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Individualized Tx in NSCLC:Individualized Tx in NSCLC:How Do We Tackle Advanced How Do We Tackle Advanced
Squamous Cell Ca of the LungSquamous Cell Ca of the Lung
Corey J Langer MD, FACPCorey J Langer MD, FACPProfessor of MedicineProfessor of Medicine
Director of Thoracic OncologyDirector of Thoracic OncologyAbramson Cancer CenterAbramson Cancer CenterUniversity of PennsylvaniaUniversity of Pennsylvania
Philadelphia, PA 19104Philadelphia, PA [email protected]
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DisclosuresDisclosures Grant/Research SupportGrant/Research Support::
– Bristol Myers SquibbBristol Myers Squibb, Pfizer, , Pfizer, Imclone, Imclone, Lilly, Schering-Plough Lilly, Schering-Plough Research Institute, Sanofi-Aventis, Amgen, Cell Therapeutics Research Institute, Sanofi-Aventis, Amgen, Cell Therapeutics Inc., OrthoBiotech, Celgene, Vertex, Inc., OrthoBiotech, Celgene, Vertex, Genentech, OSIGenentech, OSI, , AstraZeneca, AstraZeneca, Pfizer, Active Biothech, MedimmunePfizer, Active Biothech, Medimmune
Scientific Advisor:Scientific Advisor:– Bristol Myers Squibb, Imclone, Bristol Myers Squibb, Imclone, Sanofi-Aventis, Pfizer-Sanofi-Aventis, Pfizer-
Pharmacia, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Pharmacia, Intrabiotics, GlaxoSmithKline, Pharmacyclics, Amgen, Amgen, AstraZeneca, AstraZeneca, Novartis, Novartis, Genentech, OSI, Genentech, OSI, Savient, Savient, Bayer/Onyx, Abraxis, Clarient, SyntaBayer/Onyx, Abraxis, Clarient, Synta
Speakers Bureau:Speakers Bureau: curtailed as of 12/10 curtailed as of 12/10– Bristol Myers Squibb, Imclone, Bristol Myers Squibb, Imclone, Sanofi- Aventis, Lilly, Sanofi- Aventis, Lilly,
OrthoBiotech, OrthoBiotech, Genentech, OSIGenentech, OSI
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Lung CancerLung Cancer In 2010, ~213,380 new cases and ~160,390 deaths In 2010, ~213,380 new cases and ~160,390 deaths
are predicted in the United Statesare predicted in the United States Second most common cancer in men and women Second most common cancer in men and women
and leading cause of cancer deathsand leading cause of cancer deaths Accounts for more deaths than breast, colon and Accounts for more deaths than breast, colon and
prostate cancer combinedprostate cancer combined Unfavorable stage distribution at the time of Unfavorable stage distribution at the time of
diagnosisdiagnosis Types of lung cancerTypes of lung cancer
– Non–small cell lung cancer (NSCLC): 87%Non–small cell lung cancer (NSCLC): 87% 1/2 to 2/3 adenoca1/2 to 2/3 adenoca 1/3+ squamous and other histologies1/3+ squamous and other histologies
– Small cell lung cancer (SCLC): 13%Small cell lung cancer (SCLC): 13% Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007.
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Non-small Cell Lung cancerNon-small Cell Lung cancerAdenocarcinomaAdenocarcinoma
–Glandular patternGlandular pattern–Mucin positivity (50%)Mucin positivity (50%)–CK7+/CK20-CK7+/CK20-–TTF-1+ (75%)TTF-1+ (75%)
Squamous cell carcinomaSquamous cell carcinoma–Cellular keratinizationCellular keratinization–Intercellular bridgesIntercellular bridges–Keratin “pearl” formationKeratin “pearl” formation–CK7-/CK20-CK7-/CK20-–TTF-1 negTTF-1 neg–P63 or p40+ or CK5/6+P63 or p40+ or CK5/6+
Common, but not 100%Common, but not 100%
WHOWHO
Common, Common, but not 100%but not 100%
WHOWHO
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Histologic Distinctions in Histologic Distinctions in NSCLCNSCLC
Squamous:Squamous: – More central presentationMore central presentation– Higher incidence of locoregional recurrenceHigher incidence of locoregional recurrence– Decreased incidence of metastatic spreadDecreased incidence of metastatic spread– Relatively more common in men, Eastern Europe, smokersRelatively more common in men, Eastern Europe, smokers– Declining incidence overallDeclining incidence overall
Adenocarcinoma: Adenocarcinoma: – More often peripheralMore often peripheral– Higher incidence of metastatic spreadHigher incidence of metastatic spread– Less profound link with tobacco useLess profound link with tobacco use– Increasing incidence; relatively more common in womenIncreasing incidence; relatively more common in women
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Therapeutic ImplicationsTherapeutic ImplicationsHistologic PrismHistologic Prism Tendency until 2005 to “lump” NSCLC histologiesTendency until 2005 to “lump” NSCLC histologies
– Little difference in Tx outcomeLittle difference in Tx outcome Therapeutic EmpiricismTherapeutic Empiricism
– Increasing NOS designationIncreasing NOS designation Insufficient tissueInsufficient tissue Pathologic “laziness”Pathologic “laziness”
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ECOG 1594:ECOG 1594: Overall Overall Survival by Treatment Survival by Treatment GroupGroup 1207 patients, stage IIIB/IV :(15/85%), PS 0–2; Median age 63, M/F (64/36%)
Schiller JH et al. NEJM. 2002;346(2):92-98.
