Lungcancerbiologi – en uppdatering
Stéphanie Mindus, specialistläkare Lung- och Allergisektionen, Akademiska sjukhuset, Uppsala
Strålbehandling
Stort behov av nya lungcancerbehandlingar!
Immunterapi
Targeted Therapies
Science. 2002;297(5578):63-64.
Nana-Sinkam. Chest. 2013;143(5_suppl):e30S-e39S.
Tumördrivande mutationer vid NSCLC
J Clin Oncol 2013; 31: abst 8019
► Testing for all genetic alteration is recommended
► NGS and multiplex techniques are recommended
http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf
LuxLung 3
Response rate
56% vs 23%
Lux Lung 3&6. ASCO 2014. Presenter: James Chih-Hsin Yang
Profile 1001 - Crizotinib
ORR ratio: 3.4 (95% CI: 2.5 to 4.7);
P<0.0001
Crizotinib (n=173b)
Chemotherapy (n=174b)
80
65.3
ORR (%)
60
40
19.5
20
0
Treatment
Shaw AT, et al. N Engl J Med 2013;368:2385–94
Lung Cancer 76 (2012) 1– 18
Vilka tester på vilket tumörmaterial?
ALK translocation
EGFR mutation
MET
Herbst RS, Hirsch FR. Lancet 373 (2009)
Internationella guidelines
Society
Targeted therapy
recommended
Molecular pathology
ACCP
yes
yes
NCCN
yes
yes
ESMO
yes
yes
ASCO, ATS, CAP,
NiCE, ERS;
National societies
yes
(yes)
(n.e.)
(n.e.)
Fr. Rainer Wiewrodt. ERS 2014
Kerr et al. Annals of Oncology 2014, 25:1681-1690, 2014 (September 2014)
EGFR och ALK-testning i klinisk praxis
89%
71%
40%
50%
50% 36%
Univ.
14%
all
Pul.
Clinic
EGFR
3%
ALK
ALK
EGFR
ALK
► Normative force of financial needs and dependencies
► Reimbursement; stable price even in case of increasing number of mutations
Fr. Wiewrodt. ERS 2014
Geografiska skillnader
ERS White Book 2013
Resistensmekanismer
EGFR Mut+
Unknown
18%
Small cell +
MET
1%
MET
amplification
3%
Small cell
1%
Small cell +
T790M
2%
MET+ T790M
3%
EML4-ALK+
HER2
8%
HER2 + T790M
4%
inc. L1196M
Unknown
Target gene
alteration
(29%)
*
T790M
60%
*
Bypass track
activation
(45%)
ALK amplification
ALK mutation
EGFR mutation
CKIT amplification
Unknown
*more than one resistance mechanism
Common themes
Second site mutations in target (e.g., T790M / L1196M)
Use of alternative signalling pathways (e.g., MET / EGFR)
Fr. Cotrot ERS 2014
Behandling av förvärvad EGFR-resistens
1st generation
2nd generation
3rd generation
drugs
core
binding
gefitinib,
erlotinib
quinazoline
reversible
No
No
afatinib,
quinazoline irreversible
dacomitinib
Yes
No
Yes
Yes
AZD9291,
CO-1686
pyrymidine
irreversible
Efficacy on
Efficacy on
T790M in vitro T790M+ NSCLC
patients
Behandling av förvärvad TKI-resistens
AZD9291
• 3rd
generation TKIs
• Phase I study with expansion
cohort
• Patients with EGFR-mutated
NSCLC, progression upon TKI,
n = 232
• T790M+ = 60%
• ORR = 53% (65% in T790M+
pts, 22% in T790M- pts), DCR
= 83%
40
20
0
-20
-40
-60
-80
-100
Complete Response
Partial Response
No response
– Toxicity
• Few rash and diarrhea
• No DLT
• 6 ILD
Fr. Cotrot. ERS 2014
Resistensmekanismer vid ALK+
Camidge, Doeble. Nature Rev. 2012.
