OTRAS DIANAS MOLECULARES

TRATABLES Rosario García Campelo

Servicio de Oncología Médica

Complejo Hospitalario Universitario A Coruña, CHUAC

A propósito de un caso….

Mujer 34 años

Fumadora ocasional < 10 paq/año

Dx de Adenocarcinoma de pulmón cTxN3M1b, estadio IV

EGFR WT

ALK WT

PE tras CDDP+Pemetrexed

PE tras Docetaxel

PS 0-1

¿Y ahora qué?....

Minuti G et al. Exp Opin Biol Ther 2013; 13(10): 1401-1412

THE “SO LIMITED OTHERS” CONCEPT

Targetable oncogenes in lung ADC

The so low frecuency…

Mostly non-overlapping

Never/ light smokers (exceptions: KRAS, BRAF)

Growing understanding of resistance

mechanisms

Gerber D et al. Educational Book ASCO 2014

Rationale for targeting the ROS receptor tyrosine kinase

El-Deeb et al., Med Res Rev. 2010

FN-III-like repeats

TK domain

ROS overexpression in brain, lung, gastric, breast, and liver tumors/cell lines

ROS mutations in colon and kidney cancer cell lines

ROS fusions identified in cancer

Glioblastoma: FIG-ROS1

NSCLC: SCL34A2-, CD74-, FIG-, SDC4-,TPM3-, ERZ-,LRIG3-ROS1

Cholangiocarcinoma: FIG-ROS1

Drosophila homolog: sevenless

Drosophila ligand homolog: son of sevenless

Growth of cell lines with ROS fusion genes inhibited by crizotinib

Structure of ROS

ROS1 Rearrangements in NSCLC

Present in ~1% of NSCLC cases (also found in some GBMs and cholangiocarcinomas)

Enriched in younger never or light smokers with adenocarcinoma histology

No overlap with other oncogenic drivers

Bergethon et al., JCO 30(8): 863-70, 2012; Takeuchi et al., Nat Med 18(3): 378-81, 2012

TPM3-ROS1

SDC4-ROS1

CD74-ROS1

EZR-ROS1

LRIG3-ROS1

ROS1

SLC34A2-ROS1

Study 1001: Clinical Characteristics of Patients with

ROS1-positive NSCLC

Characteristic Crizotinib (N=42)

Age, years Median (range) 52 (31–77)

Sex, n Male/female 19/23

Smoking history, n (%) Never 33 (79)

Former 9 (21)

Race, n (%)

Caucasian 21 (50)

Asian 18 (43)

Other 3 (7)

Histology, n(%) Adenocarcinoma 41 (98)a

ECOG PS, n (%) 0 21 (50)

1 20 (48)

2 1 (2)b

Prior regimens for advanced/metastatic disease, n (%)

None 6 (14)

1 regimen 18 (43)

>1 regimen 18 (43) aIncludes one patient with adenocarcinoma-favored, poorly differentiated NSCLC

bPatient had an ECOG PS of 1 at screening and 2 on cycle 1 day 1

Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)

Study 1001: Best Tumor Responses in Evaluable Patients with Advanced

ROS1-positive NSCLCa

+Treatment ongoing; duration of response/SD is from first documentation of tumor response/first dose to the time of PD or death. For ongoing patients, duration of response/SD is from first documentation of tumor response/first dose to last available on-treatment scan Duration is in weeks aExcludes patients with early death (n=2)

*This patient was ALK+ Data as of April 24, 2013

Bes

t ch

ange

fro

m b

asel

ine

(%)

PD

Best overall response

SD

PR

CR

36 evaluable patients; 2 CRs and 20 PRs

Overall response rate: 61% (95% CI: 44–77) Disease control rate: 81% (8 weeks), 67% (16 weeks)

100

80

60

40

20

0

–20

–40

–60

–80

–100

*

Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)

Study 1001: PFS in Patients with

ROS1-positive NSCLC (N=42)

Median PFS not reached

26 patients (62%) still in follow-up for progression

Event-free probability: 76% (95%CI: 55–88) at 6 months

100

80

60

40

20

0

0 5 10 15 20 25

PF

S P

rob

ab

ility

Time (months) Censored 95% Hall-Wellner Band

Number

at risk 42 22 12 8 2 1

Ou S-HI, et al. J Thorac Oncol 2013;8(Suppl 2):S295 (Presentation MO07.03)

Epidemiology HER2 mutation

• 403 stage I-III adenocarcinomas in caucasian patients: mutation in 9 (2.2%).

