1. Squamous Cell Lung Cancers in 2013: New Targets and Promising Therapies
Paul K Paik, MD
Assistant Attending Physician
Thoracic Oncology Service
Memorial Sloan-Kettering Cancer Center

2. Disclosures
None

3. NSCLC Histology Memorial Sloan-Kettering 2000-2010
Large cell carcinoma 2%
Adenosquamous carcinoma 1%
Squamous cell carcinoma
25%
Adenocarcinoma
72%
Worldwide incidence SQCLC= 350,000 patients annually

4. Erlotinib/Gefitinib/Afatinib
NSCLC Therapies
Approved Treatments
Adenocarcinoma
Squamous
Chemotherapy 
Bevacizumab 
Erlotinib/Gefitinib/Afatinib ?
Crizotinib

5. Actionable Targets in Lung Adenocarcinomas
1999
2004
Unknown
75%
Unknown
60%
EGFR
Kris M et al. IASLC 2012 Targeted Therapies Conference

6. Actionable Targets in Squamous Cell Lung Cancers
1999
2013
FGFR1
amplification
Unknown
100%
Unknown
100%
PIK3CA mutation
PTEN mutation
PTEN
loss
DDR2 mutation
Okudela et al. Cancer Res 2008
Yamamoto et al. Pathol Int 2007
Weiss et al. Sci Transl Med 2010
Hammerman et al. Cancer Discovery 2011
TCGA Nature 2012

7. Novel Therapeutic Targets and Ongoing Paired Clinical Trials
FGFR1 amplification
DDR2 mutations
PI3K pathway
EGFR

8. FGFR1 amplification

9. FGFR1 amplification Bass et. al. Nature 2009 TCGA Nature 2012
Weiss et. al.
Sci Transl Med 2010

10. Chromosomal gain is common
FGFR1 amplification
Amplification (FGFR1:CEP8 ≥ 2)
16-25%
Correlation with protein expression unknown
TCGA Nature 2012
Paik ASCO 2012
Heist J Thorac Oncol 2012

11. FGFR1 signaling: PI3K, Ras/MAPK, and PKC activation
Fibroblast growth factors
Receptor dimerization
Ras/Raf/
MAPK
PI3K
PKC
Growth, division, angiogenesis

12. Amplification predicts sensitivity to drug in vitro and in vivo
H520 was the only SCC cell line. ¾ of the sensitive cell lines had FGFR1 amplification (copy number ≥ 4)
Weiss et. al. Sci Transl Med 2010

13. FGFR1 and PI3K: not mutually exclusive
cBio GDAC Lung Squamous TCGA data
Significant biomarker overlap may complicate target validation in trials

14. FGFR1-directed trials are abundant
Drug
Target(s)
Clinicaltrials.gov #
AZD4547
Pan-FGFR
NCT (phase 2)
NCT (phase 1 expansion)
BGJ398
NCT (phase 1)
GSK305220
FGF ligands
NCT (phase 1)
Debio 1347
FGFR1-3
JNJ
NCT (phase 1)
Radiographic PRs reported in response to BGJ398
All trials are ongoing

15. DDR2

16. Discoidin domain receptor 2 (DDR2): ECM/collagen signaling
Stimulated by collagen as a ligand
Downstream signaling in cancer cells is poorly understand
May be via SRC and STAT signaling pathways.
Similar to integrin receptors, DDR2 may play a role in modulating cellular interactions with the extracellular matrix

17. DDR2 mutations are sporadic and uncommon
Sanger sequencing of 290 SQCLC resections uncovered 11 mutations in DDR2 (3.8%)
No hotspots
Hammerman et. al. Cancer Discovery 2012

18. DDR2 is druggable with dasatinib: in vivo data
DDR2 I638F mutant

19. Clinical response to dasatinib (DDR2 S768I): 2 case reports
50F heavy smoker with CML and a RUL squamous lung cancer
Began dasatinib for CML, plan for RUL lobectomy after disease controlled
10 week PET for restaging of lung cancer showed:
Hammerman et. al. Cancer Discovery 2012
Pitini et al. Lung Cancer 2013

20. DDR2 clinical trials Drug Target(s) Clinicaltrials.gov # dasatinib
DDR2 mutations
NCT (phase 2)

21. PI3K pathway

22. FGFR and HER families are common PI3K-associated receptors in SQCLC

23. Oncogenic PI3K pathway changes are common in SQCLC
PIK3CA mutation
PTEN mutation
PTEN loss
PI3K alterations (PIK3CA mutations, PTEN mutations, PTEN loss) occur in ~30-50% of SQCLCs
PIK3CA amplification occurs in another 20-30%
TCGA Nature 2012

24. PI3K pathway clinical trials
Drug
Target(s)
Clinicaltrials.gov #
BKM120
PIK3CA
NCT (phase 2)
carboplatin + paclitaxel + BKM120
NCT (phase 1)
Overlap with FGFR1 amplification, NFE2L2/KEAP1 mutations complicates clinical validation

25. EGFR

26. EGFR alterations in SQCLC
Canonical exon 19 deletions and exon 21 L858R mutations do not occur in SQCLCs
Exception in underdiagnosed adenosquamous lung cancers
NCCN recommends EGFR mutation testing in never smokers diagnosed with SQCLC from small biopsy specimens
EGFR amplification occurs in 7-10% of SQCLCs
Rare EGFR L861Q mutations have been reported
EGFR expression by IHC is common
Role of H-score awaits prospective validation

27. FLEX trial subgroup analysis

28. Retrospective FLEX H-score analysis
Pirker Lancet Oncol 2012

29. Completed and ongoing trials
Title
Treatment
Clinicaltrials.gov #
SWOG 0819
Randomized carbo/pacli or carbo/pacli/bev +/- cetuximab
NCT (accruing)
SQUIRE
Cisplatin + gemcitabine +/- necitumumab
NCT (closed)
August 2013 SQUIRE: top-sheet results released by Lilly, OS endpoint met
Planned sample size to show median OS increase from 11 to months

30. Conclusions

31. Oncogene Landscape in Lung Cancer: 2013

32. Molecular testing options
Local trial center where focused testing can be performed
Academic center with molecular testing program in SQCLC
Foundation Medicine