Targeting oncogenic drivers in NSCLC
Rolf Stahel
University Hospital of Zürich
1 |
Seoul, 28.10.2016
Molecular profiling of thoracic malignacies: NSCLC2 |
Lopez-Chavez, JCO 2015
RETROS1
RET and ROS1 targeted by ALK inhibitors3 |
First line crizotinib versus chemotherapy in ALK-positive NSCLC4 |
Mok, NEJM 2014
Ceritinib or alectinib in n ALK positive NSCLC progressing under
crizotinib
5 |
Shaw,N Engl J Med 2014 Gadgeel, Lancet Oncol 2014
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
Ceritinib versus chemotherapy in ALK-positive NSCLC
previously treated with chemotherapy and crizotinib (ASCEND-5)
7 |
Scagliotti, ESMO 2016
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
J-ALEX: Alectinib or crizotinib first line in Japanese patients9 |
Nokihara, ASCO 2016
Future treatment algorithm based on molecular data?10 |
Gainor, Cancer Discovery 2016
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
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 |
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
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
RET rearrangements in NSCLC
Levatinib in RET positive adenocarcionoma:Velcheti, ESMO 2016
15 |
RET rearrangements in NSCLC
Levatinib in RET positive adenocarcionoma:Velcheti, ESMO 2016
16 |
RET rearrangements in NSCLC
• RET registry data
17 |
Gautschi, ASCO 2015, Michels, JTO 2016
RET rearrangements in NSCLC
• Durable benefits withpemetrexed-based therapiesin RET-rearranged NSCLCDrilon, Ann Onol 2016
18 |
RET rearrangements in NSCLC
• Alectinib shows potent activityagainst RET-rearranged NSCLCKodama, Mol Cancer Ther 2014
19 |
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
…….
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
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 |
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 |
ROS1 rearrangement in NSCLC: Activity of crizotinib
•
24 |
Shaw, NEJM 2014
Response rate 72% Median PFS 19.2 months
ROS1 rearrangement in NSCLC: Update on activity of crizotinib
•
25 |
Shaw, ESMO 2016
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
Ceritinib in ROS1-rearranged NSCLC: A Korean nationwide
phase II study
27 |
Min, ESMO 2016
MET Amplification
• Activity of Crizotinib in a NSCLC patient with De Novo MET AmplificationOu, JTO 2011
• Crizotinib in MET amplified NSCLCCamidge, ASCO 2014
28 |
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
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
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
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
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
Neurotropic tyrosine kinase (NTRK) fusion34 |
ETOP | Name Project | Title Presentation | Zurich, July 27, 2009
Several NRTK inhibitors are in clinical testing35 |
Passiglia, Exp Opin Invest Drugs, 2016
Entrectinib targets NTRK, ROS1 and ALK36 |
KM12 cells
Ardini, Mol Cancer Ther 2016
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 |
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 |
Vemurafenib basket trial v600 BRAF mutations (NSCLC cohort)39 |
Response rate 42%Median PFS 7.3 months
Hyman, NEJM 2015
Paradoxial pathway activation by BRAF inhibition40 |
Phase 2 study of dabrafenib + trametinib in previously-treated
BRAF V600E mutated NSCLC
41 |
Planchard, ASCO 2015
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
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
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 |
Pulse afatinib* for HER2 insertion mutations45 |
Costa, JTO 2016
3 pts treated with pulse afatinib
* 280 mg qw
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
Trastuzumab emtansine (T-DM1)
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
Slide 48
q2 HISTOGENEX: Usually the results are delivered in 3-5 Business days, if no queries to answer!q802234, 04/12/2014
Targeted therapy in non-squamous NSCLC lung cancer49 |
Vandetanib
LevatinibAlectinib
Crizotinib
TDM-1
Crizotinib/Ceritinib/Alectinib
Afatinib
Crizotinib
Dabrafenib/Trametinib
Vermurafenib
NTRK fusion Entrectinib
50 |
ETOP | Name Project | Title Presentation | Zurich, July 27, 2009