Lung Cancer
May 31 - June 4, 2013
Chicago, Illinois
Lung Cancer
CCO Independent Conference Coverage
of the 2013 American Society of Clinical Oncology Annual Meeting*
*CCO is an independent medical education company that
provides state-of-the-art medical information to healthcare
professionals through conference coverage and other
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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
– Phase III RTOG 0617: 74 Gy vs 60
Gy RT
– Phase III START: tecemotide (L-
BLP25) vs placebo
EGFR TKIs in Advanced NSCLC
– Phase III PRONOUNCE:
Pem/Carbo → Pem vs Pac/Carbo
→ Bev
– Phase III PROSE: serum protein
test in predicting survival for
patients on second-line erlotinib vs
chemotherapy
Extensive-Stage Small-Cell Lung
Cancer
– Phase II CALGB 30504: chemo ±
maintenance sunitinib
Targeted Therapy
– Phase III LUME Lung 1: docetaxel ±
nintedatinib in advanced/metastatic
NSCLC
– Phase II GALAXY-1: docetaxel ±
ganetespib in adenocarcinoma
– Phase I study of nivolumab (anti–PD
-L1 antibody) monotherapy in
NSCLC
– Phase IA study of MPDL3280A (anti
–PD-L1 antibody) in solid tumors
– Phase I study of LDK378 in
advanced ALK+ NSCLC
– Phase II study of dabrafenib (BRAF
V600E kinase inhibitor) in stage IV
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
Primary endpoint: OS
Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.
*CT consisted of carboplatin/paclitaxel.
†400 mg/m2 loading dose on Day 1, followed by weekly dose of 250 mg/m2
Patients with newly
diagnosed, unresectable
stage IIIA/IIIB NSCLC
(N = 464)
Stratified by RT technique,
Zubrod status, PET staging,
histology
Concurrent Treatment Consolidation Treatment
Standard-Dose RT +
concurrent CT*
(n = 125)
Consolidation CT*
High-Dose RT +
concurrent CT*
(n = 121)
Consolidation CT*
Standard-Dose RT +
concurrent CT* +
Cetuximab†
(n = 108)
Consolidation CT* +
Cetuximab†
High-Dose RT+
concurrent CT* +
Cetuximab†
(n = 110)
Consolidation CT* +
Cetuximab†
Lung Cancer
RTOG 0617: Survival
Efficacy
Outcome
Standard-Dose RT
(n = 213)
High-Dose RT
(n = 206)
HR
(95% CI)
P Value
Median OS, mos
()
.0007
18-mo PFS, %
()
.0116
18-mo local
failure, %
()
.0319
18-mo distant
failure, %
()
.1576
Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.
Lung Cancer
RTOG 0617: Safety
Grade 3 esophagitis occurred significantly more often with high-
dose vs standard-dose RT (% vs %; P = .0003)
Adverse Events Definitely, Probably,
or Possibly Related to Treatment, %
Standard-Dose RT
(n = 213)
High-Dose RT
(n = 206)
Worst nonhematologic events
Grade 3
Grade 4
Grade 5
Worst overall
Grade 3
Grade 4
Grade 5
Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.
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
Bradley JD, et al. ASCO 2013. Abstract 7501. Used with permission.
Lung Cancer
Tecemotide (L-BLP25):
Novel Lipopeptide Cancer Vaccine
Adjuvant = Monophosphoryl lipid A
The adjuvant supports T-cell response by inducing pro-inflammatory cytokines (via TLR4 stimulation)
Antigen = BLP25 lipopeptide
The amino acids of the lipopeptide provide antigenic epitopes for T cells
MUC1 mucin
Structural lipids = cholesterol, DPPC, and DMPG
Further enhancement of antigen delivery/uptake into APCs and immune reaction
G S T A P P A H G V T S A P D T R P A P
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
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
Lung Cancer
START: Study Design
Patients with unresectable
stage IIIA/B NSCLC without
disease progression following
chemoradiotherapy
(N = 1239)
Tecemotide 806 µg SC weekly for 8 wks,
then every 6 wks thereafter +
Best Supportive Care
(n = 829)
Placebo +
Best Supportive Care
(n = 410)
Randomized 2:1; stratified by
disease stage, response
to chemoradiotherapy, concurrent
vs sequential chemoradiotherapy,
geographic region
Treated
until PD
1 dose of cyclophosphamide 300 mg/m2 or saline given 3 days prior to first tecemotide or placebo dose,
respectively.
