Thierry Le Chevalier, MD

The Role of Translational Research in NSCLC

Outline of Talk

• The importance of translational research in improving treatment of NSCLC

• Key remaining unmet needs• Overview of promising approaches/agents in the future treatment of

NSCLC

What Is Lung Cancer? The Old Perception

In Daily Practice, Histology Remains the Main Classifier of NSCLC

Classification CharacteristicsNon-squamous‡

Adenocarcinoma 30–50%*

• Malignant epithelial tumours with glandular differentiation

• Subtypes are acinar, papillary, bronchoalveolar carcinoma (BAC), and solid adenocarcinoma with mucin production

• Usually peripherally located

Large-cell carcinoma10%*

• Involves large cells (subtypes are giant-cell, clear-cell) with large nuclei

• No evidence of squamous or glandular differentiation

• Usually peripherally located

Squamous

Squamous-cell carcinoma30%†

• Involves cells of the squamous epithelium• Usually centrally located

*Image from www.surgical-pathology.com; †Image from http://www.lmp.ualberta.ca/resources/pathoimages/PC-S.htm;‡Other less-common subtypes of non-squamous NSCLC include adenosquamous carcinoma and sarcomatoid carcinoma.

Current Definition of Cancer

A tumour

An organ

A pathological sample=

A definition from the XIXth century

Most relevant mutated pathways in adenocarcinoma

of the lung

1. Ding et al. Nature. 2008;455:1069-1075.

©2010 American Society of Clinical Oncology

1. MacConaill, Garraway. J Clin Oncol. 2010;28:5219-5228.

Driver Pathways Will Increase in Number, Notably Because of the Reduced Cost of Sequencing

Incidence of Driver Mutations in Adenocarcinoma1

No mutation detected 33%

KRAS (28%)

EGFR (13%)

STK11( 10%)

ALK -EML4 (2%)

NRAS (2%)

BRAF (2%)

PDK1 (2%)

HER2 (1%)

KDR (1%)

MET (1%)

PI3K (1%)

TOP1 (1%)

FGFR4 (1%)

ALK amplification (2%)

Mutations found in 67% of patients (IGR experience)

KRAS

EGFR

STK11ALK

NRASBRAF PDK1

HER2KDRMET

PI3KTOP1FGFR4

No mutation

ALK (ampl)

1. Planchard et al. European Lung Cancer Conference. 2012.

The “Targeted Therapome” in Lung Adenocarcinoma

3% ERBB2

15%

2-3%

20-30%2%

<1%

xx%

20% STK11

4-6% ALK fusion

60% TP53

~1% ROS fusion

~1% RET fusion

10% KEAP1

Courtesy of Meyerson. Nature. 2012;489:519-525.Pao and Chmielecki. Nat Rev Cancer. 2010;10:760-74.

Actionable Alterations Leading to Clinical Benefit and Approval of Multiple Novel Targeted Agents for NSCLC

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Gefitinib:Conditional

approval1

Gefitinib2

1. http://www.cancer.gov/cancertopics/druginfo/fda-gefitinib; 2. http://www.astrazeneca.com/Media/Press-releases /Article/20090423--IRESSA-Gefitinib-Recommended-for-Approval-; 3. http://www.cancer.gov/cancertopics/druginfo/fda-erlotinib-hydrochloride;4. http://www.roche.com/investors/updates/inv-update-2010-04-29b.htm; 5. http://www.roche.com/media/media_releases/med-cor-2011-09-01.htm;6. http://www.gpo.gov/fdsys/pkg/FR-2012-04-25/html/2012-9944.htm; 7. https://www.boehringer-ingelheim.com/news/news_releases/press_releases/2013/25_september_2013oncology.html; 8. http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm360574.htm; 9. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ ucm269856.htm; 10. http://press.pfizer.com/press-release/pfizers-xalkori-receives-conditional-marketing-authorization-european-commission-treat;11. http://www.novartis.com/newsroom/media-releases/en/2014/1776962.shtml; 12. https://investor.lilly.com/releasedetail.cfm?ReleaseID=88794413. http://www.boehringer-ingelheim.com/news/news_releases/press_releases/2014/27_november_2014_oncology.html.

