CCO Clin Onc June 2013 Downloadable Slides

Lung Cancer
clinicaloptions.com/oncology
Lung Cancer
CCO Independent Conference Coverage
of the 2013 American Society of Clinical Oncology Annual Meeting*
May 31 - June 4, 2013

Chicago, Illinois
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provides state-of-the-art medical information to healthcare
professionals through conference coverage and other
educational programs.
This
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Lung Cancer
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Lung Cancer
Faculty
David R. Gandara, MD
Professor of Clinical Medicine
UC Davis Comprehensive Cancer Center
Sacramento, California
Heather Wakelee, MD
Associate Professor of Medicine, Oncology
Department of Medicine/Oncology
Stanford University
Stanford, California
Lung Cancer
Disclosures
David R. Gandara, MD, has disclosed that he has received
funds for research support from Abbott, Bristol-Myers Squibb,
Eli Lilly and Company, Genentech, ImClone, Merck, Novartis,
and Pfizer; and has received consulting fees from Amgen,
AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb,
Celgene, GlaxoSmithKline, Genentech, ImClone, Merck,
Novartis, Pfizer, Response Genetics, Sanofi-Aventis, and
Syntia.
Heather Wakelee, MD, has disclosed that she has received
consulting fees from Gilead Sciences and funds for research
support from Agennix, Arqule, AstraZeneca, Celgene, Clovis,
Eli Lilly and Company, Exelixis, Genentech, Merck, Novartis,
Pfizer, and Regeneron.
Lung Cancer
Overview
Local-Regional NSCLC Targeted Therapy
Phase III RTOG 0617: 74 Gy vs 60 Phase III LUME Lung 1: docetaxel
Gy RT nintedanib in advanced/metastatic
Phase III START: tecemotide (L- NSCLC
BLP25) vs placebo
Phase II GALAXY-1: docetaxel
Chemotherapy and EGFR TKIs in ganetespib in adenocarcinoma
Advanced NSCLC
Phase I study of nivolumab (antiPD-
Phase III PRONOUNCE: Pem/Carbo
L1 antibody) monotherapy in NSCLC
Pem vs Pac/Carbo Bev
Phase III PROSE: serum protein test Phase IA study of MPDL3280A (anti
in predicting survival for patients on PD-L1 antibody) in solid tumors
second-line erlotinib vs chemotherapy
Phase I study of LDK378 in advanced
Extensive-Stage Small-Cell Lung ALK+ NSCLC
Cancer
Phase II study of dabrafenib (BRAF
Phase II CALGB 30504: chemo V600E kinase inhibitor) in stage IV
maintenance sunitinib NSCLC
Lung Cancer
Local-Regional NSCLC
Lung Cancer
RTOG 0617: Phase III Trial of 74 Gy vs 60

Gy RT in Unresectable Stage III NSCLC
Stratified by RT technique,
Zubrod status, PET staging,
histology
Concurrent Treatment Consolidation Treatment
Standard-Dose RT +
concurrent CT* Consolidation CT*
(n = 125)
High-Dose RT +
concurrent CT* Consolidation CT*
(n = 121)
Patients with newly
diagnosed, unresectable Standard-Dose RT +
stage IIIA/IIIB NSCLC concurrent CT* + Consolidation CT* +
(N = 464) Cetuximab Cetuximab
(n = 108)
High-Dose RT+
concurrent CT* + Consolidation CT* +
Cetuximab Cetuximab
(n = 110)
*CT consisted of carboplatin/paclitaxel.

400 mg/m2 loading dose on Day 1, followed by weekly dose of 250 mg/m 2
Primary endpoint: OS
Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.
Lung Cancer
RTOG 0617: Survival

Efficacy Standard-Dose RT High-Dose RT HR P Value
Outcome (n = 213) (n = 206) (95% CI)
1.56
Median OS, mos 28.7 19.5 .0007
(1.19-2.06)
1.30
18-mo PFS, % 36.6 26.3 .0116
(1.04-1.63)
18-mo local 1.37
25.1 34.3 .0319
failure, % (0.99-1.89)
18-mo distant 1.15
42.4 47.8 .1576
failure, % (0.87-1.51)
Lung Cancer
RTOG 0617: Safety

Grade 3 esophagitis occurred significantly more often with high-
dose vs standard-dose RT (20.9% vs 7.0%; P = .0003)
Adverse Events Definitely, Probably, Standard-Dose RT High-Dose RT
or Possibly Related to Treatment, % (n = 213) (n = 206)
Worst nonhematologic events
Grade 3 46.0 46.1
Grade 4 9.9 11.2
Grade 5 0.9 4.9
Worst overall
Grade 3 46.5 41.7
Grade 4 26.8 31.6
Grade 5 0.9 4.9
Lung Cancer
Summary
High-dose RT (74 Gy) associated with higher risk of death,
locoregional recurrence, and incidence of fatal AEs vs low-
dose RT (60 Gy) when administered with concurrent CT in
patients with newly diagnosed, unresectable stage III
NSCLC
Analysis of the addition of cetuximab to high- and low-
dose RT with concurrent CT is ongoing
Lung Cancer
Tecemotide (L-BLP25):
Novel Lipopeptide Cancer Vaccine
MUC1 mucin
G S T AP P AH G V T S AP D T R P AP
S T A P P A H G V T S A P D T R P A P G S T A P P - Lys (PAL) G
Antigen = BLP25 lipopeptide

The amino acids of the lipopeptide provide antigenic epitopes for T cells
Adjuvant = Monophosphoryl lipid A

The adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4
stimulation)
Structural lipids = cholesterol, DPPC, and DMPG
Further enhancement of antigen delivery/uptake into APCs and immune reaction
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
Lung Cancer
START: Study Design

Randomized 2:1; stratified by
disease stage, response
to chemoradiotherapy, concurrent
vs sequential chemoradiotherapy,
geographic region
Tecemotide 806 g SC weekly for 8 wks,

then every 6 wks thereafter +
Best Supportive Care
Patients with unresectable
(n = 829)
stage IIIA/B NSCLC without Treated
disease progression following until PD
chemoradiotherapy
(N = 1239) Placebo +
Best Supportive Care
(n = 410)
1 dose of cyclophosphamide 300 mg/m 2 or saline given 3 days prior to first tecemotide or placebo dose,
respectively.
Lung Cancer
START: Overall Survival

