1. Advanced NSCLC: Treatment algorithms 2014
Prof. Christian Manegold
Medical Faculty Mannheim
University of Heidelberg
Was gibt es neues

2. NSCLC: Incidence of single driver mutations
Mutation found in 54% (280/516) of tumours completely tested (CI 50-59%)
Kris et al. J Clin Oncol 29 (suppl 15) 477 (abstr 7506); 2011

3. Advanced NSCLC: Current Treatment algorithm
Mutant tumors
Wild type tumors
Non-Squamous
Squamous
Platinum-Doublets (Pem!) plus Bev
Platinum-Doublets
(No Pem, no Bev)
1st-line
EGFR-TKI
Switch:
Pemetrexed
Erlotinib
Continuous:
Switch:
Erlotinib
Treatment until progression
Maintenance
Oligo progression:
Cont. TKI + Local therapy
Diffuse progression
Cont. TKI + Chemo
Chemo  TKI re-expo
2nd generation TKI
2nd-line
Single agent
Non-cross resistant
Single agent
Non-cross resistant
ALK-Inhibitor 3

4. Advanced NSCLC: Treatment for non-mutant tumors
First-line – (induction) – therapy
Selection by histo-type
Maintenance therapy
Switch / continuation
Second-line / subsequent-line therapy

5. NSCLC: International 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, , 2011
Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012

6. Advanced NSCLC: Medical management – practical aspects
Feasibility / tolerability: Cis-platin vs carbo-platin
Hotta et al. J Clin Oncol 22, , 2004, Rudd et al. J Clin Oncol 23, , 2005
Artizoni et al. J Natl Cancer Inst 99, , 2007
Co-morbidity / regimen: Platin based / free
D‘Addario et al. J Clin Oncol 23, , 2005
Laack et al. J Clin Oncol 22, , 2004,
Age ≥ 70 years: Single agent / combination
Gridelli et al. J Clin Oncol 23, , 2005; Gridelli et al. J Natl Cancer Inst 95, , 2003
Gridelli et al. J Natl Cancer Inst 91, 66-72, 1999; Sederholm et al. J Clin Oncol 23, , 2005
Performance status ≥ 2: Single agent / combination
Gridelli et al. Ann Oncol 15, , 2004,
Patient’s expectations: Active therapy / BSC
Gridelli et al. J Clin Oncol 23, , 2005

7. Selection by histo-type according to efficacy (non-squamous vs squamous)

8. Survival Time (months) Survival Time (months)
Advanced NSCLC: Treatment by histology Cisplatin plus Pemetrexed or Gemcitabine
Nonsquamous* (n=1252)
Squamous (n=473)
HR=0.844
(95% CI: 0.74–0.96)
p=0.011
HR=1.229
(95% CI: 1.00–1.51)
p=0.051
Survival Probability
Pemetrexed+Cisplatin
Median OS: 11.0 mos
Survival Probability
Gemcitabine+Cisplatin
Median OS: 10.8 mos
Gemcitabine+Cisplatin
Median OS: 10.1 mos
Pemetrexed+Cisplatin
Median OS: 9.4 mos
Survival Time (months)
Survival Time (months)
Scagliotti et al J Clin Oncol, 26, , 2008 8

9. Efficacy by Histology in Pemetrexed Studies
NSCLC Histologic Group
Second-line Pem vs. Docetaxel
First-line Pem/Cis vs. Gem/Cis
Maintenance Pem vs. Placebo
Pem
Doc
Cis/Pem
Cis/Gem
Placebo
Non-squamous
n=205
n=194
n=618
n=634
n=325
n=156
Median OS, months
9.3
8.0
11.0
10.1
15.5
10.3
Adjusted HR (95% CI)
P value
0.78 (0.61–1.00)
0.84 (0.74–0.96) 0.011
0.70 (0.56–0.88) 0.002
Squamous
n=78
n=94
n=244
n=229
n=116
n=66
6.2
7.4
9.4
10.8
9.9
Adjusted HR (95% CI) P value
1.56 (1.08–2.26) 0.018
1.23 (1.00–1.51) 0.050
1.07 (0.77–1.50) 0.678
As you are aware of, more recently it has been demonstrated that pemetrexed it is not a good choice for patients with squamous cell lung cancer and this findings have been consistently reported across different lines of therapy
Non-squamous = adenocarcinoma, large cell carcinoma, and other/indeterminate NSCLC histology
Scagliotti et al. J Thorac Oncol 6, 64-70, 2011 9

