Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors

Advanced NSCLC: treatment options for non-squamous,

EGFR wildtype tumors

Prof. Christian ManegoldProf. Christian ManegoldInterdisciplinary Thoracic Oncology

Department of surgeryMedical Center Mannheim – University Heidelberg

Disclosures

• Consultancy: Hoffmann-La Roche, Pfizer, Eli Lilly, Merck-Serono, Novartis, Amgen, Boehringer Ingelheim, AstraZeneca

• Speaking: Hoffmann-La Roche, Eli Lilly, Merck-Serono, AstraZeneca

• Grant support: Merck-Serono, Sanofi-Aventis, Eli Lilly

• Travel Support: Hoffmann-La Roche, Merck-Serono, Eli Lilly, AstraZeneca

NSCLC: Incidence of single driver mutations

Mutation found in 54% (280/516) oftumours completely tested (CI 50-59%)

Kris et al. J Clin Oncol 29: 2011 (suppl; abstr 7506)

Stage IIIB-IV Stage I-IIIoperable

Stage I-IIIinoperable

ChemotherapyPS 0-1 / 2

Elderly

First –line Maintenance

Second / Third –

line

Chemotherapy adjuvant / postoperative

Chemotherapy neoadjuvant / preoperative

ChemoRadiotherapy sequential

ChemoRadiotherapyconcomitant

Treatment Strategies for NSCLC

1st-line1st-line Platinum-Doublets (Pem!) plus Bev or Cet

Platinum-Doublets (Pem!) plus Bev or Cet

Non-SquamousNon-Squamous

Advanced NSCLC: Treatment algorithm in 2012

EGFR-TKI;ALK-Inhibitor

Platinum-Doublets

(No Pem, no Bev)

plus Cet

Maintenance in case of

non-PD/SD


non-PD/SD

Switch:Pemetrexed

ErlotinibContinuous:Pemetrexed

Switch:Pemetrexed


Switch:Erlotinib

2nd-line

Dealer’s choice

Single agentNon-cross resistant


3rd-line

Dealer’s choice

Dealer’s choice

Dealer’s choice

SquamousMutated tumours

NSCLC: ASCO treatment recommendations for advanced disease

• Chemotherapy prolongs survival and is most appropriate for individuals with good performance status (PS 0 or 1, and possibly 2).

• Chemotherapy should be a platinum-based two-drug combination regimen.

• Non-platinum containing regimens may be used as alternatives to platinum-based regimens. For elderly patients, or patients with PS 2, available data support the use of single-agent chemotherapy.

• Chemotherapy should be stopped at 4 cycles in patients who are not responding to treatment, and should be administered for no more than six cycles .

• If chemotherapy is to be given it should be initiated while the patient still has good PS.

Azzoli et al. J Clin Oncol 29, 3825-3831, 2011

Study Schedule

Gem mg/m² / DDP mg/m²

ORR%

TTPmos

MSmos

1-YS%

Sandler 2000 1000 d1, 8, 15 /100 d1 q4w 34 5.6 9.1 39

Schiller 2002 1000 d1, 8, 15 /100 d1 q4w 21 4.2 8.1 36

Crinò 1999 1000 d1, 8, 15 /100 d2 q4w 38 5.0 8.6 33

Melo 2002 1000 d1, 8, 15 /100 d15 q4w 48.4 n.r. 9.6 n.r.

Cardenal 1999 1250 d1, 8 /100 d1 q3w 40.6 6.9 8.7 32

Smit 2003 1250 d1, 8 / 80 d1 q3w 31.8 5.1 8.9 33

Giaccone 2002 1250 d1, 8 / 75 d1 q3w 35 6.0 11.1 34

Scagliotti 2002 1250 d1, 8 / 70 d2 q3w 30 5.3 9.8 37

Alberola 2003 1250 d1, 8 / 100 d1 q3w 42 6.3 9.3 38

First line Gemcitabine/Cisplatin combination therapy for advanced NSCLC: outcome plateau

NSCLC: Pivotal phase III trails in stage IIIB/IV disease relevant for the treatment of non-mutated,

non-squamous tumours

Bevacizumab

Bevacizumab

AVAiL: Cis/GemAVAiL: Cis/Gem PD

PD

PD

Bev15mg/kg + CG

Bev15mg/kg + CG

Bev7.5mg/kg + CG

Bev7.5mg/kg + CG

Placebo + CGPlacebo + CG

Previously untreated, stage

IIIB/IV non-squamous

NSCLC

Previously untreated, stage


NSCLC

RANDOMISE

Placebo + CGPlacebo + CG

2

1

Previously untreated stage


NSCLC

Previously untreated stage


NSCLC

CP CP

Bev (15mg/kg) every 3 weeks +

CP

Bev (15mg/kg) every 3 weeks +

CP

PD

PDBev every

3 weeks until progression

Bev every 3 weeks until progression

ECOG 4599: Carbo/TaxolECOG 4599: Carbo/Taxol

Advanced NSCLC: Bevacizumab plus Standard CT

2

1

Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints

12.3 m

Time Months

10.3 m

6.7 m

6.1 m

6.5 m

6.1 m

Sandler et al N Engl J Med 355, 2542-2550, 2006Reck et al, Ann Oncol 21, 1804-1809, 2010Reck et al, J Clin Oncol 27, 1227-1235, 2009

ECOG 4599: Carbo/TaxolECOG 4599: Carbo/Taxol AVAiL: Cis/GemAVAiL: Cis/Gem

NSCLC: Bevacizumab - EMA Registration

• BEV at a dose of 7.5mg/kg or 15mg/kg, in combination with platinum-based chemotherapy, for the first-line treatment of patients with unresectable advanced, metastatic or recurrent NSCLC other than predominantly squamous cell histology

• Removal of Bev- contraindication in patients with untreated CNS metastases (2008)

NSCLC: Bevacizumab - Key eligibility criteria

Inclusion criteria Exclusion criteria

non-squamous NSCLC

chemo-naïve

ECOG PS of 0–1

grade 2 haemoptysis

radiological evidence of tumour invasion of major blood vessels

spinal cord compression

uncontrolled hypertension

history of thrombotic or haemorrhagic disorders

therapeutic anticoagulation within 10 days of first dose

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

RandomizationFactors

• Stage

• PS

• Gender

• Histo vs cyto

• Brain mets

R

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

Vitamin B12, folate, and dexamethasone given in both arms

Each cycle repeated q3 weeks up to 6 cycles

Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008

Primary endpoint: survival; non-inferiority design

JMDB: Pemetrexed vs Gemcitabine

Pemetrexed+CisplatinMedian OS: 11.0 mos

Gemcitabine+CisplatinMedian OS: 10.1 mos

HR=0.844(95% CI: 0.74–0.96) p=0.011

Pemetrexed+CisplatinMedian OS: 9.4 mos

Gemcitabine+CisplatinMedian OS: 10.8 mos

HR=1.229(95% CI: 1.00–1.51)p=0.051

Nonsquamous* (n=1252) Squamous (n=473)

Survival Time (months) Survival Time (months)

Su

rviv

al

Pro

bab

ilit

y

Su

rviv

al

Pro

bab

ilit

y

JMDB: Pemetrexed vs Gemcitabine

Scagliotti et al J Clin Oncol, 26, 3543-3551, 2008

Treatment-by-Histology Interaction Analyses in Three Phase III Trials Show Superiority of Pemetrexed in Nonsquamous

NSCLC

Scagliotti J Thorac Oncol 6, 64–70, 2011

FLEX: First-Line ErbituX in lung cancer

Pirker et al. Lancet 373, 1525-1531, 2009

Flex: Kaplan-Meier estimates of overall survival time in the intention-to-treat population

Pirker et al. Lancet 373, 1525-1531, 2009

FLEX: Stained tumour sections from study patients

Pirker et al. Lancet Oncol 13: 33–42, 2012

FLEX: Objective response rate by IHC score


CT CT + cetuximab

High EGFR expression (≥200) n=345 (31%)

Low EGFR expression (<200)n=776 (69%)

0

50

40

30

20

10

44.4

28.1

Re

spo

nse

rat

e (

%)

0

50

40

30

20

10

29.6 32.6

p=0.36 p=0.002

Treatment interaction test p=0.040

FLEX: Response rate by EGFR-IHC expression


FLEX: Overall survival for patients according to treatment group and EGFR expression group


Low EGFR High EGFR






Platinum-Doublets

(No Pem, no Bev)

plus Cet


non-PD/SD


non-PD/SD

Switch:Pemetrexed


Switch:Pemetrexed


Switch:Erlotinib

2nd-line

Dealer’s choice



3rd-line

Dealer’s choice

Dealer’s choice

Dealer’s choice


NSCLC – Erlotinib switch maintenance

1:11:1

Chemonaïve advanced

NSCLCn=1,949

Chemonaïve advanced

NSCLCn=1,949

Non-PDn=889

Non-PDn=889

4 cycles of first-line platinum doublet

chemotherapy*

4 cycles of first-line platinum doublet

chemotherapy* PlaceboPlacebo PDPD

Erlotinib150mg/day

Erlotinib150mg/day PDPD

Mandatory tumour sampling

Mandatory tumour sampling

Stratification factors:• EGFR IHC (positive vs negative vs indeterminate)• Stage (IIIB vs IV)• ECOG PS (0 vs 1)• CT regimen (cis/gem vs carbo/doc vs others)• Smoking history (current vs former vs never)• Region

Co-primary endpoints:• PFS in all patients• PFS in patients with EGFR IHC+ tumours

Secondary endpoints:• OS in all patients and those with EGFR IHC+

tumours, OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; QoL

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel

NSCLC – Erlotinib switch maintenanceProgression free survival

Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

Progression free Survival

Cappuzzo et al. Lancet Oncol 11, 521-529; 2010

NSCLC – Erlotinib switch maintenanceOverall survival

Overall Survival

Ove

rall

Surv

ival

1.0

0.8

0.6

0.4

0.2

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

Time (months)

9.6 11.9

1.0

0.8

0.6

0.4

0.2

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

Time (months)

12.012.0 12.5

Log-rank p=0.0019HR=0.72 (0.59–0.89)

Erlotinib (n=252)

Placebo (n=235)

Log-rank p=0.6181HR=0.94 (0.74–1.20)

Erlotinib (n=184)

Placebo (n=210)

Stable disease CR/PR

Measured from time of randomisation into the maintenance phase

NSCLC: Erlotinib switch maintenanceOverall survival by response

Coudert et al. Ann Oncol 23, 388-394, 2012Coudert et al. Ann Oncol 23, 388-394, 2012

NSCLC: Erlotinib switch maintenanceOverall survival by response (subgroups)


NSCLC: Erlotinib switch maintenanceSurvival for SD in wild-type tumours


NSCLC – Erlotinib switch maintenance (registration)

Erlotinib Maintenance :

as single agent in patients with stable disease after 4 cycles of platinum based first-line chemotherapy

EMA: 2010

NSCLC – Pemetrexed switch maintenance

• Stage IIIB/IV NSCLC

• PS 0-1• 4 prior cycles of

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

• Randomization factors:

• gender• PS• stage• best tumor

response to induction

• non-platinum induction drug

• brain mets

Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*Pemetrexed 500 mg/m2 (d1,q21d) + BSC (N=441)*

Primary Endpoint = PFS

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

*B12, FOLATE, AND DEXAMETHASONE GIVEN IN BOTH ARMS

2:1 Randomization

Ciuleanu T. et al. Lancet 374, 1432-1440; 2009

NSCLC – Pemetrexed switch maintenancePFS by histology

Time (months)

Pro

gres

sion

-fre

e P

roba

bilit

y

Time (months)

Non-squamous Squamous

Placebo: 1.8 mos

Pemetrexed: 4.4 mos Placebo: 2.5 mos

Pemetrexed: 2.4 mos

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

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


NSCLC – Pemetrexed switch maintenanceOS by histology

Non-squamous Squamous

Time (months) Time (months)

Ove

rall

Su

rviv

al

Placebo: 10.3 mos

Pemetrexed: 15.5 mos

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

Placebo: 10.8 mos

Pemetrexed: 9.9 mos

HR=1.07(95% CI: 0.49-0.73)p=0.678


NSCLC – Pemetrexed continuation maintenance

Stadium IVNon-squamousSD nach 4-6x Induktions-CTCisplatin/Pemetrexed

Stadium IVNon-squamousSD nach 4-6x Induktions-CTCisplatin/Pemetrexed

Rand

omis

ation

2:1 Pemetrexed

3qw bis PDPemetrexed3qw bis PD

Placebo3qw bis PD Placebo3qw bis PD

Non PDNon PD

Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011

PARAMOUNT

NSCLC – Pemetrexed continuation maintenance


NSCLC – Pemetrexed continuation maintenanceProgression free survival

Pro

gres

sion

fre

e S

urvi

val


NSCLC – Pemetrexed continuation maintenanceProgression free survival (subgroups)


NSCLC – Pemetrexed continuation maintenanceAdverse events


NSCLC-maintenance: ASCO 2011

For patients with SD or response after 4 cycles, immediate treatment with an alternative, single-agent chemotherapy such as pemetrexed in patients with non-squamous histology, docetaxel in unselected patients, or erlotinib in unselected patients may be considered

(alternative to second-line therapy!)

Azzoli et al. J Clin Oncol 29, 3825-3831, 2011

NSCLC – Pemetrexed switch and continuation maintenance (registration)

Pemetrexed Maintenance :

as single agent following platinum based therapy (predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy)

EMA: 2009 / 2011






Platinum-Doublets

(No Pem, no Bev)

plus Cet


non-PD/SD


non-PD/SD

Switch:Pemetrexed


Switch:Pemetrexed


Switch:Erlotinib

2nd-line

Dealer’s choice



3rd-line

Dealer’s choice

Dealer’s choice

Dealer’s choice


Advanced NSCLC - Medical Treatment Standard Approach

Combination CTor single agent defined number of cycles (4-6)

single agent , Non-cross-resistant

until progression

single agent , Non-cross-resistant

until progression

single agent, Non-cross-resistant

until progression

single agent, Non-cross-resistant

until progression

In case of PD In case of PD 1st-line 2nd-line2nd-line 3rd-line3rd-line

DocetaxelPemetrexed

ErlotinibGefitinib

DocetaxelPemetrexed

ErlotinibGefitinib

ErlotinibGefitinibErlotinibGefitinib

Documents

Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors