The Evolving Management of Advanced Lung … 1 The Evolving Management of Advanced Lung Cancerof Advanced Lung Cancer CAGPO October 19th, 2013 M. Vincent MB ChB, FRCPC, MRCP(UK) Staff

2013-11-21

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The Evolving Management of Advanced Lung Cancerof Advanced Lung Cancer

CAGPO October 19th, 2013

M. Vincent

MB ChB, FRCPC, MRCP(UK)Staff Medical Oncologist

Thoracic & GI MDT

London Regional Cancer Program

Professor

(Senate Stream)

Dept. of Oncology

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CONFLICT OF INTEREST• CEO:

Sarissa, Inc.• Scientific Advisory Boards:

SYM BioSciencesCritical Outcomes Technology Inc.Capital Royalty, Inc.

• Board of Directors:Lorus Therapeutics Inc.

• Speaker’s BureauBristol Myers SquibbBristol Myers SquibbEli Lilly, Inc.

• Honoraria:AmgenAstra ZenecaBristol Myers SquibbEli Lilly Inc.Hoffman La RocheSanofi-AventisBoehringer-Ingleheim

• Research Funding:Hoffman La Roche

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OBJECTIVES

• Clear overview of both A-NSCLC and SCLC

• Explore areas of research and interest in Small Cell Lung Cancer

• Emphasize biomarker testing & Rx decision impact

• Intro www.MyOncologyResource.com, online A-NSCLC Rx guide

• Case Study

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Lung Cancer: Histology

10% to 15%

Small-cellcarcinoma

L ll

Adenocarcinoma

40%10% to 15%

2 % 30%

Large-cell carcinoma

American Cancer Society. Lung cancer (non-small-cell). 2013.

25% to 30%

Squamous cell carcinoma

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Sensitivity.........87%Specificity.........98%

Sensitivity.........93%...........94%Specificity.........87%...........97%

Histopathology, 61:1017

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Lung Cancer: Biomarkers in Adenocarcinoma

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EGFR Mutations Associated with Sensitivity to EGFR-TKIs

Nat Rev Cancer. 2007; 7: 169-81.

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GEFITINIB

a | Simplified illustration of signal transduction through the epidermal growth factor receptor (EGFR).

Ligand binding causes receptor dimerization. This leads to receptor autophosphorylation, which is inhibited by gefitinib.

b | Structure of gefitinib and its in vitro inhibitory activity against various tyrosine kinases. Gefitinib was originally

identified from structure–activity studies based around a 4-anilinoquinazoline lead series MAPK

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2003, June 12 2003, Nov. 28

CASE REPORT: Response to an EGFR-TKI

A RARE EVENT IN AN UNSELECTED CAUCASIAN

, ,

This was at a time before the mutation was recognised

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Rapid Response to CrizotinibRapid Response to Crizotinib

Pre-TreatmentPre-Treatment Crizotinib x 12 weeksCrizotinib x 12 weeks

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SO, HOW DO WE RECONCILE

HISTOLOGYHISTOLOGY

WITH

MOLECULAR BIOMARKERS?

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A-NSCLC

Non-Squamous

First, we need an approach to histopathology

Squamous Squamous

“NestedSets”AdenoCa LargeSets

Signet Cribri- BAC BAC Pap- Micro- Acinar SolidRing form Muc Non- illary pap

Muc

Non-N-E

Neuro-endocrine

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Acinar AdenocaAcinar Adenoca(±13% EGFR mt) (±35% EGFR mt)

Papillary AdenocaPapillary Adenoca Cribriform

80% ALK +

(? 35% EGFR mt+)

Micropapillary Micropapillary Solid Adenoca with MucinSolid Adenoca with Mucin Signet Ring

65% ALK +(Never EGFR mt+)

Bronchioloalveolar Adenoca, Bronchioloalveolar Adenoca, NonNon--mucinousmucinous

Bronchioloalveolar Adenoca,Bronchioloalveolar Adenoca,MucinousMucinous

(50% EGFR mt+) (Never EGFR mt+)

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A-NSCLC: Algorithm Scaffold

Non-Squamous Squamousq

NOS Adenoca Large

EGFR M+

ALK+ WT/WT UNKNOWN

1L

1LM

2L2L

3L

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NOS Adenoca Large

EGFR M+ ALK+ WT/WT UNKNOWN

1L

1LM

2L

3L

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Adenocarcinoma –Estimated Genomic Probabilities of KRAS and EGFR

Mutations

East Asia West

(Japan, Korea, Taiwan, HK) (USA, Australia)