10. Ifosfamide in NSCLC: MIC Regimen
Mitomycin C 6 mg/m² i.v. Bolus day 1
Ifosfamide mg/m² i.v./3 h day 1
Cisplatin 50 mg/m² i.v./1 h day 1
Cycle repeated q3w
MESNA-Uroprotection
20 % (IFO) i.v. fractionated (0 hours) 4 h + 8 h
100 % (IFO) i.v. continuous (0 hours) during IFO
+ for additional 12 q 24 h
Cullen et al, Br J Cancer 58, , 1988

11. MIC `s Efficacy is not inferior to other Platinum Doublets
n RR TTP MST 1-y-s Ref.
NVB / CIS % n.r mo* 37 % Le Chevalier
VDS / CIS % n.r. 7.6 mo 28 % (1994)
PAC 135 / CIS Total 27 %* 4.5 mo* 9.6 mo* 37 % Bonomi
PAC 250 / CIS %* 5.3 mo* 10 mo* 39 % (1996)
ETO / CIS 12 % 3.0 mo 7.7 mo 32 %
GEM / CIS % 4.8 mo 8.6 mo 33 % Crino
MIC % 5.0 mo 9.5 mo 34 % (1998)
GEM / CIS %* 6.9 mo* 8,7 mo 32 % Cardenal
ETO / CIS % 4.3 mo 7.2 mo 26 % (1999)
PAC / CARBO %* 4.0 mo 7.7 mo 32 % Belani
ETO / CIS % 3.3 mo 8.2 mo 37 % (1998)
*p<.05

12. PAC 250 mg/m² (3h), d 1 IFO 1600 mg/m² , d 1-3 Phase II Stage IIIb/IV
Platinum-free, Ifosfamide based doublets have been developed
PAC mg/m² (3h), d 1
IFO mg/m² , d 1-3
q3w x 6
Arm A
n=48
Arm B
n=45
Phase II
Stage IIIb/IV
NAV mg/m², d 1-3
IFO mg/m², d 1-3
q3w x 6
RR MS 1yS
A: 38% 9mo 35%
B: 31% 8mo 38%
Perry et al, Lung Cancer 48,63-68, 2000

13. Phase III Stage IIIb/IV PS 0-2
Platinum-free, Ifosfamide based doublets have been developed
Cis mg/m², d x 6 (n=166)
Gem 1250 mg/m² , d 1, 8
Phase III
Stage IIIb/IV
PS 0-2
Cis mg/m², d x 6 (n=176)
Gem 1000 mg/m², d 1, 8
Vin mg/m², d 1, 8
Gem 1000 mg/m², d 1, 8 x 3 (n=175)
Vin mg/m², d 1, 8
Ifo mg/m², d x 3
RR: 41% 40% 24%
MS: 10m 8m 11m
Ntp3/4: 26% 30% 18%
Tbp3/4: 18% 23% 7%0
Alberola et al, J Clin Oncol, 21: , 2003

14. Selection by toxicity profile (non-squamous vs squamous)

15. Advanced NSCLC: Bevacizumab plus Standard CT Results by primary endpoints
ECOG 4599: Carbo/Taxol
AVAiL: Cis/Gem
6.7 m
6.1 m
12.3 m
10.3 m
6.5 m
6.1 m
Time Months
Sandler et al N Engl J Med 355, , 2006
Reck et al, Ann Oncol 21, , 2010
Reck et al, J Clin Oncol 27, , 2009

16. NSCLC: Bevacizumab - Eligibility
Inclusion criteria
Exclusion criteria
non-squamous NSCLC
chemo-naïve
ECOG PS of 0–1
grade 2haemoptysis
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
Sandler et al N Engl J Med 355, , Crino et al, LancetOncol 11, , 2010
Reck et al, J ClinOncol 27, , Reck et al, Ann Oncol 21, ,2010
Sandler et al J Thorac Oncol 5, , Soria et al Ann Oncol 24,20-30,2013

