david r. gandara, md professor of clinical medicine university of california davis cancer center...
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David R. Gandara, MDProfessor of Clinical MedicineUniversity of California Davis Cancer CenterDavis, California
Therapeutic Decision Making in Advanced NSCLC:A 2012 Perspective
This program is supported by educational grants from
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
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clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
David R. Gandara, MD, has disclosed that he has received research grants from Bristol-Myers Squibb, Genentech, ImClone, Eli Lilly and Company, Merck, and Novartis; served as consultant for Amgen, Array, AstraZeneca, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, ImClone, Merck, Novartis, Response Genetics, and sanofi-aventis.
Faculty Disclosure
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Histology Maintenance
Predictive Biomarkers
Factors are interlinking and not independent
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
65-yr-old malesmoker,
squamous
KRAS Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
39-yr-old female
never-smoker,adenoca
EGFR Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
65-yr-old malesmoker,
squamous
KRAS Mt
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
ALK fusion
54-yr-old malenever-smoker,
adenoca
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
In 2012: Most oncologists would agree that these patients have very different malignancies
Most oncologists would agree that these patients should receive different therapy
39-yr-old female
never-smoker,adenoca
EGFR Mt
65-yr-old malesmoker,
squamous
KRAS Mt
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
CCO survey. 2012.
Nonsquamous Histology
Molecular Marker Status: EGFR Mutation Positive, ALK Fusion Negative
*Assume “standard risk” patient (no hemoptysis, no brain mets, no severe comorbidities that would alter decision making).†Assume patient has had a PR to first-line therapy and now has a PS of 0 and is asymptomatic.
Therapy Choices
Targeted therapyT0. No targeted therapyT1. BevacizumabT2. CetuximabT3. Erlotinib T4. Crizotinib
PlatinumP0. No platinumP1. CisplatinP2. Carboplatin
Nonplatinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide
Age , Yrs
Zubrod PS Smoking History
Your Treatment Recommendations
Primary Patient Desire: Response and Survival
Primary Patient Desire: QoL and Low Risk for AEs
First line* Maintenance† First line* Maintenance†
Younger than 70 0, 1 Never/former light
T0P0C0
T0P0C0
T0P0C0
T0P0C0
Younger than 70 0, 1 Former heavy/current
T0P0C0
T0P0C0
T0P0C0
T0P0C0
Younger than 70 2 Never/former light
T0P0C0
T0P0C0
T0P0C0
T0P0C0
Younger than 70 2 Former heavy/current
T0P0C0
T0P0C0
T0P0C0
T0P0C0
70 or older 0, 1 Never/former light
T0P0C0
T0P0C0
T0P0C0
T0P0C0
70 or older 0, 1 Former heavy/current
T0P0C0
T0P0C0
T0P0C0
T0P0C0
70 or older 2 Never/former light
T0P0C0
T0P0C0
T0P0C0
T0P0C0
70 or older 2 Former heavy/current
T0P0C0
T0P0C0
T0P0C0
T0P0C0
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Algorithm for Therapy of Advanced-Stage NSCLC: 2009
*Docetaxel, paclitaxel, vinorelbine.
