1. BEST OF ASCO LUNG CANCER 2012
David R. Gandara, MD
University of California Davis Comprehensive Cancer Center

2. Disclosures
Research Grants: Abbott, BMS/ImClone, Genentech, GSK, Lilly, Merck, Novartis
Consultant: Abbott Molecular, AstraZeneca, Biodesix, Boehringer-Ingelheim, BMS/ImClone, Caris, Celgene, GlaxoSmithKline, Genentech, Lilly, Merck, Novartis, Pfizer, Response Genetics, Sanofi-Aventis

3. BEST OF ASCO LUNG CANCER 2012
Abstracts for Discussion:
Small Cell Lung Cancer (SCLC):
Limited & Extensive Stage
Non Small Cell Lung Cancer(NSCLC):
Genomics: The “Big Bang” effect
Advanced Stage NSCLC
Targeted Therapies: “Coming of Age”
ALK
ROS1
MEK
Emerging Role of Immunotherapy

4. SCLC Abstracts for Discussion
#7004: Concurrent TRT-Chemotherapy: 1st Cycle vs 3rd Cycle. Phase III (Park et al)
#7003: Amrubicin-Cisplatin vs Irinotecan-Cisplatin in E-SCLC. Phase III JCOG 0509 (Kotani et al)
#7005: Weekly Topotecan +/- AVE0005 (Aflibercept) in 2nd line therapy of E-SCLC. Randomized Phase II S0802 (Allen et al)
#7004
Limited Stage:
Timing of
Chemo-Radiation
#7003
Extensive Stage
1st Line Chemotherapy:
Amrubicin
#7005
2nd Line Therapy:
AVE0005

5. Demographic, Biologic, Clinical & Therapeutic Differences between SCLC & NSCLC
Feature
SCLC
NSCLC
Incidence
Decreasing
Increasing
Association with Smoking
Universal
Highly Variable
Growth Kinetics
~Rapid
Variable
Biologic Diversity
(Histologic & Molecular)
~Homogeneous
Distinct Subtypes
Early Metastases
Sensitivity to DNA-damaging chemotherapy (1st line)
High
Sensitivity to Radiotherapy
Advances in Therapy ~15 years
Few Advances
Dramatic Advances

6. PCI for patients with PR or CR
#7004: 1st versus 3rd Cycle TRT + Cisplatin-Etoposide in L-SCLC (Park et al)
1st Cycle
arm
(n=111) E P E P E P E P
PCI for patients with PR or CR
TRT
LD-SCLC
Treatment-naïve
N=219
EP: Etoposide 100mg/m2 D1-3
Cisplatin 70mg/m2 D1, q3 w
TRT: 52.5 Gy/25 fxs (2.1 Gy/fx, once daily) R
1:1
3rd Cycle
Delayed
arm
(n=108) E P E P E P E P
Definition of limited disease: cancer confined to the ipsilateral hemithorax and can be encompassed within a tolerable radiation port. Thus, contralateral SCNx, recurrent laryngeal nerve involvement, and SVC obstruction was included. Malignant pleural effusion & pericardial effusion was excluded.
Definition of CR: Disappearance of tumor
TRT
Primary end point: Complete response rate (WHO criteria)
Secondary end point: ORR, OS, PFS, and toxicity (NCI-CTC ver. 2.0)
Enrollment between 2003 and 2010 (7 years)
Median Follow Up is 59.4 months (about 5 years)

7. Efficacy Comparisons: 1st (initial) vs 3rd (delayed) cycle TRT
Favors Cycle 1 but not significantly different

8. Perspective on this Abstract: Therapy of Limited Stage SCLC
Platinum/Etoposide (PE) + 1st cycle concurrent thoracic radiotherapy (TRT) has been standard of care in the U.S. for ~20 years
Regimens adding new systemic agents or substituting agents have generally failed to show sufficient promise to replace PE
Advance: Twice day hyperfractionated RT + PE was proven superior to once daily standard fraction RT (Turrisi et al: NEJM, 1999), but has not been widely adopted in practice
A great deal of attention has already been paid to optimizing
the timing of TRT in L-SCLC.
Why Revisit It Now?
In reality, 1st cycle concurrent TRT is not feasible in a substantial subset of patients with L-SCLC
Radiation volume considerations (V20 or other parameters)
Delays in radiation planning in some settings/countries
Need for systemic therapy on an urgent basis in some cases

