Please note, these are the actual video-recorded proceedings from the live CME event and may include the use of trade names and other raw, unedited content. Select slides from the original presentation are omitted where Research To Practice was unable to

1
Please note, these are the actual video-recorded
proceedings from the live CME event and may
include the use of trade names and other raw,
unedited content. Select slides from the original
presentation are omitted where Research To
Practice was unable to obtain permission from the
publication source and/or author. Links to view
the actual reference materials have been provided
for your use in place of any omitted slides.
2
Non-Small Cell Lung CancerYear in Review 2012

• Corey J Langer, MD
• Director of Thoracic Oncology
• Abramson Cancer Center
• Professor of Medicine
• University of Pennsylvania
• Vice Chair, Radiation Therapy Oncology Group

3
Have you attempted to obtain a ROS1 mutational
analysis for any of your patients with non-small
cell lung cancer (NSCLC)?
4
Clinical Activity of Crizotinib in Advanced
Non-Small Cell Lung Cancer (NSCLC) Harboring ROS1
Gene Rearrangement
Shaw AT et al. Proc ASCO 2012Abstract 7508
5
ROS1

• New driver mutation ROS1
• ROS1 18/1,073 (1.7) tumors
• Receptor Tyrosine Kinase
• ATP binding like ALK
• 77 identical
• Detected by Break-apart FISH
• Younger pts
• Never-smokers
• Adenocarcinoma

Bergethon JCO 30863, 2012 Janne JCO 30878 2012
6
ROS1 Crizotinib Activity

• ROS1 included in crizotinib dose escalation
• At 250 mg bid dosing
• Reported on 15 pts
• 7/15 had PR 1 CR and only 1 with PD
• Very similar RR and toxicity as in ALK pts

7
Clinical tumor responses in ROS1 NSCLC treated
with crizotinib

• Restaging scans at 8 weeks demonstrated near
  complete resolution of multifocal lung tumor,
  which was subsequently confirmed at 12 weeks1
• 1 of 48 patients tested positive for
  rearrangement, and this patient showed tumor
  shrinkage upon treatment with crizotinib2

1. Bergethon et al. JCO 2012 2. Davies et al.,
accepted AACR 2012
8
Study Design
Phase II, single-arm, multicenter study 1100
patients (enrollment ongoing)
Treatment

• Key eligibility criteria
• ALK NSCLC by central laboratory
• Local test allowed on case-by-case basis per
  protocol amendment (January 2011)
• ECOG PS 03
• 1 prior line of chemotherapy
• Stable/controlled brain metastases allowed

Crizotinib 250 mg po BIDcontinuous daily dosing

• Primary endpoints
• ORR
• safety/tolerability
• Secondary endpoints include
• OS
• PFS
• Duration of response
• Time to response
• PRO/HRQOL

Riely G et al. Chicago IASLC/ASTRO 2012Abstract
3.
9
Patient Characteristics
Mature population (n261) Overall population (n901)
Median age, years (range) 52.0 (24.082.0) 53.0 (1883.0)
Women, n () 142 (54.4) 514 (57.0)
Baseline ECOG PS, n () 0-123 216 (82.8) 42 (16.1) 3 (1.1) 736 (81.7) 134 (14.9) 31 (3.4)
Adenocarcinoma histology, n () 245 (93.9) 826 (91.7)
Smoking status, n () Never smokerFormer/current smoker 176 (67.4) 85 (32.6) 592 (65.7)309 (34.3)
Prior therapies, n () 0 123 0 (0) 32 (12.3) 91 (34.9) 138 (52.8) 3 (lt1.0)248 (27.5)299 (33.2)351 (39.0)
Riely G et al. Chicago IASLC/ASTRO 2012Abstract
3.
10
Best Response of Indicator Lesions
Mature population
100
PD SD PR CR
80
60
40
20
0
Decrease or increase from baseline ()
20
40
60


80
Status Response-evaluable patients n259
Complete Response 4 (2)
Partial Response 151 (58)
Stable Disease 69 (27)
Progressive Disease 19 (7)
100


120
n240 response-evaluable patients from the
mature population, and excludes patients with
early death, indeterminate response and
non-measurable disease Responses observed in
untreated CNS mets Per RECIST 1.1, percent
change from baseline for subjects with best
overall response of CR can be less than 100 when
lymph nodes are included as target lesions
With permission from Riely G et al. Chicago
IASLC/ASTRO 2012Abstract 3.
11
ESMO 2012 NSCLC

• PROFILE 1007 Phase III study of crizotinib vs
  pemetrexed or docetaxel chemotherapy in advanced
  ALK-positive NSCLC. Shaw AT et al. Abstract
  LBA1_PR.
• Median PFS 7.7 mo vs 3.0 mo (HR 0.49 Plt0.0001)
• ORR 65 vs 20 (Plt0.0001)
• These findings establish crizotinib as the
  standard of care for pts with previously treated
  advanced ALK-positive NSCLC

12
A 60-year-old patient with adenocarcinoma of the
lung, PS 0 and exon 19 EGFR mutation experiences
a 1-year response to erlotinib but then develops
slow, objective, asymptomatic disease
progression. What is your likely approach?
13
In a recent Phase III study, afatinib was shown
to be superior to __________ as first-line
treatment for patients with advanced EGFR
mutation-positive NSCLC.
14
Erlotinib versus Standard Chemotherapy as
First-Line Treatment for European Patients with
Advanced EGFR Mutation-Positive Non-Small-Cell
Lung Cancer (EURTAC) A Multicentre, Open-Label,
Randomised Phase 3 Trial

• Rosell R et al.
• Lancet Oncology 201213(3)239-46.

15
EURTAC Study Design
Erlotinib 150mg/day
PD

• Chemona?ve
• Stage IIIB/IV NSCLC
• EGFR exon 19 deletion or exon 21 L858R mutation
• ECOG PS 02
• (n 174)

• Stratification
• Mutation type
• ECOG PS (0 vs 1 vs 2)

R
Platinum-based doublet chemotherapy q3wks x 4
cycles
PD

• Secondary endpoints
• Objective response rate
• Overall survival (OS)
• Location of progression
• Safety
• EGFR mutation analysis in serum
• Quality of life

• Primary endpoint
• Progression-free survival (PFS)
• interim analysis planned at 88 events

ECOG Eastern Cooperative Oncology Group PS
performance status PD progressive
diseaseCisplatin 75mg/m2 d1 / docetaxel 75mg/m2
d1 cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2
d1,8carboplatin AUC6 d1 / docetaxel 75mg/m2 d1
carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8
16
PFS in ITT Population

• PFS
• Erlotinib (n 86), 9.7 months
• Chemotherapy (n 87), 5.2 months
• HR 0.37 (0.25-0.54)
• Log-rank plt0.0001 (data cut-off 1-26-11)

OS HR 1.04, NS MST 19.3mo-E vs 19.5mo-C
Rosell R et al. Lancet Oncology 201213(3)239-46.
17
EGFR TKI vs Platinum-Based Therapy
Trial Comparison ORR PFS (HR) OS
IPASS (n 261) Gefitinib vs. Carbo/paclitaxel 71.2 vs. 47.3 P lt .001 0.48, P lt .001 9.5 vs. 6.3 mos HR 1.00, P .990 MST 21.6 vs. 21.9 mos
NEJSG (n 200) Gefitinib vs. Carbo/paclitaxel 73.7 vs. 30.7 P lt .001 0.30, P lt .001 10.8 vs. 5.4 mos MST 30.5 vs. 23.6 mos P .31
WJTOG (n 172) Gefitinib vs. Cisp/doc 62.1 vs. 32.2 P lt .0001 0.49, P lt .0001 9.2 vs. 6.3 mos Not available
CTONG (n 165) Erlotinib vs. Carb/gem 83.0 vs. 36 P lt .0001 0.16, P lt .001 13.1 vs. 4.6 mos Not available
1st-signal (n 42) Gefitinib vs. Cisp/gem 84.6 vs. 37.5 P .002 0.61, P .084 8.4 vs. 6.7 mos HR 0.823, P .648 30.6 vs. 26.5 mos
EURTAC (n 174) Erlotinib vs. Platinum doublet 58 vs. 15 0.37, P lt .0001 9.7 vs. 5.2 mos HR 1.04, P .87 19.3 vs. 19.5 mos
Numbers represent EGFR mutation positive subsets
Mok et al. NEJM 2009 Fukuoka et al. JCO 2011
Maemondo et al. NEJM 2010 Mitsudomi et al.
Lancet Oncology 2010 Zhou et al. Lancet Oncology
2011 Lee 13th WLC 2009, Rosell et al. Lancet
Oncology 2012
18
LUX-Lung 3 A Randomized, Open-Label, Phase III
Study of Afatinib vs Cisplatin/Pemetrexed as
1st-Line Treatment for Patients with Advanced
Adenocarcinoma of the Lung Harboring
EGFR-Activating Mutations

