CCO Metastatic NSCLC Slides

Non-Small-Cell Lung Cancer:
Transformations in the Care of

Metastatic Disease
This program is supported by educational grants from

Celgene Corporation and Lilly.
Transformations in the Care of Metastatic Disease

clinicaloptions.com/oncology
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Core Faculty
Corey J. Langer, MD, FACP
Director, Thoracic Oncology
Abramson Cancer Center
Professor of Medicine
Hematology-Oncology Division
University of Pennsylvania
Philadelphia, Pennsylvania
Heather Wakelee, MD
Associate Professor of Medicine, Oncology

Department of Medicine/Oncology
Stanford University
Stanford, California

Faculty Disclosures
Corey J. Langer, MD, FACP, has disclosed that he has received
funds for research support from Bristol-Myers Squibb, Genentech,
GlaxoSmithKline, Lilly, Merck, Nektar, OSI, and Pfizer and
consulting fees from Abbott, Abraxis, Amgen, AstraZeneca,
Bayer/Onyx, Biodesix, Boehringer Ingelheim, Bristol-Myers
Squibb, Caris Dx, Celgene, Clarient, Genentech, ImClone, Lilly,
Morphotek, Novartis, Pfizer, sanofi-aventis, Synta, and Vertex and
served on a DSMC for Amgen, Agennix, Lilly, and Synta.
Heather Wakelee, MD, has disclosed that she has received
consulting fees from Peregrine and funds for research support
(paid to Stanford) from AstraZeneca, Bristol-Myers Squibb,
Celgene, Clovis, Exelixis, Genentech/Roche, Lilly, Novartis, Pfizer,
Regeneron, and Xcovery.
Individualizing Therapy for

Advanced/Metastatic NSCLC

Changes in the Therapeutic Landscape of

Stage IV Lung Cancer
HER2
EGFR mutants
ALK
ROS/RET BRAF
KRAS
KRAS
Adeno
LCC-NOS
SqCC
SCLC

Paradigm Shift in Pathology . . .

Tissue sent to pathology
Morphologic analysis
Tumor genotyping
IHC, special stains
Tumor biomarkers

NSCLC Biopsy: Key Factors

Adequate tissue for molecular analysis is critical to best select
first-line NSCLC therapy
Determination of EGFR mutation and ALK translocation status
is indicated
Should other genes be evaluated? ROS1, KRAS, BRAF, HER2,
others
Rebiopsy at time of progression helpful in determining

resistance mechanisms
Bone biopsy less ideal due to decalcification and degradation
of DNA
Liquid biopsies in development

Circulating Tumor DNA

Tumors continually shed DNA into the circulation
ctDNA analysis (liquid biopsy or blood sample)
Can identify both genetic and epigenetic aberrations
Can provide the genetic landscape of all cancerous lesions
(primary and metastases)
Opportunity to systematically track genomic evolution
Potential utility in inaccessible lesions and bone-only tumor
Crowley E, et al. Nat Rev Clin Oncol. 2013;10:472-484.
Tumor Histology

Histology in Management of AdvancedStage Non-OncogeneDriven NSCLC

What is the current treatment
algorithm in the absence of a
known and targetable
oncogenic driver?
Is NSCLC histologic subtype
prognostic (ie, portends pt
outcome independent of
therapeutic intervention)?
Is NSCLC histologic subtype
predictive of differential
benefit from available
therapies?
Adenocarcinoma
Squamous
Large Cell

Pathologic Assessment of Histology Helps

Determine Optimal Treatment
Histology still guides the therapeutic choice for the vast
majority of pts
Classify pts as squamous or nonsquamous
Adenocarcinomas are TTF1 positive (70% to 90%) and
generally negative for p63 (70%) and p40 (97%)[1-4]
Squamous cells are typically p63 (or p40) positive and
TTF1 negative[1-4]
All pts who do not have bona fide squamous NSCLC
should be considered nonsquamous
1. Di Loreto C, et al. J Clin Pathol. 1997;50:30-32. 2. Fabbro D, et al. Eur J Cancer. 1996;32A:512-517.
3. Rekhtman N, et al. Mod Pathol. 2011;24:1348-1359. 4. Bishop JA, et al. Mod Pathol. 2012;25:405-415.

Histologic Subtypes of NSCLC: US

Decreasing Incidence of Squamous Cell Subtype Over Time
45
10% to 15%
25% to 30%
Adenocarcinoma
Squamous cell carcinoma
Large cell carcinoma
Other or not otherwise specified
85% of lung cancers are NSCLC

American Cancer Society database.
40
35
30
25
20
15
10
5
0
19
80
19
82
19
84
19
86
19
88
19
90
19
92
19
94
19
96
19
98
20
00
20
02
40%
Cancer Incidence (%)
20%
Yr of Diagnosis (3-Yr Moving Average)

Adenocarcinoma
Squamous cell
Large cell
Wahbah M, et al. Ann Diagn Pathol. 2007;11:8996.
Tumor Molecular Profile

Molecular Subsets of Lung Cancer

Defined
NRAS
by Driver Abnormalities*
Frequency of Driver
MEK1
HER2
BRAF
PIK3CA
Abnormalities in NSCLC, %
AKT1
ALK
3-7
AKT1
BRAF
1-3
ALK
EGFR
10-35
HER2
2-4
KRAS
15-25
MEK1
NRAS
PIK3CA
1-3
RET
1-2
ROS1
RET
ROS1
KRAS
Unknown
EGFR
www.mycancergenome.org.
*Double mutations are rare (<

3%)