9. Meta-Analysis of TRT Timing: Overall Survival
2-3 Year OS
Meta-Analysis
Favors Early TRT
5 Year OS
Pijls-Johannasma et al:
Cancer Treat Rev, 2007

10. Two Ongoing Phase III Trials in L-SCLC:
Testing Radiation Dose Schedules
Amended to allow Cycle 1 or Cycle 2 TRT
Testing Cycle 2 TRT in both arms
Both are focused on TRT Dose Schedule
Neither is investigating timing of TRT

11. Summary: #7004 Timing of TRT
The results add to literature concluding that early TRT is important (but not necessarily cycle 1) in optimizing efficacy of Chemo-Radiation in L-SCLC
Cycle 1 TRT leads to an increase in some toxicities
Other ongoing Phase III trials are investigating alternative TRT dose schedules but not timing or radiation volume issues
New systemic agents for inclusion into chemo-radiation regimens for L-SCLC are needed

12. #7003: JCOG 0509 (Kotani et al) IP AP Primary Endpoint= OS
ED-SCLC
20-70 yrs
PS 0-1
Stratification
● PS
● institution
● sex
Sample size
n= 282
(n= 141 per Arm) R A N D O M I Z E IP
Irinotecan 60 mg/m2 D1,8,15
Cisplatin mg/m2 D1
Q4 weeks x 4 cycles
PCI if CR
(2.5Gy/10 Fx)
Amrubicin* 40 mg/m2 D1-3
Cisplatin mg/m2 D1
Q3 weeks x 4 cycles AP
Primary Endpoint= OS
IP dose schedule was identical to J9511 & SWOG 0124
Amrubicin dose amended to 35 mg/m2 due to FN
Trial was closed early by the DSMC

13. Efficacy Comparisons: AP versus IP (JCOG0509)

14. Phase III Investigation of “Newer” Chemotherapeutic Agents in E-SCLC
Response Rate in Phase II:
1st line/2nd line
Results (1st line in combination with Platinum)
Paclitaxel
~35%/~25%
Negative Phase III trial
(Niell et al)
Gemcitabine
~25%/14%
Phase II: not promising
(Hesketh et al)
Topotecan
?/~18%
“Positive” Phase III:
but not adopted
(Heigener et al)
Irinotecan
Conflicting results of
Phase III trials
(Noda; Lara; Hanna)
Pemetrexed ?
(Socinski et al)
Amrubicin
~40%
Negative Phase III trial as
2nd line- single agent
( Jotte et al)
from Gandara et al: NCI Early Drug Development Symposium, April 2012

15. Comparative Efficacy of JCOG 9511 versus SWOG 0124
S0124 did not confirm results of J9511
Efficacy of Irinotecan greater in Japanese patients
Toxicity was also greater in Japanese patients
Population-related Pharmacogenomics may have influenced results
Lara et al: JCO, 2009

16. Summary: #7003: AP vs IP in 1st Line Therapy of E-SCLC
Another promising drug in SCLC has failed to pass the Phase III test
Approaches exploiting the initial high sensitivity of SCLC to 1st line DNA-damaging chemotherapy are worth pursuing (ECOG 2511: PARPi ABT888)
Demonstrating new agent activity in the 2nd line setting in platinum-refractory disease may be a logical prerequisite for testing in the 1st line setting