• 78% in frame duplications insertions in exon 20

• Frequency higher in females and in never smokers

• 394 adenocarcinoma, HER2 mutations preferentially in oriental ethnicity

(3.9% vs 0.7%)

• All HER2 mutations were in-frame insertions in exon 20, significantly more

frequent in never smokers and adenocarcinoma

Buttitta, Int J Cancer 2006, Shigematsu, CCR 2005, Arcila CCR 2012, Mazieres JCO 2013

• 6% of EGFR/KRAS/ALK-negative specimens

• More frequent among never-smokers but no associations with sex, race, or

stage

• HER2 mutation was not associated with concurrent HER2 amplification

• 3.800 p: HER2 mut in 1.7%, all insertions in exon 20, 69% women, never-

smokers 52.3%

Mazieres JCO 2013

Therapeutic Perspectives

22 patients receiving anti HER2 therapy

• ORR: 50%

• DCR 82%

• Median PFS: 5.1m

DCR Trastuzumab based therapies (n= 15): 96%

DCR Afatinib based therapy (n=4): 100%

No responses to lapatinib or to masatinib

68.2 m

22.9 m

KRAS mutation: PROGNOSTIC, PREDICTIVE OR DRUGGABLE

677 patients with advanced NSCLC and KRAS

mutation seen at the MSKCC between 2005 and 2011

Yu A J Clin Oncol 2013 Abstr 8025

• 2nd most common mutation

in human cancer

• Lung Cancer: mutation at

codon 12,13, 61

• Smokers: G12C,G12V

• A greater oncogenic

potential for KRas G12V

compared to other

mutations

• Non smokers: G12D

MEKi (Selumetinib or Trametinib) plus docetaxel for KRAS mutant

advanced NSCLC

Jänne, Lancet Oncol 2013

Gandara D et al. J Clin Oncol 2013 Abstr 8028

LY2835219 (Abemaciclib): a cell cycle inhibitor CDK4 and CDK6

Goldman et al. J Clin Oncol 2014 Abstr 8026

DIRECT KRAS G12C INHIBITORS

Lim SM et al. Angew Chem Int Ed 2014

SUMMARIZE OF CURRENT STRATEGIES TARGETING KRAS MUT NSCLC

PATIENTS

Vasan et al. Clin Cancer Res 2014

1046 NSCLC

• 4.9% ADC

• 0.3% SCC

• More common in current /former

smokers

V600 56.8% (more diverse mutation

profile than in melanoma)

V600 more prevalent in females: 8.6%

vs 0.9%

V600 showed agressive histotype and

shorter PFS and OS

Activity of BRAF inhibitors in BRAF mut NSCLC patients

Response to Dabrafenib in a V600E mutated

NSCLC patient

Rudin et al. JTO 2013

Best response n=20

Complete response (CR), n (%) 0

Partial response (PR), n (%) 8 (40)

Stable disease (SD), n (%) 4 (20)

Progressive disease, n (%) 6 (30)

Not evaluable, n (%) 2 (10)

Response rate (confirmed CR/PR), % (95% CI)

40 (19.1–63.9)

Disease control rate (CR + PR + SD), % (95% CI)

60 (36.1–80.9)

Planchard et al. ASCO 2013

RET: a new kid on the rock

Incidence of RET fusions

95% CI

[3–27%]

n=5/34

Lipson et al1

Nature 2012 Wang et al2

JCO 2012

Never-Smokers

Pan-Negative

Lung AdenoCAs

Pan-Negative

NSCLCs

Unselected

NSCLCs Inci

denc

e (%

)

Drilon et al Cancer Discovery 2013

KIF5B, CCDC6

1% of lung cancer

Vandetanib, sorafenib, sunitinib, cabozantinib have

RET activity

Met alterations in cancer

• MET gene copy alterations

(amplification or polisomy)

• MET gene mutations

• MET RNA over expression • Met protein overexpression

• Met porttranslational modifications

(e.g. phosphorylation)

RNA DNA Protein

1 2 3 4 5

6 7 8 9 10 11 12

18 17 16 15 14 13

19 20 21 22 X

C-MET receptor tyrosine kinase

• Amplified, mutated, and overexpressed in many tumors

• Associated with worse prognosis in NSCLC

• Met activation, implicated in resistance to EGFR inhibition

• MET inhibitors in NSCLC: ARQ 197 and MetMAb

Erlotinib/placebo v erlotinib/ARQ 197

Erlotinib/placebo v erlotinib/MetMAb

Met inhibitor TKI, daily PO Mab, Iv q 3W

Trial phase, design Randomised Phase II, Placebo Randomised Phase II, Placebo

N pts 167 128

Eligibilitty > 1 prior line 2nd-3rd line

Tissue required

End-point PFS PFS-all pts

PFS in “Met High” pts

MARQUEE TRIAL

MET LUNG TRIAL

NEGATIVE

Crizotinib is a first-in-class, potent and selective ATP

competitive inhibitor of c-Met

Camidge et al. J Clin Oncol 2014 Abstr 8001

Kinase IC50 (nM) mean* Selectivity ratio

Met 8 –

ALK 40–60 5–8X

ROS 55 7X

RON 80 10X

Axl 294 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

Squamous cell lung cancer: The forgotten one

A significant minority of NSCLC

No effective targeted therapy

Lack of efficacy or toxicity for

Pemetrexed

Bevacizumab Some KRAS and PIK3CA mutations

Ongoing systematic genomics efforts

The Cancer Genome Atlas

Dominant Mutations in Lung Cancer

Some time ago…

KRAS

EGFR

EML4-ALK

BRAF

PIK3CA

ERBB2

Other

Lung adenocarcinoma Lung squamous cell carcinoma

Genetic alterations in SCC 2014

Perez-Moreno et al. CCR 2012

Dasatinib shrinks DDR2-mutant tumors in vivo

Hammerman et al. Cancer Discovery 2011

• Discoidin death receptor 2

(DDR2)

• Mutation in 4% SCC and 1%

NSCC

• Dasatinib has shown

preclinical and clinical

activity

FGFR1 amplification occurs in 20% of primary squamous-cell

lung cancers

Weiß et al. Science Trans Med 2010

Targeting FGFR1 in SCC FGFR-amplified NSCLC

Nogora et al. J Clin Oncol 2014 Abstr 8034 Paik et al. J Clin Oncol 2014 Abstr 8035

Not a true driver?

Cutoff for amplification?

Tumor heterogeneity?

BGJ398 AZD4547

Clinical application of

molecular subsets is not

easy, however....

A propósito de un caso….

PE tras CDDP+Pemetrexed

PE tras Docetaxel

34 años, PS 0-1

No muestra tumoral disponible para análisis molecular

¿Y ahora qué?...

Re-biopsia adenopatía retroperitoneal:

Kras negativo

BRAF-

FISH HER2 negativo

Ros negativo

MET: 3 (+) 65% (positivo) por IHQ

H&E IHQ MET

The complex history of “other genomic alterations

in our daily practice”

The “Cancer Biomarker Problem”

Rebiopsies procedures at different moments of the disease evolution

New technologies (NGS, WGS…)

Are we using the right biomarker?

Cost

What should I do if after all this effort I find a genetically

defined NSCLC patient?

EMERGING TECHNOLOGIES FOR TUMOR GENOMIC PROFILING

MacConaill L E JCO 2013;31:1815-1824

NGS to identify genomic alterations in “pan negative lung cancer

patients”

Drilon et al. J Clin Oncol 2014 Abstr 8029

1 genomic alteration identified in 94% of patients

Tumor tested was obtained from the same procedure as tumor used for

non-NGS testing in 71% of cases

LCMC: Molecular characterization network and associated

clinical trials

Some notes to conclude… many targets, many drugs

A pletora of new agents in the horizon that target specific molecularly defined

patients, let´s say

PERSONALIZED THERAPY:

– Establish molecular profile

– Availability of tumor tissue

Newer technologies allow testing all of these mutations at the same time

Some of these genetic alterations have a low incidence, but…

Every single patient is unique: it´s worthwhile