• Yang JCH et al.
• Proc ASCO 2012Abstract LBA7500.

19
LUX LUNG3 Study Design
Stage IIIB (wet)/IV lung adenocarcinoma (AJCC
version 6)
EGFR mutation in tumor (central lab testing
Therascreen EGFR29 RGQ PCR)
Randomization 21 Stratified by EGFR mutation
(Del19/L858R/other) Race (Asian/non-Asian)
Afatinib 40 mg/day
Cisplatin Pemetrexed 75 mg/m2 500 mg/m2
i.v. q21 days, up to 6 cycles
Primary endpoint PFS (RECIST 1.1, independent
review) Secondary endpoints ORR, DCR, DoR, tumor
shrinkage, OS, PRO, safety, PK
72 Asian, 65 women, 68 NS 49 del19, 40
L858R, 11 other
Yang JC et al. Proc ASCO 2012Abstract LBA7500.
20
Primary Endpoint PFS Independent review all
randomized patients
1.0
Afatinib n 230 Cis/pem n 115
PFS event, n () 152 (66) 69 (60)
Median PFS (months) 11.1 6.9
Hazard ratio(95 confidence interval) 0.58 (0.430.78)p 0.0004 0.58 (0.430.78)p 0.0004
0.8
0.6
Progression-free survival (probability)
HR 0.47 if other excluded
47
0.4
0.2
22
0.0
0 3 6 9 12 15 18 21 24 27
Progression-free survival (months)
With permission from Yang JC et al. Proc ASCO
2012Abstract LBA7500.
21
Most Frequent Related Adverse Eventsgt20
difference between treatment arms
Afatinib (n 229) Afatinib (n 229) Afatinib (n 229) Cis/pem (n 111) Cis/pem (n 111) Cis/pem (n 111)
All Gr () Gr 3 () Gr 4 () All Gr () Gr 3 () Gr 4 ()
Diarrhea 218 (95.2) 33 (14.4) 0 17 (15.3) 0 0
Rash/acne 204 (89.1) 37 (16.2) 0 7 (6.3) 0 0
Stomatitis/mucositis 165 (72.1) 19 (8.3) 1 (0.4) 17 (15.3) 1 (0.9) 0
Paronychia 130 (56.8) 26 (11.4) 0 0 0 0
Dry skin 67 (29.3) 1 (0.4) 0 2 (1.8) 0 0

Nausea 41 (17.9) 2 (0.9) 0 73 (65.8) 4 (3.6) 0
Decreased appetite 47 (20.5) 7 (3.1) 0 59 (53.2) 3 (2.7) 0
Fatigue 40 (17.5) 3 (1.3) 0 52 (46.8) 14 (12.6) 0
Vomiting 39 (17.0) 7 (3.1) 0 47 (42.3) 3 (2.7) 0
Neutropenia 2 (0.9) 1 (0.4) 0 35 (31.5) 17 (15.3) 3 (2.7)
Anemia 7 (3.1) 1 (0.4) 0 31 (27.9) 5 (4.5) 2 (1.8)
Grouped term. No grade 5 events for the
presented AEs.
Yang JC et al. Proc ASCO 2012Abstract LBA7500.
22
SELECT A Multicenter Phase II Trial of Adjuvant
Erlotinib in Resected EGFR Mutation Positive NSCLC