17. Advanced NSCLC: Basics of medical management
First-line – (induction) – therapy
Selection by histo-type
Maintenance therapy
Switch / continuation
Second-line / subsequent-line therapy

18. Advanced NSCLC: Medical Treatment in wild type tumors
Traditional (standard) approach
1st-line
2nd-/subsequent line
Combination
or single agent CT
defined number
of cycles (4-6)
single agent ,
Non-cross-resistant
until progression
Tumor progression
New (maintenance) approach
1st-line
Maintenance
Combination
or single agent CT
defined number
of cycles (4-6)
one of the first line agents until progression (continuation)
„new“ non-cross-resistant agent until progression (switch)
Non- progression
2nd-/ subsequent line

19. Advanced NSCLC: Switch/continuation maintenance
PARA-MOUNT
JMEN
Saturn
Inform
Boston
IFCT
ECOG 5508
Design
2-arms
phase III
2-arms phase III
Phase III
2- arms phase III
3-arms phase III
Primary endpoint
PFS OS
Agents
Pemetrexed Placebo
Erlotinib Placebo
Gefitinib Placebo
Doc early/late
Erlotinib
Observation Gem
Bev Pem Bev/Pem
No. of Pts.
539
663
889
296
566
464
1282
Induction CT
Cis/Pem
Platinum doublets
Cis/Gem
Carbo/ Pac/Bev
Cappuzzo et al. Lancet Oncol 11, ; 2010
Ciuleanu T. et al. Lancet 374, ; 2009
Paz-Ares Lancet Oncol 13, , 2012
Zhang et al. Lancet Oncol 13, ,2012
Fidias et al J Clin Oncol 27, , 2008
Perol et al J Clin Oncol 30, , 2012
Paz-Ares et al J Clin Oncol 31, , 2013

20. Advanced NSCLC: Maintenance
Switch type („early second line“)
Docetaxel
Fidias et al J Clin Oncol 27, , 2009

21. Advanced NSCLC - Maintenance:
Docetaxel following Standard Doublet Chemotherapy
Immediate vs delayed (2nd-line) Docetaxel
n=552
CR, PR SD
n=142/153
Immediate
Docetaxel 75 mg/m2 d1, q3w x 6 R A N D O MI Z E
Stage IIIb/IV
ECOG PS = 0–2
CNS Mets allowed
Gem, 1000 mg/m2, d1, 8
Carbo AUC 5, d1,
q3w x 4
Delayed
Docetaxel 75 mg/m2 d1, q3w x 6
Off study: n=245
n=307
n=91/154
Primary endpoint: overall survival
Fidias et al., J Clin Oncol 27, , 2009

22. Advanced NSCLC - Maintenance: Extension by Docetaxel following Standard Doublet Chemotherapy
Immediate vs delayed (2nd-line) Docetaxel
Overall survival time (months)
Immediate Doc (n=153)
Delayed Doc (n=154)
p-value
PFS, mos
(95% CI)
6.5
(4.4–7.2)
2.8
(2.6–3.4)
<0.0001
1-yr-PFS, %
20% (13–26)
9% (5–14)
Immediate Doc (n=153)
Delayed Doc (n=154)
p-value
MS, mos (95% CI)
11.9 (10.0–13.7)
9.1 (8.0–11.2)
0.071
1-yr-S % (95% CI)
48.5% (39.9–57.1)
38.3 (30.0–46.5)
Fidias et al., J Clin Oncol 27, , 2009

23. Advanced NSCLC: Maintenance
Switch type („early second line“)
Erlotinib
Cappuzzo et al, Lancet Oncol 11, , 2010

24. Advanced NSCLC: Erlotinib switch maintenance (Saturn)
150mg/day
Chemonaïve advanced NSCLC
n=1,949
4 cycles of first-line platinum doublet chemotherapy* PD
Non-PD
n=889
1:1
Placebo PD
Mandatory tumour sampling
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
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
889 is the intention to treat population (ITT)
*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel carboplatin/paclitaxel 24