6 studies 2 studies

n = 814 n = 116

Neversmokers

EGFR mt

KRAS mt

neither

70%

1%

29%

37%

0%

63%

Ever-smokers

EGFR mt

KRAS mt

neither

29%

17%

54%

8%

41%

51%

Shigematsu, Sakema, Takema, Bae, Tam

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IPASS Study design

PatientsEndpoints

Gefitinib250 mg/day

1:1 randomization

Patients• Age ≥18 years

• Life expectancy≥ 12 weeks

• Adenocarcinoma histology

• Never smokers or light ex-smokers*

Primary• Progression free survival (non-inferiority)

Secondary• Objective response rate• Quality of life• Disease related symptoms

Carboplatin AUC 5 or 6 and Paclitaxel 200mg/m2 3 wkly

• PS 0-2

• Stage IIIB/IV

• Measurable disease

y p• Overall survival• Safety and tolerability

Exploratory• Biomarkers

•EGFR mutation•EGFR gene copy number•EGFR protein expression

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*Never smokers:<100 cigarettes in lifetime; light ex-smokers: stopped 15 years ago and smoked 10 pack yrs

Carboplatin/paclitaxel was offered to gefitinib patients upon progression

PS, performance status; EGFR, epidermal growth factor receptor

EGFR protein expression

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Objective response rate in EGFR mutation positive and negative patients

Gefitinib Carboplatin / paclitaxel

EGFR M+ odds ratio (95% CI)= 2.75 (1.65, 4.60), p=0.0001

EGFR M- odds ratio (95% CI)= 0 04 (0 01 0 27) p=0 0013

Overallresponse

71.2%

47.3%

= 0.04 (0.01, 0.27), p=0.0013 rate (%)

1.1%

23.5%

(n=132) (n=129) (n=91) (n=85)

Odds ratio >1 implies greater chance of response on gefitinib Mok et al, Chicago 2008

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Progression-free survival in EGFR mutation positive and negative patients

EGFR mutation positive EGFR mutation negative

G fiti ib ( 91)

HR (95% CI) = 0.48 (0.36, 0.64)

p<0.0001

Gefitinib (n=132)Carboplatin / paclitaxel(n=129)

HR (95% CI) = 2.85 (2.05, 3.98)p<0.0001

0.6

0.8

1.0

rog

ress

ion-

free

vi

val

0.6

0.8

1.0

rog

ress

ion-

free

viva

l

Gefitinib (n=91)Carboplatin / paclitaxel (n=85)

0 4 8 12 16 20 240.0

0.2

0.4

6

Pro

babi

lity

of p

rsu

rv

At risk :

0 4 8 12 16 20 240.0

0.2

0.4

6

Pro

babi

lity

of p

rsu

rv

Months Months

Treatment by subgroup interaction test, p<0.0001

ITT populationCox analysis with covariates

132 71 31 11 3 0129 37 7 2 1 0

108103

GefitinibC / P

At risk :91 4 2 1 0 085 14 1 0 0 0

2158

Mok et al, Chicago 2008

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Overall Survival in EGFR mutation positive and negative

patientspatients

Fukuoka et al. JCO 2011

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EURTAC: 1L CHEMO vs ERLOTINIB

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EURTAC: 1L CHEMO vs ERLOTINIB

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EGFR M+M+

Iressa … IPASS

or

Tarceva … EURTAC

or

1L+

1LM

Tomtovok … LUX-Lung 3

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A-NSCLC


NOS Adenoca Large


1L+1LM

IressaorTarcevaorTomtovokTomtovok

2L Platinum doublet Alimta

3L TKI re-challenge?

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TKI Re-Challenge: May be a realistic option

Chemotherapy Alimta-based

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NOS Adenoca Large

EGFR M+

ALK+ WT/WT UNKNOWN

1L

1LM

2L2L

3L

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ALK +

Xalkori (crizotinib)1L

US FDA 26/8/11+1LM

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Crizotinib(n=172a)

Pemetrexed(n=99a)

Docetaxel(n=72a)

PROFILE 1007:PFS of 2L Crizotinib vs Pemetrexed or Docetaxel

t

100(n=172 ) (n=99 ) (n=72 )

Events, n (%) 100 (58) 72 (73) 54 (75)

Median, mo 7.7 4.2 2.6

HRb (95% CI) 0.59 (0.43 to 0.80) 0.30 (0.21 to 0.43)

P 0.0004 <0.0001

of

surv

ival

wit

ho

ut

ress

ion

(%

)

80

60

40

Pro

bab

ility

op

rog 40

20

00 5 10 15 20 25

Time (months)

172 93 38 11 2 099 36 12 3 1 072 13 3 1 0

No. at riskCrizotinib

PemetrexedDocetaxel

aAs-treated population: excludes 1 patient in crizotinib arm who did not receive study treatment and 3 patients in chemotherapy arm who did not receive study treatment; bvs crizotinib

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ORRa by Independent Radiologic Review

ORR ratio: 3 4 (95% CI: 2 5 to 4 7); P<0 0001

65.3

ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.0001

Crizotinib (n=173b)

Chemotherapy (n=174b)80

60

65.7

Crizotinib (n=172c)

Pemetrexed (n=99c)

Docetaxel (n=72c)80

60

19.5OR

R (

%)

60

40

20

29.3

6 9

60

40

20

aRECIST v1.1; bITT population; cas-treated population

20

0Treatment

6.9

Treatment

20

0

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A-NSCLC: alternative schema for ALK +

Non-Squamous SquamousSquamous

NOS Adenoca Large


1L

Platinum doublet

X 4

1LM Alimta PD

2L XalkoriPD…and

beyond?

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NOS Adenoca Large


1L

1LM

2L2L

3L

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NON-SMALL CELL LUNG CANCER

1st generation 2nd generation 3rd generation

Cyclophosphamide Ifosphamide PaclitaxelDocetaxel

Doxorubicin Mitomycin C GemcitabineDoxorubicin Mitomycin C Gemcitabine

Cisplatin (low dose) Cisplatin (high dose)Carboplatin

Oxaliplatin

Vincristine VinblastineVindesine

Vinorelbine

Methotrexate Etoposide Irinotecan

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BMJ Meta-Analysis (1995)

“N id i d h f“No evidence existed that any group of patients specified by … histological type … benefited more or less from chemotherapy”.chemotherapy .

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NON-SMALL CELL LUNG CANCER

1st generation 2nd generation 3rd generation

Cyclophosphamide Ifosphamide PaclitaxelDocetaxel

Doxorubicin Mitomycin C GemcitabineDoxorubicin Mitomycin C Gemcitabine

Cisplatin (low dose) Cisplatin (high dose)Carboplatin

Oxaliplatin

Vincristine VinblastineVindesine

Vinorelbine

Methotrexate Etoposide Irinotecan

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Hitting the WallFirst-line chemotherapy options in NSCLC(E1594): comparable efficacy with platinum

doublets

1.0

0.8

0.6

Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxelf

surv

ival

Therapeutic plateau: overall survival <12 months

0.6

0.4

0.2

Cisplatin/docetaxelCarboplatin/paclitaxel

Pro

bab

ility

of

Schiller, et al. NEJM 2002

00 5 10 15 20 25 30

Time (months)

NSCLC = non-small cell lung cancer

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• Log-rank test for comparing

ECOG 1594: Efficacies by Histology

– OS and PFS distributions among different histology groups

– Survival in each histology group for different chemotherapy regimen

• Results:

– No difference in OS and PFS between the four histology groups

– No survival difference between the four chemotherapy regimens in each histology group

Regardless of histology types, OS and PFS were similar in

WCLC 2009 – Hoang et al, Abstract # PD6.4.1

chemonaive NSCLC patients treated with standard platin-based doublets involving paclitaxel, docetaxel, or gemcitabine!

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JMDB:Cis/Pem vs. Cis/Gem in First-Line NSCLC: Study Design

Randomization Factors

• Stage

• Performance status (PS) (0 vs 1)

Cisplatin 75 mg/m2 day 1 + Pemetrexed 500 mg/m2 day 1

Each cycle repeated

Cisplatin 75 mg/m2 day 1 + Gemcitabine 1250 mg/m2 days 1 & 8

(PS) (0 vs 1)

• Gender

• Histologic vs cytologic diagnosis

• History of brain metastases

REach cycle repeated

every 3 weeks up to 6 cycles

Gemcitabine 1250 mg/m days 1 & 8

Vitamin B12, folate, and dexamethasone given in both arms

Scagliotti et al. J Clin Oncol 2008 (In Press).

Cis/Pem, cisplatin/pemetrexed; Cis/Gem, cisplatin/gemcitabine

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Cis/Pem vs. Cis/Gem in First-line NSCLC: Overall Survival in Squamous Cell

Carcinoma and Adenocarcinoma / Large C llCell

1.0

ab

ilit

y

0.7

0.8

0.9 Cis/Pem in Ad or La (N=512) 11.8 mos (10.4, 13.2)

Cis/Gem in Ad or La (N=488) 10.4 mos (9.6, 11.2)

OS Median (95% CI)

Cis/Pem in Sq (N=244) 9.4 mos (8.4,10.2)

Cis/Gem in Sq (N=229) 10.8 mos (9.5, 12.1)

vera

ll S

urv

iva

l P

rob

a

0 2

0.3

0.4

0.5

0.6

0 q ( ) ( , )

Overall Survival Time (months) in Squamous Patients0 6 12 18 24 30

Ov

0.0

0.1

0.2

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Figure 1. Kaplan–Meier overall survival curves foroverall survival curves for the pemetrexed versus docetaxel study for each of the histologic . Subgroups:adenocarcinoma,large cell carcinoma, squamous cell carcinoma, and other NSCLC/NOS histologieshistologies.

Scagliotti, The Oncologist 2009; 14: 253-63

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NOS Adenoca Large


1L

1LM

2L2L

3L

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Adenoca/NOS/Large Cell:UNKNOWN WT/WTUNKNOWN, WT/WT

Platinum doublet x 4-6:

Cisplatin/gemcitabineCisplatin/gemcitabineCisplatin/docetaxel

Carboplatin/paclitaxelCarboplatin/gemcitabine

1L

But also considerCisplatin/pemetrexed

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Double-blind Placebo-controlled Multicenter Phase III Trial

JMEN: Study Design

Stage IIIB/IV NSCLC ECOG PS 0-1 4 prior cycles of gem,

doc or tax + cis or

Double-blind, Placebo-controlled, Multicenter, Phase III Trial

Pemetrexed 500 mg/m2

(d1,q21d) + BSC (N=441)*

doc, or tax + cis or carb, with CR, PR, or SD

Randomization factors: • gender• PS

Primary Endpoint = PFS2:1

Randomization

• PS• stage• best tumor

response• non-platinum drug• brain mets

*B12, folate, and dexamethasone given in both arms

Placebo (d1, q21d) + BSC (N=222)*

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Progression-free Survival by Histology

NonNon--squamous squamous Squamous Squamous

0 70.80.91.0

0 70.80.91.0

qq

Pro

babi

lity

HR=0.47 (95% CI: 0.37-0.6)P <0.00001

HR=1.03 (95% CI: 0.77-1.5)P =0.896

0.10.20.30.40.50.60.7

0 00.10.20.30.40.50.60.7

Pemetrexed 4.4 mos Pemetrexed 2.4 mos

Placebo 1 8 mos

Placebo 2.5 mosog

ress

ion-

free

P

0 3 6 9 12 15 18 21 240.0

0 3 6 9 12 15 18 21 240.01.8 mos 5 os

Time (months) Time (months)

Pro

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Overall Survival by Histology

NonNon--squamous (n=481)squamous (n=481) Squamous (n=182)Squamous (n=182)

0.8

0.9

1.0

0.8

0.9

1.0

HR=0.70 (95% CI: 0.56-0.88)P =0.002

HR=1.07 (95% CI: 0.49–0.73)P =0.678

bilit

y

0.2

0.3

0.4

0.5

0.6

0.7

0.2

0.3

0.4

0.5

0.6

0.7

Pemetrexed 15.5 mos Pemetrexed 9.9 mos

Placebo 10.3 mos

Placebo 10.8 mosSu

rviv

al P

roba

b

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480.0

0.1

S

Time (months) Time (months)

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Pemetrexed(N = 441)

Placebo(N = 222)

Treatment-related Toxicities*

( )%

( )%

Grade 3/4 Grade 3/4

Neutropenia‡ 3 0

Anemia 3 1

Leukopenia 2 1eu ope a

Fatigue‡ 5 1

Anorexia 2 0

Infection 1 0

Diarrhea 1 0

Nausea 1 1Nausea 1 1

Vomiting <1 0

Sensory neuropathy 1 0

Mucositis/Stomatitis 1 0*NCI CTC version 3.0‡P <0.05 for grade 3/4 rates of neutropenia and fatigue

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Tarceva maintenance therapy after first-line chemotherapy treatment – SATURN

Stage IIIb/IV NSCLC Non-PD

Tarceva150mg/day

Off studyPD

1:1

4 cycles of a first-line standard

Tumour samples

EGFR protein expression

(IHC) results

Placebo

NSCLC (n=1,700*)

Non-PD

PD

(n = 850)

1:1standard platinum-

based doublet

PD

Off study

TITAN or Off study

*planned; PD = progressive disease

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OS in patients with non-squamous disease

1.0

0.8

0 6bili

ty

HR=0.79 (0.64–0.96)

Log-rank p=0.0194

Erlotinib (n=272)0.6

0.4

0.2

OS

pro

bab

Erlotinib (n=272)

Placebo (n=257)

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

10.5 13.7

Cappuzzo et al. ESMO 2009

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OS according to response to first-line chemotherapy (ITT population)

bili

ty

1.0

0.8

0.6

1.0

0.8

0.6

Log-rank p=0.0019HR=0.72 (0.59–0.89)

Log-rank p=0.6181HR=0.94 (0.74–1.20)

SD CR/PR

OS

pro

ba 0.6

0.4

0.2

09.6 11.9

0.6

0.4

0.2

012.0 12.5

Erlotinib (n=252)

Placebo (n=235)

Erlotinib (n=184)

Placebo (n=210)

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

Measured from time of randomisation into the maintenance phase

Multivariate HR for OS in SD population 0.71, p=0.0019

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OS in patients with SD on first-line chemotherapy according to histology

S ll NSquamous-cell1.0

0.8

0.6

HR=0.76 (0.59–1.00)Log-rank p=0.0457

Erlotinib (n=155)

Non-squamous

HR=0.67 (0.48–0.92)Log-rank p=0.0116

Erlotinib (n=97) bili

ty

1.0

0.8

0.6

0.4

0.2

Placebo (n=142)( )

Placebo (n=93)

OS

pro

bab

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

10.6 13.70

0 3 6 9 12 15 18 21 24 27 30 33 36

Time (months)

8.3 11.3

Measured from time of randomisation into the maintenance phase

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A-NSCLC


NOS Adenoca Large

EGFR M+ ALK+ WT/WT/WT UNKNOWN

1L Platinum doublet x 4

1LM

PemetrexedPemetrexed(or erlotinib)

2L

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NOS Adenoca Large


1L Platinum Doublet

(non-pemetrexed)

1LMSurveillance

(erlotinib)

2L

3L

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Doc75 (n=55)

Survival – TAX 317BDocetaxel 75mg/m2 vs BSC: Superior in 2nd Line

Median 7.5 mo vs. 4.6 moLog-rank p = 0.010

Doc75 (n=55)

BSC75 (n=49)1.0

0.9

0.8

0.7

rob

abili

ty

1-year 37% vs. 12%Chi-square p = 0.003

0.6

0.5

0.4

0.3

0.2

Cu

mu

lati

ve

P

0.1

0.0

0 3 6 9 12 15 18 21

Survival Time (months)

C

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BR.21: Erlotinib vs Placebo in 2/3LOverall Survival

100

g

60

80___ Erlotinib

_____ Placebo*HR 0.71, p <0.0001

20

40 31%

22%

0 0.0 10.0 20.0

MonthsShepherd, F. et al. N Engl J Med 2005;353:123-132

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Analysisof

Survival

Shepherd, F. et al.N Engl J Med 2005;353:123-132

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BR21: A large subgroup benefit in pts with zero EGFR mutations

Clark GM et al. Clin Lung Cancer 2006

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A-NSCLC


NOS Adenoca Large


1L Platinum doublet x 4

1LM

AlimtaAlimta(or erlotinib)

(Or Surveillance)

2L Erlotinib(docetaxel not funded, no data)

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Non-Squamous Squamous


q

NOS Adenoca Large


1L Platinum Doublet

(non-pemetrexed)

1LMS illSurveillance

(erlotinib)

2L ErlotinibOr Docetaxel

3L DocetaxelOr Erlotinib

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A-NSCLC


NOS Adenoca Large


1L GefitiniborErlotiniborAfatinib

Platinum doublet x 4

Platinum doublet x 4 Platinum Doublet

(non-pemetrexed)

PemetrexedPemetrexed Surveillance

1LMPemetrexed(or erlotinib)

SurveillanceOr erlotinib

2L Platinum doublet X 4 pemetrexed

Crizotinib Erlotinib ErlotinibOr docetaxel

3L TKI re-challenge

Erlotinib Palliative RT, BSC or clinical trial Docetaxelor erlotinib

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Met

HGF

Met plays an important role in normal cellular physiology

• Met (c Met HGFR) is a cell

Rac1 Cdc42 Ras

Grb2

Sos

Shp2

Gab1

Crk PI3K

Met(HGFR)

HGF• Met (c-Met, HGFR) is a cell surface RTK that functions as a dimer1

• Binding of HGF (scatter factor) causes receptor dimerisation1–3

Di i ti ti t lti l

Pak

Rac1 Cdc42 Ras

Raf

Shp2

ERK/MAPK

Ets1 AP1

Rap1

Crk

C36

PI3K

AKT

Motility Proliferation Migration/Invasion Survival

• Dimerisation activates multiple cell signalling cascades leading to

– Cell proliferation, survival, motility, invasion and migration4,5

HGFR= hepatocyte growth factor receptor; RTK = receptor tyrosine kinase; HGF = hepatocyte growth factor 1. Kong-Beltran M, et al. Cancer Cell 2004;6:75–84; 2. Schmidt C, et al. Nature 1995;373:699–702;

3. Uehara Y, et al. Nature 1995;373:702–5; 4. Bladt F, et al. Nature 1995;376:768–71; 5. Birchmeier C, et al. Nat Rev Mol Cell Biol 2003;4:915–25

Adapted from Birchmeier C, et al. Nat Rev Mol Cell Biol 2003;4:915–25

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I ll ll l (NSCLC) t di 1 6

The Met Pathway in Lung Cancer• In non–small cell lung cancer (NSCLC) studies1–6

– Met overexpression was detected in up to 67% of patient samples

– MET gene amplification has been observed in 1–7% of NSCLC patients samples surveyed

– Mutations in MET have been identified in patient samples and NSCLC cell lines

• Met activation has been reported in up to 5–20% of patients with EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC1,7–9

– In preclinical studies, inhibition of Met signaling was capable of restoring sensitivity to treatment in EGFR TKI-resistant NSCLC cells

1. Lawrence R, Salgia R. Cell Adh Migr 2010; 4:146–152. 2. Christensen J, et al. Cancer Lett 2005; 225:1–26.

3. Cappuzzo F, et al. J Clin Oncol 2009; 27:1667–1674. 4. Toschi L, Cappuzzo F. Future Oncol 2010; 6:239–247.

5. Kris M, et al. J Clin Oncol 2011; 29(18 suppl.): Abstract CRA7506. 6. Kong-Beltran M, et al. Cancer Res 2006; 66:283–289.

7. Engelman J, et al. Science 2007; 316:1039–1043. 8. Sequist L, et al. J Clin Oncol 2008; 26:2442–2449.

9. Sequist L, et al. Sci Transl Med 2011; 3:75ra26.

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Prognostic value of MetHigh Met expression is linked with lower OS in NSCLC

• Retrospective study; 885-year survival

rate(%) †• Retrospective study; 88 NSCLC tumours assessed by IHC*– Adenocarcinoma (n=46)

– Squamous cell carcinoma (n=29)

%)

rate(%) †

Met negative 63.2

Met positive 33.8

Intratumoural Met negative

60

80

100

– Large-cell carcinoma (n=13)

• 36/88 were intratumoural Met positive (40.9%)

• Intratumoural Met expression

OS

rat

e (%

p=0.0095

Intratumoural Met positive

0

20

40

60

Intratumoural Met expression was a significant prognostic factor– RR=2.642; p=0.0029OS = overall survival; NSCLC = non-small-cell lung cancer *IHC: rabbit polyclonal anti-Met antibody (sc10), Santa Cruz

Biotechnology†5-year survival rate, based on 52 Met negative tumours and 36 Met positive tumours

Masuya D, et al. Br J Cancer 2004;90:1555–62

Months after surgery

0 20 40 60 80 100 120

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MET IHC as a companion diagnostic in NSCLC

• ‘MET Positive’ was defined as majority (≥50%) of tumor cells with moderate or strong staining intensity

10

100

1000N

A (

2-D

ct)

M dM d SS

NegativeNegative WeakWeak MET NegativeMET Negative MET PositiveMET Positive

MET IHC score 1 2 30

1

10

0

ME

T m

R

Ventana’s CONFIRM (SP44 mAb clone)

ModerateModerate StrongStrong

• MET diagnostic status was assessed after randomization and prior to unblinding

• 93% of patients had adequate tissue for evaluation of MET by IHC

• 52% patients with evaluable tissue were “MET Positive”

IHC: immunohistochemistryRoche data on file

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One-Armed (Monovalent) antibody binds MET, but does not lead to dimerization and activation

OnartuzumabTwo-armed MET antibody

METMET METMET

1. Martens T, et al. Clin Cancer Res 2006;12:6144–52

• Onartuzumab prevents HGF binding and avoids MET “homodimerization”and activation. 1

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Cross-talk between Met and EGFR pathwaysScientific rationale for dual inhibition of Met and EGFR

ERLOTINIB THERAPYSMI RESISTANCE VIA

MET— EGFR CROSS-TALK DUAL INHIBITION

Erlotinib is a small molecule inhibitor (SMI) of EGFR used to treat NSCLC and pancreatic cancer1

Dual inhibition of Met and EGFR may overcome tumour resistance5

Tumour resistance to EGFR SMIs can occur via multiple mechanisms including cross-talk between Met and EGFR2,3

Evidence of Met amplification is seen in ~20–22% of EGFR mutant NSCLC tumours4

Onartuzumab

EGFEGFR

Erlotinib Erlotinib Erlotinib

Met

EGFR = epidermal growth factor receptor1. Tarceva SmPC; 2. Engelman JA, et al. Science 2007;316:1039–43;

3. Stommel JM, et al. Science 2007;318:287–90; 4. Bean J, et al. PNAS 2007;104:20932–37; 5. Karamouzis MV, et al. Lancet Oncol 2009;10:709–17

No activity No activityMotility, invasion, survival,

migration, proliferation

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MetMAb(15 mg/kg IV Q3W)

Phase II: Erlotinib +/- MetMAb in2nd/3rd-line NSCLC

Arm A (15 mg/kg IV Q3W)+

erlotinib(150 mg daily)

RANDOMIZA

1:1 n=69Arm A

Key eligibility:• Stage IIIB/IV NSCLC• 2nd/3rd-line NSCLC• Tissue required• PS 0–2

Stratification factors:• Tobacco history • Performance status • Histology

PlaceboATION

n=137* n=68Arm B

PD

• PS 0–2 Placebo (IV Q3W)

+

erlotinib(150 mg daily)

Co-primary objectives: Other key objectives:

*128 NSCLC patients enrolled from 3/2009 to 3/2010 plus 9 SCC patients enrolled through 8/2010

Data presented includes >5 additional months of follow-up

n=27

Must be eligible to be treated with MetMAb

Add MetMAb• PFS in ‘Met Diagnostic

Positive’ patients (est. 50%)

• PFS in overall ITT population

• OS in ‘Met Diagnostic Positive’ pts

• OS in overall ITT patients

• Overall response rate

• Safety/tolerability

5

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MetMAb plus erlotinib in Met Dx+ patients

PFS: HR=0.53 OS: HR=0.37

sio

n f

ree

0.8

1.0

Placebo +erlotinib

3.8

26

MetMAb +erlotinib

12.6

16

Median (mo)HR

(95% CI)Log-rank p-value

No. of events

viva

l 0.8

1.0

Placebo +erlotinib

1.5

27

Median (mo)HR

(95% CI)Log-rank p-value

No. of events

MetMAb +erlotinib

2.9

20

0.53(0.28–0.99)

0.04

0.37(0.19–0.72)

0.002

rob

abili

ty o

f p

rog

ress

0.2

0.4

0.6

Pro

bab

ility

of

surv

0.2

0.4

0.6

Time to progression (months)

0 3 6 9 12 15 18

Pr

0.0

Overall survival (months)

0 3 6 9 12 15 18 21

0.0

9

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MetLung(OAM4971g): A RANDOMIZED, PHASE III, MULTICENTER, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY EVALUATING

ONARTUZUMAB IN COMBINATION WITH ERLOTINIB IN PATIENTS WITH MET DIAGNOSTIC−POSITIVE mNSCLC WHO AFTER

STANDARD CHEMOTHERAPY

Treat until PD

Erlotinib + onartuzumab

Randomise 1:1

2L/3L NSCLC

Met-positive

(1 prior platinum-based line of therapy)

Central testing for:

• Met status

• EGFR mutation

Survivalfollow-up

Erlotinib + placebo

status

(N=490)

Primary endpoint:• OSSecondary endpoints:• PFS

Erlotinib: 150mg p.o. qdOnartuzumab/placebo: 15mg/kg i.v. q3w

No crossover tx

Stratification criteria

• EGFR mutation status

Key eligibility criteria

• Stage IIIb or IV Met+ NSCLC

ECOG = Eastern Cooperative Oncology Group; PFS = progression-free survival; ITT = intent-to-treat; OS = overall survival; ORR = overall response rate; PD = progressive disease

PFS• ORR• Quality of life• Safety

• EGFR mutation status

• Met 2+ or 3+ score

• Number of prior lines of therapy

• Histology

• Stage IIIb or IV Met+ NSCLC

• 1–2 prior lines of treatment

• No prior EGFR inhibitor

• ECOG PS 0 or 1

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SMALL CELL LUNG CANCER :

Limited Disease Extensive Disease

1L Cisplatin/Etoposide Carboplatin/Etoposide

S C U G C CALGORITHM

1L Cisplatin/Etoposide x 4-6 cycles

Concurrent thoracic RTProphylactic Cranial RT

Carboplatin/Etoposidex 4-6 cycles

± Palliative RTProphylactic Cranial RT

1LM Surveillance Surveillance

2L Re-challenge with Carboplatin/Etoposideor

Topotecan single-agent

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Group No. of trials

Comparison Survival HR

G 1 1 ± Ci l ti ( t id ) 0 70Group 1 1 ± Cisplatin (no etoposide) 0.70

Group 2 17 ± Etoposide (no cisplatin) 0.72

Group 3 9 Cis/Etop vs Other 0.57

Group 4 9 Cis/Etop vs Etop/other 0.74

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“It was decided to remove the reference thatEtoposide-carboplatin was biologically equivalent to etoposide-cisplatin..and to discuss the limitedamount of data on this issue.”

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Compared to patients in arm III patients treated in arms I and II survived longer with median survivals of 336 days (95% CI 275-397), 340 days (95% CI 290-390), and 293 days (95% a 266-320), respectively. The overall survival difference between the three arms was statistically significant (P = 0.04, Figure 1). P i i i b thPairwise comparison by the logrank test showed that the difference in survival betweenarm II and III was statistically significant (P - 0.02, logranktest), while the P-value of the difference betweendifference betweenarm I and arm III was 0.07.

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J Clin Oncol 1999

Similar survival, superior symptom , p y prelief, slightly better response rates;but more anemia,thrombocytopenia on topotecan.

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15 pts re-challenged;10 responses (67%)MST 5 months

However, we have identified seven studies (192patients altogether) employing so-called non-cross-resistantchemotherapy in clearly distinguishable relapsed patients

Their response rates (CR + PR) range from 6%.... Their response rates (CR + PR) ...range from 6%to 31%, and the median survival of responding patientswas usually only 3-4 months. Thus, results with re-challenge chemotherapy, although poor, appear to be no worse than with alternative second-line chemotherapy.

THERE IS NO STANDARD 2ND LINE:CAV OR TOPOTECAN PROBABLY NOTSUPERIOR TO RE-CHALLENGE WITHPLATINUM AND ETOPOSIDECONSIDER G-CSF TO PREVENT FN & MAINTAIN DOSE INTENSITY

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PCI in ED-SCLC:Cumulative Incidence of Symptomatic Brain Metastases

Slotman B et al. N Engl J Med 2007;357:664-672

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Overall Survival

PCI in ED-SCLC:

Slotman B et al. N Engl J Med 2007;357:664-672

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Bone Metastases:

Zoledronate vs Placebo

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EXPERIMENTAL TARGETS IN SMAL CEL LUNG CANCER

Teicher B. Biochemical Pharmacology 2013

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Home page

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Signing up

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Logging in

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Premise behind the website

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Resources – available to view without signing in or logging in

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Resources include a link to the actual trial, granted the computer you are working from has access ie. hospital

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User Guide tab

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New patient (can be saved) vs sample patient (teaching or review opportunity)

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Overview field

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Overview

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Entering patient characteristics allows for a personalized treatment guide

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Patient Characteristics

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Medical details

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Prior therapy considerations

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Specific notes that pertain to patient characteristics

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Drug details

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Warning symbols

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Choosing a drug eliminates subsequent choices in later lines

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Comment Boxes

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CASE REPORT (1)

An overview: Current systemic th i f d d ll lltherapies for advanced non-small cell lung cancer

Ong M and Vincent M. Lung Cancer, In Press

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CASE REPORT (cont) … (2)

• 54 yr Caucasian male• 54 yr Caucasian male

• Never-smoker

• Dyspnea, large pleural effusion

• FNA: “adenocarcinoma lung”

• Chest tube drainage pleurodhesis• Chest tube drainage, pleurodhesis

• EGFR “inconclusive” (scant 6x material)

• 6 cycles carbo/paclitaxel – minor response

• Relapsed within 3/12

Refractor to 3 c cles pemetre ed• Refractory to 3 cycles pemetrexed

• Multiple brain mets, 02 dependent

• Whole brain RT

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• Rx erlotinib 150 mg po od

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Disease burden before (Panels A, B, C) and 8 months after (Panels D, E, F) initiation of third-line erlotinib for metastatic A-NSCLC.

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• Eventual PD on erlotinib (± 1 year• Eventual PD on erlotinib (± 1 year remission)

• Unresponsive to trial of afatinib• Unresponsive to trial of afatinib

• Dies rapidly of respiratory failure

• EGFR ? But almost certainly M+

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THE END

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Documents

The Evolving Management of Advanced Lung … 1 The Evolving Management of Advanced Lung Cancerof Advanced Lung Cancer CAGPO October 19th, 2013 M. Vincent MB ChB, FRCPC, MRCP(UK) Staff