1. New Perspectives on Second-Line
Therapy for NSCLC
Tony Mok, MD (Moderator)
Professor, Department of Clinical Oncology,
Chinese University of Hong Kong;
Honorary Consultant, Prince of Wales Hospital,
Hong Kong, China

2. Overview
• Discuss the current standards of care for secondline therapy in patients with advanced NSCLC
• Examine the unique and unmet needs of patients
without targetable activating mutations
• Review emerging research findings on second-line
therapy in NSCLC and their implications for clinical
practice
NSCLC = non-small cell lung cancer

3. Panelists
Luis Paz-Ares Rodríguez, MD, PhD
Martin Reck, MD, PhD
Chair, Department of Oncology,
Seville University Hospital,
Seville, Spain
Head, Department of Thoracic
Oncology,
Hospital Grosshansdorf,
Grosshansdorf, Germany

4. Single-Driver Mutations in NSCLC
Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer.
Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

5. NSCLC Without Targetable Mutations:
An Unmet Need
Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer.
Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

6. NSCLC Histology
Howlader N, et al (eds). SEER Cancer Statistics Review, 1975-2010,
National Cancer Institute. Bethesda, MD, 2013.

7. Single-Driver Mutations in NSCLC
Gene
Incidence
KRAS
15% − 25%
EGFR
10% − 35%
ALK
3% − 7%
MET
2% − 4%
HER2
2% − 4%
BRAF
1% − 3%
PIK3CA
1% − 3%
AKT1
1%
MAP2K1
1%
NRAS
1%
ROS1
1%
RET
1%
Lovly C, et al. http://www.mycancergenome.org/content/disease/lung-cancer.
Pao W, Girard N. Lancet Oncol. 2011;12:175-180.

8. Outcomes With First-Line Doublet Therapy:
ECOG 1594
OS = overall survival; PFS = progression-free survival
Schiller JH, et al. New Engl J Med. 2002;346:92-98.
Months

9. Outcomes With First-Line Triplet Therapy:
ECOG 4599
Months
CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; HR = hazard ratio
Sandler A, et al. New Engl J Med. 2006;355:2542-2550.

10. Second-Line Therapy: Options & Outcomes
7.0
37.0%
4.6
12.0%
Pemetrexed (N = 283)
8.3
29.7%
Docetaxel (N = 288)
7.9
29.7%
Gefitinib (N = 723)
7.6
32.0%
Docetaxel (N = 710)
8.0
34.0%
5.3
26.0%
Chemotherapy (N = 221: 116
docetaxel, 105 pemetrexed)
5.5
24.0%
Treatment Arms
[a]
Hanna et al. 2004[b]
INTEREST
[c]
TITAN[d]
Docetaxel (N = 103)
Erlotinib (N = 203)
TAX 317
1-Year
Survival
Best supportive care (N = 100)
Study
Median OS
(mos)
a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
c. Kim ES, et al. Lancet. 2008;372:1809-1818.
d. Ciuleanu T, et al. Lancet Oncol. 2012;13:300-308.

11. Second-Line Therapy: Grade 3/4 Toxicities
Erlotinib[a] ≈ Pemetrexed[a,b] << Docetaxel[b]
Percent Reporting
40.2%
a. Vamvakas L, et al. ASCO 2010.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
Adverse Event

12. Selecting Second-Line Therapy
Patient Factors
•PS
•Age
•Patient preference
Treatment History
•First-line regimen
•Duration of response to
first-line treatment
Tumor Characteristics
•Tumor burden
•Histology
•EGFR?
•ALK?
•KRAS?
Good PS + good response to first-line chemo
Chemotherapy
Adenocarcinoma + targetable mutation/rearrangement
Targeted therapy
(erlotinib, gefitinib,
crizotinib)
Wild-type or KRAS mutations
Chemotherapy
PS = performance status