Molecular Clinical (PS)
Progression
Clinical
Histologic
Second
line
First line
Ma
inte
na
nce
Bevacizumab or erlotinib or pemetrexed
Pemetrexed or erlotinib Erlotinib Based on previous
therapy
Chemotherapy by algorithm
Based on previous therapy
Based on previous therapy Based on previous therapy
End of first-line chemotherapy
Platinum/pemetrexed (or other*) ± bevacizumab
Platinum/pemetrexed (or other*)
Platinum/gemcitabine (or other*)
Bevacizumab eligible
Bevacizumab ineligible
Single-agent chemotherapy
SquamousNonsquamousErlotinib
EGFR mutation positive Good PS POOR PS
Proposed Treatment Algorithm
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Advanced-Stage NSCLC & PS 0-1
EFGR mutation and ALK negative and nonsquamous
histology
EFGR mutation and ALK negative and squamous
histology
Bevacizumab appropriate
Bevacizumab inappropriate
EGFR mutation positive
Erlotinib or gefitinibfirst line
Consider crizotinib first or second line
ELM4-ALK positive
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012
Consider carboplatin/paclitaxel +
bevacizumab or
cisplatin/pemetrexed± bevacizumab
Considercisplatin or carboplatin
combined with docetaxel or
gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
Considercisplatin or carboplatin
combined with pemetrexed, docetaxel
or gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Molecular
Advanced-Stage NSCLC & PS 0-1
EFGR mutation and ALK negative and nonsquamous
histology
EFGR mutation and ALK negative and squamous
histology
Bevacizumab appropriate
Bevacizumab inappropriate
EGFR mutation positive
Erlotinib or gefitinibfirst line
Consider crizotinib first or second line
ELM4-ALK positive
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012
Consider carboplatin/paclitaxel +
bevacizumab or
cisplatin/pemetrexed± bevacizumab
Considercisplatin or carboplatin
combined with docetaxel or
gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
Considercisplatin or carboplatin
combined with pemetrexed, docetaxel
or gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
Histology: Clinical
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Histology Maintenance Therapy
Predictive Biomarkers
Factors are interlinking and not independent
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Observation: Differential efficacy of pemetrexed in squamous vs nonsquamous subtypes of NSCLC
JMDB: Pemetrexed/cisplatin vs gemcitabine/cisplatin in first-line therapy of advanced NSCLC[1]
JMEI: Pemetrexed vs docetaxel in second-line therapy of advanced NSCLC[2]
JMEN: Pemetrexed vs placebo as maintenance therapy of NSCLC[3]
1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.2. Otani S, et al. Gan To Kagaku Ryoho. 2012;39:59-62.3. Greenhalgh J, et al. Health Technol Assess. 2010;14(suppl 2):33-39.
Hypothesis: Treatment of NSCLC Should Be Histology Based
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
No difference in overall PFS or survival between study arms
Cis/Pem improves survival over CG in non-SCCA (HR: 0.81; P = .005)
Cis/Gem improves survival over CP in SCCA (HR: 1.23; P = .05)
Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.
JMDB Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC
0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0
Survival Time (Mos) in All Patients
Su
rviv
al
Pro
bab
ilit
y
CPCG
CP vs CG
Median (95% CI)10.3 (9.8-11.2)10.3 (9.6-10.9)
Adjusted HR (95% CI)0.94 (0.84-1.05)
0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0
Survival Time (Mos) in All PatientsWith Nonsquamous Histology
Su
rviv
al
Pro
bab
ilit
y
CPCG
CP vs CG
Median (95% CI) 11.8 (10.4-13.2)10.4 (9.6-11.2)
Adjusted HR (95% CI)0.81 (0.70-0.94)
0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0
Survival Time (Mos) in All Patients
Su
rviv
al
Pro
bab
ilit
yCPCG
CP vs CG
Median (95% CI) 9.4 (8.4-10.2)10.8 (9.5-12.1)
Adjusted HR (95% CI)1.23 (1.00-1.51)
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
SWOG Database Analysis of Taxane/Vinca- Based Therapy in Adv NSCLC by Histology N = 741
S9806, S0003, and CDDP/vin arm of S9308
No difference in any efficacy outcome by histology
Histology N (%)
OS PFS
Median, Mos Adjusted HR* Median, Mos Adjusted HR*
Adeno 424 (57) 8.5 1.00 (referent) 4.3 1.00 (referent)
SCCA 128 (17) 8.4 0.987 (P = .89)† 4.5 0.986 (P = .89)‡
Large cell 82 (11) 7.9 0.974 (P = .83) 4.2 1.03 (P = .81)
NSCLC, NOS 107 (14) 9.6 0.971 (P = .79) 5.0 0.87 (P = .20)
*HR from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex. †HR for SCCA vs all others combined, OS: 0.995 (95% CI: 0.82-1.21; P = .96). ‡HR for SCCA vs all others combined, PFS: 1.01 (95% CI: 0.83-1.22; P = .94)
Chansky K, et al. IASLC WCLC 2009. Abstract B2.7
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.
Histology Not a Predictor of Survival From Antimicrotubule or Gem.-Based Therapy
0 6 12 18 24 360
0.2
0.4
0.6
0.8
1.0
OS (Mos)
Pro
po
rtio
n S
urv
ivin
g
30
All Patients (N = 607)
AdenoOther
Large cellSquamous
0 6 12 18 24 360
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
30
PC Patients (n = 201)
AdenoOther
Large cellSquamous
OS (Mos)
0 6 12 18 24 360
0.2
0.4
0.6
0.8
1.0
OS (Mos)
Pro
po
rtio
n S
urv
ivin
g
30
VC Patients (n = 201)
AdenoOther
Large cellSquamous
0 6 12 18 24 360
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
30
GC Patients (n = 205)
AdenoOther
Large cellSquamous
OS (Mos)
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted Therapy) Histologic subtyping groups tumors based on microscopic
pattern recognition by a pathologist (using 1800s’ technology)
At best, histology = “crude molecular selection”
Molecular ProfilingMolecular ProfilingVan LeeuwenHoek
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Squamous
Small Cell
Adenocarcinoma
Normal lu
ng
TS
SCLC: highest TS Squamous: high TS Adeno: low TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.
2001;98:13790-13795.
Thymidylate Synthase Expression in Lung Cancer
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
TS mRNA Results by Histology (N = 1671):Squamous vs Adenocarcinoma
Biomarker NSCLC: Total (N = 1671)
NSCLC: SCCA (n = 316)
NSCLC: AC (n = 649)
SCCA vs AC P Value
TS Median 2.71 4.1 2.5 < .001*
Range 0.14-68.0 0.14-59.3 0.39-68.0 *Mann-Whitney test
TS (Reference < 2.33 for Pemetrexed)
% Below Reference Level
NSCLC: total 41.3
NSCLC: adenoca 45.7
NSCLC: SCCA 25.9
Gandara DR, et al. ASCO 2010. Abstract. 7513.
1412
10
TS 8
6
420
AC SCCA
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Histology Maintenance Therapy
Predictive Biomarkers
Factors are Interlinking and not independent
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Platinum-based doublet chemotherapy:4 cycles of “induction”
eg, cisplatin + agent “A”
Platinum-based doublet chemotherapy:4 cycles of “induction”
eg, cisplatin + agent “A”
Same agent “A” until PD or toxicity
Different agent “C” until PD or toxicity
Continuation maintenanceContinuation maintenance
Switch maintenanceSwitch maintenance
Maintenance Therapy Terminology:“A Rose by Any Other Name”?
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Agent/Control Arm N PFS Salvage Treatment,
%
OS
Fidias[1] DocetaxelDelayed docetaxel
309 5.7 mos HR: 0.632.7 mos P = .001
63 12.3 HR: 0.809.7 P = .085
Ciuleanu[2] PemetrexedPlacebo
663 4.0 mos HR: 0.502.6 mos P < .0001
67 13.4 HR: 0.7910.6 P = .012
Cappuzzo[3] ErlotinibPlacebo
889 12.3 wks HR: 0.7111.1 wks P < .0001
72 12.0 HR: 0.8111.0 P = .0088
Miller[4] Erlotinib + bevacizumabPlacebo + bevacizumab
768 4.8 mos HR: 0.723.8 mos P = .001
55.5 15.9 HR: 0.9013.9 P = .2686
Perol[5] ErlotinibObservation
310 2.9 mos HR: 0.821.9 mos P = .002
81.9 NA HR: .91NA
Zhang[6] GefitinibPlacebo
296 4.8 mos HR: 0.422.6 mos P < .0001
58.8 18.7 HR: .8416.9 P = .2608
1. Fidias P, et al. J Clin Oncol. 2010;28:5116-5123. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440.3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA, et al. ASCO 2009. Abstract LBA8002.5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Zhang L, et al. ASCO 2011. Abstract LBA7511.
Summary of “Switch Maintenance” Trials
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Study Yr Induction Therapy Maintenance Therapy Median PFS, Mos
Median OS, Mos
Main Grade 3/4 Toxicities
Brodowicz[1] 2006 Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4
Gemcitabine 1250 mg/m2 on Days 1,8
BSC
6.6
5.0(P < .001)
13.0
11.0
Maintenance Gem: ANC 14.9%, Plts 1.7%; blood transfusion: 20% gemcitabine vs 6.3% BSC
Belani[2] 2010 Gemcitabine 1000 mg/m2 on Days 1, 8 + carboplatin AUC 5 on Day 1 x 4
Gemcitabine 1000 mg/m2
on Days 1,8
BSC
7.4
7.7(P = .575)
8.0
9.3(P = .838)
ANC: 15% chemo, 2% BSC; Plts: 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC
Perol[3] 2010 Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4
Gemcitabine 1000 mg/m2 on Days 1,8
BSC
3.8
1.9(P < .0001)
NR
NR
At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6%
Paz Ares[4] 2011 Pemetrexed 500 mg/m2 on Day 1 + cisplatin 75 mg/m2 on Days 1 x 4
Pemetrexed 500 mg/m2 on Day 1
BSC
4.1
2.8(P
= .00006)
NR
NR
Fatigue: 4.2% pem, 0.6% BSC; Anemia: 4.5%, 0.6% BSC; ANC: 3.6% pem, 0 BSC
1. Brodowicz T, et al. Lung Cancer. 2006;52:155-163. 2. Belani CP, et al. ASCO 2010. Abstract 7506.3. Perol M, et al. ASCO 2010. Abstract 7507. 4. Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.
Continuation Maintenance Trials
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Pemetrexed: median 3.9 mos (3.0-4.2)Placebo: median 2.6 mos (2.2-2.9)Log-rank P = .0002Unadjusted HR: 0.64 (0.51-0.81)
Pem + BSC
Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.
PARAMOUNT: Continuation Pemetrexed Maintenance
Su
rviv
al P
rob
abil
ity
Mos
1.0
0.8
0.6
0.4
0.2
00 3 6 9 12 15
Placebo + BSC
Independently Reviewed PFS From Maintenance
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
“Maintenance Therapy”: Options After Platinum-Based Therapy With Non-PD
R4 (~ 6) cycles chemo stop Watch and wait
Continue same chemo “Continuation maintenance”
RDifferent chemo or another drug Early second-line therapy
R4 (~ 6) cycles chemo stop Watch and wait
Different chemo or another drug “Switch maintenance”
4 (~ 6) cycles chemo Stop Watch and wait
Options: bevacizumab, cetuximab, pemetrexed
Options: docetaxel, pemetrexed, erlotinib/gefitinib
Who decided that 4 cycles of therapy is optimal?
Gandara DR. Best of ASCO 2011.
Watch & Wait vs Maintenance/ Consolidation/Sequencing
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
The big question about maintenance therapy is WHO to treat and WHEN to treat
How do these trials relate to the patients I am treating in my office?
If 6 cycles of platinum chemotherapy are given, are the maintenance data still relevant?
If a patient achieves no response (SD) and remains symptomatic, is subsequent therapy “maintenance” or “early second-line therapy”?
If a patient achieves response and becomes asymptomatic, is “maintenance therapy” always better than “watch and wait”?
What about the underlying molecular profile of the individual patient?
In the emerging era of personalized therapy, these decisions should be made on an individual basis: “One size does not fit all”
Gandara DR. Best of ASCO 2011.
Issues to Consider Regarding Maintenance Therapy
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Histology Maintenance
Predictive Biomarkers
Factors are interlinking and not independent
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Predictive Biomarkers
Histology Maintenance Therapy
Looking Forward to 2015:Moving From Empiric to Individualized
From “One Size Fits All” to “Tailored” and “Individualized” Therapy
Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Tailored and individualized therapy
Empiric therapy
Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.
Transition From Empiric to Tailored and Transition From Empiric to Tailored and Individualized Cancer TherapyIndividualized Cancer Therapy
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
39-yr-old femaleNever-Smoker,
Adenoca
EGFR Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
CCO survey. 2012.
Nonsquamous Histology
Molecular Marker Status: EGFR Mutation Positive, ALK Fusion Negative
*Assume “standard risk” patient (no hemoptysis, no brain mets, no severe co-morbidities that would alter decision-making)**Assume patient has had a partial response to first-line therapy and now has a performance score of 0 and is asymptomatic
Therapy choices
Targeted therapyT0. No targeted therapyT1. BevacizumabT2. CetuximabT3. Erlotinib T4. Crizotinib
PlatinumP0. No platinumP1. CisplatinP2. Carboplatin
Non-platinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide
Age (years)
Zubrod PS Smoking History
Your Treatment Recommendations
Primary patient desire: Response and Survival
Primary patient desire: QOL and Low-Risk for AEs
First line* Maintenance** First line* Maintenance**
< 70 0,1 Never/Former LightT0P0C0
T0P0C0
T0P0C0
T0P0C0
< 70 0,1 Former Heavy/CurrentT0P0C0
T0P0C0
T0P0C0
T0P0C0
< 70 2 Never/Former LightT0P0C0
T0P0C0
T0P0C0
T0P0C0
< 70 2 Former Heavy/CurrentT0P0C0
T0P0C0
T0P0C0
T0P0C0
≥ 70 0,1 Never/Former LightT0P0C0
T0P0C0
T0P0C0
T0P0C0
≥ 70 0,1 Former Heavy/CurrentT0P0C0
T0P0C0
T0P0C0
T0P0C0
≥ 70 2 Never/Former LightT0P0C0
T0P0C0
T0P0C0
T0P0C0
≥ 70 2 Former Heavy/CurrentT0P0C0
T0P0C0
T0P0C0
T0P0C0
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
CCO survey. 2012.
Nonsquamous Histology
Molecular Marker Status: EGFR Mutation Positive, ALK Fusion Negative
Therapy choices
Targeted therapyT0. No targeted therapyT1. BevacizumabT2. CetuximabT3. Erlotinib T4. Crizotinib
PlatinumP0. No platinumP1. CisplatinP2. Carboplatin
Non-platinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide
Age (years)
Zubrod PS Smoking History
Your Treatment Recommendations
Primary patient desire: Response and Survival
Primary patient desire: QOL and Low-Risk for AEs
First line* Maintenance** First line* Maintenance**
< 70 0,1 Never/Former LightT3P0C0
T3P0C0
T3P0C0
T3P0C0
< 70 0,1 Former Heavy/CurrentT3P0C0
T3P0C0
T3P0C0
T3P0C0
< 70 2 Never/Former LightT3P0C0
T3P0C0
T3P0C0
T3P0C0
< 70 2 Former Heavy/CurrentT3P0C0
T3P0C0
T3P0C0
T3P0C0
≥ 70 0,1 Never/Former LightT3P0C0
T3P0C0
T3P0C0
T3P0C0
≥ 70 0,1 Former Heavy/CurrentT3P0C0
T3P0C0
T3P0C0
T3P0C0
≥ 70 2 Never/Former LightT3P0C0
T3P0C0
T3P0C0
T3P0C0
≥ 70 2 Former Heavy/CurrentT3P0C0
T3P0C0
T3P0C0
T3P0C0
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139.
EGFR Mutations and Responsiveness to Gefitinib in NSCLCPatient No.
Sex Age at Beginning of Gefitinib Therapy, Yr
Pathological Type
Previous Regimens,
n
Smoking Status
Duration of Therapy,
Mos
OS, Mos EGFR Mutation
Response
1 F 70 BAC 3 Never 15.6 18.8 Yes Major; improved lung lesions
2 M 66 BAC 0 Never > 14.0 > 14.0 Yes Major; improved bilateral lung
lesions
3 M 64 Adeno 2 Never 9.6 12.9 Yes Partial; improved lung lesions and soft-tissue mass
4 F 81 Adeno 1 Former > 13.3 > 21.4 Yes Minor; improved pleural disease
5 F 45 Adeno 2 Never > 14.7 > 14.7 Yes Partial; improved liver lesions
6 M 32 BAC 3 Never > 7.8 > 7.8 Yes Major; improved lung lesions
7 F 62 Adeno 1 Former > 4.3 > 4.3 Yes Partial; improved liver and lung
lesions
8 F 58 Adeno 1 Former 11.7 17.9 Yes Partial; improved liver lesions
9 F 42 BAC 2 Never > 33.5 > 33.5 No Partial; improved lung nodules
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Trial/Patient Group
N
Median PFS, Mos OS, Mos
Gefitinib Erlotinib
Chemo HR(95% CI)
Gefitinib Erlotinib
Chemo
Selected by Clinical Factors
I-PASS[1] East Asian, light/nonsmoker,
adeno
261 10.7 6.0 0.35 (0.23-0.52)
21.6 21.9
First-SIGNAL[2] Korean, nonsmoker, adeno
42 8.4 6.7 0.613 (0.31-1.22)
30.6 26.5
Selected by Molecular Parameter
NEJ002[3] Japan, EGFR mutant
194 10.4 5.5 0.35(0.25-0.50)
28.0 23.6
WJTOG3405[4] Japan, EGFR mutant
172 9.2 6.3 0.48 (0.33-0.71)
30.9 NR
OPTIMAL[5] China, EGFR mutant
154 13.1 4.6 0.16 (0.1-0.26)
NR NR
Spain[6] Spain, EGFR mutant
217 14.0 27.0
1. Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874. 2. Lee JS, et al. WCLC 2009. Abstract PRS.4. 3. Maemondo M, et al. N Engl J Med. 2010;362: 2380-2388. 4. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 5. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 6. Rosell R, et al. N Engl J Med. 361:958-967.
EGFR TKIs vs Chemotherapy as First-line Therapy
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Carboplatin + Paclitaxel
Gefitinib
Primary EndpointPFS (noninferiority)
Secondary EndpointsObjective response rateOS Quality of lifeDisease-related symptoms Safety and tolerability
ExploratoryBiomarkers
–EGFR mutation–EGFR gene copy number–EGFR protein expression
Patients Chemo naive 18 yrs of age or
older Adenocarcinoma
histology Never or ex-light
smokers* Life expectancy
≥ 12 wks WHO PS 0-2 Measurable stage
IIIB/IV disease
Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia, Philippines, Hong Kong, and Singapore
94% never-smokers; ~ 80% femaleMok TS, et al. N Engl J Med. 2009;361:947-957.
IPASS: Importance of EGFR Mutation on Patient Outcome—Gefitinib vs Chemo
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
EGFR Mutation Positive EGFR Mutation Negative
Treatment by subgroup interaction test, P < .0001
HR: 0.48 (95% CI: 0.36-0.64; P < .0001)
Gefitinib events , n (%) 97 (73.5)C/P events, n (%) 111 (86.0)
Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)
HR: 2.85 (95% CI: 2.05-3.98; P < .0001)
Gefitinib events, n (%) 88 (96.7)C/P events, n (%) 70 (82.4)
0 4 8 12 16 20 240
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
of
PF
S
0 4 8 12 16 20 240
0.2
0.4
0.6
0.8
1.0
Pro
ba
bil
ity
of
PF
S
Gefitinib (n = 91)Carboplatin/paclitaxel (n = 85)
Mos Mos
Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy
Front-line EGFR TKI should be restricted to EGFR mutation–positive patients
Mok TS, et al. N Engl J Med. 2009;361:947-957.
IPASS: PFS in EGFR Mutation–Positive and –Negative Patients
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Mos
Su
rviv
al D
istr
ibu
tio
n F
un
ctio
n
1.00
0 6 12 18 24 30
0.75
0.50
0.25
0
ErlotinibPlacebo
HR: 0.73 (95% CI: 0.61-0.86*; P < .001†)4.7 mos
6.7 mos
BR.21 results not explained by EGFR mutation alone BR.21 survival primarily the results of increased SD and increased disease control rate This represents largely a “cytostatic effect” in patients with
EGFR wild-type cancers This disease control rate effect may also be true for
cetuximab in NSCLC (FLEX and S0342 trials)
Shepherd FA, et al. N Engl J Med. 2005;353:123-132.
*From Cox regression model.†From 2-sided log-rank test.
BR.21 (Erlotinib vs Placebo): OS
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Cytotoxic vs Cytostatic Effects of EGFR TKIs (Erlotinib) in NSCLC Cytotoxic effects (apoptosis) primarily seen in EGFR Mt+ cancers (objective response)
Cytostatic effects (growth arrest) predominate in EGFR wild-type cancers (RECIST SD; disease control rate)
Gandara DR ,et al. Clin Lung Cancer. 2009;10:148-150. Gandara DR ,et al. J Thoracic Oncol. 2010;5:1933-1938. Jänne PA ,et al. Clin Cancer Res. 2006;12:4416s-4420s.
A549 H1666 H32550
5
10
20
25
30
Per
cen
t A
po
pto
sis
15
ControlGefitinib
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
ALK fusion
54-yr-old malenever-smoker,
adenoca
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
CCO survey. 2012.
Nonsquamous Histology
Molecular Marker Status: EGFR Mutation Negative, ALK Fusion Positive
Therapy choices
Targeted therapyT0. No targeted therapyT1. BevacizumabT2. CetuximabT3. Erlotinib T4. Crizotinib
PlatinumP0. No platinumP1. CisplatinP2. Carboplatin
Non-platinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide
Age (years)
Zubrod PS Smoking History
Your Treatment Recommendations
Primary patient desire: Response and Survival
Primary patient desire: QOL and Low-Risk for AEs
First line Maintenance** First line Maintenance*
< 70 0,1 Never/Former LightT4P0C0
T4P0C0
T4P0C0
T4P0C0
< 70 0,1 Former Heavy/CurrentT4P0C0
T4P0C0
T4P0C0
T4P0C0
< 70 2 Never/Former LightT4P0C0
T4P0C0
T4P0C0
T4P0C0
< 70 2 Former Heavy/CurrentT4P0C0
T4P0C0
T4P0C0
T4P0C0
≥ 70 0,1 Never/Former LightT4P0C0
T4P0C0
T4P0C0
T4P0C0
≥ 70 0,1 Former Heavy/CurrentT4P0C0
T4P0C0
T4P0C0
T4P0C0
≥ 70 2 Never/Former LightT4P0C0
T4P0C0
T4P0C0
T4P0C0
≥ 70 2 Former Heavy/CurrentT4P0C0
T4P0C0
T4P0C0
T4P0C0
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
EML4-ALK frequency:~ 4% (64/1709)
Primarily in adenocarcinoma More common in younger patients More common in never-smokers
(~ 20%)
EML4-ALK frequency:~ 4% (64/1709)
Primarily in adenocarcinoma More common in younger patients More common in never-smokers
(~ 20%)
Soda M, et al. Nature. 2007;448:561-566.
