Christopher Azzoli, M.D., Assistant Member, Thoracic Oncology Service, Memorial Sloan-Kettering Cancer Center: Current Modalities in the Treatment of Lung Cancer Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

1. Hackensack University Medical Center
John Theurer Cancer Center
New Frontiers in the Management of Solid and
Liquid Tumors
Lung Cancer Update
2011
Harry Harper, M.D.
Christopher Azzoli, M.D.
November 4, 2011

2. Lung Cancer Update, 2011
OVERVIEW
• Lung cancer facts and figures
• Screening smokers for lung cancer
• NSCLC:
– Surgery
– Chemotherapy + XRT
– Chemotherapy
• SCLC:
– Chemotherapy
– Chemotherapy + XRT
– Prophylactic cranial irradiation

3. Cancer in the United States, 2011
New Cases Deaths
Prostate 240,890 Lung 156,940
Breast 230,480 Colorectal 49,380
Lung 221,130 Breast 39,520
Colorectal 141,210 Prostate 33,720
Jemal, Cancer Facts & Figures 2011, CA, 2011

4. Stage at Diagnosis: Females
100
Breast Cancer 100
Lung Cancer
90 All Races 90
80 White 80
Percent (%)
70 African American 70
60 61 59
60 60 55 55
51
50 50
39
40 33 32 40
30 30 22 22 22
20 20 15 15 12
10 5 4 8 10
0 0
Localized Regional Distant Localized Regional Distant
Jemal A et al. CA Cancer J Clin. 2010;60:227-300.

5. September, 2002 – February, 2004
50,000 participants randomized
Monitor through 2009
Low-dose fast spiral CT
Current, or
former heavy 0 1 2
cigarette smoker
(>1ppd x 30 years) Randomized
Age 55-74
CXR
Primary endpoint: 0 1 2
Mortality due to lung cancer Years

6. National Lung Screening Trial
24% CT scans “abnormal” (>4mm solid nodule or enlarged nodes)
7% of CXR were “abnormal”
Lung Lung Lung Lung Total Lung Cancer
cancers cancers cancers cancer deaths Deaths Avoided
detected detected detected deaths
Scan 1 Scan 2 Scan 3
CT 270 168 211 427 1877 1 for every
Total: 320 screened
649
CXR 136 65 78 503 1998 Mammogram:
Total: 1 for every
279 HR HR 570 from
0.80 0.93 age 50
NLST, NEJM 2011

7. Estimated American Smokers at Risk
CDC sponsored National Health and Nutrition Examination Survey (NHANES)
9,762 Americans polled in 2007-08
Criteria Total Smokers Current Former
55-74, ≥30 pack
7,425,000 4,027,000 3,398,000
years
50-79, ≥20 pack
years
13,500,000 9,114,000 4,386,000
55-74, any
26,627,000 7,738,000 18,889,000
smoking history
≥50, any smoking
history
46,481,000 14,729,000 31,752,000
≥21, ≥10 years of
smoking any 77,005,000 39,883,000 37,122,000
amount
Data Courtesy of Peter Bach

8. “We’re gonna need a bigger boat.”

9. “Don’t smoke cigarettes.”

10. NSCLC IIIB
Staging IIIA
LYMPH
NODES
II
I

11. Major
change:
7th-Edition
TNM
Staging
July, 2009
IIA
Node-negative tumors
>5cm are now stage II

12. Best Treatment for NSCLC: SURGERY
Surgically resected patients, 1990 – 2000
Overall Survival with Surgery
Overall Survival
8988 / 15952 : TOTAL
1 3 5 7 9
Goldstraw, et al. J Thorac Oncol. 2007;2:706-714

13. Benefit of Adjuvant Cisplatin+Vinorelbine
LACE, N=4584
Pignon , JCO 2008;26
HR 0.92
N=1371 5Y risk 36%
HR 0.83
N=1616 5Y risk 61%
HR 0.83
N=1247 5Y risk 74%

14. Benefit of Adjuvant Cisplatin+Vinorelbine
LACE, N=4584 Number Needed to Treat
Pignon , JCO 2008;26
to Save 1 Life
1 / absolute risk reduction
Stage IB HR 0.92
N=1371 5Y risk 36% 1 / 3% = 33 patients
HR 0.83
Stage II
N=1616 5Y risk 61% 1 / 10% = 10 patients
Stage III
N=1247
HR 0.83
5Y risk 74%
1 / 13% = 8 patients