25. Advanced NSCLC: Erlotinib switch maintenance Progression free survival
Cappuzzo et al. Lancet Oncol 11, ; 2010

26. Advanced NSCLC: Erlotinib switch maintenance Overall survival
Cappuzzo et al. Lancet Oncol 11, ; 2010

27. Advanced NSCLC: Erlotinib switch-maintenance Overall survival by response
Stable disease
CR/PR
1.0
0.8
0.6
0.4
0.2
1.0
0.8
0.6
0.4
0.2
HR=0.72 (0.59–0.89)
HR=0.94 (0.74–1.20)
Log-rank p=0.0019
Log-rank p=0.6181
Erlotinib (n=184)
Placebo (n=210)
Erlotinib (n=252)
Placebo (n=235)
Overall Survival
9.6
11.9
12.0
12.5
Time (months)
Time (months)
Coudert et al. Ann Oncol 23, , 2012
Cappuzzo et al. Lancet Oncol 11, ; 2010
Measured from time of randomisation into the maintenance phase

28. Advanced NSCLC: Maintenance
Switch type („early second line“)
Pemetrexed
Ciuleanu et al Lancet 374, , 2009

29. Advanced 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)*
2:1
Randomization
Primary Endpoint = PFS
Placebo (d1, q21d) + BSC (N=222)*
*B12, FOLATE, AND DEXAMETHASONE GIVEN IN BOTH ARMS
Ciuleanu T. et al. Lancet 374, ; 2009 29 29

30. Advanced NSCLC: Pemetrexed switch maintenance Progression free survival by histology
Non-squamous
Squamous
HR=0.47
(95% CI: )
p <
HR=1.03
(95% CI: )
p=0.896
Pemetrexed: 4.4 mos
Placebo: 2.5 mos
Progression-free Probability
Placebo:
1.8 mos
Pemetrexed:
2.4 mos
Time (months)
Time (months)
Ciuleanu T. et al. Lancet 374, ; 2009 30

31. Advanced NSCLC: Pemetrexed switch maintenance
Overall survival by histology
Non-squamous
Squamous
Time (months)
Overall Survival
HR=0.70
(95% CI: )
p=0.002
HR=1.07
(95% CI: )
p=0.678
Pemetrexed: 15.5 mos
Placebo: 10.8 mos
Pemetrexed: 9.9 mos
Placebo: 10.3 mos
Ciuleanu T. et al. Lancet 374, ; 2009 31

32. Advanced NSCLC: switch maintenance ASCO recommendations 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, , 2011
Fidias et al. J Clin Oncol 27, , 2009
Coudert et al. Ann Oncol 23, , 2012
Cappuzzo et al. Lancet Oncol 11, ; 2010
Paz-Ares Lancet Oncol 13, , 2012

33. Advanced NSCLC: Maintenance
Continuation type („true maintenance“)
Pemetrexed

34. Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT)
Non PD
Pemetrexed
3qw bis PD
Stadium IV
Non-squamous
SD nach 4-6x Induktions-CT
Cisplatin/Pemetrexed
Randomisation 2:1
Placebo
3qw bis PD
Paz-Ares et al Lancet Oncol 13, , 2012
Paz-Ares et al J Clin Oncol 31, , 2013

35. Advanced NSCLC: Pemetrexed continuation maintenance (PARAMOUNT) – Overall survival by response
Paz-Ares et al. J Clin Oncol 31, , 2013

36. Advanced NSCLC: Pemetrexed registration Continuation maintenance therapy
......as single agent following platinum based
therapy - predominantly other than squamous cell histology; non-progression after four cycles of chemotherapy……
EMA: 2011

37. Advanced NSCLC - Maintenance
Comparison switch vs continuation
Erlotinib (switch)
Gemcitabine (continuation)
Perol et al J Clin Oncol 30, , 2012

38. Cisplatin/Gemcitabine
Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502)
Patients stratified by sex, histology, smoking status, treatment center, and response/stabilization following first-line therapy
Primary endpoint: PFS
Other endpoints: OS, safety, symptom control, effect of EGFR status
Patients without disease progression randomized 1:1:1
Gemcitabine
(n = 154)
Pem
74 %
Chemotherapy-naive patients with stage IIIB/IV NSCLC
(N = 834)
Cisplatin/Gemcitabine
for 4 cycles
Erlotinib
(n = 155)
Pem
75%
EGFR, epidermal growth factor receptor; IFCT-GFPC, Intergroupe Francophone de Cancerologie Thoracique Groupe Francais De Pneumo-Cancerologie; NSCLC, non–small-cell lung cancer; OS, overall survival; PFS, progression-free survival.
Observation
(n = 155)
Pem
84%
Perol M et al, J Clin Oncol 30, , 2012 38 38

39. Advanced NSCLC: Erlotinib (switch) vs Gemcitabine (continuation) maintenance (IFCT-GFPC 0502)
Perol M et al, J Clin Oncol 30, , 2012 39

40. Advanced NSCLC: Basics of medical management
First-line – (induction) – therapy
Selection by histo-type
Maintenance therapy
Switch / continuation
Second-line / subsequent-line therapy

41. Current ASCO Guidelines for NSCLC
Docetaxel, EGFR-TKI’s, and Pemetrexed are acceptable as second-line therapy for patients with advanced NSCLC with adequate performance status when the disease has progressed during or after first-line platinum-based therapy
In 1997, the ASCO Guidelines stated that “there is no current evidence that either confirms or refutes that second-line chemotherapy improves survival in patients with advanced non-small cell lung cancer”.
Azzoli et al. J Clin Oncol 29, , 2011
Shepherd et al. N Engl J Med 353, , 2005
Thatcher et al. Lancet 366, , 2005
Hanna et al. J Clin Oncol 22, , 2004
Confidential

42. Advanced NSCLC: EGFR-TKIs as second-line therapy
ISEL
Interest
BR21
Titan
Tailor
HORG
Korea
Design
2-arms
phase III
Primary endpoint OS
TTP
OS/RR
Agents
Gefitinib Placebo
Gefitinib Docetaxel
Erlotinib Placebo
Erlotinib Pem or Doc
Erlotinib Docetaxel
Erlotinib Pemetrexed
Gefitinib Erlotinib
No. of Pts.
1692
1433
731
424
222
357
467
Kim et al. Cancer 116, , 2010 Karampazis et al. Cancer 119, , 2013 Garassino et al. Lancet Oncol 14, , 2013 Ciuleanu et al. Lancet Oncol 13, , 2012
Shepherd et al. N Engl J Med 353, , 2005
Kim et al. Lancet 372, , 2008
Thatcher et al. Lancet 366, , 2005

43. Meta-analysis in wild-type NSCLC favors CT over EGFR-TKI therapy: First- / second-line
Lee et al. JAMA 311, , 2014

44. Advanced NSCLC: Systemic therapy in the absence of driver mutations – Summary (1)
Chemotherapy remains standard for the majority of patients
- (first-line; platinum doublets; 4 – 6 cycles)
The selection of the platinum-partner should depend on tumor histo-type
- (non-squamous vs squamous; pemetrexed vs gemcitabine etc.)
Modification of the first-line standard is clinically advisable according to co-morbidity, performance status, and patient’s age
(single agent; platinum-free; BSC only)
Treatment until progression by the anti-angiogenic bevacizumab as recommended in selected patients
(eligibility criteria; group toxicity)
In 1997, the ASCO Guidelines stated that “there is no current evidence that either confirms or refutes that second-line chemotherapy improves survival in patients with advanced non-small cell lung cancer”.
Confidential

45. Advanced NSCLC: Systemic therapy in the absence of driver mutations – Summary (2)
Prolongation of induction chemotherapy beyond 4 – 6 cycles for maintaining “response” until progression has been established as a new strategy
- (switch/continuation maintenance)
Second/subsequent – line chemotherapy is recommended in patients with acceptable performance status
- (single agent; docetaxel; pemetrexed)
EGFR-TKI’s have also been licensed for wild-type tumors
(maintenance; second/third-line therapy)
A tight cooperation between the pathologist and the clinician is critical
(histology – subtyping; molecular testing; result reporting)
In 1997, the ASCO Guidelines stated that “there is no current evidence that either confirms or refutes that second-line chemotherapy improves survival in patients with advanced non-small cell lung cancer”.
Confidential

46. Advanced NSCLC: Current Treatment algorithm
Mutant tumors
Wild type tumors
Non-Squamous
Squamous
Platinum-Doublets (Pem!) plus Bev
Platinum-Doublets
(No Pem, no Bev)
1st-line
EGFR-TKI
Switch:
Pemetrexed
Erlotinib
Continuous:
Switch:
Erlotinib
Treatment until progression
Maintenance
Oligo progression:
Cont. TKI + Local therapy
Diffuse progression
Cont. TKI + Chemo
Chemo  TKI re-expo
2nd generation TKI
2nd-line
Single agent
Non-cross resistant
Single agent
Non-cross resistant
ALK-Inhibitor 46

47. Advanced NSCLC: EGFR-TKIs as first line therapy
Torch
Topical
Optimal
NEJ002
Lux-Lung3
EURTAC
IPASS
Design
2-arms phase III
2-arm
phase III
2- arms phase III
Primary endpoint OS
PFS
Agents
CT-Erlotinib Erlotinib-CT
Erlotinib Placebo
Erlotinib Carbo/Gem
Gefitinib Carbo/Pac
Afatinib Pemetrexed
Erlotinib
Platinum doublets
Gefitinib Carbo Pac
No. of Pts.
760
670
165
230
345
174
1200
Outcome
PE:
not met
met
exceeded
Selection Criteria
Unselected
population
Poor PFS
Mut.-Tu
Mut-Tu
Never smoker/ Adeno-CA
Mok et al. N Engl J Med, 361, , 2009 Rosell et al Lancet Oncol 13; ;2012 Lee et al Lancet Oncol 13, , 2012 Zhou et al. Lancet Oncol 12, , 2011
Mitsudomi et al Lancet Oncol 11, , 2010
Sequist et al. J Clin Oncol 31, , 2013
Gridelli et al J Clin Oncol 30, , 2012

48. Progression-free survival
First-line trials of EGFR tyrosine kinase inhibitors vs. chemotherapy in pts with EGFR mutations
EGFR
TKI
Comparator N
(Total)
EGFR mut-positive
Response rate
(%)
Progression-free survival
(months)
Overall survival
IPASS1,2
Gefitinib
Carboplatin/ paclitaxel
1217
261
71 vs 47
p=0.0001
9.5 vs 6.3
HR 0.48 (0.36‒0.64)
21.6 vs 21.9
HR 1.0 (0.76–1.33)
First-SIGNAL3
Gemcitabine/ cisplatin
309 42
85 vs 38
p=0.002
8.0 vs 6.3
HR 0.54 (0.27–1.10)
27.2 vs 25.6
HR 1.04 (0.50–2.18)
NEJ0024
224
74 vs 31
p<0.001
10.8 vs 5.4
HR 0.30 (0.22–0.41)
30.5 vs 23.6
WJTOG-34055
Cisplatin/ docetaxel
172
62 vs 32
p<0.0001
9.2 vs 6.3
HR 0.5 (0.34–0.71)
30.9 vs NR
HR 1.64 (0.75–3.6)
OPTIMAL6
Erlotinib
Gemcitabine/ carboplatin
154
83 vs 36
13.1 vs 4.6
HR 0.16 (0.10–0.26)
Not mature
EURTAC7
Chemotherapy
173
58 vs 15
9.7 vs 5.2
HR 0.37 (0.25–0.54)
19.3 vs HR 1.04 (0.65–1.68)
LUX-LUNG 38
Afatinib
Pemetrexed/ cisplatin
345
56 vs 23 p<0.0001
11.1 vs 6.9 HR 0.58 (0.43–0.78)
LUX-LUNG 69
364
67 vs 23 p<0.0001
11.0 vs 5.6 HR 0.28 (0.20–0.39)
1. Mok T et al., N Engl J Med 2009;361:947–957; 2. Fukuoka M et al., J Clin Oncol 2011; 29:2866‒2874; 3. Han J-Y et al., J Clin Oncol 2012; 30:1122‒128; 4. Maemondo M et al., N Engl J Med 2010;362:2380–2388; 5. Mitsudomi T et al., Lancet Oncol 2010;:121–128; 6. Zhou C et al., Lancet Oncol 2011;12:735‒742; 7. Rosell R et al., Lancet Oncol 2012;13:239–246; 8. Yang JC et al., J Clin Oncol 2012;30 (Suppl. 16):LBA 7500, Wu Y et al., Lancet 2014; 15:213. NR = not reported

49. Advanced NSCLC: First-line EGFR-TKI therapy ASCO / ESMO-recommendation
… EGFR-TKI therapy should be prescribed for patients with tumors bearing activated EGFR-mutations … … Patients with PS 3-4 may also be offered EGFR-TKI treatment …
Azzoli et al. J Clin Oncol 29, , 2011
Peters et al. Ann Oncol 23 (Suppl 7), 56-64, 2012

50. EGFR mutations: whom to test? (1)
EGFR molecular testing should be used to select patients for EGFR-targeted TKI therapy, and patients with lung adenocarcinoma should not be excluded from testing on the basis of clinical characteristics
Lindeman et al., J Thorac Oncol, , 2013

51. EGFR mutations: whom to test ? (2)
In the setting of more limited lung cancer specimens (biopsies, cytology) where an adenocarcinoma component cannot be completely excluded, EGFR testing may be performed in cases showing squamous or small cell histology but clinical criteria (eg, young age, lack of smoking history) may be useful in selecting a subset of these samples for testing.
Lindeman et al., J Thorac Oncol, , 2013

52. EGFR mutations: laboratory issues
Laboratories should follow similar quality control and quality assurance policies and procedures for EGFR testing in lung cancers as for other clinical laboratory assays. In particular, laboratories performing EGFR testing for TKI therapy should enroll in proficiency testing, if available.
Lindeman et al., J Thorac Oncol, , 2013

53. Second-line therapy in case of progression in first-line EGFR-TKI therapy
Oligo progression:
Continuous TKI + Local therapy
Diffuse progression
Continuous TKI + Chemotherapy
Chemotherapy  TKI re-exposition
2nd generation TKI

54. Advanced NSCLC: EMA registration for Erlotinib
Second / third line: In patients after failure of at least one prior chemotherapy
Maintenance: In patients with stable disease after 4 cycles of platinum based first-line chemotherapy
CHMP, 18 March 2010

55. Advanced NSCLC: Crizotinib for ALK-positive disease Phase III (PROFILE 1007) – 2nd line
Shaw et al. N Engl J Med 368, , 2013

56. Prior platinumbased CT,
Advanced NSCLC: Crizotinib for ALK-positive disease Phase III (PROFILE 1007) – 2nd line
Primary Endpoint: PFS
Crizotinib 250 mg bid
347 patients,
Advanced NSCLC,
Prior platinumbased CT,
all histologies,
EML4-ALK
Translocation
Randomization PD
Pemetrexed or
Docetaxel
Crizotinib 250 mg bid
Shaw et al. N Engl J Med 368, , 2013

58. Advanced NSCLC: Systemic therapy in existence of driver mutations- Role of TKI’s
Has changed significantly the treatment algorithm
(treatment by genotype)
Is specifically relevant for mutant tumors
(First-line therapy)
Has been licensed and recommended in wild type tumors and tumors with unknown EGFR-status
(Maintenance, second/third-line therapy)
Has underlined the importance of the pathologist’s and its tight cooperation with the clinicians
(molecular testing)

59. 4th International Thoracic Oncology Congress Dresden
Advances through Molecular Biology in Thoracic Cancer
September 12th – 14th 2014
Maritim Hotel and International Congress Center
Dresden, Germany
Organizers:
Christian Manegold - Mannheim
Giorgio V. Scagliotti - Torino
Nico van Zandwijk - Sydney
More Information:
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