17. #7005: Topotecan +/- AVE0005 (Aflibercept) in 2nd Line Therapy of E-SCLC (S0802- Allen et al)M I Z E
Topotecan IV
4 mg/m2 Days 1, 8, and 15
AVE0005 IV
6 mg/kg on Day 1
Platinum Sensitive
Response to 1st Line Chemotherapy and Progression > 90 days (ES) or 180 days (LS) S T R A I F Y
Eligibility Criteria
Small cell lung cancer
Extensive or limited stage
1 prior platinum-based chemotherapy regimen
ECOG PS 0-1
Adequate organ function
No “anti-angiogenic” risk factors
Topotecan IV
4 mg/m2 Days 1, 8, and 15 R A N D O M I Z E
Topotecan IV
4 mg/m2 Days 1, 8, and 15
AVE0005 IV
6 mg/kg on Day 1
Platinum Refractory
Progression ≤ 90 days (ES) or < 180 days (LS) after 1st Line Chemotherapy
Topotecan IV
4 mg/m2 Days 1, 8, and 15
* Topotecan is omitted on Day 15 for all patients starting on Cycle 5.

18. #7005: Efficacy of Topotecan +/- AVE0005

19. Perspective on this Abstract: 2nd Line Therapy of Extensive SCLC
In 2nd line therapy, a number of chemotherapeutic agents are active in “platinum-sensitive” patients, but the “platinum-refractory” subset fares poorly
Example: Topotecan is primarily active only in “platinum-sensitive” patients
Identifying agents active in the “platinum-refractory” subset is therefore a high priority in clinical research in SCLC
Additional studies evaluating novel targeted agents in SCLC are needed

20. Investigation of “Targeted Therapies” in Extensive SCLC
Selected Agents
Target(s)
Results
Imatinib
(Johnson et al)
KIT, SCF
Inactive
Bec2/BCG
(Giaccone)
GD3 ganglioside
Negative Phase III trial
Bortezomib (PS-341)
(Lara et al)
Proteasome
Insufficient activity
Sorafenib
(Gitliz et al)
VEGFR
Insufficient activity
PR: PlatSens: 5% PlatRef: 2%
Vandetanib (ZD6474)
(Arnold et al)
EGFR/VEGFR
HR 1.43 vs Placebo for OS
ABT263 & Obatoclax
(Rudin et al; Langer et al)
Bcl-2
PE + GDC0449 or IMC-A12:
E1508 (Belani/Rudin)
Hedgehog or
IGF-1R
Pending Completion
ABT888 + PE vs PE: E2511
(Owonikoko/Belani)
PARP
Pending Activation
Biologic Activity of some Targeted Agents may occur without RECIST response
Manifest as improved DCR (CR/PR + SD), PFS/OS or Biomarker/Imaging effects
“Four Dimensional Model”

21. Measuring Effects of “Novel Therapeutic Agents”:
A Four Dimensional Model
Classic Tumor Response
(RECIST)
Disease Control
(CR + PR + SD)
or Timed DCR
Survival Endpoints
(OS, PFS)
Biologic Effects on Tumor
(Biomarkers, Functional imaging)
adapted from Gandara et al,
Clin Lung Cancer, 2007

22. Biologic Activity without RECIST Response

23. Phase II Study of Aflibercept in Refractory NSCLC
Number of patients 98
Treatment
Aflibercept 4 mg/kg
q 2 wks
Prior treatment
69.4% pts ≥ 3 lines
Primary Objective (RECIST)
ORR 2 %
95% CI [0.2 – 7.2%] 40
Best response vs baseline 20
Best % Tumor Shrinkage
-20
-40
Patients
Leighl et al: J Thorac Oncol , 2010

24. SHARP Trial: Sorafenib vs Placebo in Hepatocellular Cancer
Llovet et al: NEJM 2008

25. Summary: #7005: Topotecan +/-VE0005
The S0802 trial met the primary endpoint of improved 3-month PFS
RECIST response was low & there was no impact on OS
These data remain hypothesis-generating & require confirmation (Predictive Biomarker development is essential)
How to best combine VE0005 & Chemotherapy remains unclear