15. Best Treatment for Unresectable/Inoperable NSCLC:
RADIATION THERAPY
Unresectable Stage III (N2-N3) NSCLC:
MST 3YS Febrile G3-4
(mos) (%) Illness Esophagitis
XRT only (>6000 rads) 11 m < 10% 3% 3%
Cisplatin-based chemo, then XRT 15 m 10-20 8% 5%
“SEQUENTIAL”
Cisplatin-based chemo plus XRT 17 m 20-30 15% 30%
“CONCURRENT”
REFERENCES:
1. Dillman, NEJM 1990
2. RTOG 94-10, Curran, JNCI, 2011
3. Chemo before chemo+RT (induction) is toxic, does not improve overall survival (CALGB 39801)
4. Docetaxel after chemo+RT (consolidation) is toxic, does not improve overall survival (HOG 01-24)

16. Important clinical trials in unresectable stage
IIIB NSCLC
Cisplatin + Pemetrexed x 3
R Pemetrexed x 4
A Concurrent XRT to 6600cGy
N
D
N=600 O
M Dealer’s choice x 4:
I Cisplatin + Etoposide x 3 Etoposide
Z
E Concurrent XRT to 6600cGy Vinorelbine
Paclitaxel
US NIH, 2011.

17. Best treatment for stage IV NSCLC:
DRUG THERAPY
Survival No Cytotoxic Chemo + Target
Chemo chemo anti- EGFR
angio mutation
genesis
MST (mo) 4 8 12 30
1-year (%) 10 20 50 90
2-year (%) 0 3 10 30
• Improving length of life
• Improving quality of life

18. “Cytotoxic” Chemotherapy
for Stage IV NSCLC
n=1725 Cisplatin 75 mg/m2 Day 1 plus Pemetrexed
500 mg/m2 Day 1
Stage IV
NSCLC R One cycle = 3 weeks, stop at 6 cycles
Record
Cisplatin 75 mg/m2 Day 1 plus
histology
Gemcitabine 1,250 mg/m2 Days 1, 8
Results Pem/Cis Gem/Cis HR
No. patients 862 863
Median survival (mos) 10.3 10.3 0.94
Adenocarcinoma (847) 12.6 10.9
Large cell (153) 10.4 6.7
SqCC (473) 9.4 10.8 1.23
Scagliotti et al, 2008.

19. “Continuation Maintenance” Chemotherapy
Four cycles of pemetrexed (500 mg/m2, Day 1) +
cisplatin (75 mg/m2, Day 1)* n=900
CR, PR, or SD and ECOG PS of 0 or 1
Pemetrexed 500 mg/m2 Placebo + BSC*
+ BSC* (D1, q21d) (D1, q21d)
until disease 2:1
until disease
progression randomization progression
N=372 pts N=186 pts
PFS HR=.62, OS results pending
Paz-Ares et al, 2011
Paz-Ares et al, 2011.

20. Biologic/Molecular Targets for New Drugs
Tumor cell bevacizumab
VEGF Endothelial cell
MetMab cetuximab figitumumab
VEGF
PDGF
IGFR VEGFR
EGFR PDGFR
MET
Sorafenib
Gefitinib CC CC Sunitinib
P P Erlotinib P P Axitinib
P P Sorafenib
ARQ197 P P Vandetanib P P
Pazopanib Sunitinib
XL-184 EML4-ALK Axitinib
Crizotinib Motesanib
Crizotinib Vandetanib Pazopanib
P P XL-184 Motesanib
Pi3K Pi3K
Raf Raf
Akt Akt
MEK MEK
mTOR mTOR
ERK ERK
Gene Transcription Gene Transcription
Angiogenesis Proliferation Metastasis Adhesion Angiogenesis Survival

21. Target Angiogenesis: Bevacizumab
SQUAMOUS HISTOLOGY EXCLUDED
(for squamous histology, rate of hemoptysis 30% in phase 2 testing
PFS OS
100 CbP 100 CbP
CbP + Bevacizumab CbP + Bevacizumab
Patients Surviving (%)
Patients With PFS (%)
80 80
p < .001; HR = 0.66 p = .003; HR = 0.79
Median PFS: 6.2 mos vs. Median OS: 12.3 mos vs.
60 4.5 mos 60 10.3 mos
6-Mos PFS: 55% vs. 33% 1-Yr OS: 51% vs. 44%
1-Yr PFS: 15% vs. 6% 2-Yr OS: 23% vs. 15%
40 40
20
20
0 0
0 6 12 18 24 30 36 0 6 12 18 24 30 36
Time (mos) Time (mos)
RR: 15% for CbP Vs. 35% for CbP + Bevacizumab
Sandler et al, NEJM 2006.