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Therapeutic ImplicationsTherapeutic ImplicationsHistologic PrismHistologic Prism
Tendency until 2005 to “lump” NSCLC histologiesTendency until 2005 to “lump” NSCLC histologies– Little difference in Tx outcomeLittle difference in Tx outcome
Therapeutic EmpiricismTherapeutic Empiricism
– Increasing NOS designationIncreasing NOS designation Insufficient tissueInsufficient tissue Pathologic “laziness”Pathologic “laziness”
Since 2004, histology and molecular fingerprints have Since 2004, histology and molecular fingerprints have become ascendantbecome ascendant– Tx restrictions and risk: bevacizumabTx restrictions and risk: bevacizumab– Histologic Variations in outcomeHistologic Variations in outcome
Adenocarcinoma: better outcome with EGFr TKI, pemetrexedAdenocarcinoma: better outcome with EGFr TKI, pemetrexed– Province of Actionable molecular markers [EGFR; ALK; ROS-1, etcProvince of Actionable molecular markers [EGFR; ALK; ROS-1, etc
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Therapeutic ImplicationsTherapeutic ImplicationsHistologic PrismHistologic Prism Tendency until 2005 to “lump” NSCLC histologiesTendency until 2005 to “lump” NSCLC histologies
– Little difference in Tx outcomeLittle difference in Tx outcome Therapeutic EmpiricismTherapeutic Empiricism
– Increasing NOS designationIncreasing NOS designation Insufficient tissueInsufficient tissue Pathologic “laziness”Pathologic “laziness”
Since 2004, histology and molecular fingerprints have become Since 2004, histology and molecular fingerprints have become ascendantascendant– Tx restrictions and risk: bevacizumabTx restrictions and risk: bevacizumab– Histologic Variations in outcomeHistologic Variations in outcome
Adenocarcinoma: better outcome with EGFr TKI, pemetrexedAdenocarcinoma: better outcome with EGFr TKI, pemetrexed– Province of Actionable molecular markers [EGFR; ALK; ROS-1, etcProvince of Actionable molecular markers [EGFR; ALK; ROS-1, etc
Squamous ca: tendency for better outcome Squamous ca: tendency for better outcome – gemcitabine vs pemetrexedgemcitabine vs pemetrexed– Nab-paclitaxel vs standard paclitaxel (RR%)Nab-paclitaxel vs standard paclitaxel (RR%)– Immunologic Tx: Ipilimumab; PD1Immunologic Tx: Ipilimumab; PD1– FGFR and PI3K as targets: still investigationalFGFR and PI3K as targets: still investigational
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An Evolving View of An Evolving View of AdenocarcinomaAdenocarcinomaEmergence of “Actionable” Molecular MarkersEmergence of “Actionable” Molecular Markers
MEK
KRAS
2000
Pending
EGFR BRAF
PIK3CA
EML4-ALK
ROS1 HER2
2014
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An Evolving View of An Evolving View of Squamous Cell CaSquamous Cell CaEmergence of “Actionable” Molecular MarkersEmergence of “Actionable” Molecular Markers
2000 2014
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An Evolving View of An Evolving View of Squamous Cell CaSquamous Cell CaEmergence of “Actionable” Molecular MarkersEmergence of “Actionable” Molecular Markers
2000 2014
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Squamous Cell Ca: Squamous Cell Ca: Wallflower at the DanceWallflower at the Dance
Safety Signals: Safety Signals: BevacizumabBevacizumab Lack of Efficacy: Lack of Efficacy: PemetrexedPemetrexed Lack of Actionable Molecular Lack of Actionable Molecular
Markers: Markers:
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Rand Phase II: Bevacizumab +Rand Phase II: Bevacizumab +Paclitaxel/Carboplatin in Advanced Paclitaxel/Carboplatin in Advanced NSCLC NSCLC
Excluded: CNS metastasis On therapeutic anticoagulation
Objectives = time to progression, response, survival, and safety
* Crossover to 15 mg/kg q3w bevacizumab allowed
Paclitaxel 200 mg/m2 carboplatin
AUC 6(PC) q3w × 6
PC × 6 + bevacizumab 15 mg/kg q3w
PC × 6+ bevacizumab7.5 mg/kg q3w
Previously untreated
metastatic NSCLC(N=98)
Bevacizumab 7.5 mg/kg q3w to PD
or unacceptable toxicity
Progression of disease*
Bevacizumab 15 mg/kg q3w to PD
or unacceptable toxicity
1. Johnson et al. J Clin Oncol. 2004;22:2184–2191.
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Randomized Phase II Trial: Randomized Phase II Trial: Pulmonary BleedingPulmonary Bleeding
6 cases of severe or fatal pulmonary hemorrhage6 cases of severe or fatal pulmonary hemorrhage– 4 (31%) of 13 bevacizumab-treated patients with squamous cell 4 (31%) of 13 bevacizumab-treated patients with squamous cell
histologyhistology– 2 (4%) of 53 bevacizumab-treated patients with histology other 2 (4%) of 53 bevacizumab-treated patients with histology other
than squamous cellthan squamous cell Patients receiving chemotherapy alone (N=32) had no Patients receiving chemotherapy alone (N=32) had no
pulmonary hemorrhagespulmonary hemorrhages On the basis of this analysis, squamous cell histology and On the basis of this analysis, squamous cell histology and
bevacizumab therapy were identified as risk factors for bevacizumab therapy were identified as risk factors for pulmonary hemorrhagepulmonary hemorrhage
These phase II data were used to design the phase III trial These phase II data were used to design the phase III trial exclusion criteria [exclusion criteria [squamous histology has been excluded ever squamous histology has been excluded ever since]since]
1. Johnson et al. J Clin Oncol. 2004;22:2184–2191.
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Study Design
Gemcitabine 1250 mg/m2 days 1 + 8 Cisplatin 75 mg/m2 day 1;
Stage IIIB/IV NSCLC
PS 0 - 1 No prior chemo Randomization:
gender, PS, stage, histo vs cyto dx, brain mets
RRRR
Pemetrexed 500 mg/m2 + Cisplatin 75 mg/m2 day 1
Primary objective: Overall Survival
15% Non-inferiority margin (HR 1.17)
N = 1700 Patients , Power 80%
B12, folate, and dexamethasone given in both arms
Scagliotti GV et al. JCO 2008; 26:3543
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Ceppi, P et al. Cancer 107:1589, 2006
“May be useful inselecting patients withNSCLC who should receive treatment withTS-inhibiting agents”
TS Expression Levels Are Higher in TS Expression Levels Are Higher in Squamous Versus AdenocarcinomaSquamous Versus Adenocarcinoma
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Phase III Trial: Cisplatin/Pemetrexed vs Phase III Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine - Cisplatin/Gemcitabine - Overall Survival in Patients with Overall Survival in Patients with Adenocarcinoma or Large Cell Ca Adenocarcinoma or Large Cell Ca --