100 L-BLP25 Placebo
90 (n = 829) (n = 410)
80 Median OS, mos 25.6 22.3

Adjusted HR 0.88 (95% CI: 0.75-1.03;
70
P = .123*)
Survival (%)
60
Median follow-up, mos 39.9 37.7
50
40
30 L-BLP25
20 Placebo
10 *2-sided, strata and multiplicity adjusted

0
0 6 12 18 24 30 36 42 48 54 60 66
Pts at Risk, n Mos
Placebo 410 353 285 188 127 108 88 59 33 18 4 0
L-BLP25 829 757 617 429 301 255 204 128 73 33 8 0
Lung Cancer
START: OS Analyses by Randomization

Strata
Median OS, Mos HR* (95% CI)
L-BLP25 vs Placebo
Stage Stage IIIA (n = 487) 27.6 vs 23.1 0.86 (0.67-1.11)
Stage IIIB (n = 752) 23.7 vs 20.9 0.90 (0.74-1.09)
Region NA and Aus. (n = 321) 34.1 vs 21.7 0.79 (0.58-1.09)
W. Europe (n = 475) 24.2 vs 22.3 0.91 (0.71-1.17)
Rest of world (n = 443) 21.8 vs 22.7 0.95 (0.73-1.22)
Response SD (n = 396) 20.4 vs 17.8 0.85 (0.65-1.11)

to chemo/RT
Obj. response (n = 843) 27.8 vs 23.9 0.91 (0.75-1.10)
Chemo/ Concurrent (n = 806) 30.8 vs 20.6 0.78 (0.64-0.96)

RT type
Sequential (n = 433) 19.4 vs 24.6 1.11 (0.86-1.43)
0.5 1.0 2.0

*Not adjusted for strata.
Favors L-BLP25 Favors Placebo
Lung Cancer
START: OS in Patients With Concurrent

Chemo/RT
100 L-BLP25 Placebo
90 (n = 538) (n = 268)
80 Median OS, mos 30.8 20.6

HR 0.78 (95% CI: 0.65-0.95;
70
P = .016*)
Survival (%)
60
50
40
30 L-BLP25
20 Placebo
10 *2-sided, adjusted for strata

0
0 6 12 18 24 30 36 42 48 54 60 66
Pts at Risk, n Mos
Placebo 268 227 186 118 73 62 54 40 26 16 4 0
L-BLP25 538 499 412 295 205 176 147 89 51 24 7 0
Lung Cancer
START: Safety
AE, % Tecemotide Placebo
(n = 1024) (n = 477)
100
91.6 90.6
Most frequent AEs Tecemotide (n = 1024)
(> 10% in tecemotide arm) 90
Placebo (n = 477)
Cough 33.0 27.9 80
Dyspnea 23.2 23.5 70
Patients (%)
Fatigue 19.2 21.4 60
Back pain 14.3 11.1 50
Nausea 13.7 8.2 40 33.4 35.8
Chest pain 13.2 9.4 29.6 31.7
30
Nasopharyngitis 12.5 9.2
20
Headache 12.1 11.3
10 7.3
Decreased appetite 10.6 9.2
4.5
0
Arthralgia 10.5 7.1
Any AE Any Any Any AE
Influenzalike symptoms Grade Serious Leading
Any 38.2 33.1 3/4 AE AE to Death
Grade 3/4 1.5 1.7
Lung Cancer
Summary
Study did not meet primary endpoint of significant
improvement in OS with use of tecemotide maintenance
Prespecified subgroup analysis identified significant
10.2-mo OS benefit with tecemotide in patients who
received concurrent initial chemotherapy and radiotherapy
Tecemotide therapy was well tolerated
AE incidence similar to placebo
Lung Cancer
Defining the Continuing Role of

Chemotherapy and EGFR TKIs
in Advanced NSCLC
Lung Cancer
PRONOUNCE: Phase III Superiority Trial of

Pem/Carbo Pem vs Pac/Carbo Bev
Induction (q21d, 4 cycles) Maintenance (q21d until
PD)
Bev-Eligible Population
Pemetrexed Pemetrexed
Inclusion: (folic acid & vitamin B12)
(folic acid & vitamin B12)
Chemo-naive patients
+ Carboplatin
PS 0/1
R
Stage IV, nonsquamous 1:1 180 patients each
Stable treated CNS mets
Exclusion:
Uncontrolled effusions Paclitaxel
+ Carboplatin Bevacizumab
+ Bevacizumab
Primary objective: PFS without grade 4 AE

Composite endpoint considers the first occurrence of either:
Grade 4 AE (lower grade AEs are not considered) or disease progression or death (PFS)
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.

Lung Cancer
PRONOUNCE: Primary Endpoint (G4PFS)

100
Pem + Cb, median G4PFS: 3.9 mos

80 Pac + Cb + Bev, median G4PFS: 2.9 mos
Log-rank P = 0.176
60
Pts (%)
HR: 0.85 (95% CI: 0.70-1.04)
40
20
0
0 3 6 9 12 15 18 21 24 27
Mos
Pts at Risk, n
Pem + Cb 182 87 44 26 14 7 5 3 1 0
Pac + Cb + Bev 179 75 33 17 9 3 0 0 0 0
Lung Cancer
PRONOUNCE: OS (ITT)
100 Pem + Cb, median OS: 10.5 mos
Pac + Cb + Bev, median OS: 11.7 mos
80 HR: 1.07 (95% CI: 0.83-1.36;
log-rank P = .615)
Patients, %
Pem + Cb, % Pac + Cb + Bev, %

60 (n = 182) (n = 179)
1 yr 43.7 48.8
40 2 yrs 18.0 17.6
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
Mos
Pts at Risk, n
Pem + Cb 182 156 125 102 72 48 33 20 11 11 5 5 5 5 5
Pac + Cb + Bev 179 151 121 96 73 59 38 28 10 3 1 1 0 0 0
Lung Cancer
Possibly Drug-Related Grade 3/4 CTCAE

Event Pem + Cb, % Pac + Cb + P Value
(n = 171) Bev, %
(n = 166)
Anemia 19 5 < .001
Thrombocytopenia 24 10 < .001
Neutropenia 25 49 < .001
Febrile neutropenia 0 2 .118
Hypertension 0 2 .058
Thrombosis/embolism 0 2 .058
Any hemorrhagic events 1 0 .499

Lung Cancer
Summary
Study failed to establish that first-line pemetrexed/
carboplatin superior to paclitaxel/carboplatin/bevacizumab
for PFS without grade 4 AEs
PFS, OS, and ORR similar between arms
AE profiles of each arm differed, but both tolerable
Pem + Cb arm with more anemia and thrombocytopenia
Pac + Cb + Bev arm with more neutropenia
No unexpected AEs in either arm
Zinner R, et al. ASCO 2013. Abstract LBA8003.

Lung Cancer
PROSE: Validation of Multivariate Serum

Protein Test
Background: EGFR-activating mutations associated with
improved PFS on erlotinib, but:
Most pts with NSCLC have wild-type or unknown EGFR status
Additional predictive biomarkers needed to guide treatment choice
Multivariate protein-based serum test developed for NSCLC
Test classifies patients according to protein signature: good or
poor
Study aim: prospectively validate ability of test to predict
survival outcomes in setting of second-line NSCLC (erlotinib vs
chemotherapy)
Lazzari C, et al. ASCO 2013. Abstract LBA8005.

Lung Cancer
PROSE: Multicenter Randomized Phase III

Trial of Second-line Erlotinib vs CT
Stratified by multivariate serum protein test status

(patients and investigators blinded to results),
ECOG PS, smoking status
Erlotinib 150 mg/day

EGFR inhibitornaive (n = 134)
patients with stage IIIB-IV Crossover
NSCLC who received permitted at
1 previous line of progression
platinum-based therapy Pemetrexed 500 mg/m2 or
Docetaxel 75 mg/m2
(n = 129)

Lung Cancer
PROSE: OS by Treatment Arm

1.0 Median OS,
Mos (95% CI)
0.8 CT 9.0 (6.8-10.9)
ERL 7.7 (5.9-10.4)
Survival
0.6
HR: 1.14 (95% CI: 0.88-1.49;
0.4 log-rank P = .313)
0.2
0
0 6 12 18 24
Pts at Risk, n Mos From Randomization
134 78 42 22 14
120 87 51 24 12
Third-line treatment at progression:
CT arm: 41% overall (48% Good and 27% Poor)
ERL arm: 52% overall (56% Good and 39% Poor)
Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission

Lung Cancer
PROSE: OS by Multivariate Serum Protein

Test Classification
Good Classification Poor Classification
1.0 Median OS, Mos 1.0 Median OS,

(95% CI) Mos (95% CI)
CT 10.92 (8.39-15.13) CT 6.38 (2.96-7.37)
0.8 0.8
ERL 10.95 (9.34-12.89) ERL 2.98 (2.04-3.85)
HR: 1.06 (95% CI: 0.77-1.46; HR: 1.14 (95% CI: 0.88-1.49;
0.6 0.6
Survival
Survival
log-rank P = .714) log-rank P = .313)
0.4 0.4
0.2 0.2
0.0 0.0
0 6 12 18 24 0 6 12 18 24
Pts at Risk, n Mos From Randomization Pts at Risk, n Mos From Randomization
96 68 40 21 14 38 10 2 1 0
88 66 42 19 11 41 21 9 5 1
Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission.

Lung Cancer
Treatment Adjusted Interaction Analysis

for OS
Covariate HR (95% CI) P Value
ECOG PS, 2 vs 0-1 2.55 (1.51-4.33) < .001
Smoking history, ever vs never 1.39 (0.90-2.15) .138
Histology, squamous vs nonsquamous 1.02 (0.71-1.45) .930
Sex, female vs male 0.84 (0.60-1.17) .292
Age, yrs 0.99 (0.97-1.00) .138
Classification, poor vs good 1.89 (1.25-2.85) .002
Treatment, erlotinib vs chemotherapy 1.12 (0.81-1.56) .484
Classification/treatment interaction 1.98 (1.10-3.56) .022
ECOG PS and multivariate serum protein test classification are prognostic for outcome
independent of treatment
Multivariate serum protein test predictive of significant differential treatment benefit

between CT and erlotinib when adjusted for potential confounding factors
Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission
Lung Cancer
Summary
Classification of patients with a novel multivariate serum
protein test validated as providing useful information for
guiding treatment decisions in second-line NSCLC
Patients classified as poor (30% to 35%) attained better
survival with single-agent chemotherapy vs erlotinib
Patients classified as good (65% to 70%) attained similar
survival outcomes with either single-agent chemotherapy or
erlotinib

Lung Cancer
Extensive-Stage
Small-Cell Lung Cancer
Lung Cancer
CALGB 30504 (ALLIANCE): Chemo

Maintenance Sunitinib in ES SCLC
Randomized, placebo controlled phase II study
Sunitinib
37.5 mg/day,
Untreated ES SCLC; until progression
4-6 cycles of chemo; (n = 44)
SD, PR, CR;
PCI allowed
(n = 85)
Primary endpoint: PFS from randomization

Ready NE, et al. ASCO 2013. Abstract 7506.
Lung Cancer
CALGB 30504: Progression-Free Survival

1.0
Median PFS, Mos
Sunitinib: 3.77
0.8 Placebo: 2.30
0.6 HR: 1.53 (90% CI: 1.03-2.27; stratified

1-sided log-rank P = .037)
0.4 Sunitinib
Placebo
0.2
0
0 3 6 9 12 15
Mos From Randomization
Ready NE, et al. ASCO 2013. Abstract 7506. Used with permission.
Lung Cancer
CALGB 30504: Overall Survival

1.0 Median OS, Mos
Sunitinib: 8.95
Placebo: 6.89
0.8 HR: 1.17 (90% CI: 0.77-1.78; stratified
log-rank 1-sided P = .27)
0.6
0.4 Sunitinib
Placebo
0.2
0
0 5 10 15 20 25 30 35 40
Mos From Randomization
Lung Cancer
CALGB 30504: Maintenance Toxicity

