALK Inhibitors
Crizotinib
Ceritinib
Alectinib
Marsilje et al., J Med Chem 56:5675-90, 2013; Johnson et al., J Med Chem 57:4720-44, 201
Brigatinib
Lorlatinib
Next Generation ALK Inhibitors Can Induce Rapid
Responses in Crizotinib-Resistant Patients
Baseline
Shaw et al., NEJM 370(13): 1189-97, 2014
After 3.5 weeks
of ceritinib
Activity of Alectinib in Crizotinib-Resistant,
ALK+ NSCLC
Global Phase 2 Study
140
120
Systemic BOR:
Sum of longest diameter,
maximum decrease from baseline (%)
100
PD (n=22)
SD (n=35)
PR (n=61)
80
60
40
20
*
**
0
–20
–40
–60
–80
–100
Ou et al., ASCO 2015
*
* *
** **
* ***
**
*
**
* ** *
*
**
Acquired Resistance to Next Generation
ALK Inhibitors
Baseline
WT EML4-ALK
After 8 weeks
of crizotinib
After 34 months
of crizotinib
After 12 weeks
of ceritinib
After 15 months
of ceritinib
ALK S1206Y
ALK G1202R
(sensitive to
ceritinib)
(resistant to
ceritinib)
Friboulet et al., Cancer Discov 4(6): 662-73, 2014
Shifting Profile of ALK Resistance Mutations
Depending on the ALK Inhibitor
+EMT
L1196M
G1202R
F1174C
Multiple ALK
mutations
No ALK
mutations
Post-crizotinib
(N=51)
G1202R
F1174C
Post-ceritinib
(N=21)
Lorlatinib (PF-06463922) Is Effective Against ALK
G1202R
Patient 1: ALK+ NSCLC
Previously treated with crizotinib and
ceritinib
Local molecular testing after ceritinib with
ALK G1202R
Started lorlatinib at 75 mg QD
Dose reduced to 50 mg QD
Ongoing at >16 months
Patient 2: ALK+ NSCLC
Previously treated with crizotinib and
brigatinib
Local molecular testing after brigatinib with
ALK G1202R
Started lorlatinib at 200 mg QD
Dose reduced to 100 mg QD
Ongoing 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”
4
3 ‘Priming’ en activatie
Actieve T cel
Actieve T cel
‘Trafficking’ van T cellen
naar tumoren
5
Infiltratie van
T cellen in de
tumor
Toenadering tot
de tumor
Dendritische
cel
Initieren en propageren
anti-cancer immuniteit
TUMOR MICROENVIRONMENT
6
kankercel herkenning
en start cytotoxiciteit
Antigenen
Apoptotische tumorcel
2
Antigeen
presentatie
Herkenning
van
kankercellen
door T cellen
Tumorcel
1
Vrijkomen van kankercel
antigenen
Modified from Chen and Mellman. Immunity 2013
7
Doden van kanker cellen
Tumor Infiltrerende Lymfocyten (TIL)
(HNSCC)
Diffuse infiltration with CD8+ TILs in HNSCC
Keck et al., Clin Canc Res 2014
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
Pre-treated-pts
+/- gp100
HLA-A2
3mg/kg
Re-induction possible
1 Year
Ipi + gp100 N=403
44%
1 Year
2 Year
3 Year
Ipilimumab+
DTIC
N=250
47.3
28.5
20.8
Placebo+
DTIC
N=252
36.3
17.9
12.2
2 Year
22%
Ipi + pbo N=137
46%
24%
gp100 + pbo
N=136
25%
14%
Hodi et al 2010 NEJM
naive-pts
+ DTIC
10 mg/kg
Maintenance possible
Robert et al NEJM 2011
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 antiCTLA-4 mAb treatment
hypophysitis
colitis
thyroiditis
hepatitis
meningitis
etc.
vitiligo
dermatitis
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 antiPD1/PDL1
Zeer snelle complete remissie na combinatie
immuuntherapie met anti-CTLA4 en anti-PD1
CheckMate 067: Study Design
Randomized, double-blind, phase III study
to compare NIVO + IPI or NIVO alone to IPI alone
NIVO 1 mg/kg +
IPI 3 mg/kg Q3W
for 4 doses then
NIVO 3 mg/kg Q2W
N=314
Stratify by:
Unresectable or
Metatastic Melanoma
• Previously untreated
Randomize
1:1:1
• 945 patients
• PD-L1
expression*
N=316
• BRAF status
NIVO 3 mg/kg Q2W +
IPI-matched placebo
• AJCC M stage
Co-primary endpoints:
PFS and OS (intent-to-treat population)
N=315
Treat until
progression**
or
unacceptable
toxicity
IPI 3 mg/kg Q3W
for 4 doses +
NIVO-matched placebo
Secondary and other endpoints:
ORR by RECIST v1.1
Predefined tumour PD-L1 expression level as a predictive
biomarker of efficacy
Safety profile (in patients who received ≥1 dose of study drug)
*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.
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)
100
Progression-free
PercentageSurvival
of PFS (%)
90
NIVO + IPI
(N=314)
NIVO (N=316)
IPI (N=315)
80
Median PFS, months
(95% CI)
11.5 (8.9–
16.7)
6.9 (4.3–9.5)
2.9 (2.8–3.4)
70
HR (99.5% CI) vs. IPI
0.42 (0.31–
0.57)*
0.55 (0.43–
0.76)*
--
60
HR (95% CI) vs. NIVO
0.76 (0.60–
0.92)**
-- log-rank P<0.00001
-- vs. IPI
*Stratified
49%
50
40
**Exploratory endpoint
46%
42%
39%
30
20
NIVO+IPI
18%
NIVO
10
14%
IPI
0
0
3
6
9
12
15
18
21
24
27
103
94
25
48
46
15
8
8
3
0
0
0
PFS per Investigator (months)
Number of patients at risk:
Nivolumab + Ipilimumab 314
Nivolumab 316
Ipilimumab 315
219
177
137
174
148
78
156
127
58
133
114
46
126
104
40
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
NIVO + IPI
(N=313)
Patients Reporting Event, %
NIVO
(N=313)
Any Grade
Grade
3–4
Any Grade
Grade
3–4
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
36
29
8
5
Treatment-related AE
Treatment-related AE leading to discontinuation
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
PD-L1 = 0% positief
PD-L1 = 2% positief
PD-L1 = 100% positief
Negatief
Zwak Positief
(1%-49%)
Sterk Positief
(50%-100%)
PD-L1 en respons in Melanoom en NSCLC
Melanoom
NSCLCs
Pembrolizumab
Pembrolizumab
ORR – “PDL1+”
1% cut-off: 49%
10% cut-off: 52%
ORR – “PDL1+”
1% cut-off: 25%
50% cut-off: 37%
ORR – PDL1-
1% cut-off: 13%
10% cut-off: 23%
ORR – PDL1-
1% cut-off: 7%
50% cut-off: 11%
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
Mutational load en uitkomst na ipilimumab
Snyder et al. NEJM 2014
Tobacco expositie en anti-PD-1 respons bij
NSCLC
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
Mutational load correleert met klinische uitkomst op anti-PD-1 in NSCLC
Validation cohort
p = 0.02
p = 0.04
# nonsynonymous mutations/tumor
Discovery cohort
Durable clinical
benefit
Rizvi et al, Science 2015
Non-durable
benefit
Durable clinical
benefit
Non-durable
benefit
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).