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 second- line 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
Martin Reck, MD, PhD
Head, Department of Thoracic Oncology,
Hospital Grosshansdorf,
Grosshansdorf, Germany

4. Single-Driver Mutations in NSCLC
Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:

5. NSCLC Without Targetable Mutations: An Unmet Need
Lovly C, et al. Pao W, Girard N. Lancet Oncol. 2011;12:

6. NSCLC Histology
Howlader N, et al (eds). SEER Cancer Statistics Review, , 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
BRAF
1%  3%
PIK3CA
AKT1 1%
MAP2K1
NRAS
ROS1
RET
Lovly C, et al.
Pao W, Girard N. Lancet Oncol. 2011;12:

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

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:

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

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

12. Tumor Characteristics
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
Targeted therapy (erlotinib, gefitinib, crizotinib)
Adenocarcinoma + targetable mutation/rearrangement
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
Median OS (mo)
Tax 317
Docetaxel (D75/100) vs BSC
7.5 (D75) vs 4.6
BR.21
Erlotinib vs placebo
6.7 vs 4.7
JMEI
Pemetrexed vs docetaxel
FAILED
Tax 320
Docetaxel (D75/100) vs ifosfamide or vinorelbine
ISEL
Gefitinib vs placebo
ZODIAC
Vandetanib + docetaxel vs docetaxel
ZEAL
Vandetanib + pemetrexed vs pemetrexed
ZEST
Vandetanib vs erlotinib
VITAL
Aflibercept + docetaxel vs docetaxel
BETA
Bevacizumab + erlotinib vs erlotinib
TAILOR
Docetaxel vs erlotinib, non-EGFR mutations
TITAN
Docetaxel/pemetrexed vs erlotinib
Vinflunine
Vinflunine vs docetaxel
Topotecan
Oral topotecan vs docetaxel
SUN1087
Sunitinib + erlotinib vs erlotinib
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
Drug
Target
EGFR
FGFR
PDGFR
VEGF
VEGFR
Axitinib β
R-1, 2, 3
Bevacizumab* 
BMS
Brivanib
R-1
R-2
Cediranib
α/β
Linifanib
MGCD265
Motesanib
Nintedanib
Pazopanib
R-1, 3
Sorafenib
R-2, 3
Sunitinib
Vandetanib
* 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: b. Ellis PM, et al. Clin Cancer Res. 2010;16: c. Doebele RC, et al. Ann Oncol. 2012;23: d.

17. LUME-Lung 1: Trial Design
Patients with NSCLC who have failed first-line chemotherapy
Randomization
Oral nintedanib + Chemotherapy (docetaxel)
Placebo + Chemotherapy (docetaxel)
Second-line treatment
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
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 80 60 40 20
Nintedanib + docetaxel (n = 655)
Placebo + docetaxel (n = 659)
Median, mo
3.4
2.7
HR (95% CI)
0.79 (0.68 to 0.92) P
.0019
Probability of survival without progression (%)
Time (months)
Reck M, et al. ASCO 2013.

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

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

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

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

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

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. Nintedanib + docetaxel
LUME-Lung 1: Toxicities Associated with VEGF/VEGFR Inhibitors
Adverse event
Nintedanib + docetaxel
Placebo + docetaxel
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
VTE
2.8
1.2
1.5
1.1
ATE
0.6
0.5
1.4
GI perforation
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
Characteristic
HR (95% CI)
P value
Prior bevacizumab
.241
Yes
0.61 (0.31, 1.20) No
0.85 (0.71, 1.01)
Best response to first-line therapy
.189
CR/PR/SD
0.90 (0.73, 1.10) PD
0.62 (0.41, 0.94)
Time since start of first-line therapy
.419
< 9 months
0.75 (0.60, 0.92)
≥ 9 months
0.89 (0.66, 1.19)
CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease
Reck M, et al. ASCO 2013.

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

31. Nintedanib + pemetrexed
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
Target enrollment: 1300
Nintedanib + pemetrexed
(N = 353)
Placebo + pemetrexed
(N = 360)
Disease Progression
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. LUME-Lung 2: Centrally-Reviewed PFS
Time from randomization (months)
Estimated patients alive and progression-free (%)
Nintedanib + pemetrexed (n = 353)
Placebo + pemetrexed (n = 360)
Median PFS, mo
4.4
3.6
HR (95% CI)
0.83 (0.70 to 0.99)
Log-rank p value
.0435
Hanna NH, et al. ASCO 2013.

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

34. Nintedanib + docetaxel
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%
Histology
Adenocarcinoma
49.2%
51.0%
Squamous cell carcinoma
42.1%
42.2%
Other
8.7%
6.7%
Prior therapy
Platinum
95.9%
96.5%
Bevacizumab
4.1%
3.5%
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
Characteristic
HR (95% CI)
P value
Prior bevacizumab
.241
Yes
0.61 (0.31, 1.20) No
0.85 (0.71, 1.01)
Best response to first-line therapy
.189
CR/PR/SD
0.90 (0.73, 1.10) PD
0.62 (0.41, 0.94)
Time since start of first-line therapy
.419
< 9 months
0.75 (0.60, 0.92)
≥ 9 months
0.89 (0.66, 1.19)
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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