22. Bevacizumab with other Drugs
SQUAMOUS HISTOLOGY EXCLUDED
1.0 PFS 1.0 PFS
Possibility of PFS (%)
0.8 CG + Placebo 0.8 CG + Placebo
CG + Bevacizumab CG + Bevacizumab
7.5 mg/kg 15 mg/kg
0.6 0.6
0.4 0.4
0.2 0.2
0.0 0.0
0 3 6 9 12 15 18 0 3 6 9 12 15 18
Time (mos) Time (mos)
End Point CG + Placebo CG + Bev (7.5 mg/kg) CG + Bev (15 mg/kg)
0.75 (0.62–0.91); 0.82 (0.68–0.98);
PFS, HR (95% CI) NA
p = .0026 p = .0301
Median PFS (mos) 6.1 6.7 6.5
RR (%) 20 34 (p < .0001) 30 (p < .017)
Median Survival (mos) 13.6 13.4
HR, p value 13.1 (0.92, p = .3664) (1.02, p = .8420)
Reck et al, 2010, 2009.

23. Ongoing BevacizumabTrials
Determination of Eligibility
Primary Endpoint: OS
Arm A - 450 Patients Arm B - 450 Patients
Pemetrexed Paclitaxel
500 mg/m2 iv q21d 200 mg/m2 iv q21d
Induction Therapy: Carboplatin Carboplatin
up to four 21-day cycles AUC 6 iv q21d AUC 6 iv q21d
Bevacizumab Bevacizumab
Patients with CR, PR, or SD 15 mg/kg iv q21d 15 mg/kg iv q21d
After induction therapy
Continue on to maintenance therapy
Pemetrexed Bevacizumab
Maintenance Therapy:
until PD or treatment discontinuation
500 mg/m2 iv q21d 15 mg/kg iv q21d
Bevacizumab
Patients with PD: 15 mg/kg iv q21d
follow up q90d until death
Patients without PD:
follow up q6w until PD;
thereafter, follow up q90d until death Post discontinuation follow up
Patel et al, 2009.

24. Testing Bevacizumab for
Early-stage NSCLC: ECOG 1505
Eligibility
• Resected IB (>4cm) – IIIA R Chemotherapy* x 4 cycles
• ≥ lobectomy A
• Adequate MLND sampling N
• All pts: level 7 D
O
• Left: level 5 or 6 M
• Right: level 4 I Chemotherapy* x 4 cycles +
• No previous chemotherapy Z bevacizumab x 1 year
• No planned XRT E
• No CVA / TIA / ATE
N = 1500 Primary endpoint: overall survival
• Cisplatin and vinorelbine
• Cisplatin and docetaxel Secondary endpoints: disease-free survival, safety
• Cisplatin and gemcitabine [bleeding and arterial thromboembolic events]
• Cisplatin and pemetrexed
No molecular markers being studied prospectively
Accrual has been slow. Results anticipated in 2016.

25. Angiogenesis: Targeted Agents on the Horizon
Agent Description Reference
Sorafenib Multi-kinase inhibitor including VEGFR Spigel et al, 2010
Sunitinib Multi-kinase inhibitor including VEGFR Govindan et al, 2010
Axitinib Multi-kinase inhibitor including VEGFR Kelly et al, 2010
BIBF 1120 Multi-kinase inhibitor including VEGFR, PDGFR, FGFR Reck, 2010
(intedanib)
Cediranib Multi-kinase inhibitor including VEGFR Mitchell et al, 2010
Vandetanib Multi-kinase inhibitor including EGFR and VEGFR Morabito et al, 2010
HuMV833 Antibody to VEGF-A Jayson et al, 2002
IMCL 1121b Antibody to VEGFR2 Spratlin et al, 2010
(ramucirumab)
IMC-18F1 Antibody to VEGFR1 Schwartz et al, 2010
VEGF Trap Antibody to VEGF-A Leighl et al, 2010
(aflibercept)
VEGFR = vascular endothelial growth factor receptor; PDGFR = platelet-derived growth factor receptor;
FGFR = fibroblast growth factor receptor.