13. Second-Line Therapy: Outstanding Needs
• Options for patients with wild-type mutations
(EGFR, etc)
• Predictive biomarkers
• New agents with efficacy in the second-line setting

14. Second-Line Therapy: Research To Date
Study
Treatment
Tax 317
BR.21
JMEI
Docetaxel (D75/100) vs BSC
Erlotinib vs placebo
Pemetrexed vs docetaxel
Tax 320
Docetaxel (D75/100) vs ifosfamide or vinorelbine
ISEL
Gefitinib vs placebo
ZODIAC
Vandetanib + docetaxel vs docetaxel
ZEAL
ZEST
VITAL
Vandetanib + pemetrexed vs pemetrexed
Vandetanib vs erlotinib
Aflibercept + docetaxel vs docetaxel
BETA
Bevacizumab + erlotinib vs erlotinib
TAILOR
Docetaxel vs erlotinib, non-EGFR mutations
TITAN
Docetaxel/pemetrexed vs erlotinib
Vinflunine
Topotecan
SUN1087
Median OS (mo)
7.5 (D75) vs 4.6
6.7 vs 4.7
Vinflunine vs docetaxel
Oral topotecan vs docetaxel
Sunitinib + erlotinib vs erlotinib
FAILED
In pre-treated patients, only 2 out of 15 trials to date have shown an improvement in OS
All of these trials are against placebo only (no active comparator arm). Direct comparison is not possible. List contains examples and is not
exhaustive.

15. Angiogenesis Inhibitors in NSCLC
Target
Drug
EGFR
Axitinib
Bevacizumab*
BMS-690514
Brivanib
Cediranib
Linifanib
MGCD265
Motesanib
FGFR
PDGFR
VEGF
β
VEGFR
R-1, 2, 3



R-2
R-1, 2, 3
R-1, 2, 3

R-1, 2, 3
R-1
α/β
Nintedanib
R-1, 2, 3
α/β
R-1, 2, 3
Pazopanib
Sorafenib
Sunitinib
Vandetanib
R-1, 3
α/β
β
α/β
R-1, 2, 3
R-2, 3
R-1, 2, 3
R-2, 3

* Currently approved for first-line therapy of NSCLC, in combination with a platinum and taxane
Ellis PM & Al-Saleh K. Critical Rev Onc/Hem. 2012;84:47-58.

16. Angiogenesis Inhibitors in NSCLC:
Nintedanib
• Investigational oral agent
• Can be combined with chemotherapy
-
Docetaxel[a]
Pemetrexed[b]
Paclitaxel/carboplatin[c]
Gemcitabine/cisplatin[d]
a. Bousquet G, et al. Br J Cancer. 2011;105:1640-1645.
b. Ellis PM, et al. Clin Cancer Res. 2010;16:2881-2889.
c. Doebele RC, et al. Ann Oncol. 2012;23:2094-2102.
d. http://clinicaltrials.gov/show/NCT01346540.

17. LUME-Lung 1: Trial Design
Patients with NSCLC who have failed first-line chemotherapy
Randomization
Oral nintedanib +
Chemotherapy (docetaxel)
Second-line
treatment
Placebo +
Chemotherapy (docetaxel)
Number of docetaxel cycles not restricted
Monotherapy with nintedanib/placebo allowed after ≥ 4 cycles
Primary endpoint: PFS
Key secondary endpoint: OS
Results presented at ASCO 2013
Reck M, et al. ASCO 2013.

18. LUME-Lung 1: Inclusion Criteria
Inclusion criteria:
•Male or female patients, aged ≥ 18 years
•Patients with IIIB/IV or recurrent NSCLC (all histologies)
•Progression after prior first-line chemotherapy
•ECOG score of 0 and 1
1314 patients: recruitment completed
Reck M, et al. ASCO 2013.

