1. 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

2. 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
I think this should be on EMA approved indications, and assume best practice:
For ALK+: exculde criz as first line as not EMA approved. Only pem-platinum these patients get pem maintenance. Second line they get criz and 3rd line line ceritinib
FOR EGFR M+ on 2nd line delete “prior chemo box” as asuming best practice within license
EGFR TKI or docetaxel or nivolumab
Crizotinib
Docetaxel (±nintedanib)
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

3. Nivolumab vs docetaxel: Overall survival
Squamous NSCLC
(CheckMate-017)
Non-squamous NSCLC
(CheckMate-057)
100
100
Nivolumab
(n=135)
Docetaxel (n=137)
Median OS (months)
9.2
6.0
HR 0.59 (95% CI: 0.44–0.79): p=
Nivolumab
(n=292)
Docetaxel (n=290)
Median OS (months)
12.2
9.4
HR 0.73 (95% CI: 0.59–0.89): p=0.0015 80 80 60 60
Overall survival (%)
Overall survival (%) 40 40 20 20 3 6 12 9 18 21 15 24 3 6 12 9 18 21 15 27 24
Time (months)
Time (months)
Patients at risk
Nivolumab
135
113 86 69 52 31 15 7
Docetaxel
137
103 68 45 30 14 2
Patients at risk
Nivolumab
292
232
194
169
146
123 62 32 9
Docetaxel
290
244
150
111 88 34 10 5
CI, confidence interval; HR, hazard ratio; OS, overall survival. Brahmer J, et al. N Engl J Med. 2015;373(2):123–35; Paz-Ares, L. et al. J Clin Oncol 33, 2015 (suppl; abstr LBA109) and presentation.

4. Nivolumab vs docetaxel (CheckMate-057): OS and PFS
Impact of PD-L1 expression on survival in non-squamous NSCLC
PD-L1 expression level
Nivolumab/docetaxel (n)
Interaction
p value*
Overall survival
≥1%
123/123
0.0646
<1%
108/101
≥5%
95/86
0.0004
<5%
136/138
≥10%
86/79
0.0002
<10%
145/145
Not quantifiable baseline
61/66
PFS
0.0227
<0.0001
0.25
0.5
1.0
2.0
Nivolumab
Docetaxel
PD-L1 not quantifiable
PD-L1 non-expressors
PD-L1 expressors
*Interaction p value from Cox proportional hazard model with treatment, PD-LI expression and treatment by PD-L1 expression interaction.
CI, confidence interval; HR, hazard ratio; OS, overall survival. Paz-Ares, L. et al. J Clin Oncol 33, 2015 (suppl; abstr LBA109) and presentation.

5. Question: In your opinion, what is the most important consideration to guide treatment choice in NSCLC?
Overall survival
Progression-free survival
Disease control
Symptom improvement/control
Quality-of-life
Safety and tolerability
A combination of the above
Other

6. Patient selection in lung cancer: Evolution over time
~1990s Lung cancer
~2000
Non-small cell lung cancer
Small-cell lung cancer
2008
Adenocarcinoma
Large-cell carcinoma
Squamous cell carcinoma
Today
Established targets
Mutation negative/unknown
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

7. EGFR mutation testing in selected patients
Question: What validated biomarkers do you routinely use for patient selection in advanced NSCLC?
EGFR mutation testing in selected patients
ALK testing in selected patients
Both EGFR mutation testing and ALK testing in selected patients
Multiplex/next generation sequencing
Other

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. Use of multiplexed testing in lung cancer: Improved OS in patients receiving matched targeted agents
Kris M, et al. JAMA 2014;311(19):1998–2006

10. Personalised medicine studies
Molecular Analysis for Therapy Choice Study (NCI-MATCH)
Adults with solid tumours/lymphomas and disease progression ≥1 systemic therapy
Tumour accessible to biopsy
Performance status ECOG 0-1
Adequate organ function
Actionable mutation detected by genetic sequencing
Patient assigned study agent
(patients with PD checked for additional actionable mutations)
ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) study
Advanced solid tumour, multiple myeloma, or B cell non-Hodgkin lymphoma
Targetable genomic variation
No longer responding to standard treatment
Molecular Tumour Board agrees treatment
Patient assigned study drug based on profile
EORTC Screening Patients for Efficient Clinical Trial Access (SPECTA)-Lung
Any lung cancer, malignancy, malignant pleural mesothelioma or thymic malignancy
Availability of tumour tissue
Any line of therapy
Molecular tumour profile established from next-generation sequencing
Patient assigned targeted treatment based on molecular profile
(Accessed: Sept 2015); research/targeted-agent-and-profiling-utilization-registry-study (Accessed: Sept 2015); (Accessed: Sept 2015)

11. Frequency of actionable mutations in NCI-MATCH
Bold text indicates mutations frequently found in NSCLC.
Lovly CL, Horn W, Pao. Molecular Profiling of Lung Cancer (2015).  Sept 2015)

12. Question: In your opinion, what is the biggest barrier to widespread use of next generation sequencing?
Availability of tumour tissue
Timeliness of results (takes too long)
Access to technology/testing
Cost
Ethical concerns
Other

13. Questions and discussion