This document discusses advances in multiplexed genotyping and its impact on the treatment of lung cancers. Key points include: 1) The era of "one size fits all" treatment of lung cancers is over due to advances in identifying oncogenic drivers through multiplexed testing of tumor samples. 2) Identifying these drivers through comprehensive genomic profiling allows for matching patients to targeted therapies, improving outcomes over previous untargeted approaches. 3) The MSK-IMPACT assay profiles 341 cancer genes and has identified targets for both approved and investigational targeted therapies, improving personalized treatment of lung cancer patients.

1. Multiplex Genotyping and the
Treatment of Lung Cancers
Mark G Kris, MD The William and Joy Ruane Chair of Thoracic Oncology
Attending Physician, Thoracic Oncology Service
Lead Physician, MSK-IBM Watson Oncology Project
Memorial Sloan Kettering Cancer Center
Professor of Medicine
Weill Cornell Medical College

2. 13%

3. 2003: Discovery of EGFR exon 19 deletion at MSK
1 JUL 2002 29 JUL 2002 23 OCT 2003
ATP-binding site
EGF binding Tyrosine kinase
TM K Y Y Y Y
Auto-phos
Exon 19
PVAIKELREATSPKAN
6 aa del
*
Serial radiographs of a 73-year old never smoking woman with adenocarcinoma, mixed cell-type with BAC
features, who demonstrated radiographic regression while on gefitinib. She took gefitinib from July 2002 until
October 2003. B. Schematic of the EGFR protein and the 6 amino acid (aa) deletion detected in A.G.’s tumor.
(K-lysine residue, Y-tyrosine). C. Immunoblotting analyses demonstrate that compared to wild type (WT)
EGFR, the A.G. mutant has less autophosphorylation activity but may be more stable in transient transfections.
(2 identical but individual WT clones and 3 identical but individual A.G. mutant clones were assessed.
Pao PNAS 2004

4. Frequency of Oncogenic Drivers in
3026 Lung Adenocarcinomas at MSK
Dogan Clin Cancer Res, 2012

5. Marc Ladanyi
“Looking for a Target on Every Tumor” Science 2009; 326: 218-220 www.science mag.org

6. LCMC: Frequency of Oncogenic Drivers
in Lung Adenocarcinomas
Kris and Johnson JAMA 2014

7. Survival with the five most frequent oncogenic drivers
0 1 2 3 4 5
0.0 0.2 0.4 0.6 0.8 1.0
YEARS
SURVIVAL
group=ALK
group=Doub
group=EGFR(o)
group=EGFR(s)
group=KRAS
p=0.001
Altered Gene N Median Survival (95% CI)
EGFR (sensitizing) 140 4.0 years (2.7 to 5.4)
EGFR (other) 50 3.3 years (2.2 to 6.2)
ALK 73 4.3 years (3.0 to NA)
KRAS 231 2.4 years (1.9 to 3.6)
Two Drivers 32 2.0 years (1.6 to 4.6)

8. Survival of Patients with Drivers: Targeted
Therapy vs No Targeted Therapy
(C)
(B)
(A)
(C) 264 233 146 80 40 25
(B) 361 255 123 61 44 27
(A) 313 200 109 64 45 23
0 1 2 3 4 5
0.0 0.2 0.4 0.6 0.8 1.0
YEARS
SURVIVAL
(A)
(B)
(C)
Group N Median Survival (95% CI)
Driver, no targeted therapy (A) 313 2.4 years (1.8 to 2.9)
No driver (B) 361 2.1 years (1.8 to 2.5)
Driver, targeted therapy (C) 264 3.5 years (3.2 to 4.6)
S U R V IV AL
Driver with targeted therapy
Driver with NO targeted therapy
Kris
JAMA 2014

11. Krisk
k

12. Response to Vemurafenib
BRAF V600E Mutant Lung Cancer
baseline 6 weeks on vemurafenib

13. Evolution of Multiplexed Testing Platforms
Now-Gen
MSK LC-MAP
8 genes
Point mutations only
Next-Gen
MSK IMPACT
341 genes
Point mutations plus deletions, insertions,
amplifications
Comparable time and cost

14. MSK-IMPACT: Assay of 341 Cancer Genes
ABL1 BRAF CSF1R ETV6 H3F3C KLF4 MYD88 PIK3CB RECQL4 SPEN
AKT1 BRCA1 CTCF EZH2 HGF KRAS MYOD1 PIK3CD REL SPOP
AKT2 BRCA2 CTLA4 FAM123B HIST1H1C LATS1 NBN PIK3CG RET SRC
AKT3 BRD4 CTNNB1 FAM175A HIST1H2BD LATS2 NCOR1 PIK3R1 RFWD2 STAG2
ALK BRIP1 CUL3 FAM46C HIST1H3B LMO1 NF1 PIK3R2 RHOA STK11
ALOX12B BTK DAXX FANCA HNF1A MAP2K1 NF2 PIK3R3 RICTOR STK40
APC CARD11 DCUN1D1 FANCC HRAS MAP2K2 NFE2L2 PIM1 RIT1 SUFU
AR CASP8 DDR2 FAT1 ICOSLG MAP2K4 NKX2-1 PLK2 RNF43 SUZ12
ARAF CBFB DICER1 FBXW7 IDH1 MAP3K1 NKX3-1 PMAIP1 ROS1 SYK
ARID1A CBL DIS3 FGF19 IDH2 MAP3K13 NOTCH1 PMS1 RPS6KA4 TBX3
ARID1B CCND1 DNMT1 FGF3 IFNGR1 MAPK1 NOTCH2 PMS2 RPS6KB2 TERT
ARID2 CCND2 DNMT3A FGF4 IGF1 MAX NOTCH3 PNRC1 RPTOR TET1
ARID5B CCND3 DNMT3B FGFR1 IGF1R MCL1 NOTCH4 POLE RUNX1 TET2
ASXL1 CCNE1 DOT1L FGFR2 IGF2 MDC1 NPM1 PPP2R1A RYBP TGFBR1
ASXL2 CD274 E2F3 FGFR3 IKBKE MDM2 NRAS PRDM1 SDHA TGFBR2
ATM CD276 EED FGFR4 IKZF1 MDM4 NSD1 PRKAR1A SDHAF2 TMEM127
ATR CD79B EGFL7 FH IL10 MED12 NTRK1 PTCH1 SDHB TMPRSS2
ATRX CDC73 EGFR FLCN IL7R MEF2B NTRK2 PTEN SDHC TNFAIP3
AURKA CDH1 EIF1AX FLT1 INPP4A MEN1 NTRK3 PTPN11 SDHD TNFRSF14
AURKB CDK12 EP300 FLT3 INPP4B MET PAK1 PTPRD SETD2 TOP1
AXIN1 CDK4 EPCAM FLT4 INSR MITF PAK7 PTPRS SF3B1 TP53
AXIN2 CDK6 EPHA3 FOXA1 IRF4 MLH1 PALB2 RAC1 SH2D1A TP63
AXL CDK8 EPHA5 FOXL2 IRS1 MLL PARK2 RAD50 SHQ1 TRAF7
B2M CDKN1A EPHB1 FOXP1 IRS2 MLL2 PARP1 RAD51 SMAD2 TSC1
BAP1 CDKN1B ERBB2 FUBP1 JAK1 MLL3 PAX5 RAD51B SMAD3 TSC2
BARD1 CDKN2A ERBB3 GATA1 JAK2 MPL PBRM1 RAD51C SMAD4 TSHR
BBC3 CDKN2B ERBB4 GATA2 JAK3 MRE11A PDCD1 RAD51D SMARCA4 U2AF1
BCL2 CDKN2C ERCC2 GATA3 JUN MSH2 PDGFRA RAD52 SMARCB1 VHL
BCL2L1 CHEK1 ERCC3 GNA11 KDM5A MSH6 PDGFRB RAD54L SMARCD1 VTCN1
BCL2L11 CHEK2 ERCC4 GNAQ KDM5C MTOR PDPK1 RAF1 SMO WT1
BCL6 CIC ERCC5 GNAS KDM6A MUTYH PHOX2B RARA SOCS1 XIAP
BCOR CREBBP ERG GREM1 KDR MYC PIK3C2G RASA1 SOX17 XPO1
BLM CRKL ESR1 GRIN2A KEAP1 MYCL1 PIK3C3 RB1 SOX2 YAP1
BMPR1A CRLF2 ETV1 GSK3B KIT MYCN PIK3CA RBM10 SOX9 YES1
Ladanyi
Berger
Solit
Acila

15. Using Driver Mutations to Classify
and Treat All Lung Cancers
Carcinoid
Large Cell
Large Cell Neuroendocrine
5%

16. Oncogenic Drivers In Lung Cancers

17. Impact of MSK IMPACT
MSK Patients with Thoracic Cancers
Many Targets, Drugs, and Protocols
Gene Targets in NCCN Guidelines 7
Targeted Drugs in NCCN Compendia 12
Gene Targets for Investigational Agents 17
Trials of Targeted Therapies for Specific Genes 30

19. Multiplex Genotyping and the Treatment of Lung Cancers
Conclusions
• The “one size fits all” treatment era of lung cancers is over
• Advances in cancer biology have changed care. Targeted
therapies are biology-based and patient specific
• Precise pathologic diagnoses a must. Tissue needed.
• Test …. Don’t Guess. No “patient profile” adequate to select
• Do multiplexed testing at diagnosis. Tissue needed.
• Targeted therapies are standard for patients with stage IV.
Results justify use with local therapies in stages I-III
• Personalized care for lung cancers is here. A model for other
cancers.

20. 2005 2012
“ Here's my sequence...”
Kris
Kris
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