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
Lung Cancer
L-BLP25
(n = 829)
Placebo
(n = 410)
Median OS, mos
Adjusted HR (95% CI: ;
P = .123*)
Median follow-up, mos
START: Overall Survival
353
757
188
429
Placebo
L-BLP25
410
829
285
617
127
301
108
255
88
204
59
128
33
73
18
33
4
8
0
0
Pts at Risk, n
S
ur
vi
va
l (
%
)
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
*2-sided, strata and multiplicity adjusted
Mos
L-BLP25
Placebo
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66
Lung Cancer
Region
()
()
()
()
()
()
()
()
()
Favors L-BLP25
Stage IIIA (n = 487)
Stage IIIB (n = 752)
NA and Aus. (n = 321)
W. Europe (n = 475)
Rest of world (n = 443)
SD (n = 396)
Obj. response (n = 843)
Concurrent (n = 806)
Sequential (n = 433)
Stage
Response
to chemo/RT
Chemo/
RT type
Median OS, Mos
L-BLP25 vs Placebo
HR* (95% CI)
Favors Placebo
*Not adjusted for strata.
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
START: OS Analyses by Randomization
Strata
vs
vs
vs
vs
vs
vs
vs
vs
vs
Lung Cancer
START: OS in Patients With Concurrent
Chemo/RT
L-BLP25
(n = 538)
Placebo
(n = 268)
Median OS, mos
HR (95% CI: ;
P = .016*)
227
499
118
295
Placebo
L-BLP25
268
538
186
412
73
205
62
176
54
147
40
89
26
51
16
24
4
7
0
0
Pts at Risk, n
S
ur
vi
va
l (
%
)
*2-sided, adjusted for strata
Mos
L-BLP25
Placebo
100
90
80
70
60
50
40
30
20
10
0
0 6 12 18 24 30 36 42 48 54 60 66
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
Lung Cancer
START: Safety
AE, % Tecemotide
(n = 1024)
Placebo
(n = 477)
Most frequent AEs
(> 10% in tecemotide arm)
Cough
Dyspnea
Fatigue
Back pain
Nausea
Chest pain
Nasopharyngitis
Headache
Decreased appetite
Arthralgia
Influenzalike symptoms
• Any
• Grade 3/4
P
at
ie
nt
s
(%
)
Butts CA, et al. ASCO 2013. Abstract 7500. Used with permission.
100
90
80
70
60
50
40
30
20
10
0
Any AE Any
Grade
3/4 AE
Any
Serious
AE
Any AE
Leading
to Death
Tecemotide (n = 1024)
Placebo (n = 477)
Lung Cancer
Summary
Study did not meet primary endpoint of significant
improvement in OS with use of tecemotide maintenance
Prespecified subgroup analysis identified significant
-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
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)
PRONOUNCE: Phase III Superiority Trial of
Pem/Carbo → Pem vs Pac/Carbo → Bev
Induction (q21d, 4 cycles) Maintenance (q21d until PD)
Pemetrexed
(folic acid & vitamin B12)
+ Carboplatin
Paclitaxel
+ Carboplatin
+ Bevacizumab
R
1:1
Pemetrexed
(folic acid & vitamin B12)
Bevacizumab
180 patients each
Bev-Eligible Population
Inclusion:
Chemo-naive patients
PS 0/1
Stage IV, nonsquamous
Stable treated CNS mets
Exclusion:
Uncontrolled effusions
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
Lung Cancer
PRONOUNCE: Primary Endpoint (G4PFS)
Pem + Cb, median G4PFS: mos
Pac + Cb + Bev, median G4PFS: mos
Log-rank P =
HR: (95% CI: )
Pts at Risk, n
Pem + Cb
Pac + Cb + Bev
0 3 6 9 12 15 18 21 24 27
0
20
40
60
80
100
Mos
P
ts
(%
)
182
179
87
75
44
33
26
17
14
9
7
3
5
0
3
0
1
0
0
0
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
Lung Cancer
PRONOUNCE: OS (ITT)
Pem + Cb, median OS: mos
Pac + Cb + Bev, median OS: mos
HR: (95% CI: ;
log-rank P = .615)
0 3 6 9 12 15 18 21 24 42
0
20
40
60
80
100
Mos
P
at
ie
nt
s,
%
182
179
156
151
125
121
102
96
72
73
48
59
33
38
5
0
5
0
5
0
Pem + Cb, %
(n = 182)
Pac + Cb + Bev, %
(n = 179)
1 yr
2 yrs
27 30 33 36 39
20
28
11
10
11
3
5
1
5
1
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
Pts at Risk, n
Pem + Cb
Pac + Cb + Bev
Lung Cancer
Possibly Drug-Related Grade 3/4 CTCAE
Event Pem + Cb, %
(n = 171)
Pac + Cb +
Bev, %
(n = 166)
P Value
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
Zinner R, et al. ASCO 2013. Abstract LBA8003. Used with permission.
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
EGFR inhibitor–naive
patients with stage IIIB-IV
NSCLC who received
1 previous line of
platinum-based therapy
Erlotinib 150 mg/day
(n = 134)
Pemetrexed 500 mg/m2 or
Docetaxel 75 mg/m2
(n = 129)
Stratified by multivariate serum protein test status
(patients and investigators blinded to results),
ECOG PS, smoking status
Crossover
permitted at
progression
PROSE: Multicenter Randomized Phase III
Trial of Second-line Erlotinib vs CT
Lazzari C, et al. ASCO 2013. Abstract LBA8005.
Lung Cancer
PROSE: OS by Treatment Arm
Third-line treatment at progression:
CT arm: 41% overall (48% Good and 27% Poor)
ERL arm: 52% overall (56% Good and 39% Poor)
Median OS,
Mos (95% CI)
()
()
HR: (95% CI: ;
log-rank P = .313)
CT
ERL
0
S
ur
vi
va
l
Mos From Randomization
0 6 12 18 24
134
120
78
87
42
51
22
24
14
12
Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission
Pts at Risk, n
Lung Cancer
PROSE: OS by Multivariate Serum Protein
Test Classification
Good Classification Poor Classification
Median OS,
Mos (95% CI)
()
()
HR: (95% CI: ;
log-rank P = .313)
CT
ERL
Median OS, Mos
(95% CI)
()
()
HR: (95% CI: ;
log-rank P = .714)
CT
ERL
S
ur
vi
va
l
Mos From Randomization
0 6 12 18 24
96
88
68
66
40
42
21
19
14
11
Mos From Randomization
0 6 12 18 24
38
41
10
21
2
9
1
5
0
1
S
ur
vi
va
l
Lazzari C, et al. ASCO 2013. Abstract LBA8005. Used with permission.
Pts at Risk, n Pts at Risk, n
Lung Cancer
Treatment Adjusted Interaction Analysis
for OS
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
Covariate HR (95% CI) P Value
ECOG PS, 2 vs 0-1 () < .001
Smoking history, ever vs never () .138
Histology, squamous vs nonsquamous () .930
Sex, female vs male () .292
Age, yrs () .138
Classification, poor vs good () .002
Treatment, erlotinib vs chemotherapy () .484
Classification/treatment interaction () .022
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
Lazzari C, et al. ASCO 2013. Abstract LBA8005.
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
Primary endpoint: PFS from randomization
Untreated ES SCLC;
4-6 cycles of chemo;
SD, PR, CR;
PCI allowed
(n = 85)
Sunitinib
mg/day,
until progression
(n = 44)
Placebo
until progression
(crossover allowed)
(n = 41)
Ready NE, et al. ASCO 2013. Abstract 7506.
Lung Cancer
CALGB 30504: Progression-Free Survival
Median PFS, Mos
Sunitinib:
Placebo:
HR: (90% CI: ; stratified
1-sided log-rank P = .037)
Mos From Randomization
P
FS
P
ro
ba
bi
lit
y
0 3 6 9 12 15
0
Placebo
Sunitinib
Ready NE, et al. ASCO 2013. Abstract 7506. Used with permission.
Lung Cancer
CALGB 30504: Overall Survival
Median OS, Mos
Sunitinib:
Placebo:
HR: (90% CI: ; stratified
log-rank 1-sided P = .27)
Mos From Randomization
O
S
P
ro
ba
bi
lit
y
0 5 10 15 20 25 30 35 40
0
Placebo
Sunitinib
Ready NE, et al. ASCO 2013. Abstract 7506. Used with permission.
Lung Cancer
%
Grade 4 toxicities: sunitinib, 1 case GI hemorrhage and 1 case pancreatitis;
placebo, 1 case platelets
CALGB 30504: Maintenance Toxicity
Grade 3/4 ≥ 5%
All Fatigue
7 5 2 2 0
19
14
7 7 5
0
10
20
30
40
50
60
70
80
90
100
Placebo
Sunitinib
P
at
ie
nt
s
(%
)
Neutrophils Leukocytes Platelets Hyponatremia
Ready NE, et al. ASCO 2013. Abstract 7506. Used with permission.
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 α/β 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.
M, et al. Ann Oncol. 2011;22:1374-1381. Used with permission.
Lung Cancer
Patients with stage
IIIB/IV or recurrent
NSCLC and
1 previous line of
chemotherapy
(N = 1314)
Nintedanib 200 mg BID on Days 2-21 +
Docetaxel 75 mg/m2 on Day 1 of a 21-day cycle*
(n = 655)
Placebo BID on Days 2-21 +
Docetaxel 75 mg/m2 on Day 1 of a 21-day cycle*
(n = 659)
Stratified by ECOG PS,
previous bevacizumab,
histology, brain metastases
Treatment
until PD
LUME Lung 1: Randomized, Double-Blind,
Placebo-Controlled Phase III Trial
*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
100
80
60
40
20
0
P
ro
ba
bi
lit
y
of
P
FS
(%
)
Mos
Nintedanib +
Docetaxel
Placebo +
Docetaxel
Median, mos
HR (95% CI) ()
P value .0019
Nintedanib + docetaxel
Placebo + docetaxel
0 2 4 6 8 10 12 14 16 181 3 75 9 11 13 15 17
Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with
permission.
Lung Cancer
LUME Lung 1: OS in All Patients
100
80
60
40
20
0
P
ro
ba
bi
lit
y
of
O
S
(%
)
Mos
Nintedanib +
Docetaxel
Placebo +
Docetaxel
Median, mos
HR (95% CI) ()
P value .2720
Nintedanib + docetaxel
Placebo + docetaxel
655
659
34
28
374
344
271
250
200
162
147
120
67
58
516
511
106
91
607
600
444
411
316
290
130
100
Pts at Risk, n
Nintedanib
Placebo
0 4 8 12 16 20 24 28 32 362 6 1410 18 22 26 30 34
14
13
234
207
171
144
88
74
51
51
27
25
Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with
permission.
Lung Cancer
LUME Lung 1: OS in Patients With
Adenocarcinoma Histology
100
80
60
40
20
0
P
ro
ba
bi
lit
y
of
O
S
(%
)
Mos
Nintedanib +
Docetaxel
Placebo +
Docetaxel
Median, mos
HR (95% CI) ()
P value .0359
Nintedanib + docetaxel
Placebo + docetaxel
322
336
25
15
203
184
163
139
131
101
96
73
46
33
263
269
72
55
302
312
230
219
180
159
87
62
Pts at Risk, n
Nintedanib
Placebo
0 4 8 12 16 20 24 28 32 362 6 1410 18 22 26 30 34
10
7
149
119
113
88
59
46
36
29
22
13
%
% %
%
Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with
permission.
Lung Cancer
LUME Lung 1: Summary of AEs
Patients With AE, n (%) Nintedanib +
Docetaxel
(n = 652)
Placebo +
Docetaxel
(n = 655)
Any AE, all grades 610 () 609 ()
Drug-related AE, all grades 498 () 446 ()
Any AE, grade ≥ 3 465 () 421 ()
Drug-related AE, grade ≥ 3 331 () 275 ()
Any AE leading to discontinuation 148 () 142 ()
Any serious AE 224 () 206 ()
Common Terminology Criteria for Adverse Events version was used
Reck M, et al. ASCO 2013. Abstract LBA 8011. Used with
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
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.
Patients with advanced
adenocarcinoma who
received 1 previous
regimen
(N = 252)
Ganetespib 150 mg/m2 on Days 1, 15 +
Docetaxel 75 mg/m2 on Day 1
of a 21-day treatment cycle*
(n = 125)
Docetaxel 75 mg/m2 on Day 1
of a 21-day treatment cycle
(n = 127)
Stratified by ECOG PS, time
since diagnosis of advanced
disease, baseline serum LDH,
smoking status
*Combination arm could continue ganetespib monotherapy following completion of docetaxel treatment.
Lung Cancer
G + D
(n = 125)
D
(n = 127)
Events, n 90 90
Median, mos
GALAXY-1: PFS in All Adenocarcinoma
Mos
D
G+D
Pts at
Risk, n
S
ur
vi
va
l P
ro
ba
bi
lit
y
HR: (90% CI: ; P = .038)
Cox regression:
HR: (90% CI: ; P = .108)
0
0
127
125
104
104
81
88
58
73
52
67
36
51
20
24
13
19
11
13
5
9
3
5
2
5
2
3
1
0
0
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.
Lung Cancer
GALAXY-1: OS in All Adenocarcinoma
G + D
(n = 125)
D
(n = 127)
Deaths, n 64 70
Median, mos
HR: (90% CI: ; P = .082)
Cox regression:
HR: (90% CI: ; P = .041)
Mos
D
G+D
S
ur
vi
va
l P
ro
ba
bi
lit
y
0
0 5 10 15 20
127
125
118
119
111
111
101
105
92
98
80
92
61
80
44
61
40
46
37
35
29
29
3
4
2
2
1
1
0
0
22
24
17
20
13
16
10
10
6
8
4
6
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.
Pts at
Risk, n
Lung Cancer
GALAXY-1: OS Forest Plot
(All Adenocarcinoma)
Favors Treatment Favors Control
Test for interaction of time since diagnosis of advanced disease with study treatment: P = .0064
HR (90% CI) P Value
()
()
()
()
()
()
()
()
()
()
()
()
()
()
()
()
()
.3133
.1440
.4314
.0972
.0093
.8924
.0462
.4613
.0390
.7488
.4256
.1032
.5411
.0266
.1777
.0471
.2745
Mutation Status
mKRAS (63)
KRAS no mut/NA (189)
mEGFR (20)
EGFR no mut/NA (232)
Diagnosis of Adv Dis
> 6 mos (176)
≤ 6 mons (76)
LDH
Elevated (76)
Normal (176)
Smoking Status
Ever (189)
Never (63)
ECOG
0 (104)
1 (146)
Sex
Male (142)
Female (110)
Geographic Region
North America (42)
Western Europe (45)
Eastern Europe (165)
1 10
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.
Lung Cancer
GALAXY-1: Safety
G + D, n (%)
(n = 123)
D, n (%)
(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
Ramalingam SS, et al. ASCO 2013. Abstract CRA8007. Used with permission.
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-L2–mediated
inhibition of TH2 T cells
Stromal PD-L1
modulation of T cells
Sznol M, et al. Clin Cancer Res. 2013;19:1021-1034.
PD-1 Blockade: Binding to PD-L1 (B7-H1)
and PD-L2 (B7-DC) Revives T Cells
PD-L1 expression on
tumor cells induced by
interferon-γ
Activated T cells that
could kill tumors are
specifically disabled
PD-1
PD-L1
PD-L2
T-cell receptor
MHC-1
CD28
Shp-2
IFN-γ–mediated
upregulation of
tumor PD-L1 PD-L1/PD-1–mediated
inhibition of tumor cell killing
Priming and
activation of
T cells
Immune cell
modulation of T cells
Tumor Cell
IFN-γR
IFN-γ
Tumor-associated
fibroblast M2
macrophage
Treg
cell
Th2
T cell
Other NFκB P13K
CD8+ cytoxic
T lymphocyte
T-cell polarization
TGF-β
IL-4/13
Can you generate
tumor-killing T cells?
Dendritic
Cell
Antigen priming
Can the T cells
get to the tumor?
T-cell trafficking
Can the T cells
see the tumor?
Peptide-MHC
expression
Can the T cells
be turned off?
Inhibitory cytokines
Can the T cells
be turned off?
PD-L1 expression
on tumor cells
Lung Cancer
Nivolumab (Anti–PD-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
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.
Eligible NSCLC
patients
randomized
among
3 nivolumab
dose levels
(n = 129)
Nivolumab 1 mg/kg IV every 2 wks
(n = 33)
Nivolumab 3 mg/kg IV every 2 wks
(n = 37)
Nivolumab 10 mg/kg IV
every 2 wks (n = 59)
Lung Cancer
Efficacy of Nivolumab Monotherapy in
Patients With NSCLC
Brahmer JR, et al. ASCO 2013. Abstract 8030. Used with permission.
Dose,
mg/kg
ORR,* %
(n/N)
Estimated
Median DOR,†
Wks (Range)
SD Rate,* % (n/N) Median PFS,‡
Mos (95% CI)
Median OS,‡§
Mos (95% CI)≥ 24 Wks ≥ 48 Wks
All
doses
(22/129)
(+, +)
(13/129)
(6/129)
()
()
1
(1/33)
(, )
(5/33)
(2/33)
()
()
3
(9/37)
NR
(+, +)
(3/37)
(2/37)
()
(-NE)
10
(12/59)
(+, +)
(5/59)
(2/59)
()
()
*Tumors and responses were assessed after each cycle per modified RECIST . CIs for 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
*AE severity was graded based on the Common Terminology Criteria for Adverse Events,
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
Brahmer JR, et al. ASCO 2013. Abstract 8030. Used with permission.
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. . NCT01642004. .
NCT01673867.
Lung Cancer
MPDL3280A (Anti–PD-L1) Inhibits the
Binding of PD-L1 to PD-1 and
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.
Tumor cell Patient’s T cells
MHC TCR
PD-L1
PD-1
B7-1
B7-1
PD-1PD-L1
MHC TCR
+ Anti-PD-L1
T-cell
inhibition
T-cell
activated
T cell
T cells
Tumor
cell
growth
Tumor
cell
deathGranzymes and perforin
X
X
Lung Cancer
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
Key Eligibility Criteria
Measurable disease per RECIST
ECOG PS 0 or 1
MPDL3280A: Phase IA Objectives and
Schema
Herbst RS, et al. ASCO 2013. Abstract 3000. Used with permission.
*CT scans every 6 wks for 6 mos, then every 12 wks; treatment beyond RECIST PD allowed per MD.
D-28 to D-1 Response assessed by CT scan (RECIST and irRC)*
Prescreen/
screening
Treatment period
MPDL328OA IV every 3 wks x 16 cycles (-1y)
Follow-up
Patients with CR/PR/SD
followed q12wks
until PD
Lung Cancer
MPDL3280A Phase IA: Efficacy Summary
Investigator Assessed
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
Herbst RS, et al. ASCO 2013. Abstract 3000. Used with permission.
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.
RECIST
Response Rate (ORR*), %
SD of Wks or Longer,
%
24-Wk PFS, %
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
Lung Cancer
MPDL3280A Phase Ia: Summary of
Response by PD-L1 IHC Status
Herbst RS, et al. ASCO 2013. Abstract 3000. Used with permission.
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)
*CRR includes investigator-assessed unconfirmed PR/CR and confirmed PR/CR by RECIST
†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.
100
80
60
40
20
0
P
at
ie
nt
s
(%
)
50
33
28
13
41
20
Best Response
CR
PR
Stable response
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
crizotinib[1-3 ]
– ORR: 60%
– Median PFS: 8-10 mos
Most patients with develop
resistance to crizotinib[4,5]
– Usually within 1-2 yrs
– CNS relapses are common[6]
Mechanisms of resistance are
diverse[4,5]
– ALK resistance mutations
– Alternative signaling pathways
Unknown
Bypass tracks
EGFR MT
KRAS MT
A
m
pl
ifi
ed
L1
19
6M
G1269A
S1206Y
G1202R1151TinsL1152RC1156Y
No ALK
amp or mut
ALK
amp
ALK
mutALK+
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
Primary objective: determination of MTD
Secondary objectives: safety, pharmacokinetics and preliminary antitumor
activity
Shaw AT, et al. ASCO 2013. Abstract 8010. Used with permission.