Gefitinib:Restricted label1

FDA approval:

EMA approval:

Erlotinib:2nd-line3

Erlotinib:Maintenance3 Erlotinib:

1st-line3

Erlotinib:1st-line5

Erlotinib:Maintenance4

Gefitinib:Withdrawal of approval6

Afatinib:1st-line7

Afatinib:1st-line8

Crizotinib:Conditionalapproval9

Crizotinib:Condtionalapproval10

Ceritinib11

Nintedanib:2nd-line13

Ramucirumab12

Crizotinib:Full approval in 1st-line10

Remaining Challenges in the Treatment of NSCLC

A Need to Improve Clinical Outcomes in Patients With EGFR M+ NSCLC

• First-generation, reversible EGFR TKIs improved clinical outcomes in patients. However, patients will eventually progress due to resistance

– >50% of patients with acquired resistance to gefitinib or erlotinib develop the T790M mutation

– The resistant tumour remains dependent on EGFR/ErbB Family signalling pathway for survival

• There is a lack of good options for 50% of patients with alternative resistance mechanisms and patients who cannot be rebiopsied or who have a biopsy with non-informative T790M testing results

• Novel therapeutic approaches are needed to overcome treatment-related resistance and to improve clinical outcomes

1. Ohashi et al. J Clin Oncol. 2013;31:1070-1080.

Potential Approaches to Overcome Treatment-Related or Secondary Resistance

Third-Generation EGFR TKIs in the Treatment of NSCLC

Inhibits both activating and drug-resistant EGFR mutations (eg, T790M) with minimum activity on EGFR WT protein

• Current 3rd-generation EGFR TKIs under clinical development for the treatment of NSCLC:

– AZD92911,2

– CO-16863

– HM617134

c+uORR = confirmed and unconfirmed overall response rate; DCR = disease control rate.1. Janne et al. ASCO 2014. Abstract 8009; 2. http://www.clinicaltrial.gov/ct2/show/NCT02151981?term=AZD9291&rank=9;3. http://www.clinicaltrial.gov/ct2/show/NCT02147990?term=co-1686&rank=3; 4. Kim et al. ASCO 2014. Abstract 8011.

Third-Generation EGFR TKIs in the Treatment of NSCLC

• Inhibits both activating and drug-resistant EGFR mutations (eg, T790M) with minimum activity on EGFR WT protein

c+uORR = confirmed and unconfirmed overall response rate; DCR = disease control rate.1. Janne et al. ASCO 2014. Abstract 8009; 2. http://www.clinicaltrial.gov/ct2/show/NCT02151981?term=AZD9291&rank=9;3. http://www.clinicaltrial.gov/ct2/show/NCT02147990?term=co-1686&rank=3; 4. Kim et al. ASCO 2014. Abstract 8011.

AZD92911

• c+uORR in EGFR T790M+ patients (n=89) was 64% (95% CI = 53-74)1

• c+uORR in EGFR T790M– patients (n=43) was 23% (95% CI = 12-39)1

• Currently in phase III:–vs chemo in patients with

NSCLC who progressed on previous EGFR-targeted TKI therapy and whose tumours harbour a T790M mutation (NCT02151981)2

CO-16863

• Currently in a phase II trial in patients with exposure to one EGFR-targeted TKI and harbouring T790M mutation (NCT02147990)

HM617134

• Phase I trial in EGFR M+ patients who failed previous EGFR TKIs (NCT01588145)

• T790M+ tumours: ORR=29.2%, DCR=75.0%; T790M– tumours: ORR=11.8%, DCR=55.9%

Afatinib + Cetuximab in Patients With TKI-Resistant NSCLC With or Without T790M Mutations

Trial design• Open-label, multicentre, phase Ib study in the USA and the Netherlands• Comprises 3 phases:

1. Dose-finding phase (MTD of afatinib + cetuximab)2. Expansion phase (afatinib + cetuximab at MTD until disease progression)3. Sequential therapy phase (single-agent afatinib until progression, then

afatinib + cetuximab)

ORR = objective response rate; DOR = duration of objective response; PFS = progression-free survival. 1. Janjigian et al. Cancer Discov. 2014;4:1036-1045.

Key eligibility criteria:• Stage IIIB/IV NSCLC harbouring EGFR drug-sensitising mutations or RECIST response, or

SD ≥6 months on prior EGFR TKI• Failed erlotinib or gefitinib within 30 days of starting this study with no systemic Tx

• ECOG PS 0-2• Adequate organ function

Afatinib 40 mg/d+

Cetuximab 500 mg Q2W

until disease progression

Efficacy endpoints include: ORR (investigator review), DOR, PFS and safety

Afatinib + Cetuximab: Tumour Shrinkage

Data available from 119 patients. Tumour tissue from 2 patients was uninformative as to T790M status .1. Janjigian et al. Cancer Discov. 2014;4:1036-1045.

