Mutational Analysis in NSCLC Adenocarcinoma
to Guide Therapy
Anne S. Tsao, M.D.
Associate Professor
Director, Mesothelioma Program
Director, Thoracic Chemo-XRT Program
The University of Texas
MD ANDERSON
CANCER CENTER
Department of Thoracic/Head & Neck
Medical Oncology
Outline: NSCLC
Background
Epidemiology
Histology
Molecular Profiling
EGFR mutants
IPASS
EURTAC
LUX LUNG 3
EML 4 ALK,
ROS 1
Crizotinib
Upcoming agents
Lung Cancer
• During 2013, ~228,190 new cases
and ~159,480 deaths are expected
in the United States
5-Year Relative Survival Rate
by Stage at Diagnosis
Localized
(stage I/II)
15%
Stage at Diagnosis
Distant
(stage IV)
56%
Regional
(stage III)
22%
Stage at Diagnosis
Survival (%)
• Second most common cancer and
leading cause of cancer death
100
90
80
70
60
50
40
30
20
10
0
53%
24%
4%
Localized
Regional
American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer
Society; 2013; Siegel. CA Cancer J Clin. 61(4):212.
Distant
2004 WHO Classification of Lung Tumors
NSCLC (87%)
Adenocarcinoma (45%)
SCC (33%)
SCLC (13%)
LCC (9%)
Mixed subtype
Acinar
Papillary
BAC
Nonmucinous
Mucinous
Mixed
Papillary
Clear cell
Small cell
Basaloid
LCNEC
Combined LCNEC
Clear cell
Combined
SCLC
Basaloid
Lymphoepithelioma-like
LCC with rhabdoid phenotype
Solid
Emerging data indicate that specific regimens show greater benefit
depending on tumor histology.
BAC=bronchioloalveolar carcinoma; LCC=large cell carcinoma; LCNEC=large cell
neuroendocrine carcinoma; SCC=squamous cell carcinoma; SCLC=small cell lung cancer;
WHO=World Health Organization.
American Cancer Society. Cancer Facts and Figures 2008. Atlanta: American Cancer Society; 2008; Travis, ed.
WHO Pathology & Genetics Tumours of the Lung, Pleura, Thymus and Heart. Lyon, France: IARC Press; 2004;
Kufe. Cancer Medicine 7. Hamilton, Ontario: BC Decker, Inc.; 2006:1185; Georgoulias. Lancet. 2001;357:1478;
Scagliotti. J Clin Oncol. 2008;26(21):3543; Ciuleanu. Lancet. 2009;374(9699):1432.
Lung Cancer Mutation Consortium
Organization
• Headquarters: University of Colorado
• Paul Bunn, Principal Investigator
• 14 Sites: SPORE, P01, NCI Intramural Programs
• Plan: Genotype 1000 patients with advanced lung
adenocarcinoma, 2009-2011
• Assay 10 “driver” mutations in CLIA-certified laboratories:
EGFR, KRAS, BRAF, HER2, AKT1, NRAS, PIK3CA, MEK1,
EML4-ALK, MET amp
Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01
Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506
LCMC Objectives
• Characterize 1000 tumor specimens from patients with
lung adenocarcinoma for KRAS, EGFR, BRAF, HER2,
PIK3CA, AKT1, NRAS, MEK1, and EML4-ALK, and
MET amplification
• To use the information in real time to either select
erlotinib with EGFR mutations or recommend a clinical
trial of an agent targeting the specific mutation identified
Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01
Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506
Lung Cancer Mutation Consortium
Incidence of Mutations Detected (n=516)
NO MUTATION
DETECTED
AKT1
NRAS
EML4-ALK
9%
KRAS
23%
EGFR
18%
MEK1
MET AMP
HER 2
PIK3CA 2%
BRAF 2%
A driver mutation was found in 54% (280/516) of
tumors completely tested (CI 50-59%)
Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01
Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506
Lung Cancer Mutation Consortium Conclusions
• An actionable driver mutation in 54% of patients with lung
adenocarcinoma
– 23% KRAS mutations
– 18% EGFR mutations
– 9% EML4-ALK
2% BRAF mutations
2% PIK3CA mutations
• EGFR mutations correlate with younger age, female gender,
and never smokers
• KRAS mutations correlate with older age and smoking
history
• Plans are underway to expand the scope of the LCMC when
ARRA funding ends-LCMC 2.0
Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01
Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506
Outline: NSCLC
Background
Epidemiology
Histology
Molecular Profiling
EGFR mutants
IPASS
EURTAC
LUX LUNG 3
EML 4 ALK,
ROS 1
Crizotinib
Upcoming agents
Tsao Algorithm: Histology and Molecular Profiling
NSCLC PATIENT
SCC
Non-SCC
Neuroendocrine
Platinumetoposide;
Switch
Maintenance:
pemetrexed,
erlotinib
EGFR TKI
1st or 2nd line
Maintenance
(IPASS, BR.21,
SATURN)
Adenocarcinoma
EGFR mutation
Avoid pemetrexed
or bevacizumab
EGFR wild-type
EML 4 ALK or ROS 1
Consider 2nd line EGFR
TKI or maintenance
erlotinib
(BR.21, SATURN)
crizotinib
Platinum-doublet-bevacizumab
Platinum-pemetrexed + bevacizumab
Non-platinum or platinum based doublet
Switch Maintenance: pemetrexed, erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)
EGFR mutations
•
Found in 10% - 15% of all lung cancer patients and 85%
who clinically respond to EGFR TKIs
•
Found more commonly in never-smokers,
adenocarcinomas, BAC, women, Asians
•
Predominantly located in EGFR exons 19 - 21
•
EGFR mutations are not the same. There are sensitive
mutations and acquired resistance mutations (T790M).
•
85% of EGFR mutations are either deletion exon 19 or
L858 mutation.
Pao, Miller. J Clin Oncol. 2005;23:2556-2568; Wu et al. J Thorac Oncol. 2007;2:430-439.
Patient with EGFR mutation deletion exon 19
12-00
12-02
Patient with L858 EGFR mutation
Newly diagnosed
3-16-07
3 months of erlotinib
6-18-07
EGFR T790M: Frequently Found in
Tumor Cells From Patients With Acquired Resistance
to EGFR TKIs
Pao W, et al. PLoS Med. 2005;2:e73; Balak MN, et al. