istituto toscano tumori –livorno, italy federico cappuzzo istituto toscano tumori ospedale civile...

Istituto Toscano Tumori –Livorno, Italy

Federico CappuzzoIstituto Toscano Tumori

Ospedale CivileLivorno-Italy

New targets in NSCLC

Istituto Toscano Tumori – Livorno, Italy

Molecular events in lung cancerAdenocarcinoma

Unknown53.8%

KRAS27%

EGFR9.5%

EGFR resistance mutations0.8%

HER20.9%

BRAF1.7%

PI3K2.6%ALK

3.7%

Squamous-cell carcinoma

Barlesi F, ASCO 2013 Paik PK et al, ASCO 2012

ROS1 Translocations in NSCLC

SDC4 exon 2 ROS1 exon 32

SDC4 exon 2 ROS1 exon 34


Patients with ROS1 rearrangements share many features in common with ALK-positive patients (adenocarcinoma histology, younger age at diagnosis, never or light smokers)Mutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK or translocationPrognostic role is not defined

ROS1 fusion partners in NSCLC


Stumpfova and Janne PA, CCR 2013


Crizotinib: selective inhibitor of ALK, MET and ROS

KinaseIC50 (nM)

mean*Selectivity

ratio

Met 8 –

ALK 40–60 5–8X

ROS 55 7X

RON 80 10X

Axl294 34X

322 37X

Tie2 448 52X

Abl 1,159 166X

IRK 2,887 334X

Lck 2,741 283X

Sky >10,000 >1000X

VEGFR2 >10,000 >1000X

PDGFRβ >10,000 >1000X

Cellular selectivity on 10 of 13 relevant hits

Upstate 102 kinase panel

13 ‘hits’ <100X

selective for Met

High probability of ALK, MET

and ROS inhibition at clinically

relevant doses

Kinase % InhibitionMet(h) 94Tie2(h) 103

TrkA(h) 102

ALK(h) 100

TrkB(h) 100

Abl(T315I)(h) 98

Yes(h) 96

Lck(h) 95

Rse(h) [SKY] 94

Axl(h) 93

Fes(h) 93

Lyn(h) 93

Arg(m) 91

Ros(h) 90

CDK2/cyclinE(h) 87

Fms(h) 84

EphB4(h) 80

Bmx(h) 79EphB2(h) 77

Fgr(h) 73Fyn(h) 68IR(h) 64

CDK7/cyclinH/MAT1(h) 58cSRC(h) 58

IGF-1R(h) 56Aurora-A(h) 54

Syk(h) 52FGFR3(h) 50PKCµ(h) 50BTK(h) 35

CDK1/cyclinB(h) 25p70S6K(h) 24PRK2(h) 22

PAR-1Bα(h) 21PKBß(h) 21Ret(h) 21

GSK3ß(h) 18Flt3(h) 17

MAPK1(h) 17ZAP-70(h) 17

Abl(h) 16c-RAF(h) 16PKD2(h) 15

ROCK-II(h) 14Rsk3(h) 14

GSK3α(h) 11CDK5/p35(h) 10PDGFRα(h) 10

Rsk1(h) 7SGK(h) 6

CHK1(h) 5ErbB4(h) 5Rsk2(h) 5

JNK1α1(h) 4PKBα(h) 4Blk(m) 3

CDK3/cyclinE(h) 3PKCι(h) 3PKCθ(h) 3

CDK2/cyclinA(h) 2PAK2(h) 2PKCßI(h) 2Pim-1(h) 1PKCη(h) 1

SAPK4(h) 1CaMKII(r) 0MKK7ß(h) 0CaMKIV(h) -1CHK2(h) -1CK2(h) -1

JNK2α2(h) -1MKK6(h) -1CK1δ(h) -2PKCα(h) -2

MAPK2(h) -3MEK1(h) -3PKCδ(h) -3PKCε(h) -3Plk3(h) -3

PKCßII(h) -5MSK1(h) -6

PDGFRß(h) -6PKCζ(h) -6

SAPK3(h) -6MAPKAP-K2(h) -7

PKA(h) -7AMPK(r) -9

CDK6/cyclinD3(h) -9CSK(h) -9

SAPK2a(h) -9JNK3(h) -10PKBγ(h) -10IKKα(h) -11NEK2(h) -11

*Measured using ELISA capture method Bang Y, et al. ASCO 2010

Activity of crizotinib in ROS1+ NSCLC

Shaw AT, et al. NEJM 2014


ORR 72%; DCR 90%

Median DOR of Crizotinib in ROS1+ NSCLC

Shaw AT, et al. NEJM 2014


Median DOR 17.6 mos (95%CI,14.5 – NR)