Grade
% 3/4 5%
100
90 Sunitinib
80 Placebo
70
Patients (%)
60
50 46.5
40
30
19.5 19
20 14
10 7 5 7 7 5
2 2 0
0
All Fatigue Neutrophils Leukocytes Platelets Hyponatremia
Grade 4 toxicities: sunitinib, 1 case GI hemorrhage and 1 case pancreatitis; placebo, 1 case
platelets
Lung Cancer
Summary
Trial met its primary endpoint of PFS, with an OS trend
Only 59% received maintenance
Maintenance sunitinib was safe and feasible?
46% grade 3/4 toxicity, 19% grade 3 fatigue
Biomarker analysis of blood samples is being planned
ALLIANCE will propose a phase III trial to confirm
Lung Cancer
Targeted Therapies
Lung Cancer
Characteristics of Nintedanib
Oral angiokinase inhibitor targeting

VEGFR 1-3, FGFR 1-3, and
PDGFR / as well as RET[1,2]
Manageable safety profile in
combination with
Docetaxel[3]
Pemetrexed[4]
Paclitaxel/carboplatin[5]
Gemcitabine/cisplatin[6]
Afatinib[7]
Single-agent nintedanib active in a
phase II trial in recurrent NSCLC[8]
1. Hilberg F, et al. Cancer Res. 2008;68:4774-4778. 2. Data on file. 3. Stopfer P, et al. Xenobiotica. 2011;41:297-311.
4. Bousquet G, et al. Br J Cancer. 2011;105:1640-1645. 5. Ellis PM, et al. Clin Cancer Res. 2010;16:2881-2889.
6. Doebele RC, et al. Ann Oncol. 2012;23:2094-2102. 7. Soria JC, et al. Ann Oncol. 2012;23(suppl 9): Abstract 979.
8.Reck M, et al. Ann Oncol. 2011;22:1374-1381. Used with permission.
Lung Cancer
LUME Lung 1: Randomized, Double-Blind,

Placebo-Controlled Phase III Trial
Stratified by ECOG PS,
previous bevacizumab,
histology, brain metastases
Nintedanib 200 mg BID on Days 2-21 +

Docetaxel 75 mg/m2 on Day 1 of a 21-day cycle*
Patients with stage (n = 655)
IIIB/IV or recurrent Treatment
NSCLC and until PD
1 previous line of Placebo BID on Days 2-21 +
chemotherapy Docetaxel 75 mg/m2 on Day 1 of a 21-day cycle*
(N = 1314) (n = 659)
*Docetaxel monotherapy allowed after 4 cycles of combination therapy.
Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with

permission.
Lung Cancer
LUME Lung 1: Primary Endpoint, PFS

Independent Central Review in All Patients
Nintedanib + Placebo +
100 Docetaxel Docetaxel
Median, mos 3.4 2.7
80
Probability of PFS (%)
HR (95% CI) 0.79 (0.68-0.92)

P value .0019
60
Nintedanib + docetaxel
Placebo + docetaxel
40
20
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
Mos

permission.
Lung Cancer
LUME Lung 1: OS in All Patients

100
Nintedanib + Placebo +
Docetaxel Docetaxel
80 Median, mos 10.1 9.1
Probability of OS (%)
HR (95% CI) 0.94 (0.83-1.05)

60 P value .2720
40 Nintedanib + docetaxel
Placebo + docetaxel
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Pts at Risk, n Mos

Nintedanib 655 607 516 444 374 316 271 234 200 171 147 130 106 88 67 51 34 27 14
Placebo 659 600 511 411 344 290 250 207 162 144 120 100 91 74 58 51 28 25 13
permission.
Lung Cancer
LUME Lung 1: OS in Patients With

Adenocarcinoma Histology
100 Nintedanib + Placebo +
Docetaxel Docetaxel
80 Median, mos 12.6 10.3

Probability of OS (%)
HR (95% CI) 0.83 (0.70-0.99)
60 P value .0359
52.7%
Nintedanib + docetaxel
40 Placebo + docetaxel
44.7% 25.7%
20
19.1%
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Pts at Risk, n Mos
Nintedanib 322 302 263 230 203 180 163 149 131 113 96 87 72 59 46 36 25 22 10
Placebo 336 312 269 219 184 159 139 119 101 88 73 62 55 46 33 29 15 13 7
permission.
Lung Cancer
LUME Lung 1: Summary of AEs

Patients With AE, n (%) Nintedanib + Placebo +
Docetaxel Docetaxel
(n = 652) (n = 655)
Any AE, all grades 610 (93.6) 609 (93.0)
Drug-related AE, all grades 498 (76.4) 446 (68.1)
Any AE, grade 3 465 (71.3) 421 (64.3)
Drug-related AE, grade 3 331 (50.8) 275 (42.0)
Any AE leading to discontinuation 148 (22.7) 142 (21.7)
Any serious AE 224 (34.4) 206 (31.5)
Common Terminology Criteria for Adverse Events version 3.0 was used

permission.
Lung Cancer
Summary
Second-line combination therapy with nintedanib and
docetaxel significantly improved PFS vs docetaxel alone in
patients with NSCLC independent of disease histology
Addition of nintedanib to docetaxel also significantly
improved OS vs docetaxel in patients with
adenocarcinoma
Safety profile of nintedanib in combination with docetaxel
was manageable, with no unexpected safety signals
Lung Cancer
Ganetespib
Biologic effects of several oncoproteins rely on chaperone
function of HSP-90
Ganetespib: highly potent second-generation inhibitor of HSP-90
Demonstrates activity in ALK-positive and/or BRAF-mutant NSCLC
Associated with lower rates of visual AEs (< 3%) compared with
other HSP-90 inhibitors (> 50%)
Combination therapy with ganetespib and docetaxel may yield
synergistic effects in NSCLC based on single-agent activity
profiles
Manageable safety profile as monotherapy and in combination with
docetaxel
Proia DA, et al. Invest New Drugs. 2012;30:2201-2209.
Lung Cancer
GALAXY-1: Randomized, Open-Label

Phase II Investigation of Ganetespib
Stratified by ECOG PS, time
since diagnosis of advanced
disease, baseline serum LDH,
smoking status
Ganetespib 150 mg/m2 on Days 1, 15 +

