Audio and slides for this presentation are available on YouTube: http://youtu.be/rt_O7m2eTYA David Barbie, MD, of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, discusses the stages of lung cancer, how the disease is treated, and new targeted therapies for patients. This presentation was originally given at Dana-Farber's "Living with Lung Cancer" forum on Nov. 2, 2013.

1. Lung Cancer: Stages, Treatments and
Targeted Therapies
David Barbie, M.D.
Lowe Center for Thoracic Oncology
Dana-Farber Cancer Institute
Assistant Professor of Medicine, Harvard Medical School
November 2, 2013

2. Lung Cancer Incidence and Mortality in U.S.
KRAS Mutation
~30%
~50%
~90%

3. Lung Cancer Stages and Treatments

4. Lung Cancer Stages and Treatments
Stage 1: Localized

5. Lung Cancer Stages and Treatments
Stage 1: Localized
Stage 2: Larger (> 5 cm) or spread to local lymph nodes
Surgery, +/-chemotherapy

6. Lung Cancer Stages and Treatments
Stage 1: Localized
Stage 2: Larger (> 5 cm) or spread to local lymph nodes
Surgery, +/-chemotherapy
Stage 3: Locally advanced
Chemotherapy and radiation, +/- surgery

7. Lung Cancer Stages and Treatments
Stage 1: Localized
Stage 2: Larger (> 5 cm) or spread to local lymph nodes
Brain
Surgery, +/-chemotherapy
Stage 3: Locally advanced
Chemotherapy and radiation, +/- surgery
Bone
Stage 4: Advanced/metastatic
Chemotherapy +/- palliative radiation
Liver
Adrenals

8. Oncogenes are the Jammed Accelerators
of Cancer Cells

11. BCR-ABL -
BCR-ABL +
Shtivelman et al. Nature 1985;315:550
Daley et al. Science 1990;247:824
Buchdunger et al. Cancer Res 1996;56:100
Deininger et al. Blood 1997;90:3691
Druker, BJ. Nat Med 2009;15:1149

12. Lynch et al. NEJM 2004;350:2129
Paez et al. Science 2004;304:1497

13. Mok et al. NEJM 2009;361:947

14. Better than chemotherapy,
but tumors become resistant
after 10-12 months
Mok et al. NEJM 2009;361:947

15. Genomic complexity of lung cancer
CML
Lung Adenocarcinoma
http://www.path.cam.ac.uk
http://www.utoronto.ca/cancyto

16. Lung Cancer Then and Now
Many different oncogenes can get jammed
No known
genotype
1984 - 2003
No known
genotype
2004
Erlotinib
X
X
2009
Crizotinib
2012
Courtesy of Stephanie Cardarella, MD, DFCI Thoracic Oncology

17. Chemotherapy Targets the
Engine, Targeted Therapy the Accelerator
EGFR inhibitor
ALK inhibitor
BRAF inhibitor
Carboplatin +
Alimta or Taxol

18. DFCI Patient with NSCLC and BRAF
mutation treated with Dabrafenib
August 10, 2012
September 19, 2012
Courtesy of Stephanie Cardarella, MD, DFCI Thoracic Oncology

19. MSKCC Patient with NSCLC and BRAF
mutation treated with Dabrafenib
February 2012
June 2012
Courtesy of Gregory Riely, MD, Memorial Sloan-Kettering Cancer Center

20. KRAS is Difficult To Target Directly
KRAS inhibitor – failed clinical trials

21. Alternatives to Targeting KRAS
1. Block known downstream pathways (between pedal and engine)
Also failing in clinical trials

22. Alternatives to Targeting KRAS
1. Block known downstream pathways (between pedal and engine)
XX
Also failing in clinical trials
X
X

23. Alternatives to Targeting KRAS
2. Use genomics to identify currently unknown pathways
needed for survival (that keep car from crashing)
TBK1

24. CYT387 Impairs Viability of Lung cancer Cells
A549 Lung Cancer Cells
DMSO
CYT387 (5mM)

25. Activity of CYT387 in Kras-driven Murine Lung Cancer
Murine KRAS-Driven Lung Cancer
CYT387 100mg/kg/d
H
Baseline
H
Week 16
Kwok Wong
Travis Cohoon

26. Activity of CYT387 in Kras-driven Murine Lung Cancer
H
E
pA
ST
T3
A
B
Uee
n ad
t t
r
2m
5
µ
C
2m
5
µ
D
Tor an
a t el e
xe o
2m
5
µ
E
2m
5
µ
F
C an
Yl e
To
2m
5
µ
2m
5
µ

27. Alternatives to Targeting KRAS
Blocking multiple unique pathways

28. Alternatives to Targeting KRAS
Blocking multiple unique pathways
X
X
X
X

29. Activity of CYT387 in Kras-driven Murine Lung Cancer
KrasLSL-G12D/WT;p53flox/flox model with established tumor burden
*p<0.01
**p<0.0001
CYT387: 100 mg/kg/daily by oral gavage
Selumetinib: 25 mg/kg/twice daily by oral gavage
Kwok Wong
Travis Cohoon

30. Activity of CYT387 in Kras-driven Murine Lung Cancer
KrasLSL-G12D/WT;p53flox/flox model with established tumor burden
*p<0.01
**p<0.0001
Treatment well tolerated other than
initial gavage trauma
CYT387: 100 mg/kg/daily by oral gavage
Selumetinib: 25 mg/kg/twice daily by oral gavage
Kwok Wong
Travis Cohoon

31. Immunotherapy – “Immune Checkpoint Blockade”

32. Immunotherapy – “Immune Checkpoint Blockade”

33. Immunotherapy – “Immune Checkpoint Blockade”
PD-L1
PD-L1
PD-L1

34. Immunotherapy – “Immune Checkpoint Blockade”
T cell
T cell
PD1
PD1
PD-L1
PD-L1
PD-L1
PD1
T cell

35. Immunotherapy – “Immune Checkpoint Blockade”
T cell
X
T cell
PD1
X
PD1
PD-L1
PD-L1
PD-L1
T cell
X
PD1

36. Immunotherapy – “Immune Checkpoint Blockade”
T cell
PD-L1 targeted
drugs
T cell
X
PD1
X
PD1
PD-L1
PD-L1
PD-L1
T cell
X
PD1

37. Immunotherapy – “Immune Checkpoint Blockade”
T cell
T cell
PD1
PD1
PD1
T cell

38. Immunotherapy – “Immune Checkpoint Blockade”
T cell
T cell
PD1
PD1
PD1
T cell

39. Summary
• Lung cancer can be treated with a
combination of surgery, radiation, and
chemotherapy depending on the stage

40. Summary
• Lung cancer can be treated with a
combination of surgery, radiation, and
chemotherapy depending on the stage
• We continue to develop new ways to target
lung cancer more directly, with increasing
success

41. Summary
• Lung cancer can be treated with a
combination of surgery, radiation, and
chemotherapy depending on the stage
• We continue to develop new ways to target
lung cancer more directly, with increasing
success
• With combinations of these new targeted
therapies the future is very bright