Shaw A et al, NEJM 2014

Crizotinib in ROS1+ NSCLC: PFS

Median PFS: 19.2 months

Acquired resistance to crizotinib in ROS1 NSCLC


Awad MM, et al. NEJM 2013


Second generation ROS1 inhibitors

Crizotinib in MET amplified or ROS1 translocated NSCLC: The METROS trial


Clinical characteristics of MET amplified NSCLC

Characteristic N %

Total amplified (ratio ≥2.2) 16 100

Squamous 5 31.2

Non-squamous 11 68.8

Never smokers 0 0

Current/former 15 93.7

Smoking unknown 1 6.3

Cappuzzo F et al., J Clin Oncol 2009


Survival of Resected NSCLC According to MET Copy Number

<2 copies/cell

≥2 - <3 copies/cell




≥6 copies/cell

100806040200

1,0

,8

,6

,4

,2

0,0

MONTHS

CUM

ULA

TIVE

SU

RVIV

AL

MET <5 copies/cell(N=383)

MET ≥5 copies/cell (N=48)

120100806040200

1,0

,8

,6

,4

,2

0,0

MONTHSCU

MU

LATI

VE S

URV

IVAL

p=0.0045

Median survival:MET FISH-:47.5 monthsMET FISH+: 25.8 months

Cappuzzo et al., JCO 2009


High levels of MET amplification drive resistance to EGFR-TKIs

MET amplification in HCC827 GR6Ratio MET/centromere >5

NO MET amplification in HCC827Ratio MET/centromere <2

Gefitinib Resistant Gefitinib Sensitive

Modified from Cappuzzo F, et al. Ann Oncol 2008


Smolen GA et al., PNAS 2006, Tanizaki J et al., JTO 2011

Sensitivity to anti-Met agents only in presence of high levels of MET amplification

Garcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy

Tumor Shrinkage Seen in Intermediate and High MET Cohorts

aConfirmed objective responses.bBased on investigator assessment.cTwo patients in the intermediate MET group had an unconfirmed PR that was not confirmed in a second assessment.

Best percent change from baseline in target tumor lesionsa by patient

Low METn=2

Intermediate METn=6

High METn=6

100

80

60

40

20

0

–20

–40

–60

–80

–100

100

80

60

40

20

0

–20

–40

–60

–80

–100

Disease progressionStable diseasePartial responseb

Complete responseb

% C

han

ge

Fro

m B

asel

ine

100

80

60

40

20

0

–20

–40

–60

–80

–100

Threshold for partial responsec

c

Garcia L, University of Colorado, personal communication Istituto Toscano Tumori – Livorno, Italy


RET rearrangements in lung adenocarcinoma

• 11,294,741-bp pericentric inversion on chromosome 10 generating a new gene fusion joining exons 1-15 of KIF5B to exons 12-20 of RET

• Mutually exclusive with EGFR, HER2, KRAS, BRAF mutations and with ALK or ROS1 translocation

• Exclusively identified in moderately to poorly differentiated adenocarcinomas with solid predominant subtype, younger age never or light smokers and with a particular pattern of metastatic spread (lymph nodes)

RET translocation and sensitivity to anti-RET drugs

Lipson et al. Nature Med. 2012



RET FISH+ve NSCLC succesfully treated with vandetanib

Gautschi O, J Thor Oncol 2013

• 58 y-o man, past smoker (5 pck/yr)

• ADC, stage IV for supraclavicular,

mediastinal, retroperitoneal and

inguinal nodes abdominal,

• Pre-treated with standard

carboplatin-pemetrexed for 2 cycles

with evidence of progression

• Second-line* Vandetanib 300 mg

daily

* Patient unsuitable for standard chemotherapy due to recent myocardial infarction

Drilon et al, Cancer Discov 2013


Activity of cabozantinib in RET + NSCLC

HER2 dysregulation in lung cancer

Overexpression

Amplification

Mutation

<10%

<10%

<3%


HER2 amplification is not prognostic in resected NSCLC

Cappuzzo et al., JTO 2012


Takezawa et al., Cancer Discovery 2012


High levels of HER2 amplification are responsible for acquired resistance to EGFR-