19. LUME-Lung 1: PFS (All Patients)
100
Placebo + docetaxel
(n = 655)
Probability of survival
without progression (%)
Nintedanib + docetaxel
(n = 659)
3.4
2.7
Median, mo
80
HR (95% CI)
0.79 (0.68 to 0.92)
P
60
.0019
40
20
0
0
2
4
6
8
10
Time
(months)
Reck M, et al. ASCO 2013.
12
14
16
18

20. LUME-Lung 1: OS (All Patients)
Probability of survival (%)
100
Nintedanib + docetaxel
Placebo + docetaxel
10.1
9.1
(n = 655)
Median, mo
80
HR (95% CI)
0.94 (0.83 to 1.05)
P
60
(n = 659)
.2720
40
20
0
0
4
8
12
16
20
Time
(months)
Reck M, et al. ASCO 2013.
24
28
32
36

21. LUME-Lung 1: OS (Adenocarcinoma Patients)
Nintedanib + docetaxel
Probability of survival (%)
Placebo + docetaxel
(n = 322)
100
(n = 336)
12.6
10.3
Median, mo
80
HR (95% CI)
0.83 (0.70 to 0.99)
P
60
.0359
52.7%
40
25.7%
44.7%
20
19.1%
0
0
4
8
12
16
20
Time
(months)
Reck M, et al. ASCO 2013.
24
28
32
36

22. LUME-Lung 1: Adverse Events of Special Interest
Nintedanib + docetaxel
Patients Reporting (%)
Placebo + docetaxel
Adverse Events, All Grades
(incidence ≥ 15%)
Reck M, et al. ASCO 2013.
Adverse Events, Grade ≥ 3
(incidence ≥ 1%)

23. LUME-Lung 1: Summary
• Met primary endpoint of delaying tumour growth
following failure of first-line therapy
• Showed a significant survival benefit in patients
with adenocarcinoma compared with an active
comparator
• Well tolerated with manageable safety profile

24. OS (mo)
Combination Therapy With Angiogenesis
Inhibitors: First-Line vs Second-Line Outcomes
HR, 0.79;
95% CI, 0.67 to 0.92
P = .003
[a]
a. Sandler A, et al. New Engl J Med. 2006;355:2542-2550.
b. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011.
HR, 0.83;
P = .0359
LUME-Lung 1[b]
(Adenocarcinoma subset)

25. LUME-Lung 1: OS by Histology
Nintedanib +
docetaxel
(n = 322)
Nintedanib +
docetaxel
(n = 655)
100
10.1
9.1
Probability of survival (%)
12.6
10.3
HR (95% CI)
HR (95% CI)
P
80
Placebo +
docetaxel
(n = 336)
Median, mo
0.94 (0.83 to 1.05)
Median, mo
Placebo +
docetaxel
(n = 659)
0.83 (0.70 to 0.99)
P
.2720
.0359
60
40
20
0
0
4
8
12
16
20
24
All patients
Reck M, et al. ASCO 2013.
28
32
36
0
4
8
12
16
20
24
28
Adenocarcinoma subset
32
36

26. Nintedanib in Squamous Cell Carcinoma:
Outstanding Issues
• Benefit demonstrated regarding PFS
• OS benefit seen in patients with large tumors
• Role of FGFR amplification in squamous cell
carcinoma requires further investigation

27. LUME-Lung 1: Toxicities Associated with
VEGF/VEGFR Inhibitors
Nintedanib + docetaxel
Placebo + docetaxel
All grades
%
Grade ≥ 3
%
All grades
%
Grade ≥ 3
%
Bleeding
14.1
2.3
11.6
1.8
Thromboembolism
5.1
2.1
4.6
3.1
Hypertension
3.5
0.2
0.9
0
VTE
2.8
1.2
1.5
1.1
ATE
0.6
0.5
1.4
0.6
GI perforation
0.5
0.2
0.5
0.5
Adverse event
ATE = arterial thromboembolism; GI = gastrointestinal; VTE = venous thromboembolism
Reck M, et al. ASCO 2013.

28. Looking Forward: Research Needs
• Combination vs monotherapy
− Biomarkers to assist in patient selection
− Role of clinical factors, histology, etc

29. LUME-Lung 1: Characteristics Associated With
Improved OS in Nintedanib-Treated
Adenocarcinoma Patients
CR = complete response; PD = progressive disease; PR = partial response; SD = stable
disease et al. ASCO 2013.
Reck M,

30. OS (mo)
Angiogenesis Inhibitors in the Second-Line
Setting: LUME-Lung 1 vs ZODIAC
HR, 0.94
95% CI, 0.83 to 1.05
P = .2720
LUME-Lung 1[a]
a. Reck M, et al. J Clin Oncol. 2013;31(suppl): LBAS011.
b. Herbst RS, et al. Lancet Oncol. 2010;11:619-626.
HR, 0.91
97.52% CI, 0.78 to 1.07
P = .196
[b]

31. Angiogenesis Inhibitors in the Second-Line
Setting: LUME-Lung 2
Entry Criteria
•Stage IIB/IV or recurrent NSCLC
•Non-squamous histology
•Relapsed/failed one prior line of chemotherapy
•Measurable lesion(s)
•ECOG PS 0 or 1
Randomization 1:1
Nintedanib + pemetrexed
(N = 353)
Disease Progression
Target enrollment: 1300
Placebo + pemetrexed
(N = 360)
Disease Progression
• Study was halted after interim analysis suggested the primary endpoint of PFS would
not be met
• Ongoing patients were unblinded and follow-up continued per protocol
Hanna NH, et al. ASCO 2013.

32. Estimated patients alive and
progression-free (%)
LUME-Lung 2: Centrally-Reviewed PFS
Nintedanib +
pemetrexed
Placebo +
pemetrexed
4.4
3.6
(n = 353)
Median PFS, mo
HR (95% CI)
0.83 (0.70 to 0.99)
Log-rank p value
Time from randomization
(months)
Hanna NH, et al. ASCO 2013.
(n = 360)
.0435

33. OS (mo)
Docetaxel in the Second-Line Setting: Survival
Trends
TAX 317[a]
Hanna et
al. 2004[b]
a. Shepherd FA, et al. J Clin Oncol. 2000;18:2095-2103.
b. Hanna N, et al. J Clin Oncol. 2004;22:1589-1597.
c. Kim ES, et al. Lancet. 2008;372:1809-1818.
d. Herbst RS, et al. Lancet Oncol. 2010;11:619-626.
e. Reck M, et al. ASCO 2013.
INTEREST[c]
ZODIAC[d]
LUMELung 1[e]

34. LUME-Lung 1: Patient Characteristics
Characteristic
Nintedanib + docetaxel
(N = 655)
Placebo + docetaxel
(N = 659)
Age < 65 years
69.5%
67.5%
Current/former smoker
74.8%
75.6%
Adenocarcinoma
49.2%
51.0%
Squamous cell carcinoma
42.1%
42.2%
Other
8.7%
6.7%
Platinum
95.9%
96.5%
Bevacizumab
4.1%
3.5%
Histology
Prior therapy
Reck M, et al. ASCO 2013.

35. Clinical Questions
• Sequencing of therapy?
• Treatment beyond progression?
• Impact of maintenance therapy on subsequent
treatment decisions?

36. LUME-Lung 1: Characteristics Associated With
Improved OS in Nintedanib-Treated
Adenocarcinoma Patients
Reck M, et al. ASCO 2013.

37. Take Home Messages
• A majority of NSCLC patients do not have targetable
mutations
• Second-line treatment options for these patients have
historically been limited
• Combination therapy with the angiogenesis inhibitor
bevacizumab has been successful in the first-line setting
• In the second-line setting, combination therapy with the
angiogenesis inhibitor nintedanib has recently been shown to
− Prolong PFS in patients with NSCLC, regardless of histology
− Improve OS in patients with adenocarcinoma

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