Selection for Molecular Testing in NSCLC
All pts with an adenocarcinoma

component should be tested
Pure SCC diagnosis is appropriate for

EGFR mutation and ALK testing in some
clinical settings[1]
Young, never, or light smoker
Poor quality/small sample
East Asian ethnicity (EGFR mut testing)
Primary tumors and metastatic lesions

are equally suitable for testing[1]
Discordance between mut status primary

tumor and metastases uncommon for
EGFR mut and ALK translocation (in
previously untreated pts)[3]
Pack-Yrs[2]
EGFR Mutation, %
95% CI
Never
52
48-56
1-5
34
25-43
6-10
34
26-44
11-15
18
11-26
16-25
11
7-16
26-50
6-11
51-75
5-13
> 75
2-8
If sensitizing EGFR mutation or ALK

is unknown, consider ROS1 testing[4]
1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859. 2. DAngelo SP, et al. J Clin Oncol. 2011;29:20662070. 5. Yatabe Y, et al. J Clin Oncol. 2011;29:2972-2977. 4. NCCN. Lung cancer. v5.2015.

Molecular Testing Guideline: EGFR and

ALK
Pts SHOULD NOT be treated with first-line EGFR and ALK
inhibitors based on clinical characteristics alone
If one uses clinical characteristics alone, EGFR inhibitors will
be inappropriately given first line to 40% to 60% of pts
Pts SHOULD NOT be offered or denied testing based on

clinical characteristics alone
Pathologic sample preparations using heavy metal
fixatives or acidic solutions compromise molecular
testing[1]
eg, avoid bone biopsy for molecular testing due to
decalcifying solutions, which denature the DNA
1. Lindeman NI, et al. J Thorac Oncol. 2013;8:823-859.
Selecting Therapy Based on

Tumor Histology

Cis/Gem vs Cis/Pem in Advanced NSCLC:

OS by Histology
Nonsquamous
0.8
0.6
0.4
0.2
Median Survival
C/P 9.4 mos
C/G 10.8 mos
C/P vs C/G Adjusted HR: 1.23
(95% CI: 1.00-1.51)
1.0
Survival Probability
Median Survival
C/P 11.8 mos
C/G 10.4 mos
C/P vs C/G Adjusted HR: 0.81
(95% CI: 0.70-0.94)
1.0
Survival Probability
Squamous
0.8
0.6
0.4
0.2
0
0
0
12
18
Mos
24
30
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
12
18
Mos
24
30

Carbo/Albumin-Bound Paclitaxel vs
Carbo/Paclitaxel in Advanced NSCLC
Stratified by stage (IIIb vs IV),
age (< 70 yrs vs > 70 yrs), sex,
histology (squamous vs nonsquamous),
geographic region
Pts with stage IIIb/IV

NSCLC, ECOG PS
0-1, no previous
chemotherapy for
metastatic disease
(N = 1050)
21-day cycles
Nab-Paclitaxel 100 mg/m2 on Days 1, 8, 15 +

Carboplatin AUC 6 on Day 1
No premedication
Paclitaxel 200 mg/m2 on Day 1 +
Carboplatin AUC 6 on Day 1
Premedication: dexamethasone, antihistamines
Phase III
Primary endpoint: ORR
Secondary endpoints: PFS, OS, safety
Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Carbo/Nab-Paclitaxel vs Carbo/Paclitaxel
in Advanced NSCLC: Responses*
P < .001
RRR: 1.680
Response Rate (%)
50
P = .005
RRR: 1.31
40
41%
P = .808
RRR: 1.034
33%
30
Carboplatin/albumin-bound-paclitaxel
Carboplatin/paclitaxel
25%
24%
26%
25%
292
310
20
10
0
n=
521
531
Intent to Treat
229
221
Squamous
Nonsquamous
*Independent radiological review. Not a prespecified endpoint. Interaction P value for histology = .036
Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Bevacizumab-Containing Regimens in
Advanced Nonsquamous NSCLC
Outcome
ORR, %
HR for PFS
Median PFS, mos
HR for OS
Median OS, mos
E4599[1]
(N = 878)
AVAiL[2,3]
(N = 1043; P values vs placebo)
JO19907[4]
(N = 180)
PCB
PC
CGB
(7.5 mg/kg)
CGB
(15 mg/kg)
Placebo +
CG
PCB
Placebo
+ PC
35
15
37.8
34.6
21.6
60.7
31.0
P < .001
P < .0001
P = .0002
P = .001
0.66
P < .001
0.75
P = .0003
0.85
P = .046
0.61
P = .009
6.7
6.5
0.93
P = NS
1.03
P = NS
13.6
13.4
6.2
4.5
0.79
P = .003
12.3
10.3
6.1
6.9
5.9
0.99
P = .95
13.1
22.8
23.4
1. Sandler A, et al. N Engl J Med. 2006;355:2542-2550. 2. Reck M, et al. J Clin Oncol. 2009;27:1227-1234.
3. Reck M, et al. Ann Oncol. 2010;21:1804-1809. 4. Niho S, et al. Lung Cancer. 2012;362-367.

Maintenance Therapy for Pts With

Nonprogressive Disease*
Options:
Continuation Maintenance
Observation
Pts with at least
SD after 4 cycles
of CT,
PS 0-1
Switch Maintenance
Observation
Bevacizumab,
cetuximab, or
pemetrexed (cat 1)
Bevacizumab +
pemetrexed
Gemcitabine (2B)
Category 2B:
Docetaxel,
Pemetrexed,
Erlotinib,
Gefitinib
Early 2nd-line Therapy

Observation
*After initial platinum-based

chemotherapy.
NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.

