Individualized Tx in NSCLC: How Do We Tackle Advanced Squamous Cell Ca of the Lung

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]

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

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.

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

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

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”

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.

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


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

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


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

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

An Evolving View of An Evolving View of Squamous Cell CaSquamous Cell CaEmergence of “Actionable” Molecular MarkersEmergence of “Actionable” Molecular Markers

2000 2014

An Evolving View of An Evolving View of Squamous Cell CaSquamous Cell CaEmergence of “Actionable” Molecular MarkersEmergence of “Actionable” Molecular Markers

2000 2014

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:

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.

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.

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

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

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 --

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


Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001)

Peterson P. et al. 12th World Conference on Lung Cancer 2007

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

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)

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

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

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

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

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

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

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%

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

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

Is there any hope for Is there any hope for patients with patients with squamous cell squamous cell histology?histology?

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.

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)



Treatment by Histology Interaction: Survival Adjusted for Cofactors (p=0.001)

Peterson P. et al. 12th World Conference on Lung Cancer 2007

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

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

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

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

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

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

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

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

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


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


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


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

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

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

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)

Novel Therapeutic Novel Therapeutic TargetsTargets FGFR1 amplificationFGFR1 amplification

NFE2L2 oxidative stress pathwayNFE2L2 oxidative stress pathway

DDR2 mutationsDDR2 mutations

PI3K pathwayPI3K pathway

EGFREGFR

FGFR1 AMPLIFICATIONFGFR1 AMPLIFICATION

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

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

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)

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

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

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

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)

NFE2L2/KEAP1 NFE2L2/KEAP1 MUTATIONSMUTATIONS

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

NFE2L2 and KEAP1 NFE2L2 and KEAP1 homeostasis:homeostasis:Keap1 targets Nrf2 for Keap1 targets Nrf2 for degradationdegradation

Oxidative stress activates Oxidative stress activates Nrf2 pathwayNrf2 pathway

NFE2L2 and KEAP1: nature of NFE2L2 and KEAP1: nature of alterations in SQCLCalterations in SQCLC

Hotspot mutations

(activating)

Sporadic mutations

(inactivating)

Changes in NFE2L2 and Changes in NFE2L2 and KEAP1 are common in KEAP1 are common in SQCLCSQCLC

TCGA Nature 2012

Mutant Nrf2 is Mutant Nrf2 is oncogeniconcogenic

Isogenic HEK293 clones overexpressing T80R

(TR1/2) and L30F (LF1/2) mutations form

colonies

Mutant Nrf2 is druggable Mutant Nrf2 is druggable through mTOR inhibitionthrough mTOR inhibition

DDR2DDR2

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

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

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

DDR2 is druggable with DDR2 is druggable with dasatinib:dasatinib:in vivoin vivo data data

DDR2 I638F mutant

DDR2 clinical trialsDDR2 clinical trials


dasatinib DDR2 mutations NCT01514864 (phase 2)

Clinical response to dasatinib (DDR2 Clinical response to dasatinib (DDR2 S768I):S768I):Phase 1 dasatinib + erlotinib trialPhase 1 dasatinib + erlotinib trial

PI3K PATHWAYPI3K PATHWAY

PI3K is a canonical PI3K is a canonical downstream RTK partner in downstream RTK partner in cancercancer

Weitgelt Frontiers Oncol 2009





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

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


BKM120 PIK3CA NCT01297491 (phase 2)

carboplatin + paclitaxel +

BKM120PIK3CA NCT01723800 (phase 1)

GDC0032 PIK3CA pending

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

EGFREGFR

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

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

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

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

FLEX trial subgroup FLEX trial subgroup analysisanalysis

TCGA Nature 2012

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)

Retrospective FLEX H-score Retrospective FLEX H-score analysisanalysis

Pirker Lancet Oncol 2012

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

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

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)

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

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

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

CONCLUSIONSCONCLUSIONS

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

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

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

Documents

Individualized Tx in NSCLC: How Do We Tackle Advanced Squamous Cell Ca of the Lung