targeting oncogenic drivers in nsclc -...

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


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


Levatinib in RET positive adenocarcionoma:Velcheti, ESMO 2016

15 |


Levatinib in RET positive adenocarcionoma:Velcheti, ESMO 2016

16 |


• RET registry data

17 |

Gautschi, ASCO 2015, Michels, JTO 2016


• Durable benefits withpemetrexed-based therapiesin RET-rearranged NSCLCDrilon, Ann Onol 2016

18 |


• 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

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

targeting oncogenic drivers in nsclc -...

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