Docetaxel 75 mg/m2 on Day 1
Patients with advanced of a 21-day treatment cycle*
adenocarcinoma who (n = 125)
received 1 previous
regimen
(N = 252) Docetaxel 75 mg/m2 on Day 1
of a 21-day treatment cycle
(n = 127)
*Combination arm could continue ganetespib monotherapy following completion of docetaxel treatment.
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.
Lung Cancer
GALAXY-1: PFS in All Adenocarcinoma

1.0 HR: 0.84 (90% CI: 0.65-1.07; P = .038)
Cox regression:
0.8 HR: 0.83 (90% CI: 0.64-1.06; P = .108)
Survival Probability
G+D D
0.6 (n = 125) (n = 127)
Events, n 90 90
0.4 Median, mos 4.5 3.2
0.2
0
Pts at D 127 104 81 58 52 36 20 13 11 5 3 2 2 1 0
Risk, n G+D 125 104 88 73 67 51 24 19 13 9 5 5 3 0
0 2.5 5.0 7.5 10.0 12.5

Mos
Lung Cancer
GALAXY-1: OS in All Adenocarcinoma

1.0 HR: 0.82 (90% CI: 0.62-1.09; P = .082)
Cox regression:
0.8 HR: 0.73 (90% CI: 0.55-0.98; P = .041)
Survival Probability
0.6
0.4 G+D D
(n = 125) (n = 127)
Deaths, n 64 70
0.2
Median, mos 9.8 7.4
0
Pts at D 127 118 111 101 92 80 61 44 40 37 29 22 17 13 10 6 4 3 2 1 0
Risk, n G+D 125 119 111 105 98 92 80 61 46 35 29 24 20 16 10 8 6 4 2 1 0
0 5 10 15 20
Mos
Lung Cancer
GALAXY-1: OS Forest Plot

(All Adenocarcinoma) HR (90% CI) P Value
Mutation Status
mKRAS (63) 0.84 (0.48-1.50) .3133
KRAS no mut/NA (189) 0.81 (0.58-1.12) .1440
mEGFR (20) 0.90 (0.32-2.54) .4314
EGFR no mut/NA (232) 0.79 (0.59-1.07) .0972
Diagnosis of Adv Dis
> 6 mos (176) 0.61 (0.43-0.87) .0093
6 mons (76) 1.47 (0.88-2.45) .8924
LDH
Elevated (76) 0.63 (0.40-0.99) .0462
Normal (176) 0.98 (0.67-1.42) .4613
Smoking Status
Ever (189) 0.71 (0.52-0.98) .0390
Never (63) 1.31 (0.67-2.55) .7488
ECOG
0 (104) 0.95 (0.58-1.55) .4256
1 (146) 0.76 (0.53-1.09) .1032
Sex
Male (142) 1.02 (0.71-1.47) .5411
Female (110) 0.58 (0.36-0.93) .0266
Geographic Region
North America (42) 0.70 (0.37-1.32) .1777
Western Europe (45) 0.51 (0.26-1.00) .0471
Eastern Europe (165) 0.88 (0.61-1.26) .2745
Favors Treatment Favors Control

0.1 1 10
Test for interaction of time since diagnosis of advanced disease with study treatment: P = .0064
Lung Cancer
GALAXY-1: Safety
G + D, n (%) D, n (%)
(n = 123) (n = 125)
Any AE 120 (98) 114 (91)
Any AE grade 3 86 (70) 70 (56)
Treatment-related serious AE 21 (17) 9 (7)
Treatment discontinuation due to AE 8 (7) 6 (5)
AE Leading to hospitalization 32 (26) 23 (18)
Death on treatment* 15 (12) 14 (11)
Death, Treatment-related 0 1 (< 1)
Death due to cardiac events 1 (1) 2 (2)
*Within 30 days of last dose of study drug
AEs that occurred more often with addition of ganetespib: diarrhea, fatigue, nausea
and vomiting, anemia, dyspnea, and febrile neutropenia
Lung Cancer
Summary
Second-line combination therapy with ganetespib and docetaxel
improved PFS and OS vs docetaxel alone in patients with lung
adenocarcinoma
Survival outcomes improved in patients diagnosed with advanced
disease for longer than 6 mos prior to study enrollment
No association between improved survival and EGFR or KRAS
mutations
Safety profile of ganetespib in combination with docetaxel
deemed manageable, with no unexpected safety signals
Ongoing phase III trial (GALAXY-2): ganetespib + docetaxel in
patients with adenocarcinoma diagnosed with advanced
disease for longer than 6 mos
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007.

Lung Cancer
PD-1 Blockade: Binding to PD-L1 (B7-H1)

and PD-L2 (B7-DC) Revives T Cells
Tumor Cell PD-L1 expression on
IFN-mediated
tumor cells induced
upregulation of
IFN-R
PD-L1/PD-1mediated
by interferon-
tumor PD-L1
inhibition of tumor cell killing
IFN-
Priming and
Activated T cells that
activation of could kill tumors are
T cells
Other NFB
P13K specifically disabled
Dendritic
CD8+ cytoxic Cell
T lymphocyte
T-cell polarization
PD-1
Treg TGF-
Tumor-associated cell
Immune cell PD-L1
fibroblast modulation of T cells PD-L2
M2 Th2
macrophage T cell T-cell receptor
Stromal PD-L1 PD-L2mediated MHC-1
modulation of T cells inhibition of TH2 T cells
IL-4/13 CD28
Can you generate
tumor-killing T cells?
Can the T cells
get to the tumor?
Can the T cells
see the tumor?
Can the T cells
be turned off?
Can the T cells
be turned off?
Shp-2
B7.1
Antigen priming T-cell trafficking Peptide-MHC Inhibitory cytokines PD-L1 expression
expression on tumor cells
Sznol M, et al. Clin Cancer Res. 2013;19:1021-1034.
Lung Cancer
Nivolumab (AntiPD-1 Antibody)

Fully human IgG4 PD-1 receptor-blocking monoclonal antibody
Selectively prevents interaction with PD-L1 and PD-L2, restoring
antitumor T-cell function
Phase I study (interim results)
Durable response in 20% to 30% of patients with advanced NSCLC,
melanoma, or RCC
Manageable safety profile
Current report:
First OS data from CA209-003 study
Long-term nivolumab safety profile, updated ORR, and response duration
Brahmer JR, et al. ASCO 2013. Abstract 8030.