• Joel Neal1, Nathan Pennell2, Ramaswamy Govindan3,
  Rebecca Heist4, Alice Shaw4, Alona Muzikansky4,
  Pasi Jänne5, Thomas Lynch6, Jerry Azzoli4,7,
  Lecia Sequist4
• Proc ASCO 2012Abstract 7010

1 Stanford Cancer Institute, Stanford, CA 2
Cleveland Clinic, Cleveland, OH 3 Washington
University, St. Louis, MO 4 Massachusetts
General Hospital, Boston, MA 5 Dana-Farber
Cancer Institute, Boston, MA 6 Yale Cancer
Center, New Haven, CT 7 Memorial Sloan-Kettering
Cancer Center, New York, NY
23
SELECT Study Design

• Single arm Phase II study
• Adjuvant erlotinib following surgery and
  standard therapy

CT surveillance - Every 6 mo x 3 years
- Annually years 4 and 5

• Stage IA-IIIA NSCLC
• Surgically resected
• EGFR mutation positive
• Completed routine adjuvant chemotherapy and/or XRT

Erlotinib 150 mg PO daily
Observation

• Primary Endpoint
• Disease Free Survival
• Goal 2-year gt86
• Secondary Endpoints
• Safety and Tolerability
• Overall Survival

2 years duration
Total N 100 This report on 36 pts
24
SELECT Disease Free Survival
Median follow-up time 2.7 years
Censored observation
0 0.5 1.0 1.5
2.0 2.5 3.0 3.5 4.0
4.5 5.0
Time from initiating adjuvant erlotinib (Years)
Patients at Risk 36 35
34 34 33
19 7 3
1 0
With permission from Neal J et al. Proc Chicago
Multidisciplinary Symposium in Thoracic Oncology
2012Abstract 16.
25
What is your usual front-line and maintenance
strategy for patients with EGFR wild-type tumors
without contraindications to bevacizumab?
Carbo/paclitaxel/bev bev
Carbo/paclitaxel/bev
pemetrexed
Carbo/paclitaxel/bev
pemetrexed/bev
Carbo/pemetrexed/bev bev
Carbo/pemetrexed/bev
pemetrexed
Carbo/pemetrexed/bev
bev/pemetrexed
26
A Randomized, Open-Label, Phase III, Superiority
Study of Pemetrexed (Pem) Carboplatin (Cb)
Bevacizumab (Bev) Followed by Maintenance Pem
Bev versus Paclitaxel (Pac) Cb Bev Followed
by Maintenance Bev in Patients with Stage IIIB or
IV Non-Squamous Non-Small Cell Lung Cancer
(NS-NSCLC)
Patel JD et al. 2012 Chicago Multidisciplinary
Symposium in Thoracic OncologyAbstract LBPL1.
27
PointBreak Study Design

• Randomized, open-label, Phase III superiority
  study conducted in US
• Pemetrexed 500 mg/m2 Carboplatin AUC 6
  Bevacizumab 15 mg/kg
• Paclitaxel 200 mg/m2 Carboplatin AUC 6
  Bevacizumab 15 mg/kg

Maintenance Phase q21d until PD
Induction Phaseq21d, 4 cycles

• Inclusion
• - No prior systemic therapy for lung cancer
• - PS 0/1
• - Stage IIIB-IV NS-NSCLC
• - Stable txt brain mets
• Exclusion
• Peripheral neuropathy
• Gr 1
• - Uncontrolled pleural effusions

Pemetrexed (folic acid vitamin B12)
Carboplatin Bevacizumab
Pemetrexed (folic acid vitamin B12)
Bevacizumab
450 patients each
Bevacizumab
Paclitaxel Carboplatin Bevacizumab
Stratified for PS (0 vs 1) sex (M vs F)
disease stage (IIIB vs IV) measurable vs
nonmeasurable disease Note Randomization BEFORE
initiation of therapy
28
Two POINT-BREAK Questions

• Would it POINT the way to a new treatment
  paradigm?
• If Pemetrexed/Bevacizumab became a new standard
  during induction and maintenance, would the
  combination BREAK the bank?

