CARCINOMA ESCAMOSO DE PULMONmauriciolema.webhost4life.com/congresoacho2012/files/03... · 2012. 11....

Novel treatments for SCC

Andrés Felipe Cardona, MD MS PhD. Clinical and Transla,onal Oncology Group

Ins,tute of Oncology, Fundación Santa fe de Bogotá Clinical Epidemiology

Cochrane Colombian Branch / LATINREC / ONCOLGroup

Best diagnos>c markers for NSCLC

Characteis>c SCC Ck5/6 p63 HMWcK CD141 Rb

Sensi>vity 90 90 90 46 88

Specificity 96 91 81 98 46

PPV 91 88 80 82 77

NGV 94 93 90 89 29

Characteris>c Adenocarcinoma

Napsin-‐A TTF1 CDX2 MOC-‐31 ACE p27

Sensi>vity 81 70 93 73 51 5

Specificity 100 98 77 83 85 97

PPV 100 97 86 83 54 8

NGV 83 79 71 74 75 79

Ann Diagn Pathol (2012), http://dx.doi.org/10.1016/j.anndiagpath.2012.07.006.

TTF1

Ck5/6

Overall survival according to histology

J Thorac Oncol. 2009 Dec;4(12):1524-9.

Histology Period 1-‐y OS (%)

2-‐y OS (%)

All histologies 1990-‐1993 2002-‐2005

13.2 19.3

4.6 4.9

Adenocarcinoma 1990-‐1993 2002-‐2005

15.5 23.3

5.5 9.9

SCC 1990-‐1993 2002-‐2003

13.5 19.9

4.3 7.2

Large cell 1990-‐1993 2002-‐2005

11.5 16.6

4.3 6.6

Other 1990-‐1993 2002-‐2005

10.3 16.2

3.4 6.3

Main gene>c damages in SCC

•  Dysfunc,on in cell cycle control

•  Response to oxida,ve stress

•  Apopto,c signalling

•  Squamous cell differen,a,on

Cancer Discovery .2011;1:23-24.

• Complex genomic altera,ons (47 focal and 23 broad events per tumor) • 360 exonic muta,ons, 165 genomic rearrangements, and 323 segments of copy number altera,on per tumor • Selec,ve amplifica,on of chromosome 3q • Mean soma,c muta,on rate of 8.1 muta,ons per megabase(Mb)

Hammerman PS, et al. Nature. 2012;1-‐7. doi:10.1038/nature11404.

Significantly mutated genes in lung SQCC

Acute myelogenous leukaemia 0.56 per Mb, breast carcinoma 1.0 per Mb, ovarian cancer 2.1 per Mb, glioblastoma multiforme

2.3 per Mb and colorectal carcinoma 3.2 pe rMb

CDKN2A

• Tumor suppressor gene

• Encodes p16INK4A and p14ARF proteins

• Inactivated in 72%

Clin Cancer Res. 2012;18:2443-2451.

Soma>cally altered pathways in squamous cell lung cancer Oxidative stress response

34% altered (62% in classical subtype) Squamous cell differentiation 44% altered


• 96% of tumors contains potentially drugable targets

• 50%-77% of the mutations were predicted to have a medium or high functional effect

• 39% of tyrosine and 42% of serine/threonine kinase mutations were located in the kinase domain

Gene expression subtypes integrated with genomic altera>ons

36% 15% 25% 24%

KEAP1 NFE2L2

PTEN/PI3K Pronounced hypermethylation

Chromosomal instability

RB1 PTEN NF1

Govindan R, et al. J Clin Oncol 30, 2012 (suppl; abstr 7006). Paik PK, et al. Clin Oncol 30, 2012 (suppl; abstr 7505).

Pao W, et al. Lancet Oncol 2011; 12:175–80. Kris et al., ASCO 2011; Abs #7506.

Sivachenko et al., IASLC 2011; Abs #PRS.1.

FGFR1 PDGFRa

Altera>ons in targetable oncogenic pathways in lung SCC


Second-‐line Selume>nib plus Docetaxel in KRAS-‐mutated NSCLC

•  Phase II randomized, placebo-‐controlled trial –  Selume>nib: potent and selec,ve inhibitor of MEK1 and MEK2,

downstream targets of KRAS

Janne PA, et al. ASCO 2012. Abstract 7503.

Patients with KRAS-mutant, locally advanced or

metastatic stage IIIB/IV NSCLC who failed first-line treatment

(N = 87)

Selumetinib 75 mg BID + Docetaxel 75 mg/m2 every 21 days

(n = 44)

Placebo BID + Docetaxel 75 mg/m2 every 21 days

(n = 43)

Number of cycles determined by local practice and investigator preference

Characteris>c Selume>nib + Docetaxel (n = 44)

Placebo + Docetaxel (n = 43)

Male, % 47.7 46.5 Median age, yrs (range) 59.5 (26-‐79) 59 (37-‐76) Smoking status, %   Never   Former or current

11.4 88.6

11.6 88.4

Disease stage IIIB/IV, % 11.4/88.6 2.3/97.7 WHO PS 0/1, % 47.7/52.3 48.8/51.2 Histology, %   Adenocarcinoma   Squamous carcinoma   Adenosquamous carcinoma   Large cell carcinoma   Other

81.8 6.8 4.5 4.5 2.3

82.5 14.0 2.3 0 7.0

Second-‐line Selume>nib plus Docetaxel: pa>ent characteris>cs


Outcome Selume>nib + Docetaxel (n = 43)


HR (P Value)

Median OS, mos 9.4 5.2 0.80 (.2069) Median PFS, mos 5.3 2.1 0.58 (.0138) 6-‐mo PFS, % 37.1 15.8 (.0158) Best ORR, %   CR   PR   SD ≥ 6 wks   PD   Not evaluable

37.2 0

37.2 44.2 18.6 0

0 0 0

50.0 45.0 5.0

(< .0001)

Median response dura>on, days 182 -‐-‐ -‐-‐

Rela>ve tumor change -‐26% (.004)

Second-‐line Selume>nib plus Docetaxel: clinical outcomes


Outcome, % Selume>nib + Docetaxel (n = 44)


Any serious adverse event 59.1 31.0 Event-‐related death 9.1 7.1 Event-‐related hospitaliza>on 47.7 19.1 Event leading to discon>nua>on   Selume,nib or placebo   Docetaxel

18.2 13.6

11.9 16.7

Event-‐related dose reduc>on of selume>nib/placebo 34.1 0

Event-‐related interrup>on of selume>nib/placebo 45.5 9.5

Second-‐line Selume>nib plus Docetaxel: Safety


Most common events with selumetinib: neutropenia, diarrhea, nausea, vomiting, anemia, peripheral edema

FGFR-‐driven transforma>on is blocked by kinase inhibitors


Ponatinib BGJ398

Trial Design: Pona>nib in Lung SCC

Primary Endpoint •  Overall response rate

Secondary endpoints •  Progression free survival •  Overall survival •  Safety •  FGFR genotype subset analysis

Correla>ves •  Primary xenograks for shRNA and inhibitor profilling •  Tumor IHC (p-‐FRS2, p-‐FGFR), FGFR1 expression •  Comprehensive genomics for resistance

• Stage IV/recurrent lung SqCC

• Progression on 1st line pla,num doublet

• ECOG PS 0-‐2

Pona,nib x 2 cycles

Ineligible, screen for other study

G

If response or SD Pona>nib x 2

cycles PD

Genotyping • FGFR1 amplifica,on • FGFR2/FGFR3 muta,on • Comprehensive genotyping soon

Op,onal re-‐biopsy

N = 40

FGFR1 Inhibitor is Effec>ve in FGFR1 Amplified Cells

Weiss J, et al. Sci Transl Med. 2010.

In Vitro In Vivo

NFE2L2/KEAP1/CUL3 •  Muta,ons in KEAP1 are lof (frequent LOH of second allele). •  Muta,ons in NRF2 cluster in DLG and ETGE mo,f -‐> prevent KEAP1 interac,on <>

results in NRF2 stabiliza,on and nuclear entry.

Shibata et al. PNAS 2008.

In head and neck cancer muta,ons in NFE2L2/KEAP1/CUL3 are mutually exclusive with HPV+ (p<0.02); TP53 (p=0), CDKN2A (p<0.001).

KEAP1 mutant lung cancer lines are sensi>ve to siRNA targe>ng NFE2L2

Abazeed M, et al. ASCO 2012.

Sequencing of the tyrosine kinome of lung SCCs iden>fies recurrent muta>ons in DDR2

•  Mutations in the discoidin domain receptor 2 (DDR2) tyrosine

kinase gene 3.8%

•  DDR2, a receptor tyrosine kinase that binds collagen and promote

cell migration, proliferation, and survival

•  Activated DDR2 interacts with Src and Shc Hammerman P S et al. Cancer Discovery. 2011;1:78-89.

Radiographic response of a patient with a S768R DDR2 mutation treated with dasatinib plus erlotinib

Hammerman P S et al. Cancer Discovery. 2011;1:78-89.

A phase II study of dasa>nib in lung SCC

Primary Endpoint •  Overall response rate

Secondary endpoints •  Progression free survival •  Overall survival •  Safety •  DDR2 genotype subset analysis

• Stage IV/recurrent lung SqCC

• Progression on 1st line pla,num doublet

• ECOG PS 0-‐2

Dasa,nib x 2 cycles

Dasa,nib x 2 cycles

G

If response or SD Dasa>nib x 2

cycles PD

Genotyping • DDR2 muta1on

Op,onal re-‐biopsy

N = 40

If response or SD Dasa>nib x 2

cycles PD

Targeted exome sequencing

Discovery Cohort

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