New Perspectives on Second-Line Therapy for NSCLC

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 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. http//www.mycancergenome.org/cont
ent/disease/lung-cancer. Pao W, Girard N. Lancet
Oncol. 201112175-180.
5
NSCLC 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.
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/cont
ent/disease/lung-cancer. Pao W, Girard N. Lancet
Oncol. 201112175-180.
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.
200234692-98.
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.
20063552542-2550.
10
Second-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.
11
Second-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.
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
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 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.
15
Angiogenesis 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.
16
Angiogenesis 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.
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 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.
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)
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.
20
LUME-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.
21
LUME-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.
22
LUME-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.
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
Combination 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.
25
LUME-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.
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
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.
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
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.
30
Angiogenesis 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.
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 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.
32
LUME-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.
33
Docetaxel 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.
34
LUME-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.
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
lt 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

38
Thank you for participating in this activity.

• To proceed to the Post-Test and Activity
  Evaluation, click on the Earn CME Credits link on
  this page.