Lung Cancer
Phase I Study Design: NSCLC Cohort

Nivolumab 1 mg/kg IV every 2 wks
Eligible NSCLC (n = 33)
patients
randomized
among Nivolumab 3 mg/kg IV every 2 wks
3 nivolumab (n = 37)
dose levels
(n = 129) Nivolumab 10 mg/kg IV
every 2 wks (n = 59)
Accrual has completed

Patient assessment is ongoing
Current analysis includes patients treated through March 5, 2013, all of whom
received first treatment at least 1 yr before the analysis
Brahmer JR, et al. ASCO 2013. Abstract 8030. Used with permission.
Lung Cancer
Efficacy of Nivolumab Monotherapy in

Patients With NSCLC
Dose, ORR,* % Estimated SD Rate,* % (n/N) Median PFS, Median OS,
mg/kg (n/N) Median DOR, Mos (95% CI) Mos (95% CI)
24 Wks 48 Wks
Wks (Range)
All 17.1 74.0 10.1 4.7 2.3 9.6

doses (22/129) (6.1+, 133.9+) (13/129) (6/129) (1.9-3.7) (7.8-12.4)
1 3.0 63.9 15.2 6.1 1.9 9.2
(1/33) (63.9, 63.9) (5/33) (2/33) (1.8-3.6) (5.6-11.1)
3 24.3 NR 8.1 5.4 1.9 14.9
(9/37) (16.1+, 133.9+) (3/37) (2/37) (1.7-7.3) (9.5-NE)
10 20.3 83.1 8.5 3.4 3.6 9.2
(12/59) were assessed
*Tumors and responses (6.1+, 117.1+)
after each cycle(5/59) (2/59)v1.0. CIs for
per modified RECIST (1.9-3.8) (5.2-12.4)
ORRs and SD rates were
calculated using the Clopper-Pearson method.

Time from first response to documented progression, death, or last tumor assessment (for censored data denoted by +);
estimated median DORs were determined from Kaplan-Meier curves.

Time-to-event endpoints (PFS, OS, DOR) were estimated using the Kaplan-Meier method.

Survival data were collected retrospectively.
Lung Cancer
Select AEs (1%) Occurring in Pts With

NSCLC Treated With Nivolumab (N = 129)
Drug-related pneumonitis (any grade) occurred in 8 NSCLC pts (6%) vs 12 pts (4%) in
the overall study population
3 pts (2%) with NSCLC had grade 3/4 pneumonitis
Category Treatment-Related Select AE, % (n)
Any Grade* Grade 3/4*
Any treatment-related select AE 41 (53) 5 (6)
Skin 16 (20) 0
Gastrointestinal 12 (15) 1 (1)
Pulmonary 7 (9) 2 (3)
Endocrinopathies 6 (8) 0
Hepatic 5 (6) 1 (1)
Infusion reaction 4 (5) 1 (1)
Renal 3 (4) 0
*AE severity was graded based on the Common Terminology Criteria for Adverse Events, v3.0
Lung Cancer
Summary
In pts with heavily pretreated NSCLC (54% with 3 previous
therapies), nivolumab:
Produces durable responses
Demonstrates an encouraging survival profile
Can be used in an outpatient setting with manageable safety
Numerically higher ORRs noted at the 3- and 10-mg/kg nivolumab
doses relative to the 1-mg/kg dose
No new safety signals emerging, with all patients now with more than
1 yr and some up to 3 yrs of follow-up
Randomized, controlled phase 3 trials of nivolumab with prospective
OS endpoints are recruiting patients with NSCLC
Brahmer JR, et al. ASCO 2013. Abstract 8030. ClinicalTrials.gov. NCT01642004. ClinicalTrials.gov.
NCT01673867.
Lung Cancer
MPDL3280A (AntiPD-L1) Inhibits the

Binding of PD-L1 to PD-1 and B7.1
Tumor cell Patients T cells
MHC TCR
T cell
PD-1
PD-L1
B7-1 T-cell
inhibition
Tumor
cell
growth
MHC TCR T cells
PD-1
PD-L1
X
X T-cell Tumor
B7-1 activated cell
+ Anti-PD-L1
death
Granzymes and perforin
Blocking PD-L1 restores T-cell activity, resulting in tumor regression in preclinical models
Binding to PD-L1 leaves PD-1/PD-L2 interaction intact and may enhance efficacy and safety
Herbst RS, et al. ASCO 2013. Abstract 3000. Used with permission.
Lung Cancer
MPDL3280A: Phase IA Objectives and

Schema
Population: patients with incurable or metastatic solid tumor, heavily pretreated
Diagnostic: multimodality biomarkers, including PD-L1, being evaluated
Primary Objectives:
Evaluate safety and tolerability of MPDL3280A
Determine the MTD and identify recommended phase II dose
Prescreen/ Treatment period

Follow-up
screening MPDL328OA IV every 3 wks x 16 cycles (-1y)
Patients with CR/PR/SD

followed q12wks
until PD
D-28 to D-1 Response assessed by CT scan (RECIST v1.1 and irRC)*
Key Eligibility Criteria

Measurable disease per RECIST v1.1
ECOG PS 0 or 1
*CT scans every 6 wks for 6 mos, then every 12 wks; treatment beyond RECIST PD allowed per MD.
Lung Cancer
MPDL3280A Phase IA: Efficacy Summary

Investigator Assessed
RECIST 1.1 SD of Wks or Longer, 24-Wk PFS, %
Response Rate (ORR*), % %
Overall population
(N = 140) 21 16 45
NSCLC
(n = 41) 22 12 46
Melanoma
(n = 38) 29 5 43
RCC
(n = 47) 13 32 53
26 of 29 responders continued to respond at last assessment

Time on study in responders: 3 to 15+ mos
Additional delayed responses not reflected in above ORR
Patients first dosed at 1-20 mg/kg prior to August 1, 2012, data cutoff February 1, 2013.
7 patients who did not have a postbaseline scan were included as nonresponders.
*ORR includes unconfirmed PR/CR and confirmed PR/CR.
Lung Cancer
MPDL3280A Phase Ia: Summary of