NSCLC Maintenance Therapy:

Advantages and Disadvantages
Disadvantages
Advantages
Maintains disease control
Improves PFS
Improves OS
Maintains quality of life
Opportunity to treat more pts
Pts support maintenance therapy
Induction regimens of 4 vs 6 cycles

may achieve the same improvement
in PFS
Careful follow-up reveals more pts
available for second-line therapy
than initially estimated by early
reports
Cumulative toxicity with Grade 3/4
AEs in 30% to 40% of pts
Cost
Lack of reliable predictive
biomarkers

Second-line (or Third-line) Therapy for

Advanced NSCLC (Non-Oncogene Driven)
Commonly used options
Docetaxel ramucirumab
Pemetrexed
Erlotinib
Gemcitabine
Nivolumab
Multiple investigational options
Adapted from NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.

REVEL: Docetaxel VEGFR2 Antibody

Ramucirumab in 2nd-Line NSCLC
Overall Survival
Median (95% Cl)
Censoring Rate
Ram + Doc
10.5 (9.5-11.2)
31.8%
Pl + Doc
9.1 (8.4-10.0)
27.0%
Ram + Doc vs Pl + Doc:
Stratified HR: 0.857 (95% CI: 0.751-0.979)
Stratified log-rank P = .0235
100
80
OS (%)
Phase III Study

Ram +
Doc
Pl +
Doc
P
Value
ORR,%
(95% CI)
22.9
(19.726.4)
13.6
(11.016.5)
< .001
Median
PFS,
mos
(95% CI)
4.5
(4.2-5.4)
3.0
(2.8-3.9)
HR:
0.72
< .0001
60
40
Ram + Doc
Pl + Doc
20
0
12 15 18 21 24 27 30 33 36
Survival Time (Mos)
First study in the second-line setting to show an OS advantage for the addition of a
targeted agent to docetaxel compared with docetaxel alone
First and only study of angiogenesis inhibition in advanced NSCLC to show a benefit in
a squamous cell cancer cohort
Perol M, et al. ASCO 2014. Abstract LBA8006^.
Selecting Therapy Based on

Tumor Molecular Profile

Activity of Crizotinib in Pts With ROS1

Fusions: Best Overall Response
100
PD
SD
PR
CR
Change From Baseline (%)
80
60
40
20
0
-20
-40
-60
-80
ORR: 72%
-100
Shaw AT, et al. N Engl J Med. 2014;371:1963-1971.

Targeted Therapy Focuses on Driver Gene

Alterations: Oncogenic Addiction
EGFR mutants
ALK
ROS/RET
Gefitinib[1,2]
Erlotinib[3,4]
Afatinib[5,6]
Crizotinib[7-9]
Activity
EGFR
EGFR
EGFR
(ErbB family)
ALK, ROS1, MET
Target
EGFR
EGFR
EGFR
ALK
RR, %
60-80
50-80
~ 60
~ 60
PFS, mos
10-11
10-14
~ 11
~ 10
1~2
1~2
1.7
<1
TRD, %
1. Maemondo M, et al. N Engl J Med. 2010;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol.

2010;11:121-128. 3. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 4. Zhou C, et al. Lancet Oncol.
2011;12:735-742. 5. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334. 6. Wu YL, et al. Lancel Oncol.
2014;15:213-222. 7. Camidge DR, et al. Lancet Oncol 2012;10:1011-1019. 8. Kim DW, et al. ASCO 2012.
Abstract 7533. 9. Shaw AT, et al. N Engl J Med 2013;368:2385-2394.

Lung Cancer Mutation Consortium:

OS by Mutation and Treatment
100
Targeted therapy vs no targeted

therapy; P < .0001
OS (%)
80
60
40
Driver mutation + targeted therapy (n = 313; median OS: 3.5 yrs)

Driver mutation + no targeted therapy (n = 265; median OS: 2.4 yrs)
No driver mutation (n = 361; median OS: 2.1 yrs)
20
0
2
Yrs
Johnson B, et al. ASCO 2013. Abstract 8019.
EGFR Mutation

IPASS: First-line Gefitinib vs Paclitaxel/

Carboplatin
Pts
Chemo naive
Aged 18 yrs
Endpoints
Gefitinib
250 mg/day
Primary
PFS (noninferiority)
Adenocarcinoma
histology
Secondary
Never or light exsmokers*
OS
Life expectancy
12 wks
PS 0-2
Measurable stage
IIIB/IV disease
ORR
Paclitaxel
200 mg/m2/
Carboplatin
AUC 5 or 6
Quality of life
Disease-related symptoms
Safety and tolerability
Exploratory
Biomarkers
*Never smokers (< 100 cigarettes in lifetime) or light ex-smokers

(stopped 15 yrs ago and smoked 10-pack yrs).
Carboplatin/paclitaxel was offered to gefitinib pts upon progression.
Limited to a maximum of 6 cycles.
EGFR mutation
EGFR gene copy
number
EGFR expression
Mok TS, et al. N Engl J Med. 2009;361:947-957. Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874.

IPASS: PFS by EGFR Mutation Status
Randomized phase III trial; previously untreated pts with advanced NSCLC (N = 1217)
PFS: gefitinib superior to carboplatin/paclitaxel in ITT population
EGFR mutations strongly predicted PFS (and tumor response) to first-line gefitinib vs
carboplatin/paclitaxel
1.0
EGFR Mutation Negative

Gefitinib
Pac/carbo
0.8
HR: 0.48
(95% CI: 0.36-0.64; P < .001)
0.6
0.4
0.2
0
Probability of PFS
Probability of PFS
EGFR Mutation Positive

1.0
Gefitinib
Pac/carbo
0.8
HR: 2.85
(95% CI: 2.05-3.98; P < .001)
0.6
0.4
0.2
0
4
8
12
16 20 24
Mos Since Randomization
Mok TS, et al. N Engl J Med. 2009;361:947-957.
4
8
12
16 20 24
Mos Since Randomization

Meta-analysis of Randomized First-line

EGFR TKI Studies: Improved PFS
Study
EGFRmut (first-line therapy)
EURTAC
First-SIGNAL
GTOWG
INTACT1-2
IPASS
LUX LUNG3
NEJ002
OPTIMAL
TALENT
TOPICAL
TRIBUTE
WJTOG3405
Subtotal
HR
(95% CI)
HR
(95% CI)
0.37 (0.25-0.54)
0.54 (0.27-1.10)
1.08 (0.24-4.90)
0.55 (0.19-1.60)
0.48 (0.36-0.64)
0.58 (0.43-0.78)
0.32 (0.24-0.44)
0.16 (0.11-0.26)
0.59 (0.21-1.67)
0.90 (0.39-2.06)
0.49 (0.20-1.20)
0.52 (0.38-0.72)
0.43 (0.38-0.49)
Favors EGFR TKI
Lee CK, et al. J Natl Cancer Inst. 2013;105:595-605
Favors Chemo

Phase II Study: Erlotinib Bevacizumab in

Advanced NSCLC With EGFR Mutations
Pts with chemo-naive,
nonsquamous
NSCLC and EGFR
mutations (del 19,
L858R), no brain
mets
(N = 154)
Erlotinib 150 mg QD +
Bevacizumab 15 mg/kg q3w
(n = 77)
Erlotinib 150 mg QD
(n = 77)
Treat until
disease
progression
Open-label study
Primary endpoint: PFS (independent review; RECIST)
Secondary endpoints: OS, tumor response; QoL, safety
Seto T, et al. Lancet Oncol. 2014;15:1236-1244. Kato T, et al. ASCO 2014. Abstract 8005.

Erlotinib Bevacizumab in Advanced

NSCLC With EGFR Mutations: PFS
Probability of PFS
1.0
0.8
.0015
0.6
EB
E
0.4
0.2
0
9.7
16.0
Pts at Risk, n
EB
75 72
E
77 66
10 12 14 16 18 20 22 24 26 28
Mos
69
57
64
44
60
39
53
29
49
24
38
21
30
18
20
12
13
10
8
5
4
2
4
1
Seto T, et al. Lancet Oncol. 2014;15:1236-1244. Kato T, et al. ASCO 2014. Abstract 8005.
0
0

LUX-Lung 3+6: OS by del(19) and L858R

Mutation Status
L858R
Del(19)
Afatinib
(n = 236)
Median, mos
HR (95% CI)
31.7
20.7
0.59 (0.45-0.77)
P = .0001
0.8
0.6
0.4
0.2
0
Median, mos
HR (95% CI)
1.0
Estimated OS Probability
Estimated OS Probability
1.0
Afatinib
(n = 183)
Chemo
(n = 119)
Chemo
(n = 93)
22.1
26.9
1.25 (0.92-1.71)
P = .1600
0.8
0.6
0.4
0.2
0
12
18
24
30
36
Mos
Yang JCH, et al. Lancet Oncol. 2015;16:141-151.
42
48
12
18
24
30
Mos
36
42
48

EGFR InhibitorAssociated Skin Rash:

Management
Preventive
Topical
Systemic
Treatment
Topical
Systemic
Recommended
Not Recommended
Hydrocortisone 1% cream with

moisturizer, sunscreen twice daily
Pimecrolimus 1% cream
Tazarotene 0.05% cream
Sunscreen as single agent
Minocycline 100 mg/day

Doxycycline 100 mg BID
Tetracycline 500 mg BID
Recommended
Not Recommended
Alclometasone 0.05% cream

Fluocinonide 0.05% cream BID
Clindamycin 1%
Vitamin K1 cream
Doxycycline 100 mg BID

Minocycline 100 mg/day
Isotretinoin at low doses
(20-30 mg/day)
Acitretin
Lacouture ME, et al. Support Care Cancer. 2011;19:1079-1095.
Comments
Doxycycline is
preferred in pts
with renal
impairment;
minocycline is less
photosensitizing
Comments
Photosensitizing
agents

Acquired Resistance to Targeted TKIs:

PD Subtype Influences Clinical Practice
Continued
Therapy
Therapy
Systemic-PD
Baseline
Remission
Continued
Therapy
Therapy
Oligo-PD
Baseline
Remission
Therapy
CNS-PD
(Sanctuary)
Multiple PD Lesions
Solitary New Lesions
Continued
Therapy
Inadequate
CNS penetration?
Drug
Baseline
Complete Remission
Gandara DR, et al. Clin Lung Cancer. 2014;15:1-6.
Brain-Only PD

Acquired Resistance in NSCLC: Studies

Comparing EGFR TKIs
Pts activating EGFR TK mut
Resistance to first-line gefitinib,
No prior chemo
(planned N = 287)[1]
Primary endpoint: PFS
PIs: Tony Mok, Jean-Charles
Soria
Stage IV NSCLC
Activating EGFR TK mutation,
Resistance to first-line erlotinib,
PS 0/1
(planned N = 120)[2]
PI: Leora Horn
Cisplatin/Pemetrexed
Cisplatin/Pemetrexed +
ongoing Gefitinib
Cisplatin or Carboplatin +
Pemetrexed, ongoing Erlotinib
Cisplatin or Carboplatin +
Pemetrexed
Erlotinib retreatment
after progression
1. ClinicalTrials.gov. NCT01544179. 2. ClinicalTrials.gov. NCT01928160.
Stratified by EGFR
mutation (exons 19
vs 21), TTP on
EGFR TKIs (< vs
> 1 yr), PS (0 vs 1)

IMPRESS: Cis/Pem Gefitinib in Stage

IIIb/IV NSCLC w/EGFR Mutations and PD
Phase III trial
Pts with stage IIIb/IV
NSCLC, EGFR
mutations, chemo
naive, response 4
mos with first-line
gefitinib, PD < 4 wks
prior to randomization
(N = 265)
Cisplatin 75 mg/m2 +
Pemetrexed 500 mg/m2 ( 6 cycles) +
Gefitinib 250 mg
(n = 133)
Cisplatin 75 mg/m2 +
Pemetrexed 500 mg/m2 ( 6 cycles) +
Placebo 250 mg
(n = 132)

Secondary endpoints: OS, ORR, DCR, safety/tolerability, QoL
Exploratory endpoints: biomarkers
Randomization did not include stratification factors; analyses adjusted for
age (< vs 65 yrs) and prior gefitinib response (SD vs PR/CR)
Mok T, et al. ESMO 2014. Abstract LBA2_PR.

IMPRESS: Cis/Pem Gefitinib in Stage

IIIb/IV NSCLC w/EGFR Mutations: PFS
Probability of PFS
1.0
0.8
Median PFS, mos
0.6
Events, n (%)
Gefitinib
(n = 133)
Placebo
(n = 132)
5.4
5.4
98 (73.7)
107 (81.1)
HR: 0.86 (95% CI: 0.65-1.13; P = .273)
0.4
HR < 1 implies lower risk of progression with gefitinib
0.2
Gefitinib (n = 133)
Placebo (n = 132)
0
0
Pts at Risk, n
Gefitinib 133
Placebo 132
2
110
100
4
6
8
10
Time of Randomization (Mos)
88
85
Mok T, et al. ESMO 2014. Abstract LBA2_PR.
40
39
25
17
12
14
12
6
0
5
4
0
Med OS: 14.8 mos (G) vs 17.2 mos (P)
HR: 1.62 (P = .029) but 33% of events

Repeat Biopsies for Pts With NSCLC

and Acquired Resistance to EGFR inhibitors
Observed Resistance
Mechanisms
N = 37
T790M (total)
+ EGFR amp
+ beta-catenin
+ APC
21
4
2
1
MET amplification
PIK3CA
SCLC transformation
Epithelial-mesenchymal
transition
No changes identified
Sequist LV, et al. Sci Trans Med. 2011;3:75ra26.
With
EGFR
amp
Unknown
mechanism
(30%)
T790M
(49%)
PIK3CA
(5%)
SCLC
transformation
(14%)
MET
amp
(5%)

Third Generation EGFR TKIs

EGFR TKI
ORR*
T790M-
ORR
T790M+
PFS
Toxicity
Rociletinib
(CO-1686)[1]
256
37%
53%
~8.0 mos
Hyperglycemia
AZD9291[2]
253
21%
61%
~8.2 mos
(9.6 mos T790+,
2.8 mos T790-)
Diarrhea
HM61713[3]
34/62
12%
(300 mg)
55%
(800 mg)
NR
Dyspnea/rash
EGF816X[4]
53
60%
NR
Rash
ASP8273[5]
47
~33%
61%
NR
Hyponatremia/
diarrhea
*T790M- subgroups are very small pt populations

Multiple other agents in early development
1. Sequist LV, et al. ASCO 2015. Abstract 8001. 2. Jnne PA, et al. New Engl J Med. 2015;372:1689-1699.
3. Park K, et al. ASCO 2015. Abstract 8084. 4. Tan DSW, et al. ASCO 2015. Abstract 8013. 5. Goto Y, et al.
ASCO 2015. Abstract 8014.
ALK Translocation

Tumor Responses to ALK Inhibitor

Crizotinib in ALK+ Lung Cancer
Most pts on study had already had 2 lines of previous therapy
Objective response rate: 60.8%
Median PFS: 9.7 mos (95% CI: 7.7-12.8)

Change From Baseline (%)
100
PD
SD
PR
CR
80
60
40
20
Crizotinib in ALK-Positive NSCLC (N = 143)
0
-20
-40
-60
-80
-100
Camidge DR, et al. Lancet Oncol. 2012;13:1011-1019.

Crizotinib vs Standard Chemotherapy in ALK+

NSCLC (PROFILE 1007): PFS in 2nd or 3rd Line
Probability of Survival Without
Progression (%)
100
Crizotinib
(n = 173)
Chemotherapy
(n = 174)
Events, n (%)
100 (58)
127 (73)
Median, mos
7.7
3.0
80
60
HR (95% CI)
40
0.49 (0.37-0.64)
P value
< .0001
20
0
Pts at Risk, n 25
Crizotinib 173
Chemotherapy 174
10
15
20
11
4
2
1
Mos
93
49
38
15
0
0

Crizotinib in ALK-Positive NSCLC:

Efficacy
Outcome
PROFILE 1001[1]
(N = 143)
PROFILE 1005[2]
(N = 259)
PROFILE 1007[3]
(N = 173)
CR
3 (2)
4 (2)
1 (1)
PR
84 (59)
151 (58)
112 (65)
SD
31 (22)*
69 (27)
32 (18)
PD
NR
19 (7)
11 (6)
Objective response rate, % (95% CI)
60.8 (52.3-68.9)
59.8 (53.6-65.9)
65 (58-72)
Median duration of response,

wks (95% CI)
49.1 (39.3-75.4)
45.6 (35.3-53.6)
32.1 (2.1-72.4)
Median duration of treatment,

wks (range)
43.1 (0.1-138.6)
N/A
15.9 (2.9-73.4)
9.7 (7.7-12.8)
8.1 (6.8-9.7)
7.7 (6.0-8.8)
Best overall response, n (%)
Median PFS, mos (95% CI)

*At Wk 8.
Range.
1. Camidge DR, et al. Lancet Oncol. 2012;10:1011-1019. 2. Kim DW, et al. ASCO 2012. Abstract 7533.
3. Shaw AT, et al. N Engl J Med. 2013;368:2385-2394

PROFILE 1014: Crizotinib vs Pemetrexed/

Platinum in Advanced Untreated NSCLC
Adv ALK-pos
nonsquamous
NSCLC not
previously
treated
(N = 343)
Crizotinib 250 mg BID

Pemetrexed + Cisplatin or
Carboplatin
q3w x 6 cycles
100
Crizotinib Chemotherapy
(n = 171)
(n = 169)
80
PFS (%)
ORR, %
60
mPFS, mos
74
45
10.9
7.0
Primary
endpoint: PFS
HR (95% CI)
< .001
0.45 (0.35-0.60)
40
20
0
10
15
20
25
30
P Value
35
Solomon BJ, et al. N Engl J Med. 2014;371:2167-2177. Mok T, et al. ASCO 2014. Abstract 8002.
< .001

Ceritinib in ALK+ NSCLC: Best % Change

From Baseline in Target Lesions
Other second-generation ALK
inhibitors in development:
AP26113
X-396
ASP3026
GSK 1838705
CEP-28122
Best Change From Baseline (%)
CH5424802 (alectinib)
100
80
Prior crizotinib
treatment
No prior crizotinib
treatment
60
40
20
ORR (CR + PR): 58%

Prior crizotinib: 56%
Crizotinib naive: 62%
0
-20
-40
-60
-80
-100
Pts
Disease
progression
or death

Phase I ASCEND-1: Ceritinib in ALKPositive NSCLC
Treatment (N = 246): 750 mg/day

(MTD from dose-escalation phase)
Antitumor activity independent of

prior ALK inhibitor treatment
Most common grade 3/4 AEs:

increased ALT (29.8%) and AST
(9.8%)
Most common AEs (all grades):

diarrhea (86.7%), nausea (82.7%),
vomiting (61.6%)
ALK inhibitor treated (n = 163)

ALK inhibitor naive (n = 83)
All (n = 246)
100
PFS (%)
80
60
40
Median PFS: 18.40 mos
20

12
18
Mos
24
Felipe E, et al. ESMO 2014. Abstract 1295P.
30
36

Alectinib in Pts With ALK-Positive NSCLC:

Results
(95% CI: 26.9-NR)
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0.2
10
15
20
Mos
1.0
OS
PFS
1.0
25
30
2-yr OS rate: 79%

(95% CI: 63% to 89%)
35
10
15
20
25
Mos
ORR: 93.5% (95% CI: 82.1-98.6); CR: 19.6%; PR: 73.9%; SD: 2.2%
Tamura T, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 10.
30
35

AP26113 Antitumor Activity in ALK+

NSCLC Pts
Best Change From Baseline
in Target Lesion (%)
40
Best overall response:
PD
SD
20
0
-20
-40
-60
PR
CR
-80
-100
*Received prior crizotinib and ceritinib. TKI nave: 5/6 pts had best target lesion response data entered at time of analysis.
69% (35/51) post-crizotinib responded (95% CI: 54%
72% (41/57) objective response rate (95% CI:
to 81%)
59% to 83%)
100% (6/6) crizotinib-nave responded (incl. 1

CR)
Average time to response: 9.2 wks ( 3.22

wks)
Gettinger S, et al. ASCO 2014. Abstract 8047.
Response duration: 1.6-14.7 mos (ongoing)
Average time to response: 9.3 wks ( 3.72 wks)
Immunotherapies

PD-1 Inhibitor Nivolumab in Pts With

Progressive Squamous NSCLC
Endpoints
Primary:
Confirmed ORR
(IRC assessed)
Phase II study
Stage IIIB/IV
squamous NSCLC
2 prior systemic
therapies
ECOG PS 0-1
(N = 140 screened)
Nivolumab 3 mg/kg IV
q2w until PD or
unacceptable toxicity
(n = 117)
Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.
Secondary:
Confirmed ORR (investigator
assessed)
Exploratory:
Safety and tolerability
PFS/OS
PD-L1 expression and efficacy

Nivolumab in Pts With Squamous NSCLC:

Clinical Activity
Outcome Measures
IRC Assessed
ORR, % (n; 95% CI)
15 (17; 9-22)
Disease control rate, % (n)
40 (47)
Median DOR, mos (range)
NR (2+ to 12+)
Ongoing responders, % (n)
76 (13)
Median time to response, mos

(range)
3 (2-9)
PFS rate at 1 yr, % (95% CI)
20 (13-29)
Median PFS, mos (95% CI)
2 (2-3)
Median OS, mos
8.2
OS at 1 yr , %
41
Rizvi NA, et al. Lancet Oncol. 2015;16:257-265.
ImmuneRelated AE, %
Any Grade
Grade 3/4
Skin
15
Gastrointestinal
10
Endocrine
Pneumonitis
Renal
dysfunction
Hepatic
Be aware of immune-related
adverse events and quickly initiate
therapy with steroids in
recommended cases

CheckMate 017: Nivolumab vs Docetaxel

in Previously Treated Squamous NSCLC
Open-label, randomized phase III trial
Stratified by previous paclitaxel
therapy (yes vs no) and region
Pts with stage IIIB/IV

squamous NSCLC and ECOG
PS 0-1 with failure of 1
previous platinum doublet
chemotherapy
(N = 272)
Nivolumab 3 mg/kg IV q2w

(n = 135)
Docetaxel 75 mg/m2 IV q3w
(n = 137)
Until disease
progression or
unacceptable
toxicity
Primary endpoint: OS
Secondary endpoints: ORR, PFS, efficacy by PD-L1 expression, safety,
QoL
Spigel DR, et al. ASCO 2015. Abstract 8009.