ASCEND-1 trial: activity of LDK378 in advanced
crizotinib naïve and resistant ALK+ NSCLC
Antitumor Activity
PFS
Shaw AT, NEJM 2014 Kim D et al., ASCO 2014
Immunologisk behandling vid lungcancer
Olika behandlingsformer
AKTIV
• Tumörvacciner
• Manipulerad mikromiljö
• Adoptive T cell Transfer
PASSIV
• Antikroppar
• Check point-blockad
Paroll D. et al. JEM 2013
Tartour and Zitvogel. Lancet 2013
Passiv Immunoterapi
• Släcker nyckelfunktioner i
tumörceller
• Markera tumörceller för
destruktion via ADCC (antibodydependent cell mediated toxicity
m h a makrofager, neutrofiler
och NK-celler)
• Levererar toxiner till tumörceller
• Släcker inhibitionen av
antitumorala lymfocyter
• Cetuximab:
monoklonal Anti-EGFR-Ak
• SSP1: rekombinerat
immunotoxin mot mesotheliom
Check point-hämmare
• Immunmodulering för att
undvika T-cells medierade
skador
• CTLA-4 Ipilimumab
• PD-1 → Nivolumab
• (PD-L1)
All
Squamous
Non-squamous
Survival
Carbo-paclitaxel
8.3
Phased ipi
12.2 (HR 0.87)
HR 0.48
HR 1.17
Concurrent ipi
9.7 (HR 0.99)
HR 1.02
HR 0.96
Stadium IV NSCLC
(BMS-936558, anti-PD-1 10mg/kg)
Från Albelda SM. ERS 2014
Pågående studier med PD-1/PD-L1
Immune Checkpoint Hämmare
Antibody
Molecule
Company
Development Stage
BMS-936558/MDX1106/ONO-4538
Fully human IgG4 mAb
Bristol-Myers Squibb
Phase II multiple
tumors
CT-011
Humanized IgG1 mAb
Target
Phase II multiple
tumors
MK-3475
Humanized IgG4 mAb
Merck
Phase I
AMP-224
B7-DC/IgG1 fusion
protein
Amplimmune
Phase I
PD-L1
MDX-1105/BMS936559
Fully human IgG4 mAb
Bristol-Myers Squibb
Phase I
PD-L1
MPDL3280A
Fully human IgG1 mAb
Genentech
Phase I
PD-1
Från Albelda SM. ERS 2014
Tumörvacciner
• Syftar till att stimulera immunförsvaret mot en specifik antigen (DNA,
RNA, peptid…)
• DNA, protein, vektor eller cell injiceras i patienten tillsammans med
ett immunstimulerande cytokin
Tumörvaccinstudier & NSCLC
Property of
Antigen
Vaccine
Randomized
Phase 2
Phase 3
MAGE 3 (MAGRIT
GSK)
Ca-testes antigen on
about 40% of pts
Protein with adjuvant
Tested in adjuvant
setting- incr. OSp=0.08
182 pts
Initial results 2200 pts
NEG
MUC1 (TG4010)
Overexpres-sed in
most pts
Vaccinia virus exp. MUC1 and IL2
Some OS benefit
with chemoRX- 148
pts
1000 pt trial underway
25 AA peptide from MUC1 plus
adjuvant
START1 (P3) negative
START 2- 1000 pts in
combination with concurrent
ChemoRad
MUC1
Tecemotide
START
Merck Serano
TGF-b
(Lucanix)
TGF inhibits ability of
tumor cells to be
immunogenic
TGF-b antisense RNA transduced
into 4 allogeneic cell lines used for
vaccination
Some OS benefit=
p=0.06
506 pts enrolled
Results reported as NEG
Racotumomab
NeuGcGM3 tumorassociated
ganglioside
an- anti-idiotype antibody that
mimics NeuGcGM3
Some OS benefit (1.5
mo) in advanced pts.
176
1000 pt trial underway
Summering
• Molekylärpatologisk testning är kliniskt användbar
• EGFR och ALK skall bedrivas upfront på Non-Squamous NSCLC
• Immunterapi visar lovande resultat, ffa check point blockad
• Kvarstående frågor och komplicerande faktorer:
• Adekvat tumörmaterial
• Rebiopsi efter 1st line med specifik hämmare?
• Skivepitelcancer?
• Etiska frågeställningar:
• Multiplex/NGS: bördan av att veta för mycket
• Hur dyr får lungcancerbehandling vara?
Tack för uppmärksamheten!
