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
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