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Non-squamous group Squamous group
Pemetrexed (n=205)
Docetaxel (n=194)
Pemetrexed (n=78)
Docetaxel (n=94)
% ECOG PS 2 12.5 10.1 8.3 17.4% TSPC <3 months 51.0 51.0 48.7 41.9
% Stage IV 81.5 78.9 57.7 66.0% Male 60.5 69.1 89.7 88.3
Median OS, months 9.3 8.0 6.2 7.4Adjusted OS HR (95% CI) 0.778 (0.607, 0.997) 1.563 (1.079, 2.264)
Median PFS, months 3.1 3.0 2.3 2.7Adjusted PFS HR (95% CI) 0.823 (0.664, 1.020) 1.403 (1.006, 1.957)
Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology
Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology
Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001)
Peterson P. et al. 12th World Conference on Lung Cancer 2007
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Progression-free Survival by Histology
JMEN Switch Maintenance Trial
0 3 6 9 12 15 18 21 240.00.10.20.30.40.50.60.70.80.91.0
0 3 6 9 12 15 18 21 240.00.10.20.30.40.50.60.70.80.91.0
Pemetrexed 4.4 mos Pemetrexed 2.4 mos
Placebo 1.8 mos
Placebo 2.5 mos
Non-Non-squamous squamous
SquamouSquamous s
Time (months) Time (months)
Pro
gre
ssio
n-f
ree P
rob
ab
ilit
y HR=0.47 (95% CI: 0.37-0.6) P <0.00001
HR=1.03 (95% CI: 0.77-1.5) P =0.896
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Overall Survival by Histology
JMEN Switch Maintenance Trial
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pemetrexed 15.5 mos Pemetrexed 9.9 mos
Placebo 10.3 mos
Placebo 10.8 mos
Non-squamous (n=481)Non-squamous (n=481) Squamous (n=182)Squamous (n=182)
HR=0.70 (95% CI: 0.56-0.88) P =0.002
HR=1.07 (95% CI: 0.49–0.73) P =0.678
Su
rviv
al P
rob
ab
ilit
y
Time (months) Time (months)
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Advanced NSCLC with Advanced NSCLC with Squamous HistologySquamous Histology
Disappointments to date have Disappointments to date have not prevented us from targeting not prevented us from targeting this group of pts in ongoing, this group of pts in ongoing, empiric trialsempiric trials
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ECOG 4508: RP2ECOG 4508: RP2Non-Bev EligibleNon-Bev Eligible
CTEP E4508
All
histology
• NSCLC
• 1st line
Carboplatin / Paclitaxel / Cetuximab Cetux
Carboplatin / Paclitaxel / A12
Carboplatin / Paclitaxel / Cetuximab / A12
1
1
1
A12
Cetux / A12
PI: N. Hanna (ECOG)PFS
N=225
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ECOG 4508: RP2ECOG 4508: RP2Non-Bev EligibleNon-Bev Eligible
CTEP E4508
All
histology
• NSCLC
• 1st line
Carboplatin / Paclitaxel / Cetuximab Cetux
Carboplatin / Paclitaxel / A12
Carboplatin / Paclitaxel / Cetuximab / A12
1
1
1
A12
Cetux / A12
PI: N. Hanna (ECOG)PFS
N=225
Suspended because of untoward toxicity in both Cetuximab arms, including an increased rate of grade 5 toxicity
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ESCAPE - Phase III Trial ESCAPE - Phase III Trial Comparing Carboplatin and Comparing Carboplatin and Paclitaxel +/- Sorafenib in NSCLCPaclitaxel +/- Sorafenib in NSCLC
Chemotherapy phase
Maintenance phase
n=900
Stratification: Geographic region ECOG PS 0 vs 1 Squamous vsnon-squamous cell
Stage IIIb (with effusion) vs Stage IV
RANDOMIZE
Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m2 d1 +
Sorafenib 400 mg bid d2-19, q3w (CPS)
Sorafenib400 mg
bid
Carboplatin AUC 6 d1 + Paclitaxel 200 mg/m2 d1 + Placebo d2-19, q3w (CPP)
Placebo
Scagliotti GV et al. Proc ESMO/IASLC 2008Scagliotti GV et al. Proc ESMO/IASLC 2008
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CPSMedian: 8.9 months95% CI: 6.1, 13.9CPP Median: 13.6 months95% CI: 9.6, —
Overall Survival by Overall Survival by HistologyHistology
97 41 12 3CPP 112 280 168 22 2CPP 35073 24 9 2CPS 107 281 173 38 5CPS 357
Su
rviv
al P
rob
ab
ilit
y
1.00
0.75
0.50
0.25S
urv
ival P
rob
ab
ilit
y
1.00
0.75
0.50
0.25
Squamous Cell Non-Squamous CellCPSMedian: 11.5 months95% CI: 9.7, 14.8CPP Median: 10.3 months95% CI: 9.3, 11.5
Months
00 20
Patients at Risk
4 8 12 16
Months
00 20
Patients at Risk
4 8 12 16
HR = 1.8195% CI: 1.19, 2.74
HR = 0.9895% CI: 0.78, 1.24
Scagliotti GV et al. Proc ESMO/IASLC 2008
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Study A1016: Phase III Study of Study A1016: Phase III Study of Carboplatin Carboplatin + Paclitaxel +/- Figitumumab in 1+ Paclitaxel +/- Figitumumab in 1stst Line Line NSCLC NSCLC of non-adenocarcinoma histologyof non-adenocarcinoma histology
Trial Design Endpoints Stratification Study Sites
FSFV
Multi-center, randomized, open-label
Primary: OSSecondary: PFS, ORR, Safety, QoL, biomarkers, pharmacoeconomics
• Gender
• Histology
(Sq vs non-Sq)
• Prior Adj Chemo (Y/N)
Global 2Q08
Key Entry Criteria
● Other than Adenoca
● Brain mets allowed
● Adjuvant > 12 month prior
RRAANNDDOOMMIIZZEE
RRAANNDDOOMMIIZZEE
N=820
Figitumumab (20 mg/kg)Paclitaxel
Carboplatin
Paclitaxel Carboplatin
N = 410
N = 410
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Overall SurvivalOverall Survival
PC
mOS = 10.3 mo
PCF
mOS = 8.5 mo
Months
% P
rob
ab
ilit
y o
f S
urv
ival
HR (95%CI):1.23 (1.0,1.5), p=0.051
Event Total
1y OS
2yr OS
PCF 184 342 34% 17%
PC 165 339 39% 20%
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ECLIPSE Study OverviewECLIPSE Study Overview
29
R
Gemcitabine + Carboplatin
+ iniparib
Gemcitabine + CarboplatinPatient Population:• Advanced squamous
cell carcinoma
N= 825
Endpoints:
Primary: OS
Secondary: PFS, TTP, ORR, safety/tolerability, QoL
First Patient Enrolled: March 5, 2010
International, Open-label
Doses: Gemcitabine 1000 mg/m2 D 1 & 8 q3wk Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk
• Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks)
• Patients may remain on study regimen after 6 cycles if there is no evidence of PD or the presence of DLTs1:
1
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ECLIPSE Study OverviewECLIPSE Study Overview
30
R
Gemcitabine + Carboplatin
+ iniparib
Gemcitabine + CarboplatinPatient Population:• Advanced squamous
cell carcinoma
N= 825
Endpoints:
Primary: OS
Secondary: PFS, TTP, ORR, safety/tolerability, QoL
First Patient Enrolled: March 5, 2010
International, Open-label
Doses: Gemcitabine 1000 mg/m2 D 1 & 8 q3wk Carboplatin AUC 5 D1 q3wk; Iniparib 5.6 mg/kg IV D 1, 4, 8 & 11 q3wk
• Patients restaged by CT scans (per RECIST 1.1 version) q 2 cycles (6 wks)
• Patients may remain on study regimen after 6 cycles if there is no evidence of PD or the presence of DLTs1:
1Negative
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Is there any hope for Is there any hope for patients with patients with squamous cell squamous cell histology?histology?
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Pemetrexed Plus Cisplatin in 1st-line: Survival Pemetrexed Plus Cisplatin in 1st-line: Survival with Gemcitabine/Cisplatin for Patients with with Gemcitabine/Cisplatin for Patients with
Squamous Cell CarcinomaSquamous Cell Carcinoma
Sur
viva
l pro
bab
ility
0 6 12 18 24 30Survival time (months)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Pemetrexed + cisplatin Gemcitabine + cisplatin
(N=244) (N=229)
Median OS (95% CI)
9.4 mos (8.4-10.2)
10.8 mos (9.5-12.1)
Adjusted HRa,b,c (95% CI)
1.23 (1.00-1.51)
Scagliotti GV et al: J Clin Oncol. 26 (21), 2008: 3543-3551.
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Non-squamous group Squamous group
Pemetrexed (n=205)
Docetaxel (n=194)
Pemetrexed (n=78)
Docetaxel (n=94)
% ECOG PS 2 12.5 10.1 8.3 17.4% TSPC <3 months 51.0 51.0 48.7 41.9
% Stage IV 81.5 78.9 57.7 66.0% Male 60.5 69.1 89.7 88.3
Median OS, months 9.3 8.0 6.2 7.4Adjusted OS HR (95% CI) 0.778 (0.607, 0.997) 1.563 (1.079, 2.264)
Median PFS, months 3.1 3.0 2.3 2.7Adjusted PFS HR (95% CI) 0.823 (0.664, 1.020) 1.403 (1.006, 1.957)
Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology
Second -Line Study of Pemetrexed vs. Docetaxel : Efficacy by Histology
Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001)
Peterson P. et al. 12th World Conference on Lung Cancer 2007
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Phase III nab-P/C vs P/CStudy Design
Chemo-naivePS 0-1 Stage IIIb/IV NSCLCN = 1,050
Stratification factors: Stage (IIIb vs IV) Age (<70 vs >70) Sex Histology (squamous vs
nonsquamous) Geographic region
nab-Paclitaxel 100 mg/m2 d1, 8 15Carboplatin AUC 6 d1No Premedicationn = 525
1:1
Paclitaxel 200 mg/m2 d1Carboplatin AUC 6 d1With Premedication of Dexamethasone + Antihistaminesn = 525
Socinski et al 2010, ASCO
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Resp
on
se R
ate
(%
)Objective Responses by Histology*
P < 0.001RR =1.680
P = 0.808RR=1.034
n = 228 n = 221 n = 292 n = 310
* Not a pre-specified subgroup analysis
41%
26%24% 25%
0%
10%
20%
30%
40%
50% Ab-P/C
P/C
Interaction p-Value for Histology: 0.036
SquamousHistology
Non-Squamous Histology
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PFS – ITT PopulationPFS – ITT PopulationP
rop
ort
ion
Not
Pro
gre
ssed
Months
Pt at riskAb-PP
521531
330321
167162
8675
3848
2319
1010
44
02
01
00
Ab-P/carboplatin (N=521)paclitaxel/carboplatin (N=531)
0 3 6 9 12 15 18 21 24 27 30 33
0.00
0.25
0.50
0.75
1.00Nab-P/ Carbo
Paclitaxel/ Carbo
HR P-Value
N/Events 521/297 531/312
Median PFS (mo)*
6.3 5.8 0.902 0.214
95% CI 5.6-7.0 5.6-6.7 0.767-1.060
* PFS based on Independent assessment
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Overall Survival – ITT Overall Survival – ITT PopulationPopulation
Pro
bab
ilit
y o
f S
urv
ival
Months
Pt at riskAb-PPac
521531
469470
381389
313308
246243
200191
163148
9889
2324
05
01
Ab-P/carboplatin (N=521)Paclitaxel/carboplatin (N=531)
0 3 6 9 12 15 18 21 24 27 30 33
0.00
0.25
0.50
0.75
1.00
00
Nab-P/Carbo
Paclitaxel/ Carbo
HR P-Value
N/Events 521/360 531/384
Median OS(mos)
12.1 11.2 0.922 0.271
95% CI 10.8-12.9 10.3-12.6 0.797-1.066
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Secondary Endpoint: Secondary Endpoint: OSOS
0.0 0.5 1.0 1.5 2.0
Stage IV
Stage IIIB
Nonsquamous
Squamous
70 yrs<70 yrs
Female
Male
North America
Russia/Ukraine
Japan
All patients
Median PFS (mo)
Events / N HR ab-P/C P/C
744 / 1052
86 / 149
521 / 724
127 / 165
589 / 789
155 / 263
639 / 896
105 / 156
343 / 450
401 / 602
142 / 218
602 / 834
0.922
0.950
1.019
0.622
0.894
0.995
0.999
0.583
0.890
0.950
0.896
0.917
12.1
16.7
11.0
12.7
11.4
16.8
11.4
19.9
10.7
13.1
12.4
12.0
11.2
17.2
11.1
9.8
10.0
16.0
11.3
10.4
9.5
13.0
13.6
11.0
Favors ab-P/C
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Secondary Endpoint: Secondary Endpoint: OSOS
0.0 0.5 1.0 1.5 2.0
Stage IV
Stage IIIB
Nonsquamous
Squamous
70 yrs<70 yrs
Female
Male
North America
Russia/Ukraine
Japan
All patients
Median PFS (mo)
Events / N HR ab-P/C P/C
744 / 1052
86 / 149
521 / 724
127 / 165
589 / 789
155 / 263
639 / 896
105 / 156
343 / 450
401 / 602
142 / 218
602 / 834
0.922
0.950
1.019
0.622
0.894
0.995
0.999
0.583
0.890
0.950
0.896
0.917
12.1
16.7
11.0
12.7
11.4
16.8
11.4
19.9
10.7
13.1
12.4
12.0
11.2
17.2
11.1
9.8
10.0
16.0
11.3
10.4
9.5
13.0
13.6
11.0
Favors ab-P/C
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Chinese Trial: RP2Chinese Trial: RP2NCI CTG 01236716; PI: Wu YilongNCI CTG 01236716; PI: Wu Yilong
RANDOMIZE
GemcitabineCarboplatin
Nab-PaclitaxelCarboplatin
•Restricted to Tx-naïve advanced NSCLC with squamous histology•N= 120; started 11/10
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Efficacy in Total NSCLC Efficacy in Total NSCLC PopulationPopulation
4141
Response
ControlPbo+ Chemo
(n=66)
ConcurrentIPI+ Chemo
(n=70)
PhasedIPI+ Chemo
(n=68)
irPFS, median mo 4.6 5.5 5.7
- - - -HR = 0.81P = 0.13
HR = 0.72P = 0.05*
mWHO-PFS, median mo
4.2 4.1 5.1
- - - -HR = 0.88P = 0.25
HR = 0.69P = 0.02*
OS, median mo 8.3 9.7 12.2
- - - -HR = 0.99P = 0.48
HR = 0.87P = 0.23
irBORR 18% 21% 32%
mWHO-BORR 14% 21% 32%
*Statistically significant per protocol-stipulated one-sided = 0.1; P values not adjusted for multiple comparisons
irPFS, PFS by immune-related response criteria (irRC); irBORR, best overall response rate by irRC; mWHO-PFS, PFS by modified WHO criteria (mWHO); mWHO-BORR, best overall response rate by mWHO
Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701
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Activity of Phased-Ipilimumab by Baseline Activity of Phased-Ipilimumab by Baseline HistologyHistology
4242
In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous
Small sample size warrants caution in interpretation
Response Patient group Events/Patients HR (95% CI)Phased vs. Control
Non-SquamousSquamous 13/21 vs 14/15 0.48 (0.22-1.03)
38/47 vs 37/51 1.17 (0.74-1.86)OSAll 51/68 vs 51/66 0.87 (0.59-1.28)
Squamous 19/21 vs 15/15 0.40 (0.18-0.87)
Non-Squamous 37/47 vs 46/51 0.81 (0.53-1.26)mWHO-PFS All 56/68 vs 61/66 0.69 (0.48-1.00)
Squamous 18/21 vs 15/15 0.55 (0.27-1.12)
Non-Squamous 36/47 vs 41/51 0.82 (0.52-1.28)irPFSAll 54/68 vs 56/66 0.72 (0.50-1.06)
FavorsPhased-Ipi Control
HR and 95% CI0.5 1 1.5
Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701
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Activity of Phased-Ipilimumab by Baseline Activity of Phased-Ipilimumab by Baseline HistologyHistology
4343
In the Phased-Ipilimumab arm, improvements in irPFS, mWHO-PFS and OS vs. Control appeared greater for squamous histology than for non-squamous
Small sample size warrants caution in interpretation
Response Patient group Events/Patients HR (95% CI)Phased vs. Control
Non-SquamousSquamous 13/21 vs 14/15 0.48 (0.22-1.03)
38/47 vs 37/51 1.17 (0.74-1.86)OSAll 51/68 vs 51/66 0.87 (0.59-1.28)
Squamous 19/21 vs 15/15 0.40 (0.18-0.87)
Non-Squamous 37/47 vs 46/51 0.81 (0.53-1.26)mWHO-PFS All 56/68 vs 61/66 0.69 (0.48-1.00)
Squamous 18/21 vs 15/15 0.55 (0.27-1.12)
Non-Squamous 36/47 vs 41/51 0.82 (0.52-1.28)irPFSAll 54/68 vs 56/66 0.72 (0.50-1.06)
FavorsPhased-Ipi Control
HR and 95% CI0.5 1 1.5
Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701
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OS: Squamous NSCLC OS: Squamous NSCLC SubsetSubset
4444
21 13 11 6 4 3 3 2 0 021 19 15 12 9 9 8 5 3 015 11 10 7 4 1 1 1 0 0
0.0
0.2
0.4
0.6
0.8
1.0
0 3 6 9 12 15 18 21 24 27
Pro
port
ion
Alive
RegimenEvents/Patients Median mo HR
ControlConcurrentPhased
14/1517/2113/21
7.9 6.2
10.9
--1.02
0.48
MonthsPatients at riskConcurrentPhasedControl
Ipilimumab and NSCLC histology, WCLC 2011, Abstr 701
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Phase 3 Trial Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin in Squamous NSCLC (CA184-104/NCT01285609)
Start Date: August 2011Estimated Study Completion Date: June 2016Estimated Primary Completion Date: September 2014Status: RecruitingStudy Director: BMS
Primary Endpoint•OS
Secondary Endpoints•OS in pts that receive one dose of blinded therapy•PFS•BORR
Key Eligibility Criteria•≥ 18 years of age•Squamous cell NSCLC•Stage IV or recurrent NSCLC•ECOG PS ≤ 1•No brain metastases or autoimmune disease
Phase 3 TrialSquamous cell NSCLC or Stage IV or recurrent NSCLC N=920
IPI 10 mg/kg IV Q3W x 4 dosesQ12W from W24
PAC 175 mg/m² IVQ3W x 6 doses
CARB AUC 6 IVQ3W x 6 doses
PBO IVQ3W x 4 doses Q12W from W24
PAC 175 mg/m² IVQ3 W x 6 doses
CARB AUC 6 IVQ3W x 6 doses
Treat until progression or unacceptable toxicity
Overall Survival (OS)
BORR, Best overall response rate; CARB, Carboplatin; ECOG PS, Eastern Cooperative Oncology Group Performance Status; IPI, ipilimumab; OS, Overall survival; PAC, Paclitaxel; PFS, Progression-free survival; PBO, Placebo; W, Week
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Actionable Targets in Actionable Targets in Lung AdenocarcinomasLung Adenocarcinomas
Unknown75%
1999 2005-2014
EGFR
2004
Unknown60%
Kris M et al. IASLC 2012 Targeted Therapies Conference
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Actionable Targets ? in Actionable Targets ? in Squamous Cell Lung Squamous Cell Lung CancersCancers
Unknown100%
1999 20142004-2010
Unknown100%
FGFR1 amplification
PIK3CA mutation
PTEN mutation
DDR2 mutation
PTEN loss
Okudela et al. Cancer Res 2008Yamamoto et al. Pathol Int 2007Weiss et al. Sci Transl Med 2010Hammerman et al. Cancer Discovery 2011TCGA Nature 2012
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2002-2012 – Changes in the 2002-2012 – Changes in the therapeutic landscape of stage IV therapeutic landscape of stage IV lung cancer lung cancer
PTENmutation
17%
PTEN loss, complete
11%
PIK3CAmutation
8%
KRASmutation
2%
DDR2mutation
0%
Unknown 37%
FGFR1amplification
25%
Target N Frequency 95% CI
FGFR1 amplification
13/52 25% 15–38%
PTEN mutation 3/18 17% 5–37%
PTEN loss, complete
3/27 11% 3–26%
PIK3CA mutation 4/52 8% 2–17%
KRAS mutation 1/52 2% 1–9%
DDR2 mutation 0/18 0% 0–15%
Paik et al. J Clin Oncol 30: 2012 (suppl; abstr 7505)
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Novel Therapeutic Novel Therapeutic TargetsTargets FGFR1 amplificationFGFR1 amplification
NFE2L2 oxidative stress pathwayNFE2L2 oxidative stress pathway
DDR2 mutationsDDR2 mutations
PI3K pathwayPI3K pathway
EGFREGFR
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FGFR1 AMPLIFICATIONFGFR1 AMPLIFICATION
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Chromosomal gain is Chromosomal gain is commoncommon
Amplification (FGFR1:CEP8 ≥ 2)Amplification (FGFR1:CEP8 ≥ 2)– 16-25%16-25%
Correlation with protein expression unknown Correlation with protein expression unknown
FGFR1 amplification
TCGA Nature 2012Paik ASCO 2012
Heist J Thorac Oncol 2012
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FGFR1 amplification in FGFR1 amplification in squamous cell squamous cell lung carcinomalung carcinoma
Abstract
No of cases
Histology subtype
Disease
stage(s)
TechniqueDefinition of amplification
% amplified
% polysomy
(if available)
7041 101 Squamous
I–IV FISH Median of 6 or more gene copies
6.9 43/94
7061 447 Squamous
I–IV FISH Mean of 6 or more gene copies
8.3 -
7063 119 Squamous
I–IV Quantitative PCR
Predicted CNV of ≥2 in ≥1 exon
24.4 -
7545 177 Squamous
I–IV FISH Copy number >2 and <9 (low); >9
(high)
25.2 -
Martinez Marti et al. J Clin Oncol 30, 2012 (suppl; abstr 7041)Toschi et al. J Clin Oncol 30, 2012 (suppl; abstr 7061)
Cote et al. J Clin Oncol 30, 2012 (suppl; abstr 7063)Wei et al. J Clin Oncol 30, 2012 (suppl; abstr 7545)
CNV, copy number variation
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Therapeutic targets in Therapeutic targets in squamous cell lung squamous cell lung carcinomacarcinomaGene Event type Frequency
CDKN2A Deletion/mutation/methylation
72
PI3KCA Mutation 16
PTEN Mutation/Detection 15
FGFR1 Amplification 15
EGFR Amplification 9
PDGFRA Amplification/Mutation 9
CCND1 Amplification 8
DDR2 Mutation 4
BRAF Mutation 4
ERBB2 Amplification 4
FGFR2 Mutation 3
Govindan et al. J Clin Oncol 30, 2012 (suppl; abstr 7006)
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FGFR1 signaling:FGFR1 signaling:PI3K, Ras/MAPK, and PKC activationPI3K, Ras/MAPK, and PKC activation
PI3K Ras/Raf/MAPK
PKC
Fibroblast growth factors
Receptor dimerization
Growth, division, angiogenesis
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Amplification predicts Amplification predicts sensitivity to drug sensitivity to drug in vitroin vitro and and in vivoin vivo
Weiss et. al. Sci Transl Med 2010
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FGFR1 and PI3K: not FGFR1 and PI3K: not mutually exclusivemutually exclusive
Significant overlap in putative oncogenes Significant overlap in putative oncogenes may complicate target validation in trialsmay complicate target validation in trials
cBio GDAC Lung Squamous TCGA data
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FGFR1-directed trials are FGFR1-directed trials are myriadmyriad
Radiographic PRs reported in response to BGJ398Radiographic PRs reported in response to BGJ398 All trials are ongoingAll trials are ongoing
Drug Target(s) Clinicaltrials.gov #
AZD4547 Pan-FGFRNCT01824901 (phase 2)NCT00979134 (phase 1
expansion)
BGJ398 Pan-FGFR NCT01004224 (phase 1)
GSK305220 FGF ligands NCT01868022 (phase 1)
Debio 1347 FGFR1-3
JNJ42756493 Pan-FGFR NCT01703481 (phase 1)
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NFE2L2/KEAP1 NFE2L2/KEAP1 MUTATIONSMUTATIONS
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NFE2L2 and KEAP1 NFE2L2 and KEAP1 overviewoverview
Members of an oxidative stress Members of an oxidative stress pathwaypathway
NFE2L2 codes for Nrf2, a transcription NFE2L2 codes for Nrf2, a transcription factor that binds Antioxidant Response factor that binds Antioxidant Response Elements (AREs) in promotersElements (AREs) in promoters– Target genes include glutathione Target genes include glutathione
synthesis, drug transport pumps, ROS synthesis, drug transport pumps, ROS eliminatorseliminators
Keap1 binds to Nrf2 and degrades itKeap1 binds to Nrf2 and degrades it
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NFE2L2 and KEAP1 NFE2L2 and KEAP1 homeostasis:homeostasis:Keap1 targets Nrf2 for Keap1 targets Nrf2 for degradationdegradation
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Oxidative stress activates Oxidative stress activates Nrf2 pathwayNrf2 pathway
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NFE2L2 and KEAP1: nature of NFE2L2 and KEAP1: nature of alterations in SQCLCalterations in SQCLC
Hotspot mutations
(activating)
Sporadic mutations
(inactivating)
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Changes in NFE2L2 and Changes in NFE2L2 and KEAP1 are common in KEAP1 are common in SQCLCSQCLC
TCGA Nature 2012
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Mutant Nrf2 is Mutant Nrf2 is oncogeniconcogenic
Isogenic HEK293 clones overexpressing T80R
(TR1/2) and L30F (LF1/2) mutations form
colonies
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Mutant Nrf2 is druggable Mutant Nrf2 is druggable through mTOR inhibitionthrough mTOR inhibition
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DDR2DDR2
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Discoidin domain receptor 2 Discoidin domain receptor 2 (DDR2): ECM/collagen (DDR2): ECM/collagen signalingsignaling• Stimulated by collagen as a ligand
• Downstream signaling in cancer cells is poorly understand
• May be via SRC and STAT signaling pathways.
• Similar to integrin receptors, DDR2 may play a role in modulating cellular interactions with the extracellular matrix
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DDR2 DDR2 mutations are mutations are sporadic and uncommonsporadic and uncommon
Hammerman et. al. Cancer Discovery 2012
• Sanger sequencing of 290 SQCLC resections uncovered 11 mutations in DDR2 (3.8%)• No hotspots
DDR2 mutations
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Purified kinase activity (TR-FRET) Collagen-dependent autophosphorylation
Eur J Pharmacol [2008] 599:44–53
IC50 = 55nMIC50 = 5.2nM
DDR2 is druggable with dasatinib
in vitro data
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DDR2 is druggable with DDR2 is druggable with dasatinib:dasatinib:in vivoin vivo data data
DDR2 I638F mutant
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DDR2 clinical trialsDDR2 clinical trials
Drug Target(s) Clinicaltrials.gov #
dasatinib DDR2 mutations NCT01514864 (phase 2)
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Clinical response to dasatinib (DDR2 Clinical response to dasatinib (DDR2 S768I):S768I):Phase 1 dasatinib + erlotinib trialPhase 1 dasatinib + erlotinib trial
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PI3K PATHWAYPI3K PATHWAY
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PI3K is a canonical PI3K is a canonical downstream RTK partner in downstream RTK partner in cancercancer
Weitgelt Frontiers Oncol 2009
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PI3K is a canonical PI3K is a canonical downstream RTK partner in downstream RTK partner in cancercancer
Weitgelt Frontiers Oncol 2009
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PI3K is a canonical PI3K is a canonical downstream RTK partner in downstream RTK partner in cancercancer
Weitgelt Frontiers Oncol 2009
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Oncogenic PI3K pathway Oncogenic PI3K pathway changes are common in changes are common in SQCLCSQCLC
PIK3CA mutation
PTEN mutation
PTEN loss
• PI3K alterations (PIK3CA mutations, PTEN mutations, PTEN loss) occur in ~30-50% of SQCLCs• PIK3CA amplification occurs in another 20-30%
TCGA Nature 2012
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PI3K pathway clinical PI3K pathway clinical trialstrials
Overlap with FGFR1 amplification, NFE2L2/KEAP1 Overlap with FGFR1 amplification, NFE2L2/KEAP1 mutations complicates clinical validationmutations complicates clinical validation
Drug Target(s) Clinicaltrials.gov #
BKM120 PIK3CA NCT01297491 (phase 2)
carboplatin + paclitaxel +
BKM120PIK3CA NCT01723800 (phase 1)
GDC0032 PIK3CA pending
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Doc or Gem
FGFRi +
Doc or Gem
Doc or
Gem
FGFR Amplification, Mutation, Fusion
CDK 4/6i Doc or
Gem
Cyclin D1 Amplification orCDKN2 loss + RB WT
PI3Ki Doc or
Gem
PI3KCAMutation
BiomarkerProfiling (NGS/CLIA)
HGFi +Erlotinib
Erlotinib
MET Expression(IHC score)
PD-L1iPD-L1i BiomarkerNon-Match BiomarkerNon-Match
Multiple Phase II- III Arms with “Rolling” Opening & Closure
MASTER LUNG-1 (S1400): MASTER LUNG-1 (S1400): Biomarker s and 2nd Line Biomarker s and 2nd Line Therapy for Squamous Cell Therapy for Squamous Cell NSCLCNSCLC
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EGFREGFR
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EGFR alterations in EGFR alterations in SQCLCSQCLC Canonical exon 19 deletions and exon 21 Canonical exon 19 deletions and exon 21
L858R mutations are extraordinarily rare in L858R mutations are extraordinarily rare in SQCLCsSQCLCs
Rare EGFR L861Q mutations have been Rare EGFR L861Q mutations have been reportedreported
EGFR amplification occurs in 7-10% of SQCLCsEGFR amplification occurs in 7-10% of SQCLCs
As with adenocarcinomas, increased EGFR As with adenocarcinomas, increased EGFR expression by IHC is commonexpression by IHC is common– Role of H-score awaits prospective validationRole of H-score awaits prospective validation
Rekhtman Modern Pathology 2012
TCGA Nature 2012
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ChemotherapChemotherapy-naïve y-naïve
advanced advanced NSCLCNSCLC
ChemotherapChemotherapy-naïve y-naïve
advanced advanced NSCLCNSCLC
Vinorelbine 25 mg/mVinorelbine 25 mg/m22 d1,8 d1,8
+ cisplatin 80 mg/m+ cisplatin 80 mg/m22 d1 q3w d1 q3w
Primary endpoint: Primary endpoint: OSOSSecondary endpoints: PFS, ORR, DCR, QoL, safetySecondary endpoints: PFS, ORR, DCR, QoL, safety
Phase III FLEX: Phase III FLEX: Vinorelbine/CisplatinVinorelbine/Cisplatin± Cetuximab in ± Cetuximab in 11stst-Line Advanced -Line Advanced NSCLCNSCLC
n=557n=557
n=568n=568
Cetuximab 400 mg/mCetuximab 400 mg/m22 d1 wk1, then 250 d1 wk1, then 250
mg/mmg/m22 qw qw
+ vinorelbine 25 mg/m + vinorelbine 25 mg/m22 d1,8 d1,8
+ cisplatin 80 mg/m+ cisplatin 80 mg/m22 d1 q3w d1 q3w
RRAANNDDOOMMIIZZEE
Up to 6 cycles of chemotherapy; patients not progressing continue on cetuximab
maintenance
Pirker R, et al. ASCO 2008. Oral presentation and abstract 3.
Stratified by IIIB or IV ECOG PS 0,1
or 2
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FLEX Overall survival
MonthsPatients at riskCT + Cetuximab 557 383 251 155 53 3CT 568 383 225 134 48 0
Overa
ll S
urv
ival (%
)
p-value = stratified log-rank test (2-sided)p-value = stratified log-rank test (2-sided)
Median OS 1-year survival
▬ CT + Cetuximab(n=557) 11.3 months 47 %
▬ CT(n=568) 10.1 months 42 %
HR=0.871 (95% CI 0.762–0.996), p=0.044
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FLEX: OS FLEX: OS in in Caucasian Caucasian SubgroupSubgroup(Pre-specified Analysis)(Pre-specified Analysis)
Pirker R, et al. ASCO 2008. Oral presentation and abstract 3.
9.19.1
10.510.5
MonthsMonths
1-year OS1-year OS45% vs 37%45% vs 37%
HR = 0.803HR = 0.803, 0.694, 0.694––0.9280.928
Log-rank Log-rank PP =.003 =.003
Cet + vin/cis, n=466Cet + vin/cis, n=466Vin/cis, n=480Vin/cis, n=480
Pati
en
ts s
urv
ivin
g,
%
100
80
60
40
20
00 6 12 18 24 30
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FLEX trial subgroup FLEX trial subgroup analysisanalysis
TCGA Nature 2012
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High and low EGFR expression
Low EGFR expressionIHC score <200
High EGFR expressionIHC score ≥200
IHC score=270 IHC score=30 IHC score=0*
IHC, immunohistochemistry; *IHC score=7 for tumor overall O’Byrne K et al. JTO 2010, 12 (suppl), S558 (LBOA1)
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Retrospective FLEX H-score Retrospective FLEX H-score analysisanalysis
Pirker Lancet Oncol 2012
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FLEX H ScoreFLEX H ScoreElevated Cohort (> 200)Elevated Cohort (> 200)
Arm C225 Control
Number 178 176
OR % 44 * 28
PFS (mos) 5.0 4.4
Med Surv (mos) 12^ 9.6
1 yr OS % 50 37
2 yr OS % 24 15
* p = 0.002^ HR = 0.73, p = 0.011
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Elevated Cohort (> 200)Elevated Cohort (> 200)Breakdown by HistologyBreakdown by HistologyArm C225 Control
Adenocarcinoma *
MS (mos) 20.2 13.3
1 yr OS % 65 52
Squamous Cell ca^
MS (mos) 11.2 8.9
1 yr OS % 45 25
* HR = 0.72^ HR = 0.62
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Completed and ongoing Completed and ongoing trialstrials
Title Treatment Clinicaltrials.gov #
SWOG 0819
Randomized carbo/paclitaxel or carbo/pac/bev
+/- cetuximab
NCT00946712 (accruing)
SQUIRECisplatin +
gemcitabine +/- necitumumab
NCT00981058 (completed)
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SQUIRE Trial*: RP3SQUIRE Trial*: RP3
RANDOMIZE
GemcitabineCisplatin X 6Necitumumab^
*Restricted to Tx-naïve advanced NSCLC with squamous histology^ Maintenance Tx includedPlanned sample size to show med OS inc from 11 to 13.75 mos N= 1093;
GemcitabineCisplatin X 6
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SQUIRE Trial*: RP3SQUIRE Trial*: RP3
RANDOMIZE
GemcitabineCisplatin X 6Necitumumab^
*Restricted to Tx-naïve advanced NSCLC with squamous histology^ Maintenance Tx includedPlanned sample size to show med OS inc from 11 to 13.75 mos N= 1093;
GemcitabineCisplatin X 6
Reported (+) mid
August 2013
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Press Release Aug 13, 2013Press Release Aug 13, 2013
Necitumumab Improves Overall Survival in Lung CancerNecitumumab Improves Overall Survival in Lung Cancer SQUIRE, a Phase 3 study met its primary endpoint, finding that patients with stage IV SQUIRE, a Phase 3 study met its primary endpoint, finding that patients with stage IV
metastatic squamous metastatic squamous non-small cell lung cancer (NSCLC) experienced increased overall (NSCLC) experienced increased overall survival (OS) when necitumumab (IMC-11F8) in combination with gemcitabine and cisplatin survival (OS) when necitumumab (IMC-11F8) in combination with gemcitabine and cisplatin was administered as first-line treatment compared to chemotherapy alone. Necitumumab is a was administered as first-line treatment compared to chemotherapy alone. Necitumumab is a fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human fully human IgG1 monoclonal antibody designed to block the ligand binding site of the human epidermal growth factor receptor (EGFR). epidermal growth factor receptor (EGFR).
SQUIRE enrolled 1093 patients with histologically- or cytologically-confirmed, stage IV SQUIRE enrolled 1093 patients with histologically- or cytologically-confirmed, stage IV squamous NSCLC, who had received no prior therapy for metastatic disease. Patients were squamous NSCLC, who had received no prior therapy for metastatic disease. Patients were randomized to receive first-line necitumumab plus chemotherapy consisting of gemcitabine randomized to receive first-line necitumumab plus chemotherapy consisting of gemcitabine and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. and cisplatin in study Arm A, or gemcitabine-cisplatin chemotherapy alone in study Arm B. Patients underwent radiographic assessment of disease status (computed tomography or Patients underwent radiographic assessment of disease status (computed tomography or magnetic resonance imaging) every six weeks (+/- 3 days), until radiographic documentation magnetic resonance imaging) every six weeks (+/- 3 days), until radiographic documentation of progressive disease (PD). Chemotherapy continued for a maximum of six cycles in each of progressive disease (PD). Chemotherapy continued for a maximum of six cycles in each arm or until there was radiographic documentation of PD, toxicity requiring cessation, or arm or until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent. Patients in Arm A continued to receive necitumumab (IMC-11F8) until withdrawal of consent. Patients in Arm A continued to receive necitumumab (IMC-11F8) until there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of there was radiographic documentation of PD, toxicity requiring cessation, or withdrawal of consent.consent.
For more information call (800) 545-5979 or visit For more information call (800) 545-5979 or visit www.lillyoncology.com
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CONCLUSIONSCONCLUSIONS
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Perspectives on First-line Tx Perspectives on First-line Tx wrt Histologywrt Histology
Based on E4599 and Scagliotti trials, use Based on E4599 and Scagliotti trials, use of Pemetrexed and Bevacizumab is of Pemetrexed and Bevacizumab is limited to NON-squamous histologylimited to NON-squamous histology
Standard cytotoxic platform for Standard cytotoxic platform for Adenoca: Adenoca: – platinum plus either pemetrexed or taxaneplatinum plus either pemetrexed or taxane
Standard platform for Standard platform for Squamous cell Squamous cell ca:ca:– platinum plus either gemcitabine or taxaneplatinum plus either gemcitabine or taxane
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Histologic Distinctions in the Histologic Distinctions in the Tx of NSCLC: Conclusions IITx of NSCLC: Conclusions II
Prognosis is generally inferior in squamous vs non-sq NSCLCPrognosis is generally inferior in squamous vs non-sq NSCLC Gemcitabine appears superior to pemetrexed in the 1Gemcitabine appears superior to pemetrexed in the 1stst line setting in squamous line setting in squamous
NSCLC [in combination with cisplatin], while pemetrexed appears superior in NSCLC [in combination with cisplatin], while pemetrexed appears superior in non-squamous cell canon-squamous cell ca
Docetaxel appears superior to pemetrexed in the 2Docetaxel appears superior to pemetrexed in the 2ndnd line setting in squamous line setting in squamous cell ca, whereas pemetrexed appears superior in adenoca cell ca, whereas pemetrexed appears superior in adenoca
C225’s survival advantage is independent of histologyC225’s survival advantage is independent of histology Though squamous ca pts fared worse overall, EGFR TKIs still conferred a survival Though squamous ca pts fared worse overall, EGFR TKIs still conferred a survival
advantage In both squamous and adenocarcinoma in the 2advantage In both squamous and adenocarcinoma in the 2ndnd /3 /3rdrd line setting line setting Necitumumab in combination with gem/plat is “superior” to chemo aloneNecitumumab in combination with gem/plat is “superior” to chemo alone The role of PARP inhibitors, Iplilumumab, and PD1 in squamous NSCLC is The role of PARP inhibitors, Iplilumumab, and PD1 in squamous NSCLC is
uncertainuncertain Actionable molecular markers may be emerging, but it remains to be seen Actionable molecular markers may be emerging, but it remains to be seen
whether FGFR inhibitors or agents targeting PTEN mutation or deletion, Death whether FGFR inhibitors or agents targeting PTEN mutation or deletion, Death receptors or PI3K will prove efficaciousreceptors or PI3K will prove efficacious
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I think we need to place more patients on
clinical trials, don’t you agree?
Corey Langer preaching to the choir at the weekly Wednesday
thoracic tumor board