26. Target EGFR: Cetuximab
R
Stage IV NSCLC A
CT + cetuximab
N
EGFR expression D cetuximab until PD
O
by IHC M
I CT
N=1,688 Z Median 1-year
ITT (n=1125)
E OS survival
▬ CT +
cetuximab 11.3 mo 47%
(n=557)
Overall survival (%)
RETROSPECTIVE SUBGROUP ▬ CT 10.1 mo 42%
ANALYSIS: (n=568)
• HR = 0.80 in the 354 patients HR=0.871, p=0.044
with the highest EGFR IHC
score
• HR = 1.05 in patients with
lower EGFR IHC score
Months
Pirker et al, 2009, and 2011

27. The Biggest Discovery:
EGFR Activating Mutations
5 days on gefitinib
Pao, Nature Reviews Cancer 10, 760-774

28. Stage IV 1st-line EGFR TKI for EGFR mutation
Study Drugs ORR PFS OS
IPASS gefitinib 71% N=261 HR 1.00
Yang, ESMO vs. HR 0.48 P=0.990
2010 carbo + paclitaxel 47% P<.0001
First-SIGNAL gefitinib 85% N=42 HR 0.82
Lee, IASLC vs. HR 0.62 P=.648
2009 cis + gemcitabine 37% P=.084
WJTOG 3405 gefitinib 62% N=172
Tsurutani vs. HR 0.49 Not reported
ESMO 2009 cis + docetaxel 32% P<.001
NEJ 002 gefitinib 74% N=228 HR NS
Maemondo vs. HR 0.30 P=0.31
NEJM 2010 carbo + paclitaxel 31% P<.001
OPTIMAL erlotinib 83% N=154
Zhou, ESMO vs. HR 0.16 Not reported
2010 carbo + gemcitabine 36% P<.0001

29. EGFR mutation is Prognostic of Survival in
Early-stage NSCLC
1.0
Probability of OS
0.8
0.6
0.4
No EGFR mutation: Median OS = 6.3yr (95%CI: 5.6 - 7.8)
EGFR mutation: Median OS = 6.9yr (95%CI: 6.3 - NA)
0.2
p (adj for stage) < 0.001
No EGFR mutation
0.0
EGFR mutation
Data
courtesy
0 1 2 3 4 5 6 7 8
Years After Surgery Sandra
No. At Risk D’Angelo
No EGFR mutation
896 778 517 293 160 104 65 26 10 MSKCC
EGFR mutation
222 204 133 91 55 33 18 7 4

30. Testing erlotinib for early-stage
NSCLC with EGFR mutation
NCI Personalized Adjuvant Trial “PAT”
Resected NSCLC R Erlotinib for 2 years
A
Tested positive for N
D
EGFR activating/ O
M
sensitizing mutation I
Z Placebo for 2 years
N=400 E
US NIH, 2011.

31. ALK gene translocation drives 3% of NSCLC
Vysis LSI ALK dual color break apart probe
Break-apart FISH assay of
tumor cells from a patient with
rearrangement of the gene
encoding ALK
Kwak et al, 2010.

32. Phase II studies of crizotinib for patients with
stage IV NSCLC and ALK translocation
• Study A (N = 136 patients), ORR 50%, median duration 10
months
• Study B (N = 119 patients), ORR 61%, median duration 12
months
• 94% had received prior systemic treatment for NSCLC
• No differences in ORR by performance status, the number of prior
chemotherapeutic regimens, or the percentage of cells found to
have the ALK gene rearrangement were noted.
FDA Approval Announcement, 8/26/2011

33. First-line crizotinib for patients with ALK Translocation
Randomized Study of Crizotinib vs Pem/Cis or Pem/Carbo in Untreated
Patients with Non-squamous Carcinoma of the Lung With EML4-ALK Mutation
Crizotinib 250 mg PO BID
Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC 5, q 21 days
1º endpoint: To demonstrate that crizotinib is superior
to first-line chemotherapy
2º endpoint: ORR, OS, Duration of Response Safety
US NIH, 2011.

34. Novel Agents Under Phase III Investigation:
Currently Recruiting Trials
Agent Mechanism of Action Study ID Primary Completion Date
Tivantinib (ARQ c-Met inhibitor NCT01244191 May 2013
197)
Tivantinib (ARQ c-Met inhibitor NCT01395758 June 2012
197)
Iniparib PARP inhibitor NCT01082549 (ECLIPSE) March 2013
PF-02341066 ALK inhibitor NCT00932893 June 2012
Afatinib EGFR/HER2 inhibitor NCT01121393 (LUX-Lung 6) May 2012
Afatinib EGFR/HER2 inhibitor NCT01085136 (LUX-Lung 5) March 2012
Talactoferrin Immunostimulant NCT00706862 (FORTIS-C) March 2013
Ipilimumab Anti-CTLA4 Antibody NCT01285609 August 2014
Ramucirumab VEGFR-2 inhibitor NCT01168973 June 2014
Necitumumab EGFR inhibitor NCT00981058 (SQUIRE) May 2013
Vargatef Multikinase inhibitor NCT00806819 (LUME-Lung 2) May 2013
MetMab Met inhibitor Recruitment will begin later this year (2011)
US NIH, 2011.

