targeting oncogenic drivers in nsclc · 2016. 10. 28. · de grève, lung cancer 2012 • 46 pts...
TRANSCRIPT
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Targeting oncogenic drivers in NSCLC
Rolf Stahel
University Hospital of Zürich
1 |
Seoul, 28.10.2016
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Molecular profiling of thoracic malignacies: NSCLC2 |
Lopez-Chavez, JCO 2015
RETROS1
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RET and ROS1 targeted by ALK inhibitors3 |
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First line crizotinib versus chemotherapy in ALK-positive NSCLC4 |
Mok, NEJM 2014
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Ceritinib or alectinib in n ALK positive NSCLC progressing under
crizotinib
5 |
Shaw,N Engl J Med 2014 Gadgeel, Lancet Oncol 2014
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Alectinib in ALK-positive, crizotinib-resistant, NSCLC:
a single-group, multicentre, phase 2 trial
6 |
RR 48% Median PFS 8.1 months
Shaw, Lancet Oncol 2016
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Ceritinib versus chemotherapy in ALK-positive NSCLC
previously treated with chemotherapy and crizotinib (ASCEND-5)
7 |
Scagliotti, ESMO 2016
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J-ALEX: Alectinib or crizotinib first line in Japanese patients8 |
Primary Endpoint: PFS by IRF (ITT Population)Alectinib(N=103)
Crizotinib(N=104)
Events, n (%) 25 (24.3%) 58 (55.8%)
Median, mo [95% CI] NR [20.3 - NR] 10.2 [8.2 - 12.0]
P-value <0.0001
HR [99.6826% CI] 0.34 [0.17 - 0.71]
0 6 12 18 27
100
80
60
40
20
0
Pro
gre
ssio
n-f
ree s
urv
ival r
ate
(%
)
24213 9 151
76
65
36
21
9
4
193
86
49
40
27
14
103
102
No. of patients at risk
AlectinibCrizotinib
103
104
Presented by: Hiroshi Nokihara 41
Time (months)
10.2 months
NR
Nokihara, ASCO 2016
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J-ALEX: Alectinib or crizotinib first line in Japanese patients9 |
Nokihara, ASCO 2016
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Future treatment algorithm based on molecular data?10 |
Gainor, Cancer Discovery 2016
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RET (REarranged during Transfection) receptor tyrosine kinase
activation in cancer
11 |
• Ligands: glial cell line-derived neurotrophic factor (GDNF) family
• Activation requires the formation of a multimer complex including
• the ligand
• a GDNF-family receptor-α protein binding binding the ligand
• and ret for signal transduction
Phay, CCR 2010
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RET rearrangements in NSCLC
• Fusion of KIF5B and RET identified in an adenocarcinoma of a young non-smoker by whole-genome and transcriptome sequencingYoung, Genome Res 2011
• 6/319 (1.9%) RET fusion transcripts in adeno-carcinoma from Japanese and 1/80 (1.3%) from Caucasian patients. Activity of vandetinibKohno, Nat Med 2012
• Description of fusion partners,
2/3 objective responses with cabozantinib
Drilon, Cancer Disc 2013
•
12 |
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A retrospective analysis of RET translocation, gene copy
number gain and expression in NSCLC patients treated with
vandetanib in four randomized Phase III studies
• Prevalence of RET rearrangements was 0.7% among 944 patients with a known RET rearrangement status. Consistent frequencies of RETrearrangement in Asian (0.7%) and non-Asian patients (0.8%). None oftreated responded to vandetinib
• Seven tumor samples were positive for RET rearrangements, 2.8% had RETamplification, 8.1% had low RET gene copy number gain (and 8.3% wereRET expression positive by ICH.
• Not in agreement with a number of studies that report a higher frequency ofRET rearrangements in non-smokers compared with smokers/ex-smokers;
13 |
Platt, BMJ Cancer 2015
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RET rearrangements in NSCLC
LURET Study (vandetanib):
• 34/1536 screened advanced NSCLC patients with RET rearrangement (2%).
• 19 patients (10 KIF5B-RET, 6 CCDC6-RET, and 3 unknown) enrolled Half of the patients had been heavily pretreated
• ORR was 53% (90% CI, 31 to 74)
• Disease control rate was 90% and median PFS was 4.7 months(95% CI, 2.8 to 8.5). I
• ORR and median PFS were 83% (5/6) and 8.3 months in CCDC6-RET20% (2/10) and 2.9 months in KIF5B-RET
14 |
Horiike, ESMO 2016
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RET rearrangements in NSCLC
Levatinib in RET positive adenocarcionoma:Velcheti, ESMO 2016
15 |
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RET rearrangements in NSCLC
Levatinib in RET positive adenocarcionoma:Velcheti, ESMO 2016
16 |
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RET rearrangements in NSCLC
• RET registry data
17 |
Gautschi, ASCO 2015, Michels, JTO 2016
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RET rearrangements in NSCLC
• Durable benefits withpemetrexed-based therapiesin RET-rearranged NSCLCDrilon, Ann Onol 2016
18 |
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RET rearrangements in NSCLC
• Alectinib shows potent activityagainst RET-rearranged NSCLCKodama, Mol Cancer Ther 2014
19 |
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ALERT: Alectinib in RET-positive adenocarcinoma20 |
Study design:
• Phase II, open-labeled, multicenter,
single arm design. ETOP sponsored,
with EORTC and Cologne Group
Screening:
• Either locally, Cologne Group, or
within SPECTAlung
Primary objectives:
• To assess safety and efficacy of alectinib
Primary endpoint:
• Response rate (Null hypothesis >35%)
Sample size:
• 41 patients
Stage
IIIB / IV
NSCLC,
pretreated
RET rear-
rangement
CT T&A
CT or MRI brain
Trial treatmentScreening, eligibility
and enrolment
Alectinib 600mg twice daily p.o.
until PD or unacceptable toxicity
CT every 9 weeks until PD
For 6 months
after enrollment
of last patient
Progression Follow up
…….
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ROS1 fusion proteins and activation of downstream signalling
pathways
21 |
• ROS1: Receptor tyrosine kinase of the insulin receptor family, little is known of its specific function
• ROS1 fusion with the transmembrane solute carrier protein SLC34A2 resulting in a constitutive kinase activity in a NSCLC cell lineRikova, Cell 2007
• 13/1529 (0.85%) ROS1 fusion positive lung adenocarcinomas identified in 1529 lung cancers. Four fusion partnersTakeuchi, Nat Med 2012
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ROS1 rearrangement in NSCLC
• Several fusion partnersGainor, Oncologist 2013
• 18/1073 (1.7%) ROS1 fusion positive tumors identified by FISH. Patients tended to be younger and non-smokers, all had adenocarcinoma. In vitro activity and clinical response to crizotinibBergethon, JCO 2012
22 |
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ROS1 rearrangement in NSCLC
• ROS1 fusion can by identified by IHCSholl, Am J Surg Path 2013
• Mouse models of ROS1-positive
lung cancer demonstrate oncogenic
driver capacityInou, Carcinogenesis 2016
• Screening for ROS1 using immunohistochemistrywith FISH confirmationSeliger, Histopathol 2016
23 |
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ROS1 rearrangement in NSCLC: Activity of crizotinib
•
24 |
Shaw, NEJM 2014
Response rate 72% Median PFS 19.2 months
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ROS1 rearrangement in NSCLC: Update on activity of crizotinib
•
25 |
Shaw, ESMO 2016
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From the EUROS1 Cohort
• 31 patients with median age of 50 years, two thirds never smokers
26 |
Response rate 80% Median PFS 9.1 months
Maziere, JCO 2015
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Ceritinib in ROS1-rearranged NSCLC: A Korean nationwide
phase II study
27 |
Min, ESMO 2016
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MET Amplification
• Activity of Crizotinib in a NSCLC patient with De Novo MET AmplificationOu, JTO 2011
• Crizotinib in MET amplified NSCLCCamidge, ASCO 2014
28 |
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MET exon 14 skip mutation
• Loss of MET exon 14 maintains the reading frame and leads to increased MET stability and prolonged signaling upon HGF stimulation, leading to increased oncogenic potential
29 |
Frampton, WLCC 2015 and Cancer Discovery 2015
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MET Amplification and Exon 14 Splice Site Mutation Define
Unique Molecular Subgroups of Non–Small Cell Lung
Carcinoma with Poor Prognosis
• Tissue from lung cancer patients underoing primary resection in HK
• MET mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamouscarcinoma, and 31.8% in sarcomatoid carcinoma.
30 |
Tong, CCR 2016
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Characterization of 298 Patients with Lung Cancer Harboring
MET Exon 14 Skipping Alterations
• Of 11,205 lung cancers profiled by comprehensivegenomic profiling, 298 (2.7%) carcinomas harbored alterations predicted to cause METex14, including adenosquamous (8.2%), sarcomatoid (7.7%), histologic subtypenototherwise specified (3.0%), adenocarcinoma (2.9%), squamous cell(2.1%), large cell (0.8%), and SCLC (0.2%)
• Concurrent METamplification (median copy number 10) was identified in15%of METex14 samples
• 8 patients received treatment with crizotinib: 2 CR, 5 PR, 2 SD
31 |
Schrock, JTO 2016
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MET exon 14 skip mutation32 |
Pt 5 (C&D)METex14 alteration (MET c.3001_3021del) and multiple others GCN = 3.8 PR with crizotinib lasting 4.6+ months
• Response to MET inhibitors crizotinib and cabozantinib in patients with advanced lung adenocarcinoma harboring MET exon 14 skip mutationsPaik, Cancer Discovery 2015
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MET exon 14 skip mutation in NSCLC associated with advanced
age and stage-dependent MET amplification
• 28/933 non-squamous cell NSCLC
• Older age than EGFR or KRAS mutated NSCLC
• 2/3 women, 1/3 non-smoker
• Advanced stage tumors morelikely to have MET amplification or strong expression by IHC
33 |
Awad, JCO 2016
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Neurotropic tyrosine kinase (NTRK) fusion34 |
ETOP | Name Project | Title Presentation | Zurich, July 27, 2009
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Several NRTK inhibitors are in clinical testing35 |
Passiglia, Exp Opin Invest Drugs, 2016
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Entrectinib targets NTRK, ROS1 and ALK36 |
KM12 cells
Ardini, Mol Cancer Ther 2016
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Targeting NTRK
• Response of a NTRK positive sarcoma to an NTRK inhibitorDoebele,
Cancer Discovery 2015
• 2/1378 (0.15%) pts with NTRK rearrangement. Durable PRwith entrectinib in one patientFarago, JTO 2015
37 |
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BRAF mutation in NSCLC
• 36/1046 NSCLC with mutations, 4.9 % of adenocarcinoma and 0.3% of squamous cell carcinoma. 56% were V600E mutations, which were associated a shorter DFSMarchetti, JCO 2011
• A patient with BRAF V600Eadenocarcinoma responding to vemurafenibGautschi, JCO 2012; Peters, JCO 2013
38 |
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Vemurafenib basket trial v600 BRAF mutations (NSCLC cohort)39 |
Response rate 42%Median PFS 7.3 months
Hyman, NEJM 2015
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Paradoxial pathway activation by BRAF inhibition40 |
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Phase 2 study of dabrafenib + trametinib in previously-treated
BRAF V600E mutated NSCLC
41 |
Planchard, ASCO 2015
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HER2 mutation as an oncologic driver
• Inducible expression of mutated HER2 (HER2YVMA):Rapid development/maintenance of adenosquamous lung tumors in mice
42 |
Perera, PNAS 2009
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HER2 mutations43 |
• Amplification and exon 20 mutation. Response
to paclitaxel and trastuzumab
Cappzuzzo, NEJM 2006
• Response to afatinib in 3 patients with HER2 mutationDe Grève, Lung Cancer 2012
• 46 pts with HER2 mutations identified, predominantly women and never smokers. 20 pts with advanced disease received targeted therapy: 9 PR and 7 SD
Mazière, ESMO 2012, JCO 2013
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HER2 mutation and HER2 amplification are distinct molecular
alteration in NSCLC
Prevalence and molecular spectrum of HER2 mutations on lung adenocarcinoma:Arcila, CCR 2012
• 25/560 „mutation negative” cases with HER2 mutation (6%)
• Exon 20 insertion in 24/25
• None of 11 mutant positive cases with HER2 amplification
HER amplification and HER2 mutation are distinct molecular targets in NSCLCLi, JTO 2016
• 5/175 adenocarcinoma with HER2 amplification
• 3/148 adenocarcinomas with HER2 mutation, none of these had HER amplification
44 |
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Pulse afatinib* for HER2 insertion mutations45 |
Costa, JTO 2016
3 pts treated with pulse afatinib
* 280 mg qw
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NICHE: Afatinib for HER2 mutated NSCLC46 |
Study design:
• Multicentre, open label,
phase II trial, ETOP
sponsored
Primary endpoint:
• Disease control (CR /
PR / SD) lasting at least
12 weeks
Sample size:
• 22 patients
Stage
IIIB / IV
NSCLC,
pretreated
HER2
mutation
confirmed
locally
CT T&A
CT or MRI brain
Trial treatmentScreening, eligibility
and enrolment
Afatinib 40mg daily p.o.
until PD or unacceptable toxicity
CT week 20, then every 8 weeks until PD
For 6 months
after enroll-
ment of last
patient
Progression Follow up
……. …….
CT
week 6
CT
week 12
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Trastuzumab emtansine (T-DM1)
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Phase II in HER2 IHC+ 2L+ NSCLC Patients
30 days ≥ 12 weeks
ENROLLMENT
N= 40
Trastuzumab Emtansine3.6 mg/kg Q3W
Trastuzumab Emtansine3.6 mg/kg Q3W
FOLLOW
UPHER2 IHC 3+
n=20
HER2 IHC 3+
n=20
SCREENING•≥ 1 prior platinum-based
chemotherapy
•Prior targeted therapy if
EGFR+ or EML4-ALK+
•ECOG 0-1
•HER2 IHC 2+/3+ centrally
confirmed
HER2 IHC 2+
n=20
HER2 IHC 2+
n=20
Every
3 mths
• Primary Endpoint: ORR by Investigator (RECIST v1.1)
• Secondary Endpoints: PFS, DOR, & CBR by Investigator, Safety & Tolerability
• Exploratory analyses: ORR in biomarker subgroups defined by HER2 mRNA levels (by qRT-PCR), HER2 gene amplification (by ISH), additional biomarker
Multicenter
single-arm
two-cohort
locally advanced or metastatic NSCLC
to evaluate the efficacy and safety
q2
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Slide 48
q2 HISTOGENEX: Usually the results are delivered in 3-5 Business days, if no queries to answer!q802234, 04/12/2014
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Targeted therapy in non-squamous NSCLC lung cancer49 |
Vandetanib
LevatinibAlectinib
Crizotinib
TDM-1
Crizotinib/Ceritinib/Alectinib
Afatinib
Crizotinib
Dabrafenib/Trametinib
Vermurafenib
NTRK fusion Entrectinib
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50 |
ETOP | Name Project | Title Presentation | Zurich, July 27, 2009