Overall survival in NSCLC Advantages and challenges as an endpoint PFS, progression-free survival. Soria J, et al. Ann Oncol 2010;21:2324–32 Continuous.

Overall survival in NSCLCAdvantages and challenges as an endpoint

PFS, progression-free survival.Soria J, et al. Ann Oncol 2010;21:2324–32

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

Treatment of advanced NSCLCBased on EMA approved indications

*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

Mai

nte

nan

ceF

irst

-lin

eA

fter

fir

st-

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e

Non-squamous cell carcinomaSquamous cell carcinoma

His

tolo

gic

alsu

bty

pe

Docetaxel (±nintedanib)

or pemetrexed or erlotinib

Mutation negative/unknownEGFR mutation-

positive

EGFR TKI*(afatinib,

erlotinib or gefitinib)

EGFR TKI

Crizotinib

Cisplatin + third-generation regimen±

bevacizumab*

Switch maintenance:

erlotinib or docetaxel

ALK-rearranged NSCLC

Pemetrexed/platinum

Pemetrexed-based doublets ± bevacizumab*

Platinum doublet

Prior EGFR TKIEGFR TKI or docetaxel or nivolumab

Platinum-based doublets

Switch maintenance:Pemetrexed or

erlotinib

Continuation maintenance:gemcitabine

Ceritinib

Continuation maintenance:pemetrexed

Continuation maintenance:pemetrexed

Nivolumab vs docetaxel: Overall survival

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.

Non-squamous NSCLC(CheckMate-057)

Squamous NSCLC(CheckMate-017)

Nivolumab(n=135)

Docetaxel(n=137)

Median OS (months) 9.2 6.0

HR 0.59 (95% CI: 0.44–0.79): p=0.00025

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

100

80

60

40

20

0

Time (months)

Ov

era

ll s

urv

iva

l (%

)

100

80

60

40

20

0

Time (months)

Ov

era

ll s

urv

iva

l (%

)

0 3 6 129 18 2115 27240 3 6 129 18 2115 24

Patients at risk

Nivolumab 292 232 194 169 146 123 62 32 9 0

Docetaxel 290 244 194 150 111 88 34 10 5 0

Patients at risk

Nivolumab 135 113 86 69 52 31 15 7 0

Docetaxel 137 103 68 45 30 14 7 2 0

Nivolumab vs docetaxel (CheckMate-057): OSand PFS

Impact of PD-L1 expression on survival in non-squamous NSCLC

*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.

PD-L1 expression level Nivolumab/docetaxel (n) Interaction p value*

Overall survival

≥1% 123/1230.0646

<1% 108/101

≥5% 95/860.0004

<5% 136/138

≥10% 86/790.0002

<10% 145/145

Not quantifiable baseline 61/66

PFS

≥1% 123/1230.0227

<1% 108/101

≥5% 95/86<0.0001

<5% 136/138

≥10% 86/790.0002

<10% 145/145

Not quantifiable baseline 61/66

0.25 0.5 1.0 2.0Nivolumab Docetaxel

PD-L1 not quantifiable

PD-L1 non-expressors

PD-L1 expressors

Question: In your opinion, what is the most important consideration to guide treatment choice in NSCLC?

1. Overall survival

2. Progression-free survival

3. Disease control

4. Symptom improvement/control

5. Quality-of-life

6. Safety and tolerability

7. A combination of the above

8. Other

Patient selection in lung cancer: Evolutionover time

Adapted from Reck M, et al. Lancet 2013;382:709–19

~1990s Lung cancer

~2000 Non-small cell lung cancer Small-cell lung cancer

2008 Adenocarcinoma Large-cell carcinoma Squamous cell carcinoma

Established targets Mutation negative/unknownTodayEGFR ALK ROS1

Adenocarcinoma

Adenocarcinoma and treatable oncogenic alterations

Large cell carcinoma

Small-cell lung cancer

Squamous cell carcinoma

Question: What validated biomarkers do you routinely use for patient selection in advanced NSCLC?

1. EGFR mutation testing in selected patients

2. ALK testing in selected patients

3. Both EGFR mutation testing and ALK testing in selected patients

4. Multiplex/next generation sequencing

5. Other

Patient selection in lung cancer in 2015: Integration of molecular profiling

FISH, fluorescence in situ hybridisation; IHC, immunohistochemistry; PCR, polymerase chain reaction.Adapted from Pao W, et al. Clin Cancer Res 2009;15:5317–22

Tumour tissue

Traditional pathology

Biomarker testing (PCR-based tests, IHC,

FISH, etc.)

Multiplex/next generation sequencing

Tumour morphology Tumour biomarkers Tumour genotype

Treatment selection

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

Personalised medicine studies

http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match (Accessed: Sept 2015); http://www.asco.org/practice-research/targeted-agent-and-profiling-utilization-registry-study (Accessed: Sept 2015); https://clinicaltrials.gov/ct2/show/NCT02214134 (Accessed: Sept 2015)

ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) study

EORTC Screening Patients for Efficient Clinical Trial Access (SPECTA)-Lung

• 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

• 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

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)

Frequency of actionable mutations in NCI-MATCH

Bold text indicates mutations frequently found in NSCLC.http://www.cancer.gov/about-cancer/treatment/clinical-trials/nci-supported/nci-match; Lovly CL, Horn W, Pao. Molecular Profiling of Lung Cancer (2015). http://www.mycancergenome.org/content/disease/lung-cancer/(Accessed: Sept 2015)

BRAF fusions or muta-tions (non-V600E or

V600K) 3%

ALK fusions/transloca-tions

4%

ROS1 transolcations 5%

mTOR mutations 5%

TSC1 or TSC2 mutations 3%

T790M mutations 2% GNAQ

2%

PTEN (mutations and loss)11%

NF1 mutations 8%

BRAF V600E or V600K 7%

GNA11 2%

cKIT 4%

EGFR activating muta-tions

3%

HER activating muta-tions

2%

MET amplifications 4%

NF2 loss 2%

SMO or PTCH1 mutations 3%

HER amplifications 5%

FGFR amplifications or FGFR muta-tions

5%

PIK3CA mutations 18%

Question: In your opinion, what is the biggest barrier to widespread use of next generation sequencing?

1. Availability of tumour tissue

2. Timeliness of results (takes too long)

3. Access to technology/testing

4. Cost

5. Ethical concerns

6. Other

Questions and discussion