26. Advances in Sequencing Technologies and Human Genomics
Automated slab gel
Manual slab gel
1st generation capillary sequencer
Gel-based Systems
Capillary sequencing
2nd generation
capillary sequencer
Microwell pyrosequencing
Short-read sequencers
Single molecule?
Massively parallel sequencing
(10)
(50)
(103)
(105)
(107)
(109)
(102)
Sequencing Technology
(kilobases/day/machine)
1980
1985
1995
2000
Future
2010
2005
1990
1975 I
Ras mutations
as 1st oncogenes (1982)
EGFR mutations
( )
ALK gene rearrangement
( )
Human Genome Project
( )
Human Genomics
& Lung Cancer (year)
Somatic mutations in lung adenocarcinoma (2008)
The Cancer Genome Atlas
(2010- )
Small cell lung cancer genome (2009)
lung adenocarcinoma genome (2008)
1000 Human Genome
(2007- )
Li, Gandara et al: JCO 2012 (in press)
Squamous cell lung cancer genome (2012)

27. Comprehensive Characterization of Squamous Cell NSCLC (SCCA) #7006
Ramaswamy Govindan, Peter Hammerman, Neil Hayes, Matthew Wilkerson, Steve Baylin and Matthew Meyerson
On Behalf of the Lung Cancer Working Group of
The Cancer Genome Atlas (TCGA) Project

28. #7006: Characterization of Genomic Alterations
in Cancer (TCGA)
Structural variants
Translocations
Fusions
Inversion
Copy number alterations
Amplifications
Deletions
LOH
Point mutations & indels
Missense
Nonsense
Splice site
Frameshift
Gene expression
Outlier expression
Isoform usage
Pathways & signatures
Wild type AGTGA
Mutant AGAGA
This presentation: Squamous Cell Cancer
Goal
Accrued so far 300
Analysis completed 178 reported here
From Govindan et al: ASCO 20`2

29. Carcinogen- Induced Cancers
#7006: NSCLC (including SCCA) has a very high rate of somatic mutations
1 / Mb
10 / Mb
100 / Mb
0.1 / Mb 81 64 38
316
100 17 82 28
n=109
119 21 40 20
Hematologic &
Childhood Cancers
Carcinogen- Induced Cancers ??
Ovarian, Breast & Prostate Cancers
“Smart Cancers”
“Stupid Cancers”
Courtesy: Gaddy Getz and Mike Lawrence,
Broad Institute, MIT

30. mRNA Expression Analysis of SCCA
15% % % %
PI3K alterations
NF1 loss

31. New Therapeutic Targets in squamous cell lung carcinoma (SCCA)
Gene
Event Type
Frequency
CDKN2A
Deletion/Mutation-Methylation
72%
PI3KCA
Mutation
16%
PTEN
Mutation/Deletion
15%
FGFR1
Amplification
EGFR 9%
PDGFRA
Amplification/Mutation
CCND1 8%
DDR2 4%
BRAF
ERBB2
FGFR2 3%

32. Summary: Characterization of Squamous Cell NSCLC (SCCA)
SCCA characterized by: Complex genomes with frequent and unique rearrangements
Proposed a molecular sub-classification (yet to be clinically validated)
Multiple mechanisms for alteration/inactivation of the same gene (e.g. CDKN2A)
Potentil therapeutic targets identified in 75% of patients, including FGFRs, PI3 kinase pathway, EGFR/ERBB2 and Cyclin/CDK complexes

33. “Targeted Therapies Coming of Age”
(from Li, Gandara et al: JCO 2012, in press)
NSCLC
as one disease
Unknown
FGFR1
Amp
EGFRvIII
PI3KCA
EGFR
DDR2
Squamous Cell Cancer
Adenocarcinoma
Histology-based Subtyping

34. Stage IIIB-IV Adenocarcinoma with EGFR mutation Pemetrexed + cisplatin
#7500: LUX-Lung 3: Phase III trial of afatinib versus pemetrexed and cisplatin as first-line treatment for EGFR mutation+ adenocarcinoma (Yang et al) R A N D O M I Z T
O N
Stage IIIB-IV Adenocarcinoma with EGFR mutation
Afatinib
2:1
Pemetrexed + cisplatin
Primary endpoint: PFS
Secondary endpoints: ORR, DCR, OS

