Novel treatments for SCC Andrés Felipe Cardona, MD MS PhD.

Transcription

1 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

2 Best diagnos>c markers for NSCLC Characteis>c SCC Ck5/6 p63 HMWcK CD141 Rb Sensi>vity Specificity PPV NGV Characteris>c Adenocarcinoma Napsin- A TTF1 CDX2 MOC- 31 ACE p27 Sensi>vity Specificity PPV NGV Ck5/6 TTF1 Ann Diagn Pathol (2012),

3 Overall survival according to histology Histology Period 1- y OS (%) All histologies Adenocarcinoma SCC Large cell Other y OS (%) J Thorac Oncol Dec;4(12):

4 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.

5 Significantly mutated genes in lung SQCC 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: /nature11404.

6 CDKN2A Tumor suppressor gene Encodes p16ink4a and p14arf proteins Inactivated in 72% Clin Cancer Res. 2012;18:

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

8 Gene expression subtypes integrated with genomic altera>ons 36% 15% 25% 24% KEAP1 NFE2L2 PTEN/PI3K Pronounced hypermethylation Chromosomal instability RB1 PTEN NF1 FGFR1 PDGFRa 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: Kris et al., ASCO 2011; Abs #7506. Sivachenko et al., IASLC 2011; Abs #PRS.1.

9 Altera>ons in targetable oncogenic pathways in lung SCC Hammerman PS, et al. Nature. 2012;1-7. doi: /nature11404.

10 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 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/m 2 every 21 days (n = 44) Number of cycles determined by local practice and investigator preference Placebo BID + Docetaxel 75 mg/m 2 every 21 days (n = 43) Janne PA, et al. ASCO Abstract 7503.

11 Second- line Selume>nib plus Docetaxel: pa>ent characteris>cs Characteris>c Selume>nib + Docetaxel (n = 44) Placebo + Docetaxel (n = 43) Male, % Median age, yrs (range) 59.5 (26-79) 59 (37-76) Smoking status, % Never Former or current Disease stage IIIB/IV, % 11.4/ /97.7 WHO PS 0/1, % 47.7/ /51.2 Histology, % Adenocarcinoma Squamous carcinoma Adenosquamous carcinoma Large cell carcinoma Other Janne PA, et al. ASCO Abstract

12 Second- line Selume>nib plus Docetaxel: clinical outcomes Outcome Selume>nib + Docetaxel (n = 43) Placebo + Docetaxel (n = 40) HR (P Value) Median OS, mos (.2069) Median PFS, mos (.0138) 6- mo PFS, % (.0158) Best ORR, % CR PR SD 6 wks PD Not evaluable Median response dura>on, days (<.0001) Rela>ve tumor change - 26% (.004) Janne PA, et al. ASCO Abstract 7503.

13 Second- line Selume>nib plus Docetaxel: Safety Outcome, % Selume>nib + Docetaxel (n = 44) Placebo + Docetaxel (n = 42) Any serious adverse event Event- related death Event- related hospitaliza>on Event leading to discon>nua>on Selume,nib or placebo Docetaxel Event- related dose reduc>on of selume>nib/placebo Event- related interrup>on of selume>nib/placebo Most common events with selumetinib: neutropenia, diarrhea, nausea, vomiting, anemia, peripheral edema Janne PA, et al. ASCO Abstract 7503.

14 FGFR- driven transforma>on is blocked by kinase inhibitors BGJ398 Ponatinib Hammerman PS, et al. Nature. 2012;1-7. doi: /nature11404.

15 Trial Design: Pona>nib in Lung SCC Stage IV/recurrent lung SqCC Progression on 1st line pla,num doublet N = 40 G Pona,nib x 2 cycles Genotyping FGFR1 amplifica,on FGFR2/FGFR3 muta,on Comprehensive genotyping soon If response or SD Pona>nib x 2 cycles PD Op,onal re- biopsy ECOG PS 0-2 Ineligible, screen for other study 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

16 FGFR1 Inhibitor is Effec>ve in FGFR1 Amplified Cells In Vitro In Vivo Weiss J, et al. Sci Transl Med

17 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. 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). Shibata et al. PNAS 2008.

18 KEAP1 mutant lung cancer lines are sensi>ve to sirna targe>ng NFE2L2 Abazeed M, et al. ASCO 2012.

19 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.

20 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.

21 A phase II study of dasa>nib in lung SCC Stage IV/recurrent lung SqCC Progression on 1st line pla,num doublet N = 40 G Dasa,nib x 2 cycles Genotyping DDR2 muta1on If response or SD Dasa>nib x 2 cycles PD Op,onal re- biopsy ECOG PS 0-2 Primary Endpoint Overall response rate Dasa,nib x 2 cycles If response or SD Dasa>nib x 2 cycles PD Secondary endpoints Progression free survival Overall survival Safety Discovery Cohort Targeted exome sequencing DDR2 genotype subset analysis