NCT01283516
Completed N = 59
Additional
N = 71
enrolled
C
ontinuous oral dosing
21 day cycles
Any advanced ALK+ cancer
Progression on standard therapy
(dose escalation starting at 50 mg/day)
Escalate to MTD (750 mg/day)
ALK+ lung cancer
Previous ALKi therapy
ALK+ lung
cancer
naive to
ALKi
Nonlung
ALK+
tumors≤ 2 mos after
previous
ALK TKI
> 2 mos
after
previous
ALK TKI
Lung Cancer
LDK378 in ALK+ NSCLC: Efficacy
ORR (CR + PR): overall, 58%; CRZ pretreated, 57%;
CRZ naive, 60%
Shaw AT, et al. ASCO 2013. Abstract 8010. Used with permission.
Best % Change From Baseline in Target Lesions
LDK378 400-750 mg/day
100
80
60
40
20
0
-20
-40
-60
-80
-100
B
es
t %
C
ha
ng
e
Fr
om
B
as
el
in
e
PFS event
Previous crizotinib
Crizotinib naive
Lung Cancer
LDK378 in ALK+ NSCLC: Safety
3 (2%) patients discontinued due to AEs
No treatment-related deaths
Shaw AT, et al. ASCO 2013. Abstract 8010. Used with permission.
Grade 3/4 AEs (≥ 5%), Regardless of Study Drug Relationship
Preferred
Term, n (%)
50-300 mg
(n = 10)
400 mg
(n = 14)
500 mg
(n = 10)
600 mg
(n = 10)
700 mg
(n = 5)
750 mg
(n = 81)
All Patients
(N = 130)
ALT
increased
0 1 (7) 2 (20) 0 4 (80) 18 (22) 25 (19)
AST
increased
0 2 (14) 0 0 3 (60) 8 (10) 13 (10)
Diarrhea 1 (10) 1 (7) 1 (10) 2 (20) 0 6 (7) 11 (8)
Lipase
increased
1 (10) 0 0 1 (10) 0 5 (6) 7 (5)
Hypokalemia 0 0 0 0 1 (20) 5 (6) 6 (5)
Nausea 0 0 1 (10) 1 (10) 0 4 (5) 6 (5)
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
Mode of Action
Reversible, small molecule
BRAF inhibitor
ATP competitive
Molecular Activity
BRAF V600E: IC50 nM
BRAF WT: IC50 nM
Selectivity
IC50 of 10-100 nM against
8 of 282 human kinases
Dabrafenib: BRAF V600E Kinase Inhibitor
PI3K/AKT/
mTOR
pathway
R
TK
s SOS
Grb2
SHC
PPPP
Proliferation, growth, survival
MEK
PP
BRAF CRAF
BRAF
V600
ERK1/2
RAS
Dabrafenib
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.
Used with permission.
Lung Cancer
Stage 2
(n = 20)
Stage 1
(n = 20)
Primary objective: investigator-assessed ORR
Secondary objectives: PFS, duration of response, OS, safety, tolerability, and
population pharmacokinetics
Stage IV NSCLC
BRAF V600E
mutation
≥ 1 line previous tx
(N = 25)
BRF113928: Study Design
Single arm, open label, phase II
Dabrafenib 150 mg twice daily
Planchard D, et al. ASCO 2013. Abstract 8009. Used with permission.
Green-Dahlberg 2-stage: H(0)—ORR ≤ 10% vs H(1)—ORR ≥ 30% (primary cohort).
Lung Cancer
Maximum Tumor Reduction by Best
Confirmed Response for the First 20 Pts†
−40
−50
−60
−90
−100
50
40
30
20
10
−10
−20
−30
−70
−80
0
*
*
*
*
*
** **
**
**
**
***
***
***
**
**
**SD
PR
PD
Best Confirmed ResponseBest Confirmed Response
*
Smoking HistorySmoking History
M
ax
im
um
P
er
ce
nt
R
ed
uc
tio
n
at
T
im
e
of
B
es
t D
is
ea
se
A
ss
es
sm
en
t
†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.
Smoker ≤ 40 pack-yrs
Nonsmoker
Smoker > 40 pack-yrs*****
Planchard D, et al. ASCO 2013. Abstract 8009. Used with permission.
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
Disease control rate (CR + PR + SD), % 60
95% CI
*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.
Planchard D, et al. ASCO 2013. Abstract 8009. Used with permission.
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)
Planchard D, et al. ASCO 2013. Abstract 8009. Used with permission.
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
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