1. Treatment of advanced NSCLC:
Where are we now?

2. Patient selection in lung cancer: Evolution over time
2000
Non-small cell lung cancer
Small-cell lung cancer
2008
Adenocarcinoma
Large-cell carcinoma
Squamous cell carcinoma
Established targets
Mutation negative/unknown
Today
EGFR ALK ROS1
Adenocarcinoma
Large cell carcinoma
Squamous cell carcinoma
Adenocarcinoma and treatable oncogenic alterations
Small-cell lung cancer
Adapted from Reck M, et al. Lancet 2013;382:709–19

3. Treatment goals in advanced NSCLC
Quality of life
Safety OS
PFS
Disease control
Symptom improvement/control
NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival.

4. Overall survival in NSCLC
Advantages and challenges as an endpoint
Continuous
(compared to PFS)
Gold standard endpoint
Clinically relevant
Easily and accurately assessed
Role of crossover
Large patient populations required
Impact of subsequent therapy
Longer follow-up times than other endpoints
Advantages
Challenges
PFS, progression-free survival. Soria J, et al. Ann Oncol 2010;21:2324–32.

5. Overall survival in NSCLC: Evolution over time
First-line treatment of advanced NSCLC
2000
Non-small cell lung cancer
Median overall survival (months)
Cisplatin+paclitaxel
Cisplatin+gemcitabine
Cisplatin+docetaxel
Carboplatin+paclitaxel
7.8
8.1
7.4 10 20 30 40
100 80 60
Survival (%)
Survival time (months)
Schiller JH, et al. N Engl J Med 2002;346:92–8

6. Overall survival in NSCLC: Evolution over time
First-line treatment: Importance of histology for patient selection
2008
Non-squamous cell carcinoma
Squamous cell carcinoma
Non-squamous* (n=1000)
Squamous (n=473)
1.0
1.0
Median overall survival (months)
Pemetrexed+cisplatin
11.8
Gemcitabine+cisplatin
10.4
HR 0.81 (95% CI 0.70–0.94)
p=0.005
Median overall survival (months)
Pemetrexed+cisplatin
9.4
Gemcitabine+cisplatin
10.8
HR 1.23 (95% CI 1.00–1.51)
p=0.05
0.8
0.8
0.6
0.6
Probability of survival
Probability of survival
0.4
0.4
0.2
0.2
0.0
0.0 6 18 12 24 30 6 18 12 24 30
Survival time (months)
Survival time (months)
* Non-squamous = adenocarcinoma and large cell carcinoma NSCLC histology.
Scagliotti GV, et al. J Clin Oncol 2008;26:3543–51

7. Overall survival in NSCLC: Evolution over time
First-line bevacizumab when added to chemotherapy
2008
Non-squamous cell carcinoma
Trial
Hazard ratio
(95% CI)
AVF-0757g 7.5
1.13 (0.52–2.42)*
AVF-0757g 15
1.18 (0.54–2.59)*
ECOG 4599
0.80 (0.69–0.93)
AVAiL 7.5
0.92 (0.75–1.13)
AVAiL 15
1.02 (0.83–1.26)
JO19907
0.99 (0.65–1.50)
Total
0.90 (0.81–0.99) p=0.03
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Favours bevacizumab
Favours control
Test for heterogeneity p=0.44
*AVF-0757g trial: direction of OS HR unknown, worst scenario chosen.
CI, confidence interval; RCTs, randomised controlled trials. Results as reported in meta-analysis.
Soria JC, et al. Ann Oncol 2013;24:20‒30

8. Patient selection in lung cancer in 2015: Integration of molecular profiling
Tumour tissue
Traditional pathology
Biomarker testing (PCR-based tests, IHC, FISH, etc.)
Multiplex/next generation sequencing
Tumour morphology
Tumour biomarkers
Tumour genotype
Treatment selection
FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; PCR, polymerase chain reaction.
Adapted from Pao W, et al. Clin Cancer Res 2009;15:5317–22

9. Overall survival in NSCLC: Evolution over time
Targeted treatment improves PFS but not OS in selected patients
Today
Established targets
EGFR
Study (patients randomised who had EGFR mutations)
TKI
Analysis population
PFS
HR (95% CI)
Overall survival
IPASS1 (n=261)
Gefitinib
EGFRM+ (n=261)
0.48 (0.36–0.64) (INV)*
1.00 (0.76–1.33)
First – SIGNAL2 (n=42)
EGFRM+ (n=42)
0.54 (0.27–1.10) (INV)
1.04 (0.50–2.18)
NEJ0023,4 (n=230)
EGFRM+ (n=224)
0.32 (0.24–0.44) (IND)*
0.89 (0.63–1.24)
WJTOG34055,6 (n=177)
Common mutations (n=172)
0.49 (0.34–0.71) (INV)*
1.25 (0.88–1.78)
EURTAC (EU)7 (n=173)
Erlotinib
Common mutations (n=173)
0.34 (0.23–0.49) (IND)*
0.93 (0.64–1.35)
OPTIMAL (China)8,9
(n=165)
Common mutations (n=154)
0.16 (0.10–0.26) (INV)*
1.19 (0.83–1.71)
ENSURE (China)10
(n=217)
Common mutations (n=217)
0.34 ( ) (IND)*
0.91 (0.63–1.31)
LUX-Lung 311,12
(n=345)
Afatinib
Common mutations (n=307)
0.47 (0.34–0.65) (IND)*
0.78 (0.58–1.06)
LUX-Lung 612,13
(n=364)
Common mutations (n=324)
0.25 (0.18–0.35) (IND)*
0.83 (0.62–1.09)
*Patients with tumours harbouring common mutations. Note: data are provided as a summary of different trial findings. Data pertaining to different trials cannot be compared due to inherent differences in trial design and methodology.
1. Fukuoka M, et al. J Clin Oncol 2011;29:2866–74; 2. Han JY, et al. J Clin Oncol 2012;30:1122–8; 3. Maemondo M, et al. N Engl J Med 2010;362:2380–2388; 4. Inoue A, et al. Ann Oncol 2013;24(1):54–9; 5. Mitsudomi T, et al. Lancet Oncol 2010;11:121–8; 6. Yoshioka et al. ASCO Poster 8117; 7. Khozin S, et al. Oncologist 2014;19:774–9; 8. Zhou C, et al. Lancet Oncol 2011;12:735–42; 9. Zhou et al Ann Oncol, 2015; 10. Wu et al. Ann Oncol 2015; 11. Sequist LV, et al. J Clin Oncol 2013;31:3327–34; 12. Yang JC, et al. Lancet Oncol 2015;16:141–51; 13. Wu SI, et al. Lancet Oncol 2014;15:213–22

10. ESMO clinical practice guidelines: Testing for EGFR mutations
Recommendations
Strength
Evidence level
EGFR mutation testing is recommended in all patients with advanced NSCLC of a non-squamous
subtype A I
Testing is not recommended in patients with a confident diagnosis of squamous cell carcinoma, except in never/former light smokers (<15 packs per year) IV
Conducted using a validated mutation detection platform in a laboratory participating in an external
quality assurance scheme – with adequate sensitivity for all clinically relevant mutations V
Reck M, et al. Ann Oncol 2014;25(suppl 3):iii27–iii39

11. EGFR mutation testing rates in advanced NSCLC
Results from an international survey*
Patients not tested for EGFR mutation status
Tested but results not available before treatment decision
Tested and results available before treatment decision
*Survey designed to assess the prevalence of mutation testing, attitudes and barriers to testing, and how results affect choice of therapy.
Spicer J, et al. Annal Oncol 2015;26(suppl 1) LBA2 PR and presentation

12. EGFR mutation testing in advanced NSCLC: Reasons for low testing frequency
Results from Europe*
*Germany, France, Italy, Spain and UK.
Spicer J. et al. Annal Oncol 2015;26(suppl 1) LBA2 PR and presentation

13. ESMO clinical practice guidelines: Testing for anaplastic lymphoma kinase (ALK) fusion genes
Recommendations
Strength
Evidence level
Testing for ALK rearrangement should be systematically carried out in advanced NSCLC with a non-squamous histology A II
Detection of the ALK translocation by FISH remains the standard, but IHC may have a role in screening
out negative cases
Reck M, et al. Ann Oncol 2014;25(suppl 3):iii27–iii39

14. Oncogenic drivers for patients with full genotyping
10 genes assayed in 733 patients
Kris MG, et al. JAMA 2014;311:1998–2006; Kris MG, et al. J Thorac Oncol 2013;8:S3

15. Use of multiplexed testing in lung cancer: Improved OS in patients receiving matched targeted agents
Kris MG, et al. JAMA 2014;311:1998–2006

16. Therapies with an impact on OS approved by the EMA*
Overall survival in NSCLC: Treatment of advanced NSCLC after first-line chemotherapy
Therapies with an impact on OS approved by the EMA*
Docetaxel: improved OS versus best supportive care1
2000
Erlotinib: improved OS versus best supportive care2
2004
Nintedanib + docetaxel: improved OS versus docetaxel in patients with adenocarcinoma histology NSCLC3
2014
Nivolumab: improved OS versus docetaxel in patients with squamous cell histology NSCLC4
2015
*Available from and Registration conditions differ internationally. Country-specific information is contained in the locally approved registration documents.
1. Shepherd FA, et al. J Clin Oncol 2000;18:2095–103; 2. Shepherd FA, et al. N Engl J Med 2005;353:123–32; 3. Reck M, et al. Lancet Oncol 2014;15:143–55; 4. Brahmer J, et al. N Engl J Med. 2015;373(2):123–35

17. Treatment of advanced NSCLC
Based on EMA approved indications
Squamous cell carcinoma
Non-squamous cell carcinoma
Histological
subtype
ALK-rearranged NSCLC
Mutation negative/unknown
EGFR mutation-positive
Platinum-based doublets
Pemetrexed/
platinum
Pemetrexed-based doublets
± bevacizumab*
Cisplatin + third-generation regimen± bevacizumab*
EGFR TKI*
(afatinib, erlotinib or gefitinib)
First-line
Switch maintenance:
erlotinib or docetaxel
Continuation maintenance:
gemcitabine
Continuation maintenance:
pemetrexed
Continuation maintenance:
pemetrexed
Switch maintenance:
Pemetrexed or erlotinib
EGFR TKI
Maintenance
EGFR TKI or docetaxel or nivolumab
Crizotinib
Docetaxel + nintedanib
or docetaxel
or pemetrexed or erlotinib
Platinum doublet
Prior EGFR TKI
After first-line
Ceritinib
*PS 3 or 4, best supportive care only. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor. Adapted from Reck M, et al. Ann Oncol 2014;25(suppl. 3):iii27–iii39 based on EMA approved indications

18. Questions and discussion