35. Problem: With so many new drugs, and
targets, how do we know we are giving
the right drug to the right patient?
Solution: Test! Don’t guess!

36. Lung Cancer Mutation Consortium
Incidence of Single Driver Mutations
At least 1 mutation was found in 54% (280/516)
of tumors completely tested (CI 50%–59%)
97% of Mutations Mutually Exclusive
Kris et al, ASCO 2011.

37. Lung Cancer Mutation Consortium Targeted
Clinical Trials
Target Agent(s)
EGFR Erlotinib + OSI 906
Erlotinib + MM 121
KRAS Tivantinib + Erlotinib
GSK1120212
MET Amplification MetMAB
EML4-ALK Crizotinib
NRAS GSK1120212
MEK1 GSK1120212
BRAF (V600E) GSK2118434
BRAF (not V600E) GSK1120212
HER2 Afatinib
PIK3CA BKM120
Kris et al, ASCO 2011.

38. Real progress for patients with stage
IV NSCLC
Survival No Cytotoxic Chemo+ EGFR
Chemo chemo bev TKI for
EGFR
mutant
MST (mo) 4 8 12 30
1-year (%) 10 20 50 90
2-year (%) 0 3 10 30
• Improving length of life
• Improving quality of life

39. SMALL CELL
LUNG CANCER
Limited Extensive
Stage Stage
Surgery rarely an option.
No molecular markers discovered yet.
No new drugs for 20 years!

40. Twice Daily Thoracic Radiotherapy for
Limited Stage SCLC
Turrisi et al, NEJM, 1999
• 417 patients with limited stage SCLC
• 4 cycles etoposide + cisplatin with concurrent once vs.
twice daily RT to 45 Gy starting with first cycle
2-year survival
41 vs. 47%
5-year survival
16 vs. 26%
p = 0.04

41. Prophylactic Cranial Irradiation
Auperin et al, NEJM, 1999
Death Brain Mets
• 7 randomized trials, 987 pts
with CR
• 5% increase in survival at 3 yrs
• Higher dose improved local
recurrence but no effect on
survival
16% ↓ risk 54% ↓ risk

42. PCI in Extensive SCLC
286 patients with extensive SCLC and response after 4-6 cycles of chemotherapy
were randomized to PCI or no PCI
Median survival: 6.7 vs 5.4 mo
1 yr survival: 27% vs 13%
Slotman et al,
NEJM 2007

43. For Extensive Stage: Cisplatin + Etoposide
1.0
0.9
Irinotecan + cis (n = 221)
0.8
Etoposide + cis (n = 110)
0.7
Probability
0.6
0.5
P = 0.6226
0.4
0.3
0.2
0.1
0
0 10 20 30 40
Months
IP: median 9.3 mo (0.1-32.6) 1yr 35.4%, 2yr 8.0%
EP: median 10.2 mo (0.3-44.6) 1yr 36.7%, 2yr 7.9%
Hanna, J Clin Oncol 24:2038, 2006

44. “2nd-line” Chemo for Extensive SCLC
Topotecan CAV
Response Rate 24% 18%
Med Survival 6 mo 6 mo
Grade 4 (% pts)
Neutropenia 70% 72%
Anemia 3% 2%
Platelets 29% 5%
Transfusions
RBCs 52% 27%
Plts 20% 2%
Greater proportion had improved dyspnea, anorexia, hoarseness and
fatigue with topotecan
von Pawel, JCO, 17:658, 1999

45. “2nd-line” Chemo for Extensive SCLC:
• Rechallenge with 1st regimen if time to
relapse > 6 months
• Topotecan n=637
• CAV amrubicin 40 mg/m2 IV on days 1-3
vs.
• Irinotecan topotecan 1.5 mg/m2 IV on days 1-5
• Paclitaxel
HR 0.82, p=NS
• Docetaxel primary refractory subgroup, HR 0.77, p=.047
• Gemcitabine
• Vinorelbine
• Amrubicin: active, but failed to
significantly improve survival vs.
topotecan in phase 3 study
Jotte R, J Clin Oncol 29: 2011;29(15s):(abstract 7000),453s

46. Lung Cancer Update, 2011
REVIEW
• Lung cancer facts and figures
• Screening smokers for lung cancer Newest stories:
• NSCLC: Screening saves lives !
– Surgery
– Chemotherapy + XRT The era of personalized
– Chemotherapy medicine has arrived !
• SCLC: EGFR, ALK …
– Chemotherapy
– Chemotherapy + XRT
– Prophylactic cranial irradiation

47. OLDEST STORY:
“Don’t smoke cigarettes.”