60

40

20

0

–20

–40

–60

–80

–100

Max

imum

cha

nge

from

bas

elin

e S

LD (%

) T790M+T790M–Unknown

Afatinib + Cetuximab

Afatinib + Cetuximab: ORR and PFS

aIncludes 2 patients for whom T790M status was unknown because tissue samples were insufficient for testing.bP=0.643.cAll ORs were PRs; no CRs were reported.dMedian duration of confirmed response: 5.6 months (range, 1.8-24.4; 8 patients censored without further imaging).eP=0.341 (T790M+ vs T790M–).1. Janjigian et al. Cancer Discov. 2014;4:1036-1045.

All patientsa T790M+b T790M−b

Total treated 126 71 53

PFS, mos 4.7 4.8 4.6

RECIST response ORc (CR/PR), n (%) SD, n (%) Unconfirmed OR

89 (71)d

37 (29)52 (41)

5 (4)

54 (76)23 (32)e

31 (44)4 (6)

33 (62)13 (25)e

20 (38)1 (2)

PD CR/PR <35 d followed by PD, n (%) SD <35 d followed by PD, n (%)

27 (21)3 (2)

15 (12)

14 (20)1 (1)8 (11)

13 (25)2 (4)

7 (13)

LUX-Lung 5: Treatment Beyond Progression

aSingle-agent chemotherapy regimen includes paclitaxel (preferred), gemcitabine, vinorelbine, cisplatin, carboplatin, and docetaxel.1. Schuler et al. ASCO 2012. Abstract 7557; 2. Schuler et al. ASCO 2014. Abstract 8019.

• Stage IIIB (wet)/IV NSCLC• At least 1 line of chemotherapy

including platinum/pemetrexed• Failed erlotinib or gefitinib after

≥12 weeks of clinical benefit• ECOG PS 0-2

Afatinib 40 mg/d +

paclitaxel 80 mg/m2 weekly

Investigator choice single-agent

chemotherapya

Afatinib 50 mg/d

CR, PRor SD

≥12 weeksfollowed by

PD

RANDOMISE

2

1

Part A Part B

Primary end point: PFS in Part B (investigator review)Secondary end points: OS in Part B, PFS in Part A, ORR in Parts A & B

• Open-label, global trial across 115 centres in 23 countries • Recruited Part A: April 2010 – May 2011• Primary analysis: randomised Part B is presented (database lock Nov 2013)• Non-randomised Part A reported previously (Schuler et al, ASCO 2012)

LUX-Lung 5: PFS (Primary End Point) Was Met

Time from treatment start (months)

Est

imat

ed p

roba

bilit

y of

PFS

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

No. of patients at risk:Afa + Pac 134 82 46 25 15 7 4 1 1 0Investigator’s choice 68 25 14 9 3 1 0 0 0 0

PFS in overall population

Afatinib +Paclitaxel

(n=134)

Investigator’s Choice (n=68)

PFS event, n (%) 105 (78.4) 54 (79.4)

Median PFS (months) 5.6 2.8

HR (95% CI)P value

0.60 (0.43–0.85)P=0.0031

1. Schuler et al. ASCO 2014. Abstract 8019.

LUX-Lung 5: ORR and DCR

32.1

74.6

13.2

45.6

Pat

ient

s (%

)

OR (95% CI) = 3.1 (1.4-6.8) P=0.0049

OR (95% CI) = 3.4 (1.9-6.3)P<0.0001

80

60

40

20

0ORR DCR

Afatinib plus paclitaxel (n=134)Investigator’s choice (n=68)

1. Schuler et al. ASCO 2014. Abstract 8019.

• In Part A, ORR was 8.5%; DCR was 63.9%

What to Do for Patients With Squamous Cell Carcinoma (SCC)?

The Cancer Genome Atlas (TCGA): Complete Cancer Genome Description

Multiple data types

• Clinical diagnosis• Treatment history• Histologic diagnosis• Pathologic report/images• Tissue anatomic site• Surgical history• Gene expression/RNA

sequence• Chromosomal copy

number• Loss of heterozygosity• Methylation patterns• miRNA expression• DNA sequence• RPPA (protein)• Subset for Mass Spec

25 forms of cancer

glioblastoma multiforme(brain)

squamous carcinoma(lung)

serouscystadenocarcinoma

(ovarian)

Etc. Etc. Etc.

Biospecimen CoreResource with more

than 150 Tissue Source Sites

6 Cancer GenomicCharacterisation

Centres

3 GenomeSequencing

Centres

7 Genome Data Analysis Centres

Data Coordinating Centre

Courtesy of Meyerson. Nature. 2012;489:519-525.

Focal Copy Number Alterations in SCC

Deletion

MYCLMCL1

RELNFE2L2

SOX2PDGFRA

EGFRFGFR1

CCND1

CRKL

ERBB2

MDM2

LRP1BERBB4FOXP1

CSMD1CDKN2A

PTEN

RB1

The Cancer Genome Atlas (TCGA) initiativeCourtesy of Meyerson. Nature. 2012;489:519-525.

Amplification

Top Mutated Genes in SCC

The Cancer Genome Atlas (TCGA) initiativeCourtesy of Meyerson. Nature. 2012;489:519-525.

Therapeutic Targets in SCC, Defined by TCGA

40 to 60% of lung SCCs have a possible therapeutic target—more if we include CDKN2A alterations—in a disease with no targeted therapies today

Targets will need to be validated In the clinical setting

FGFR1/2, PIK3CA and DDR2 inhibitor trials are ongoing

percent of cases (%)

inactivated050 50

activated

activation inhibitionProliferation, cell survival, translation

EGFR9%

ERBB24%PIK3CA

16%PTEN15%

NRAS<1%

KRAS3%

BRAF4%

PI3K/RTK/RAS signaling

FGFR32%

HRAS3%

AKT316%

AKT24%

69% altered

STK112%

AKT1<1%

TSC13%

TSC23%

RASA14%

AMPK

MTOR

FGFR23%

NF111%

FGFR17%

ERBB32%

RTK

PI3K

Alteration pattern

The Cancer Genome Atlas (TCGA) initiativeCourtesy of Meyerson. Nature. 2012;489:519-525.

Frequencies of Potentially Actionable/Targetable Genetic Abnormalities Present in SCC

Perez-Moreno et al. Clin Cancer Res. 2012;18:1-9.

What Is the Role of ErbB Family Inhibition in SCC? LUX-Lung 8

aAmerican Joint Committee on Cancer Staging Manual 7th edition.bAs determined by the investigator, tumours with mixed histology allowed.cPatients progressing within 6 months of receiving adjuvant/neoadjuvant chemo/chemoradiotherapy were allowed (as long as ≥4 cycles criterion was met).

dDose escalation to 50 mg at Cycle 2 for patients meeting adverse event criteria.Goss et al. ESMO 2014. Abstract 12220.

*In the European Union and other countries, afatinib is approved under the brand name GIOTRIF®, and in the U.S. under the brand name GILOTRIF™ for use in patients with distinct types of NSCLC. Afatinib is under regulatory review by health authorities in other countries. Afatinib has not yet been approved in other indications.

Advanced NSCLC (Stage IIIB/IV)a

Squamous histologyb

≥4 cycles of a first-line platinum doubletc

ECOG PS 0–1Adequate organ function

Afatinib*40 mg QDd

Erlotinib150 mg QD

Treatment until disease progression

or unacceptable

AEsRan

dom

isat

ion

1:1

Excluded: Patients without PDPrior EGFR TKI or antibodyActive brain metastases, interstitial lung disease

Stratification: East Asian vs non–East Asian

Tumour tissue collected for correlative science

Radiographic tumour assessment at baseline, Weeks 8, 12, 16; every 8 weeks thereafter

LUX-Lung 8: PFS (Independent Review)

CI = confidence interval; HR = hazard ratio. Goss et al. ESMO 2014. Abstract 12220.

Est

imat

ed P

FS p

roba

bilit

y

0Time (months)

0.4

0.8

1.0

0.6

0.2

01 2 3 4 5 6 7 8 9 10 11 12 13 14 15

No. of patients

Afatinib 335 266 127 96 54 45 28 25 16 15 8 8 4 2 2 1Erlotinib 334 256 112 72 43 34 15 12 6 5 0 0 0 0 0 0

 Afatinib(n=335)

Erlotinib(n=334)

Patients progressed or died, n (%) 202 (60) 212 (64)Median PFS (months) 2.4 1.9

HR (95% CI)P-value

0.822 (0.676-0.998)P=0.0427

AfatinibErlotinib

LUX-Lung 8:Objective Response (Independent Review)

Series1

9.2

3.8

Series1

46

5

31

37

3

39

*Odds ratio: 1.44 95% CI (1.06–1.96); P-value 0.0203.†Odds ratio: 1.63 95% CI (0.73–3.66); P-value 0.2332.Goss et al. ESMO 2014. Abstract 12220.

AfatinibErlotinib

50

40

30

20

10

0Disease

control rateOR Duration

of ORPD

*

†

Per

cent

ages

12

10

8

6

4

0

Tim

e (m

onth

s)

2

• OS data are eagerly awaited

Patients Without Key Driver Mutations

How Do We Move Forward for Patients With Unidentified Alterations?

No mutation detected 33%

KRAS (28%)

EGFR (13%)

STK11( 10%)

ALK -EML4 (2%)

NRAS (2%)

BRAF (2%)

PDK1 (2%)

HER2 (1%)

KDR (1%)

MET (1%)

PI3K (1%)

TOP1 (1%)

FGFR4 (1%)

ALK amplif ication (2%)

NO ALTERATION

Optimise the use of CT and XRT

Better understand DNA repair

Active immunotherapies

Predictive biomarkers

Immunotherapy for the Treatment of NSCLC:Anti-PD-1/PD-L1 Approaches

Rationale for PD-1/PD-L1 Inhibition for the Treatment of NSCLC

• PD-1/PD-L1 pathway plays an important role in suppressing the body’s anti-tumour immunity

Anti-PD-1/anti-PD-L1 mAb

Adapted from Topalian et al. ASCO 2013. Abstract 3002.

Anti-PD-1/PD-L1 Approaches in the Treatment of NSCLC

• Anti-PD-1/PD-L1 mAbs in NSCLC1-5

– Pembrolizumab– Nivolumab– MPDL3280A

• Single agent, in combination with chemotherapy or targeted agent (eg. erlotinib or ipilimumab)

• Pembrolizumab/nivolumab/MPDL3280A in NSCLC:– Single-agent ORR: ≈20%-30%– Combination (erlotinib or ipilimumab): ≈19%-47%– Durable response in responding patients

1. Garon et al. ASCO 2014. Abstract 8020; 2. Gettinger et al. ASCO 2014. Abstract 8024;3. Antonia et al. ASCO 2014. Abstract 8023; 4. Rizvi et al. ASCO 2014. Abstract 8022; 5. Horn et al. World Conference on Lung Cancer 2013. Abstract MO 18.01.

Considerations for Immunotherapeutic Approaches for the Treatment of NSCLC

• Single agent vs combination therapy?– Nivolumab + chemo shows similar efficacy with nivolumab monotherapy

(updated data from Checkmate-012)1

– Why? Specific to nivolumab or all anti-PD-1/PD-L1 approaches?

• Biomarker? – Responses seen regardless of PD-L1 expression1

1. Antonia et al. Multidisciplinary Symposium in Thoracic Oncology 2014. Abstract 3.

Additional Targets/Agents Under Clinical Evaluation for the Treatment of NSCLC

Agent Company Molecular targetsBYL713 Novartis PI3Ka

GDC-0032 Genentech PI3KaINK-1117 Intellikine PI3KaXL-147 Exelixis/Sanofi Pan-PI3K

NVP-BKM120 Novartis Pan-PI3KGDC-0941 Genentech Pan-PI3KPKI-587 Pfizer Pan-PI3KXL-765 Exelixis/Sanofi PI3K/mTOR

NVP-BEZ-235 Novartis PI3K/mTORNVP-BGT-226 Novartis PI3K/mTORPF-4691502 Pfizer PI3K/mTOR

AZD8055 AstraZeneca mTOR (catalytic)INK 128 Intellikine mTOR (catalytic)MK-2206 Merck AKT1,2,3

GDC-0068 Genentech AKT

Summary

• Translational research plays a crucial role in the identification of key driver mutations for tumour growth and development

• Multiple agents targeting these key pathways have been approved for the treatment of NSCLC

• However, there are still significant unmet needs

• There are a number of novel agents/approaches currently under investigation

• Continued support and efforts in translational research and clinical development are crucial