TKIs in absence of T790M

Yonesaka et al Science Transl Med 2011


High levels of HER2 amplification are responsible for acquired resistance to cetuximab in colorectal

cancer

HER2 mutation

770 831785

G776V,Cins

GSP781-783ins

E A Y V M A G V G S P Y V S R L I A K

YVMA776-779ins

exon19 　　　 exon20 　　 exon21


HER2 Mutations in NSCLC

Reference N Race % Never Smoker (%)

Female (%)

Sasaki 95 Japan 1.0 2.7 3.3

Marchetti 403 Caucasian 2.2 3.1 4.1

Shigematsu 671 All 1.6 3.2 3.6

Stephens 120 Caucasian 4.0 - -

Arcila 560 All 5.0* 5.0 2.0

* In EGFR and KRAS wild-type population


Trastuzumab efficacy in pretreatred NSCLC patients harboring HER2 mutation

Patient # Therapy Best Response

1 Vinorelbine-trastuzumab Partial response

2 Carboplatin-paclitaxel-trastuzumab Stable disease

3 Docetaxel-masatinib Progression


5 Carboplatin-paclitaxel-trastuzumab Partial response


7 Vinorelbine-trastuzumab Stable disease

8 Lapatinib Progression


10 Lapatinib Progression

11 Vinorelbine-trastuzumab Progression

12 Docetaxel-trastuzumab Partial response



15 Vinorelbine-trastuzumab Stable disease

16 Trastuzumab Partial response

Modified from Mazieres et al. ESMO 2012

RR: 56.2%


BRAF mutations in NSCLC

• Detectable in up to 5% of lung adenocarcinomas using high sensitive methods

• V600E is the most frequent mutation (up to 60% of all BRAF mutations)

• V600E more frequent in female and in micropapillary features

• Non-V600E mutations associate with smoking exposure with no prognostic effect

Marchetti et al, JCO 2011


Mode of Action• Reversible, small molecule BRAF inhibitor • ATP competitive

Molecular Activity:• BRAF V600E: IC50 0.65 nM • BRAF WT: IC50 3.2 nM

Selectivity:• IC50 of 10-100 nM against 8 of 282 human kinases

Davies H, et al. Nature. 2002;417:949-954; Platz A, et al. Mol Oncol. 2008;1:395-405; Karasarides M, et al. Oncogene. 2004;23:6292-6298; Curtin JA, et al. N Engl J Med. 2005;353:2135-2147; Flaherty K, et al. J Clin Oncol. 2009;27 [abstract 9000]; Kefford R, et al. J Clin Oncol. 2010;28 [abstract 8503].

PI3K/AKT/mTORpathway

RTKs SOSGrb2SHC

PPPP

Proliferation, Growth, Survival

MEK

p90RSK MSK1

PP

BRAF CRAF

BRAFV600

ERK1/2

RAS

Dabrafenib

Dabrafenib inhibits BRAF V600E Kinase


Data not registered for darafenib

−40

−50

−60

−90

−100

50

40

30

20

10

−10

−20

−30

−70

−80

0

*

**

*

*

** **

****

**

***

******

****

**Stable disease

Partial response

Progressive disease

Best Confirmed Response

**Nonsmoker

Smoker, ≤ 40 pack years

Smoker, > 40 pack years****

Smoking History

Max

imum

Per

cent

Red

uctio

n at

Tim

e of

Bes

t Dis

ease

Ass

essm

ent

Dabrafenib in V600E BRAF mutated NSCLC: results of a phase II study

Planchard et al. ASCO 2013


Dabrafenib in BRAF mutated NSCLC: 2014 update

• BRAF V600E mutations 1.5% of NSCLC, mutually exclusive to other driver alterations

• Phase II dabrafenib in NSCLC p harboring V600E muto 78 previously treated p; median age 66 yrs, 50% female, 15% ECOG 2,

37% never-smokero 32% PR / 24% SD > 12 weeks / 29% PD / 14% NEo Disease control rate: 51% independent review vs 56% investigator o Median duration of response 11.8 moo PFS 5.5 moo Safety profile manageable

Planchard et alesmo 2014


Conclusions• Crizotinib is an emerging effective treatment in ROS1+ or MET

amplified NSCLC

• MET amplification could be detected in NSCLC generally not considered for biomarker assessment

• RET translocation is a rare event but already druggable with available agents

• Strategies against HER2 mutations should be extensively investigated

• Drugs available for metastatic melanoma could represent a new option for BRAF mutated NSCLC


istituto toscano tumori –livorno, italy federico cappuzzo istituto toscano tumori ospedale civile...

Documents