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

Disclosures None

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

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

Actionable Targets in Lung Adenocarcinomas 1999 2004 2005-2013 Unknown 75% Unknown 60% EGFR Kris M et al. IASLC 2012 Targeted Therapies Conference

Actionable Targets in Squamous Cell Lung Cancers 1999 2004-2010 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

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

FGFR1 amplification

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

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

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

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

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

FGFR1-directed trials are abundant Drug Target(s) Clinicaltrials.gov # AZD4547 Pan-FGFR NCT01824901 (phase 2) NCT00979134 (phase 1 expansion) BGJ398 NCT01004224 (phase 1) GSK305220 FGF ligands NCT01868022 (phase 1) Debio 1347 FGFR1-3 JNJ42756493 NCT01703481 (phase 1) Radiographic PRs reported in response to BGJ398 All trials are ongoing

DDR2

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

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

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

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

DDR2 clinical trials Drug Target(s) Clinicaltrials.gov # dasatinib DDR2 mutations NCT01514864 (phase 2)

PI3K pathway

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

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

PI3K pathway clinical trials Drug Target(s) Clinicaltrials.gov # BKM120 PIK3CA NCT01297491 (phase 2) carboplatin + paclitaxel + BKM120 NCT01723800 (phase 1) Overlap with FGFR1 amplification, NFE2L2/KEAP1 mutations complicates clinical validation

EGFR

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

FLEX trial subgroup analysis

Retrospective FLEX H-score analysis Pirker Lancet Oncol 2012

Completed and ongoing trials Title Treatment Clinicaltrials.gov # SWOG 0819 Randomized carbo/pacli or carbo/pacli/bev +/- cetuximab NCT00946712 (accruing) SQUIRE Cisplatin + gemcitabine +/- necitumumab NCT00981058 (closed) August 2013 SQUIRE: top-sheet results released by Lilly, OS endpoint met Planned sample size to show median OS increase from 11 to 13.75 months

Conclusions

Oncogene Landscape in Lung Cancer: 2013

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