CheckMate 017: Nivolumab Significantly

Improved OS and PFS vs Docetaxel
Nivolumab
(n = 135)
Docetaxel
(n = 137)
HR (95% CI)
P Value
Median OS, mos
9.2
6.0
0.59 (0.44-0.79)
.00025
Median PFS, mos
3.5
2.8
0.62 (0.47-0.81)
.0004
ORR, %
CR
PR
SD
PD
Unevaluable
20
1
19
29
41
10
9
0
9
34
35
22
Median time to
response, mos
2.2
2.1
Median duration of
response, mos
NR
8.4
Ongoing response, %
63
33
Efficacy Outcome
Spigel DR, et al. ASCO 2015. Abstract 8009.
.0083

CheckMate 057: Nivolumab vs Docetaxel

in Advanced Nonsquamous Cell NSCLC
Primary endpoints: OS
Secondary endpoints: PFS, ORR, QoL, PD-LI
protein expression
Key eligibility criteria
18 yrs of age
Stage IIIB/IV nonsquamous NSCLC
Prior platinum-containing chemotherapy (2ndline) required: additional TKI therapy allowed (3rdline)
Pt may have received continuous or switch
maintenance with pemetrexed, erlotinib, or
bevacizumab post platinum-containing
chemotherapy
ECOG PS 1
No prior treatment with anti-PD-1, anti-PD-L1,
anti-PD-L2, anti-CD137 or anti-CTLA-4 or other
antibody targeting T-cell costimulation or
checkpoint pathways
ClinicalTrials.gov. NCT01673867.

CheckMate 057: Increased Efficacy of Nivo

vs Docetaxel in Nonsquamous NSCLC
Nivolumab
(n = 292)
Docetaxel
(n = 290)
HR (95% CI)
P Value
Median OS, mos
12.2
9.4
0.73 (0.59-0.89)
.0015
Median PFS, mos
2.3
4.2
0.92 (0.77-1.11)
.3932
ORR, %
CR
PR
SD
PD
Unevaluable
19
1
18
25
44
11
12
<1
12
42
29
16
1.72 (1.1-2.6)*
.0246
Median time to
response, mos
2.1
2.6
Median duration of
response, mos
17.2
5.6
52
14
Efficacy Outcome
Ongoing response, %
*Odds ratio (95% CI).
Paz-Ares L, et al. ASCO 2015. Abstract LBA109.

KEYNOTE 001: Pembrolizumab as Initial

Therapy in Pts With Advanced NSCLC
Treatment-naive, stage IV NSCLC
ECOG PS 0-1
Phase I trial
(N = 45)
Pembrolizumab
10 mg/kg q3w
PD
Pembrolizumab
10 mg/kg q2w
PD
EGFR negative*
No ALK rearrangement*
PD-L1 positive ( 1% staining)
No systemic steroid
No autoimmune disease
No or stable brain mets
Objectives
R
1:1*
Mandatory biopsy
within 60 days of first dose
Evaluate safety, tolerability, and clinical activity of pembrolizumab, a PD-1blocking antibody
Evaluate correlation between clinical activity of pembrolizumab and PD-L1 expression
Response assessment
Primary measure: RECIST v1.1 per independent central review
Secondary measure: immune-related response criteria per investigator assessment
*First 11 pts randomized to 2 mg/kg q3w and 10 mg/kg q3w (until protocol Amendment 07) and could have a sensitizing
EGFR mutation or ALK rearrangement.
Balmanoukian AS, et al. Chicago Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 2.

PFS (RECIST v1.1, Central Review)

100
Treatment naive
80
Previously treated
60
40
100
80
60
40
20
20
Pts at Risk, n
Treatment naive 45
Previously treated 217
16
24
Wks
32
40
48
39
159
25
81
11
33
4
13
2
2
0
0
Treatment naive
Median PFS: 27 wks (95% CI: 14-45)
24-wk PFS: 51%
Previously treated
Median PFS: 10 wks (95% CI: 9.1-15.3)
24-wk PFS: 26%
Garon E, et al. ESMO 2014. Abstract LBA43.
OS
OS (%)
PFS (%)
KEYNOTE-001 Study: Survival
Treatment naive
Previously treated
0
45
217
41
192
4
38
146
6
8
Mos
24
77
13
33
10
7
8
12
2
0
Treatment naive
Median OS: NR (95% CI: NE-NE)
6-month OS: 86%
Previously treated
Median OS: 8.2 mos (95% CI: 7.3-NR)
6-month OS: 59%
14
0
0

Ongoing Studies of Pembrolizumab in

NSCLC
KEYNOTE-010
KEYNOTE-024
KEYNOTE-042
(NCT01905657)
PD-L1+ advanced
NSCLC*
PD following platinum
doublet chemotherapy
(NCT02142738)
Strongly PD-L1+
advanced NSCLC*
No prior therapy
(NCT02220894)
PD-L1+ advanced
NSCLC*
No prior therapy
R
1:1
N = 300
R
1:1:1
N = 920
Pembro
2 mg/kg
q3w
Pembro
10 mg/kg
q3w
Pembro
200 mg
q3w
R
1:1
N = 1240
Platinumbased
chemo
Pembro
200 mg
q3w
Platinumbased
chemo
Docetaxel
Primary endpoints: OS, PFS
*As assessed using the clinical trial assay and the 22C3 antibody.
Garon EB, et al. ESMO 2014. Abstract LBA43.
Primary endpoint: OS