35. #7500: LUX-Lung 3: Phase III trial of afatinib versus pemetrexed and cisplatin as first-line treatment for EGFR mutation+ adenocarcinoma (Yang et al)
Response
Afatinib
Cis/Pem
Overall
56%
23%
E19del/L858R
69%
44%

36. The Story of “ALK” in NSCLC 2007-2012
Crizotinib
FDA approval in 2011
2010
2008
2007

37. ALK-positive NSCLC & Impact of ALK inhibition by Crizotinib Therapy
Activity of ALK inhibitor Crizotinib in patients with advanced ALK-positive NSCLC (Response Rate=61%)
Previously treated advanced NSCLC
N=116
59% male
72% never-smoker
56% ≥2 prior regimens
Camidge et al: ASCO 2011; Abs #2501

38. Potent activity in enzymatic and cell based assays
First-in-human Phase I trial of ALK inhibitor LDK378 in ALK+ solid tumors
Ranee Mehra,1 D. Ross Camidge,2 Sunil Sharma,3 Enriqueta Felip,4 Daniel Tan,5 Johan Vansteenkiste,6 Tommaso De Pas,7 Dong-Wan Kim,8Armando Santoro,9 Geoffrey Liu,10 Meredith Goldwasser,11 David Dai,12 Anthony L. Boral,11 Alice Shaw13
Assay
LDK378
IC50 (μM)
Crizotinib
Enzymatic ALK
MET
3.2
0.003
0.008
Cell-based ALK
0.027
1.3
0.11
0.028
Potent activity in enzymatic and cell based assays
LDK378 treatment results in tumor regression in EML4-ALK expressing xenografts
Mehra R, et al. ASCO. 2012; #3007

39. LDK378 has antitumor activity in ALK+ NSCLC
Initial dose (mg)
Evaluable Patients (n)
Responses (PR)
NSCLC
< 400 8
2 (25)
≥ 400 33
22 (67)
Other diseases
50 – 600 6
Of the 24 responding patients, 11 responses were confirmed, and 7 are awaiting confirmatory scans
Response rate was 81% (21/26) in patients with NSCLC treated at ≥ 400 mg who progressed following crizotinib
Mehra R, et al. ASCO. 2012; #3007

40. Response to LDK378 Baseline After 6 weeks on LDK378
Mehra R, et al. ASCO. 2012; #3007

41. #7508: Clinical Activity of Crizotinib in Advanced Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1 Rearrangement
Alice T. Shaw1, D. Ross Camidge2, Jeffrey A. Engelman1, Benjamin J. Solomon3, Eunice L. Kwak1, Jeffrey W. Clark1, Ravi Salgia4, Geoffrey I. Shapiro5, Yung-Jue Bang6, Weiwei Tan7, Lesley Tye7, Keith D. Wilner7, Patricia Stephenson8, Marileila Varella-Garcia2, Kristen Bergethon1, A. John Iafrate1, and Sai-Hong I. Ou9
1Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2University of Colorado Cancer Center, Aurora, CO, USA; 3Peter MacCallum Cancer Centre, East Melbourne, Australia; 4University of Chicago Cancer Center, Chicago, IL, USA; 5Dana Farber Cancer Institute, Boston, MA, USA; 6Seoul National University, Seoul, Korea; 7Pfizer Inc, La Jolla, CA, USA; 8Rho, Inc, Chapel Hill, NC; 9Chao Family Comprehensive Cancer Center, Orange, CA, USA
Shaw et al: ASCO Annual Meeting 2012, June 1–5, Chicago, IL

42. #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al)
ROS1 rearrangement in ~1% of NSCLC cases
More common in younger never or light smokers with adenocarcinoma
Multiple ROS1 fusion partners
Measured by “Break-Apart” FISH Assay
No overlap with other oncogenic drivers (EGFR MT)
TPM3-ROS1
SDC4-ROS1
CD74-ROS1
EZR-ROS1
LRIG3-ROS1
SLC34A2-ROS1
ROS-1 fusion partners
Break-Apart
FISH Assay
Bergethon et al., JCO 30(8): , 2012; Takeuchi et al., Nat Med 18(3): , 2012
Abstract: 7508

43. Background on ROS1 Signaling Pathways

44. #7508: Clinical activity of crizotinib in ROS1-positive NSCLC (Shaw A et al)
Bergethon et al., JCO 30(8): , 2012; Takeuchi et al., Nat Med 18(3): , 2012
Abstract: 7508

45. Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503) R A N D O M I Z T
O N
Stage IIIB-IV NSCLC with KRAS mutation
Docetaxel + AZD6244
Docetaxel
Primary endpoint: PFS
Secondary endpoints: ORR, DCR, OS
Parameter
Docetaxel
Docetaxel/AZD6244
mPFS (mos)
2.1
5.3
Response 0%
37% OS
9.4

46. Chemotherapy +/- MEK inhibition (Selumetinib or AZ6244) in KRAS mutant NSCLC (Janne et al: ASCO 2012, #7503)
PFS OS

47. #7509: Clinical Activity and Safety of Anti-PD1 (BMS , MDX-1106) in Advanced Non-Small-Cell Lung Cancer
J.R. Brahmer,1 L. Horn,2 S.J. Antonia,3
D. Spigel,4 L. Gandhi,5 L.V. Sequist,6 J.M. Wigginton,7
D. McDonald,7 G. Kollia,7 A. Gupta,7 S. Gettinger8
Highly Cofidential

48. Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)
Activation
(cytokines, proliferation, migration, lysis)
APC
T cell
MHC-Ag
B CD28
(+) Signal 2
TCR Signal 1
Tumor
From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

49. Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)
Activation
(cytokines, proliferation, migration, lysis)
APC
T cell
MHC-Ag
B CD28
(+) Signal 2
PD-1
TCR Signal 1
(-)
(-)
(-)
Tumor
PD-L1
Inhibition of
Tumor Cell Defense
Tumor
From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

50. Role of PD-1 in suppressing antitumor immunity (“Tumor Cell Defense”)
Activation
(cytokines, proliferation, migration, lysis)
APC
T cell
MHC-Ag
B CD28
(+) Signal 2
PD-1
TCR Signal 1
(-)
(-)
(-)
Anti-PD-1
Tumor
PD-L1
Inhibition
Blocked
Tumor
From Keir ME et al, Annu Rev Immunol 2008; Pardoll DM, Nat Rev Cancer 2012

51. Duration of Response (mo)
#7509: Clinical Activity and Safety of Anti-PD1 (BMS , MDX-1106) in Advanced NSCLC
Clinical Activity in NSCLC Patients
Pop
Dose
(mg/kg)
Pts n
ORR
n (%)
Duration of Response (mo)
SD 24 wk
PFSR at 24 wk (%)
ALL NSCLC
1-10 76
14 (18)
1.9+ to 30.8+
5 (7) 26
NSCLC 1 18
1 (6)
9.2+ 16 3 19
6 (32)
2 (11) 41 10 39
7 (18)
3.7 to 14.8+
2 (5) 24
ORR was assessed using modified RECIST v1.0
3 NSCLC patients had a persistent reduction in baseline target lesions in the presence of new lesions but were not classified as responders for the ORR calculation
Highly Cofidential

52. Pre/Post Anti-PD1 Treatment
58 y/o ex smoker with squam NSCLC
4 prior regimens for Stage IV disease

53. Association of PD-1 Expression in Tumor and Response to Anti-PD1 Treatment

54. Best of ASCO 2012: Lung Cancer: Gandara Summary
Incremental progress in being made in understanding the underlying biology & genomics of lung cancer
These findings are leading directly to discovery of new therapeutic targets and new therapeutic agents
The age of “personalized therapy” for lung cancer is rapidly emerging
Considerable challenges remain
In every challenge there are opportunities
We must take full advance of these opportunities to advance the care & cure of lung cancer patients