29
PointBreak Kaplan-Meier (KM) OS from
Randomization (ITT)
PemCbBev PemCbBev PacCbBev
OS median (mo) 12.6 12.6 13.4
HR (95 CI) P value 1.0 (0.86, 1.16) P0.949 1.0 (0.86, 1.16) P0.949 1.0 (0.86, 1.16) P0.949
Censoring () 27.8 27.8 27.2
Survival rate () Survival rate () Survival rate () Survival rate ()
1-year 52.7 54.1 54.1
2-year 24.4 21.2 21.2
With permission from Patel J et al. Chicago
IASLC/ASTRO 2012Abstract LBPL1.
30
Carboplatin-Based, Bevacizumab-Based Trials in
Advanced NSCLC
Study China1 China1 E45992 Patel3 Penn4 POINT-BREAK5 POINT-BREAK5
No 151 140 417 51 43 472 467
Bev 7.5 15 15 15 15 15 15
CbPac
CbGem
CbPem
Maint B B B BP B BP B
OR 37 46.4 35 55 47 34 33
PFS mo 6.8 6.7 6.2 7.8 7.1 6.0 5.6
OS mo 13.4 13.7 12.2 14.1 17.1 12.6 13.4
1Mok et al, ESMO 2011 2Sandler et al, NEJM
2006 3Patel et al, JCO 2009 4Stevenson, Cancer
2011 5Patel et al, Chicago IASLC/ASTRO, 2012
31
Carboplatin-Based, Bevacizumab-Based Trials in
Advanced NSCLC
Study China1 China1 E45992 Patel3 Penn4 POINT-BREAK5 POINT-BREAK5
No 151 140 417 51 43 472 467
Bev 7.5 15 15 15 15 15 15
CbPac
CbGem
CbPem
Maint B B B BP B BP B
OR 37 46.4 35 55 47 34 33
PFS mo 6.8 6.7 6.2 7.8 7.1 6.0 5.6
OS mo 13.4 13.7 12.2 14.1 17.1 12.6 13.4
1Mok et al, ESMO 2011 2Sandler et al, NEJM
2006 3Patel et al, JCO 2009 4Stevenson, Cancer
2011 5Patel et al, Chicago IASLC/ASTRO, 2012
32
PointBreak KM PFS from Randomization (ITT)
Pem Cb Bev Pac Cb Bev
PFS median (mo) 6.0 5.6
HR (95 CI) p-value 0.83 (0.71, 0.96) p 0.012 0.83 (0.71, 0.96) p 0.012
ORR () 34.1 33.0
OS median (mo) 12.6 12.6 13.4
HR (95 CI) p-value 1.00 (0.86, 1.16) p 0.949 1.00 (0.86, 1.16) p 0.949 1.00 (0.86, 1.16) p 0.949
Survival rate () Survival rate () Survival rate () Survival rate ()
1-year 52.7 54.1 54.1
2-year 24.4 21.2 21.2
Exploratory analysisCensoring rate for Pem Cb
Bev was 26.9 for Pac Cb Bev was 23.3
With permission from Patel JD et al. 2012 Chicago
Multidisciplinary Symp in Thoracic OncolAbstract
LBPL1.
33
PointBreak Pre-specified Exploratory Analysis of
KM OS from Randomization Maintenance Group
Pem Cb Bev (n 292) Pac Cb Bev (n 298)
OS median (mo) 17.7 15.7