EML4-ALK Translocations in NSCLC
EML4
EML4-ALK variant 1
ALK1 1058 1620
10591
1 496 981HELP
TM
Kinase
WDBasic
496
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
ALK-Positive NSCLC and Impact of ALK Inhibition
ALK Rearrangement in NSCLC
Rarely overlaps with EGFR and KRAS mutations
Clinical testing
– Break-apart FISH assay (FDA-approved test)
– IHC
– RT-PCR
Activity of ALK Inhibitor Crizotinib in Patients With Advanced ALK-FISH–
Positive NSCLC (N = 82)
Shaw AT, et al. ASCO 2011. Abstract 7507.Shaw AT, et al. ASCO 2011. Abstract 7507.
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
65-yr-old malesmoker,
squamous
KRAS Mt
Interpatient Heterogeneity in the Molecular Characteristics of NSCLC
Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
CCO survey. 2012.
Squamous Histology
Molecular Marker Status: EGFR Mutation Negative, ALK Fusion Negative
Therapy choices
Targeted therapyT0. No targeted therapyT1. BevacizumabT2. CetuximabT3. Erlotinib T4. Crizotinib
PlatinumP0. No platinumP1. CisplatinP2. Carboplatin
Non-platinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide
Age (years)
Zubrod PS Smoking History
Your Treatment Recommendations
Primary patient desire: Response and Survival
Primary patient desire: QOL and Low-Risk for AEs
First line Maintenance* First line Maintenance*
< 70 0,1 Never/Former LightT2P1C2
T2P0C0
T2P2C1
T2P0C0
< 70 0,1 Former Heavy/CurrentT2P1C2
T2P0C0
T2P2C1
T2P0C0
< 70 2 Never/Former LightT2P1C2
T2P0C0
T2P2C1
T2P0C0
< 70 2 Former Heavy/CurrentT2P1C2
T2P0C0
T2P2C1
T2P0C0
≥ 70 0,1 Never/Former LightT2P1C2
T2P0C0
T2P2C1
T2P0C0
≥ 70 0,1 Former Heavy/CurrentT2P1C2
T2P0C0
T2P2C1
T2P0C0
≥ 70 2 Never/Former LightT2P1C2
T2P0C0
T2P2C1
T2P0C0
≥ 70 2 Former Heavy/CurrentT2P1C2
T2P0C0
T2P2C1
T2P0C0
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Advanced-Stage NSCLC and PS 0-1
EFGR mutation and ALK negative and nonsquamous
histology
EFGR mutation and ALK negative and squamous
histology
Bevacizumab appropriate
Bevacizumab inappropriate
EGFR mutation positive
Erlotinib or gefitinibfirst line
Consider crizotinib first or second line
ELM4-ALK positive
Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.
Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012
Consider carboplatin/paclitaxel +
bevacizumab Or
cisplatin/pemetrexed± Bevacizumab
Considercisplatin or carboplatin
combined with docetaxel or
gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
Consider cisplatin or carboplatin
combined with pemetrexed, docetaxel
or gemcitabine or paclitaxel
orcisplatin/vinorelbine
± cetuximab
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Cetuximab + Cisplatin + Vinorelbine
(n = 550)
Cisplatin + Vinorelbine(n = 550)
Stage IIIB or IV EGFR positive
Survival
Eligibility criteria: EGFR-expressing, advanced-stage NSCLC; no previous CT
Primary endpoint: median OS (845 events needed)
Secondary endpoints: survival rate (1 and 2 yrs), PFS rate (6 and 12 mos), response rate, safety, QoL
Sample size: 1100 in 170 centers in EU, Latin America, Asia
R
Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.
FLEX: Chemotherapy ± Cetuximab in First-line Therapy of Advanced NSCLC
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.
FLEX: Response and OS by IHC Score
6Mos
0
2040
OS
(%
)
60
P = .36
CT + cetuximabCT
Treatment interaction test P = .040
P = .002
O’Byrne et al. JPO 20120,12 (suppl), S558 (LBOAI)
Interaction P = .044
CT + cetuximabCT
FLEX: Response Rate by EGFR Expression Levels(IHC Score)
Low EGFR Expression (< 200), n = 776 (69%)
High EGFR Expression (≥200), n = 345 (31%)
28.1
44.4
0 12 18 24 30
80100
Low EGFR High EGFR
HR: 0.99 (95% CI: 0.84-1.16)
HR: 0.73 (95% CI: 0.58-0.93)
Predictive Value of High EGFR for Survival Benefit With CT + Cetuximab
Mos
29.6 32.6
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Pts at Risk, n
CT 69 42 2 017 7CT + cetuximab 75 52 10 032 19
OS
(%
)
Mos
0
20
40
60
80
100
180 6 12 24 30
SurvivalMedian, Mos 1 Yr, %
11.2 44
8.9 25
Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.
FLEX Survival: High EGFR ExpressionSquamous Cell Carcinoma (N = 144)
HR: 0.62 (95% CI: 0.43-0.88)
▬ CT▬ CT + cetuximab
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
ClinicalTrials.gov. NCT00946712. PI: R. Herbst
Marker testing
Marker +
Marker -
Chemo
Chemo/Cetux
Chemo
Chemo/Cetux
Stratify Randomize
M+
M+
M-
M-
Chemotherapy: Paclitaxel/Carboplatin
Primary endpoints: OS for entire studyPFS for EGFR FISH
Integrated: EGFR IHC score
S0819: Chemotherapy ± Cetuximab and Predictive Biomarker Validation EGFR FISH
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
MET AMP
Gene Event Type Frequency, %
FGFR1 Amplification 20-25
FGFR2 Mutation 5
PIK3CA Mutation 9
PTEN Mutation deletion 18
CCND1 Amplification 8
CDKN2A Deletion/mutation 45
PDGFRA Amplification mutation
9
EGFR Amplification 10
MCL1 Amplification 10
BRAF Mutation 3
DDR2 Mutation 4
ERBB2 Amplification 2
Emerging “Druggable” Targets in NSCLC-Squamous SubtypeLung Cancer Molecular Lung Cancer Molecular
ConsortiumConsortium Lung AdenocarcinomasLung Adenocarcinomas
Mutations found in 54% (280/516)
Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01
Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1
Potential “Druggable” Molecular Targets?
No MutationDetected KRAS
22%
EGFR17%
NRAS
DoubleMutants 3%
AKT1
BRAF 2%
MEK1
HER2PIK3CA 2%
EML4-ALK7%
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
CASTLE Network
CASTLE BiospecimensSerumRNA/DNA
Biorepository
Genomics/Proteomics/Clinical Outcomes
Core Biopsy
Biorepository
ResponseDXTM
ERCC1 gene expressionRRM1 gene expressionKRAS mutation analysisEGFR amplificationTS expression
EGFR-TKI:a) candidate
orb) contraindicated
RNA DNA
Plasma
Submissions SubmissionVeriStrat ®
clinical
research
ALCMI (Addario Lung Cancer Medical Institute)
Moving Toward 2015: CASTLE Network
clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective
Lung Cancer Therapy: 2012 Looking Forward to 2015 We are making progress
– Histology
– Maintenance therapy
– Predictive biomarkers
Progress requires continuing change
– “Culture change”
– Requirement for more tumor tissue (molecular profiling)
– “Ungroup” NSCLC into individual patients (personalized therapy)
Reality: the transition to rationally selected and personalized therapy is challenging
– In every challenge, there are opportunities
– We must take advantage of each of these opportunities if we are to advance the care and cure of patients with lung cancer
Go Online for More CCO Coverage of Advanced Lung Cancer!
clinicaloptions.com/oncology
Interactive Decision Support Tool: With just a few clicks through pulldown menus, this Interactive Decision Support Tool allows users to enter their patients’ specific characteristics along with the treatment options they would likely choose and then provides expert insight from 5 lung cancer experts regarding optimal choices for first-line and maintenance therapy for advanced NSCLC.