Response by PD-L1 IHC Status
Investigator-Assessed Response Rate (ORR*), % (n/N)
PD-L1 Positive PD-L1 Negative All
Overall population (N = 140) 36 (13/36) 13 (9/67) 21 (29/140)
100
Best Response 80
Patients (%)
CR
PR 60 50
Stable response
40 41
28
20 33
20
13
0
*CRR includes investigator-assessed unconfirmed PR/CR and confirmed PR/CR by RECIST 1.1

All Patients include PD-L1-positive, PD-L1-negative and patients with unknown tumor PD-L1 status
Patients first dosed at 1-20 mg/kg prior to August 1, 2012; data cutoff February 1, 2013.
Lung Cancer
Summary
MPDL3280A generally well tolerated
No grade 3-5 pneumonitis
Treatment-related grade 3/4 AEs: 13%
Immune-related grade 3/4 AEs: 2%
Broad activity with durable responses in nearly all
responding patients
PD-L1 expression may be associated with clinical benefit
Registration trials of MPDL3280A are planned
Herbst RS, et al. ASCO 2013. Abstract 3000.

Lung Cancer
Acquired Resistance in ALK+ NSCLC

ALK+ NSCLC is sensitive to
Unknown
crizotinib[1-3 ]
lified
ORR: 60%
Amp
M
Median PFS: 8-10 mos 19
6
ALK L 1
amp
Most patients with develop
resistance to crizotinib[4,5] ALK G1269A
ALK+ S1206Y
mut
Usually within 1-2 yrs G1202R
115
No ALK L11 1Tins
CNS relapses are common[6] amp or mut C1 52R
15
6Y
Mechanisms of resistance are Bypass tracks
diverse[4,5] EGFR MT
KRAS MT
ALK resistance mutations
Alternative signaling pathways
1. Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019. 2. Kim DW, et al. ESMO 2012. Abstract 1230PD. 3. Show AT, et al.
ESMO 2012. Abstract LBA1_PR. 3. Katayama R, et al. Sci Trans Med. 2012;4:120ra17. 4. Doebele RC, et al. Clin Cancer
Res. 2012;18:1472-1482. 5. Takeda M, et al. J Thorac Oncol. 2013; 8:654-657. Used with permission.
Lung Cancer
Phase I Investigation of ALK Inhibitor

LDK378 in Advanced ALK+ NSCLC
Any advanced ALK+ cancer NCT01283516
Progression on standard therapy
(dose escalation starting at 50 mg/day)
Continuous oral dosing

Completed N = 59 Escalate to MTD (750 mg/day)
21 day cycles
ALK+ lung cancer
Previous ALKi therapy
Additional ALK+ lung
N = 71 Nonlung
cancer
2 mos > 2 mos ALK+
enrolled naive to
tumors
after after ALKi
previous previous
ALK TKI ALK TKI
Primary objective: determination of MTD

Secondary objectives: safety, pharmacokinetics and preliminary antitumor
activity
Shaw AT, et al. ASCO 2013. Abstract 8010. Used with permission.
Lung Cancer
LDK378 in ALK+ NSCLC: Efficacy

ORR (CR + PR): overall, 58%; CRZ pretreated, 57%;
CRZ naive, 60%
100 Best % Change From Baseline in Target Lesions
Best % Change From Baseline
80 LDK378 400-750 mg/day

60 Previous crizotinib
40 Crizotinib naive
20 PFS event
0
-20
-40
-60
-80
-100
Lung Cancer
LDK378 in ALK+ NSCLC: Safety

Grade 3/4 AEs ( 5%), Regardless of Study Drug Relationship
Preferred 50-300 mg 400 mg 500 mg 600 mg 700 mg 750 mg All Patients
Term, n (%) (n = 10) (n = 14) (n = 10) (n = 10) (n = 5) (n = 81) (N = 130)
ALT 0 1 (7) 2 (20) 0 4 (80) 18 (22) 25 (19)
increased
AST 0 2 (14) 0 0 3 (60) 8 (10) 13 (10)
increased
Diarrhea 1 (10) 1 (7) 1 (10) 2 (20) 0 6 (7) 11 (8)
Lipase 1 (10) 0 0 1 (10) 0 5 (6) 7 (5)
increased
Hypokalemia 0 0 0 0 1 (20) 5 (6) 6 (5)
Nausea 0 0 1 (10) 1 (10) 0 4 (5) 6 (5)
3 (2%) patients discontinued due to AEs

No treatment-related deaths
Lung Cancer
Summary
LDK378 demonstrated antitumor activity in ALK+ NSCLC
Both crizotinib-treated and crizotinib-naive patients
Tolerable safety profile with primarily grade 1/2 AEs
Nausea, diarrhea, vomiting, and fatigue
Breakthrough therapy designation by the FDA
Phase II and III studies recruiting patients
Shaw AT, et al. ASCO 2013. Abstract 8010.

Lung Cancer
Dabrafenib: BRAF V600E Kinase Inhibitor
RTKs
Mode of Action SOS
SOS
P P
Grb2
Grb2
Dabrafenib SHC
P P PSHC
P
Reversible, small molecule
BRAF inhibitor RAS PI3K/AKT/
PI3K/AKT/
mTOR
ATP competitive BRAF
BRAF
mTOR
pathway
pathway
Molecular Activity V600
V600 BRAF CRAF
BRAF V600E: IC50 0.65 nM
BRAF WT: IC50 3.2 nM MEK
MEK
Selectivity
ERK1/2
ERK1/2
IC50 of 10-100 nM against
8 of 282 human kinases
Davies H, et al. Nature. 2002;417:949-954. Platz A, et al.
Mol Oncol. 2008;1:395-405. Karasarides M, et al.
Oncogene. 2004;23:6292-6298. Curtin JA, et al. N Engl J
Med. 2005;353:2135-2147. Flaherty K, et al. ASCO 2009.
Abstract 9000. Kefford R, et al. ASCO. 2010. Abstract 8503.
Proliferation,
Proliferation, growth,
growth, survival
survival
Used with permission.
Lung Cancer
BRF113928: Study Design

Single arm, open label, phase II
Stage IV NSCLC
BRAF V600E
Stage 1 Stage 2
mutation
(n = 20) (n = 20)
1 line previous tx
(N = 25)
Dabrafenib 150 mg twice daily
Primary objective: investigator-assessed ORR

Secondary objectives: PFS, duration of response, OS, safety, tolerability, and
population pharmacokinetics
Green-Dahlberg 2-stage: H(0)ORR 10% vs H(1)ORR 30% (primary cohort).
Planchard D, et al. ASCO 2013. Abstract 8009. Used with permission.
Lung Cancer
Maximum Tumor Reduction by Best

Confirmed Response for the First 20 Pts
50 ***
40
Maximum Percent Reduction at Time
30
20
***
of Best Disease Assessment
10 ***
0
10 *
20 ** ** **
30
40 ** *
50 ** *
60 Best Confirmed Response Smoking History **
* **
70 PR * Nonsmoker
80 SD ** Smoker 40 pack-yrs ** *
90 PD *** Smoker > 40 pack-yrs
100

3 pts are not in the plot: 1 pt had PD on day 6 due to new lesion, target lesions were not assessed
postbaseline; and 2 pts discontinued study treatment due to serious adverse events prior to postbaseline
disease assessment.
Lung Cancer
Best Confirmed Response Among the

First 20 Patients
Best Response Patients (N = 20)
CR, n 0
PR, n (%) 8 (40)
SD,* n (%) 4 (20)
PD, n (%) 6 (30)
Not evaluable, n (%) 2 (10)
Response rate (confirmed CR/PR), % 40
95% CI 19.1-63.9
Disease control rate (CR + PR + SD), % 60
95% CI 36.1-80.9
*SD is defined as meeting SD 12 wks (planned time for the second postbaseline disease
assessment).
1 patient with SD changed to PR on Wk 36.
Lung Cancer
BRF113928: Adverse Event Overview

Category Patients, n (%)
(N = 25)
Any adverse event (AE) 24 (96)
Grade 3 11 (44)
Grade 4 0
Grade 5 1 (4)
AEs related to study treatment 23 (92)
Any serious AE 10 (40)
AEs leading to study treatment discontinuation 2 (8)
AEs leading to dose reduction 5 (20)
AEs leading to dose interruption 10 (40)

Lung Cancer
Summary
The BRAF inhibitor, dabrafenib, demonstrated clinical
activity in patients with NSCLC positive for BRAF V600E
mutation
Safety profile with dabrafenib was consistent with previous
studies in melanoma
Ongoing study has expanded sample size and now allows
enrollment of first-line patients
Planchard D, et al. ASCO 2013. Abstract 8009.

Lung Cancer
Go Online for More CCO

Coverage of Lung Cancer!
Capsule Summaries of all the key data from Chicago
(Coming soon) Additional CME-certified slideset with expert faculty
commentary on all the key studies

CCO Clin Onc June 2013 Downloadable Slides

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Lung Cancer

May 31 - June 4, 2013

About These Slides

RTOG 0617: Phase III Trial of 74 Gy vs 60

RTOG 0617: Survival

RTOG 0617: Safety

Antigen = BLP25 lipopeptide

Adjuvant = Monophosphoryl lipid A

START: Study Design

Tecemotide 806 g SC weekly for 8 wks,

START: Overall Survival

80 Median OS, mos 25.6 22.3

10 *2-sided, strata and multiplicity adjusted

START: OS Analyses by Randomization

Stage Stage IIIA (n = 487) 27.6 vs 23.1 0.86 (0.67-1.11)

Stage IIIB (n = 752) 23.7 vs 20.9 0.90 (0.74-1.09)

Region NA and Aus. (n = 321) 34.1 vs 21.7 0.79 (0.58-1.09)

W. Europe (n = 475) 24.2 vs 22.3 0.91 (0.71-1.17)

Rest of world (n = 443) 21.8 vs 22.7 0.95 (0.73-1.22)

Response SD (n = 396) 20.4 vs 17.8 0.85 (0.65-1.11)

Chemo/ Concurrent (n = 806) 30.8 vs 20.6 0.78 (0.64-0.96)

0.5 1.0 2.0

START: OS in Patients With Concurrent

80 Median OS, mos 30.8 20.6

10 *2-sided, adjusted for strata

Defining the Continuing Role of

PRONOUNCE: Phase III Superiority Trial of

Primary objective: PFS without grade 4 AE

Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.

PRONOUNCE: Primary Endpoint (G4PFS)

Pem + Cb, median G4PFS: 3.9 mos

HR: 0.85 (95% CI: 0.70-1.04)

Pem + Cb, % Pac + Cb + Bev, %

Possibly Drug-Related Grade 3/4 CTCAE

Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.

Zinner R, et al. ASCO 2013. Abstract LBA8003.

PROSE: Validation of Multivariate Serum

Lazzari C, et al. ASCO 2013. Abstract LBA8005.

PROSE: Multicenter Randomized Phase III

Stratified by multivariate serum protein test status

Erlotinib 150 mg/day

Lazzari C, et al. ASCO 2013. Abstract LBA8005.

PROSE: OS by Treatment Arm

Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission

PROSE: OS by Multivariate Serum Protein

1.0 Median OS, Mos 1.0 Median OS,

Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission.

Treatment Adjusted Interaction Analysis

Multivariate serum protein test predictive of significant differential treatment benefit

Lazzari C, et al. ASCO 2013. Abstract LBA8005.

CALGB 30504 (ALLIANCE): Chemo

Primary endpoint: PFS from randomization

CALGB 30504: Progression-Free Survival

0.6 HR: 1.53 (90% CI: 1.03-2.27; stratified

CALGB 30504: Overall Survival

CALGB 30504: Maintenance Toxicity

Oral angiokinase inhibitor targeting

LUME Lung 1: Randomized, Double-Blind,

Nintedanib 200 mg BID on Days 2-21 +

*Docetaxel monotherapy allowed after 4 cycles of combination therapy.

Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with

LUME Lung 1: Primary Endpoint, PFS

HR (95% CI) 0.79 (0.68-0.92)

Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with