Pre-specified exploratory non-comparative
subgroup analyses Censoring rate for Pem Cb
Bev was 36.0 for Pac Cb Bev was 30.2
With permission from Patel JD et al. 2012 Chicago
Multidisciplinary Symp in Thoracic OncolAbstract
LBPL1.
34
ECOG-E5508 Phase III Study of Maintenance
Bevacizumab, Pemetrexed or the Combination in
NSCLC
Study Start Date August 2010
Target Accrual 1,282

• Eligibility
• Stage IIIB/IV
• Nonsquamous
• NSCLC
• No brain mets
• stable or response after carbo/paclitaxel
  bevacizumab

Primary Endpoint Overall survival
www.clinicaltrials.gov, October 2012
35
Multidisciplinary Symposium in Thoracic Oncology
2012 (ASCO) 06-08 September 2012

• Hirsch V et al. Weekly nab-Paclitaxel in
  Combination with Carboplatin as First-Line
  Therapy in Patients (pts) with Advanced Non-Small
  Cell Lung Cancer(NSCLC) Analysis of
  Patient-Reported Neuropathy and Taxane-Associated
  Symptoms. Abstract 108 Thoracic Oncology 2012
• Socinski MA et al. Weekly nab-Paclitaxel In
  Combination With Carboplatin As First-line
  Therapy In Elderly Patients (pts) With Advanced
  Non-small Cell Lung Cancer (NSCLC). Abstract 109
  Thoracic Oncology 2012.
• Renschler MF et al. Safety and Efficacy by
  Histology of Weekly nab-Paclitaxel in Combination
  with Carboplatin as First-line Therapy in
  Patients (pts) with Advanced Non-Small Cell Lung
  Cancer (NSCLC). Abstract 110 Thoracic Oncology
  2012

36
October 15, 2012

• The FDA has approved nab-paclitaxel plus
  carboplatin for patients with untreated locally
  advanced or metastatic non-small cell lung cancer
  (NSCLC) who are not candidates for surgery or
  radiation
• The approval was based on results from the phase
  III CA031 trial, which showed that weekly
  nab-paclitaxel combined with carboplatin
  significantly improved overall response rate
  (ORR), when compared with solvent-based (sb)
  paclitaxel plus carboplatin

Source FDA Press Release
37
What is your usual first-line chemotherapy
regimen for patients with metastatic squamous
cell NSCLC?
Carboplatin/paclitaxel
Carboplatin/gemcitabine
Carboplatin/nanoparticle albumin-bound (nab)
paclitaxel
Carboplatin/pemetrexed
Other
38
Clinical Activity and Safety of Anti-PD-1
(BMS-936558, MDX-1106) in Patients with Advanced
Non-Small-Cell Lung Cancer
J.R. Brahmer,1 L. Horn,2 S.J. Antonia,3 D.
Spigel,4 L. Gandhi,5 L.V. Sequist,6 J.M.
Wigginton,7 D. McDonald,7 G. Kollia,7 A. Gupta,7
S. Gettinger8
Proc ASCO 2012Abstract 7509.
1Sidney Kimmel Cancer Center at Johns Hopkins,
Baltimore, MD 2Vanderbilt-Ingram Cancer Center,
Nashville, TN 3H. Lee Moffitt Cancer Center
Research Institute, Tampa, FL 4Sarah Cannon
Research Institute/Tennessee Oncology, PLLC,
Nashville, TN 5Dana-Farber Cancer Institute,
Boston, MA 6Massachusetts General Hospital
Cancer Center, Boston, MA 7Bristol-Myers
Squibb, Princeton, NJ 8Yale University School
of Medicine, New Haven, CT
39
Response of Metastatic NSCLC (BMS-936558, 10
mg/kg)

• Initial progression in pulmonary lesions of a
  NSCLC patient with non-squamous histology was
  followed by regression
• Dx 04, EGFR mutation Rx gem/carbo, erlotinib,
  erlotinib LBH589 (trial for T790 mutation), and
  lastly pemetrexed

With permission from Brahmer JR et al. Proc ASCO
2012Abstract 7509.