POPLAR: Atezolizumab (MPDL3280A) Efficacy

Increased With Higher PD-L1 Expression
Interim Median OS Outcomes,
mos
Atezolizumab
(n = 144)
Docetaxel
(n = 143)
HR (95% CI)
P Value
ITT population (N = 287)
11.4
9.5
0.77 (0.55-1.06)
.11
Subgroups based on PD-L1

expression*
TC0 and IC0 (n = 92)
TC1/2/3 or IC1/2/3 (n = 195)
TC2/3 or IC2/3 (n = 105)
TC3 or IC3 (n = 47)
9.7
NR
13.0
NR
9.7
9.1
7.4
11.1
1.12 (0.64-1.93)
0.63 (0.42-0.94)
0.56 (0.33-0.94)
0.46 (0.19-1.09)
.70
.024
.026
.070
*PD-L1 expression measured by SP142 IHC assay (low expression TC0/IC0, high expression - TC3/IC3).
PFS and ORR: similar trends in outcome for atezolizumab vs docetaxel based on
PD-L1 expression
Median PFS in ITT population: 2.8 vs 3.4 mos (HR: 0.98)

Median PFS in TC3 or IC3 population: 7.8 vs 3.9 mos (HR: 0.57)
ORR in ITT population: 15% vs 15%
ORR in TC3 or IC3 population: 38% vs 13%
Interim data based on minimum of 10 mos of follow-up
Spira AI, et al. ASCO 2015. Abstract 8010.

Select AntiPD-L1 Immunotherapy Trials

in Locally Advanced or Metastatic NSCLC
Trial
Design
Key Eligibility Criteria
Birch (phase II)
635
MPDL3280A
PD-L1+ tumor
Fir (phase II)*
128
MPDL3280A
PD-L1+ tumor
Poplar (phase II)*
287
MPDL3280A vs docetaxel
Failure of plt-based CT
Oak
1100 MPDL3280A vs docetaxel
Pacific
702
Arctic (planned)
*Enrollment is complete.
ClinicalTrials.gov.
MEDI4736 vs placebo
MEDI4736
tremelimumab
vs SOC CT
Failure of plt-based CT or
combined modality therapy
Stage III, 2 cycles
plt-based CT + RT

Summary
Histology still guides the therapeutic choice for the vast majority
of pts
Molecular testing is standard of care for pts with stage IV nonsmall-cell lung cancer and adenocarcinoma component
Ramucirumab, nivolumab new options for treatment
Important to factor pt age and PS as well as optimal
management of treatment-related adverse effects
Most pts relapse or are refractory to existing therapies;
promising agents under investigation include immunotherapies
and small-molecule inhibitors of EGFR and VEGFR pathways
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Transformations in the Care of

This program is supported by educational grants from

Transformations in the Care of Metastatic Disease

About These Slides

Transformations in the Care of Metastatic Disease

Associate Professor of Medicine, Oncology

Transformations in the Care of Metastatic Disease

Individualizing Therapy for

Transformations in the Care of Metastatic Disease

Changes in the Therapeutic Landscape of

Transformations in the Care of Metastatic Disease

Paradigm Shift in Pathology . . .

IHC, special stains

Transformations in the Care of Metastatic Disease

NSCLC Biopsy: Key Factors

Rebiopsy at time of progression helpful in determining

Transformations in the Care of Metastatic Disease

Circulating Tumor DNA

Crowley E, et al. Nat Rev Clin Oncol. 2013;10:472-484.

Transformations in the Care of Metastatic Disease

Histology in Management of AdvancedStage Non-OncogeneDriven NSCLC

Transformations in the Care of Metastatic Disease

Pathologic Assessment of Histology Helps

Transformations in the Care of Metastatic Disease

Histologic Subtypes of NSCLC: US

85% of lung cancers are NSCLC

Cancer Incidence (%)

Yr of Diagnosis (3-Yr Moving Average)

Tumor Molecular Profile

Transformations in the Care of Metastatic Disease

Molecular Subsets of Lung Cancer

*Double mutations are rare (<

Transformations in the Care of Metastatic Disease

Selection for Molecular Testing in NSCLC

All pts with an adenocarcinoma

Pure SCC diagnosis is appropriate for

Young, never, or light smoker

Poor quality/small sample

East Asian ethnicity (EGFR mut testing)

Primary tumors and metastatic lesions

Discordance between mut status primary

If sensitizing EGFR mutation or ALK

Transformations in the Care of Metastatic Disease

Molecular Testing Guideline: EGFR and

Pts SHOULD NOT be offered or denied testing based on

Selecting Therapy Based on

Transformations in the Care of Metastatic Disease

Cis/Gem vs Cis/Pem in Advanced NSCLC:

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

Transformations in the Care of Metastatic Disease

Pts with stage IIIb/IV

Nab-Paclitaxel 100 mg/m2 on Days 1, 8, 15 +

Socinski MA, et al. J Clin Oncol. 2012;30:2055-2062.

Transformations in the Care of Metastatic Disease

Response Rate (%)

Transformations in the Care of Metastatic Disease

Transformations in the Care of Metastatic Disease

Maintenance Therapy for Pts With

Early 2nd-line Therapy

*After initial platinum-based

NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v.5.2015.

Transformations in the Care of Metastatic Disease

NSCLC Maintenance Therapy: