advanced nsclc: treatment options for non-squamous, egfr wildtype tumors
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Advanced NSCLC: treatment options for non-squamous, EGFR wildtype tumors. Prof. Christian Manegold Interdisciplinary Thoracic Oncology Department of surgery Medical Center Mannheim – University Heidelberg. Disclosures. - PowerPoint PPT PresentationTRANSCRIPT
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
Maintenance in case of
non-PD/SD
Switch:Pemetrexed
ErlotinibContinuous:Pemetrexed
Switch:Pemetrexed
ErlotinibContinuous:Pemetrexed
Switch:Erlotinib
2nd-line
Dealer’s choice
Single agentNon-cross resistant
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
IIIB/IV non-squamous
NSCLC
RANDOMISE
Placebo + CGPlacebo + CG
2
1
Previously untreated stage
IIIB/IV non-squamous
NSCLC
Previously untreated stage
IIIB/IV non-squamous
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
Pirker et al. Lancet Oncol 13: 33–42, 2012
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
Pirker et al. Lancet Oncol 13: 33–42, 2012
FLEX: Overall survival for patients according to treatment group and EGFR expression group
Pirker et al. Lancet Oncol 13: 33–42, 2012
Low EGFR High EGFR
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
Maintenance in case of
non-PD/SD
Switch:Pemetrexed
ErlotinibContinuous:Pemetrexed
Switch:Pemetrexed
ErlotinibContinuous:Pemetrexed
Switch:Erlotinib
2nd-line
Dealer’s choice
Single agentNon-cross resistant
Single agentNon-cross resistant
3rd-line
Dealer’s choice
Dealer’s choice
Dealer’s choice
SquamousMutated tumours
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)
Coudert et al. Ann Oncol 23, 388-394, 2012Coudert et al. Ann Oncol 23, 388-394, 2012
NSCLC: Erlotinib switch maintenanceSurvival for SD in wild-type tumours
Coudert et al. Ann Oncol 23, 388-394, 2012Coudert et al. Ann Oncol 23, 388-394, 2012
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
Ciuleanu T. et al. Lancet 374, 1432-1440; 2009
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
Ciuleanu T. et al. Lancet 374, 1432-1440; 2009
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
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC – Pemetrexed continuation maintenanceProgression free survival
Pro
gres
sion
fre
e S
urvi
val
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC – Pemetrexed continuation maintenanceProgression free survival (subgroups)
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
NSCLC – Pemetrexed continuation maintenanceAdverse events
Paz-Ares J Clin Oncol 29 (Suppl 18), 478 (Abstr. 7510), 2011
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
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
Maintenance in case of
non-PD/SD
Switch:Pemetrexed
ErlotinibContinuous:Pemetrexed
Switch:Pemetrexed
ErlotinibContinuous:Pemetrexed
Switch:Erlotinib
2nd-line
Dealer’s choice
Single agentNon-cross resistant
Single agentNon-cross resistant
3rd-line
Dealer’s choice
Dealer’s choice
Dealer’s choice
SquamousMutated tumours
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