Title: New Perspectives on Second-Line Therapy for NSCLC
1New 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
2Overview
- 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
3Panelists
Luis Paz-Ares Rodríguez, MD, PhD Chair,
Department of Oncology, Seville University
Hospital, Seville, Spain
Martin Reck, MD, PhD Head, Department of Thoracic
Oncology, Hospital Grosshansdorf, Grosshansdorf,
Germany
4Single-Driver Mutations in NSCLC
Lovly C, et al. http//www.mycancergenome.org/cont
ent/disease/lung-cancer. Pao W, Girard N. Lancet
Oncol. 201112175-180.
5NSCLC Without Targetable Mutations An Unmet Need
Lovly C, et al. http//www.mycancergenome.org/cont
ent/disease/lung-cancer. Pao W, Girard N. Lancet
Oncol. 201112175-180.
6NSCLC Histology
Howlader N, et al (eds). SEER Cancer Statistics
Review, 1975-2010, National Cancer Institute.
Bethesda, MD, 2013.
7Single-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/cont
ent/disease/lung-cancer. Pao W, Girard N. Lancet
Oncol. 201112175-180.
8Outcomes With First-Line Doublet Therapy ECOG
1594
Months
OS overall survival PFS progression-free
survival
Schiller JH, et al. New Engl J Med.
200234692-98.
9Outcomes 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.
20063552542-2550.
10Second-Line Therapy Options Outcomes
Study Treatment Arms Median OS (mos) 1-Year Survival
TAX 317a Docetaxel (N 103) 7.0 37.0
TAX 317a Best supportive care (N 100) 4.6 12.0
Hanna et al. 2004b Pemetrexed (N 283) 8.3 29.7
Hanna et al. 2004b Docetaxel (N 288) 7.9 29.7
INTERESTc Gefitinib (N 723) 7.6 32.0
INTERESTc Docetaxel (N 710) 8.0 34.0
TITANd Erlotinib (N 203) 5.3 26.0
TITANd Chemotherapy (N 221 116 docetaxel, 105 pemetrexed) 5.5 24.0
a. Shepherd FA, et al. J Clin Oncol.
2000182095-2103.b. Hanna N, et al. J Clin
Oncol. 2004221589-1597.c. Kim ES, et al.
Lancet. 20083721809-1818.d. Ciuleanu T, et al.
Lancet Oncol. 201213300-308.
11Second-Line Therapy Grade 3/4 Toxicities
Erlotiniba Pemetrexeda,b ltlt Docetaxelb
40.2
Percent Reporting
Adverse Event
a. Vamvakas L, et al. ASCO 2010.b. Hanna N, et
al. J Clin Oncol. 2004221589-1597.
12Selecting 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
13Second-Line Therapy Outstanding Needs
- Options for patients with wild-type mutations
(EGFR, etc) - Predictive biomarkers
- New agents with efficacy in the second-line
setting
14Second-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 FAILED
ISEL Gefitinib vs placebo FAILED
ZODIAC Vandetanib docetaxel vs docetaxel FAILED
ZEAL Vandetanib pemetrexed vs pemetrexed FAILED
ZEST Vandetanib vs erlotinib FAILED
VITAL Aflibercept docetaxel vs docetaxel FAILED
BETA Bevacizumab erlotinib vs erlotinib FAILED
TAILOR Docetaxel vs erlotinib, non-EGFR mutations FAILED
TITAN Docetaxel/pemetrexed vs erlotinib FAILED
Vinflunine Vinflunine vs docetaxel FAILED
Topotecan Oral topotecan vs docetaxel FAILED
SUN1087 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.
15Angiogenesis Inhibitors in NSCLC
Drug Target Target Target Target Target
Drug EGFR FGFR PDGFR VEGF VEGFR
Axitinib ß R-1, 2, 3
Bevacizumab ?
BMS-690514 ?
Brivanib R-1 R-2
Cediranib a/ß R-1, 2, 3
Linifanib R-1, 2, 3
MGCD265 ?
Motesanib ? R-1, 2, 3
Nintedanib R-1, 2, 3 a/ß R-1, 2, 3
Pazopanib R-1, 3 a/ß R-1, 2, 3
Sorafenib ß R-2, 3
Sunitinib a/ß R-1, 2, 3
Vandetanib ? 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.
20128447-58.
16Angiogenesis Inhibitors in NSCLC Nintedanib
- Investigational oral agent
- Can be combined with chemotherapy
- Docetaxela
- Pemetrexedb
- Paclitaxel/carboplatinc
- Gemcitabine/cisplatind
a. Bousquet G, et al. Br J Cancer.
20111051640-1645. b. Ellis PM, et al. Clin
Cancer Res. 2010162881-2889. c. Doebele RC, et
al. Ann Oncol. 2012232094-2102. d.
http//clinicaltrials.gov/show/NCT01346540.
17LUME-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 Monother
apy 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.
18LUME-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.
19LUME-Lung 1 PFS (All Patients)
Nintedanib docetaxel(n 655) Placebo docetaxel(n 659)
Median, mo 3.4 2.7
HR (95 CI) 0.79 (0.68 to 0.92) 0.79 (0.68 to 0.92)
P .0019 .0019
Probability of survival without progression ()
Time (months)
Reck M, et al. ASCO 2013.
20LUME-Lung 1 OS (All Patients)
Nintedanib docetaxel(n 655) Placebo docetaxel(n 659)
Median, mo 10.1 9.1
HR (95 CI) 0.94 (0.83 to 1.05) 0.94 (0.83 to 1.05)
P .2720 .2720
Probability of survival ()
Time (months)
Reck M, et al. ASCO 2013.
21LUME-Lung 1 OS (Adenocarcinoma Patients)
Nintedanib docetaxel(n 322) Placebo docetaxel(n 336)
Median, mo 12.6 10.3
HR (95 CI) 0.83 (0.70 to 0.99) 0.83 (0.70 to 0.99)
P .0359 .0359
Probability of survival ()
Time (months)
Reck M, et al. ASCO 2013.
22LUME-Lung 1 Adverse Events of Special Interest
Nintedanib docetaxel
Placebo docetaxel
Patients Reporting ()
Adverse Events, Grade 3 (incidence 1)
Adverse Events, All Grades(incidence 15)
Reck M, et al. ASCO 2013.
23LUME-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
24Combination Therapy With Angiogenesis Inhibitors
First-Line vs Second-Line Outcomes
OS (mo)
HR, 0.79 95 CI, 0.67 to 0.92P .003
HR, 0.83 P .0359
LUME-Lung 1(Adenocarcinoma subset)
b
a
a. Sandler A, et al. New Engl J Med.
20063552542-2550. b. Reck M, et al. J Clin
Oncol. 201331(suppl) LBAS011.
25LUME-Lung 1 OS by Histology
Nintedanib docetaxel(n 322) Placebo docetaxel(n 336)
Median, mo 12.6 10.3
HR (95 CI) 0.83 (0.70 to 0.99) 0.83 (0.70 to 0.99)
P .0359 .0359
Nintedanib docetaxel(n 655) Placebo docetaxel(n 659)
Median, mo 10.1 9.1
HR (95 CI) 0.94 (0.83 to 1.05) 0.94 (0.83 to 1.05)
P .2720 .2720
Probability of survival ()
0 4 8 12 16
20 24 28 32 36
All patients
Adenocarcinoma subset
Reck M, et al. ASCO 2013.
26Nintedanib 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
27LUME-Lung 1 Toxicities Associated with
VEGF/VEGFR Inhibitors
Adverse event Nintedanib docetaxel Nintedanib docetaxel Placebo docetaxel Placebo docetaxel
Adverse event 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
ATE arterial thromboembolism GI
gastrointestinal VTE venous thromboembolism
Reck M, et al. ASCO 2013.
28Looking Forward Research Needs
- Combination vs monotherapy
- Biomarkers to assist in patient selection
- Role of clinical factors, histology, etc
29LUME-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
lt 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.
30Angiogenesis Inhibitors in the Second-Line
Setting LUME-Lung 1 vs ZODIAC
OS (mo)
HR, 0.94 95 CI, 0.83 to 1.05P .2720
HR, 0.91 97.52 CI, 0.78 to 1.07P .196
LUME-Lung 1a
b
a. Reck M, et al. J Clin Oncol. 201331(suppl)
LBAS011. b. Herbst RS, et al. Lancet Oncol.
201011619-626.
31Angiogenesis 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 11
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.
32LUME-Lung 2 Centrally-Reviewed PFS
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) 0.83 (0.70 to 0.99)
Log-rank p value .0435 .0435
Hanna NH, et al. ASCO 2013.
33Docetaxel in the Second-Line Setting Survival
Trends
OS (mo)
Hanna et al. 2004b
INTERESTc
LUME-Lung 1e
TAX 317a
ZODIACd
a. Shepherd FA, et al. J Clin Oncol.
2000182095-2103.b. Hanna N, et al. J Clin
Oncol. 2004221589-1597. c. Kim ES, et al.
Lancet. 20083721809-1818. d. Herbst RS, et al.
Lancet Oncol. 201011619-626. e. Reck M, et al.
ASCO 2013.
34LUME-Lung 1 Patient Characteristics
Characteristic Nintedanib docetaxel (N 655) Placebo docetaxel (N 659)
Age lt 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.
35Clinical Questions
- Sequencing of therapy?
- Treatment beyond progression?
- Impact of maintenance therapy on subsequent
treatment decisions?
36LUME-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
lt 9 months 0.75 (0.60, 0.92)
9 months 0.89 (0.66, 1.19)
Reck M, et al. ASCO 2013.
37Take 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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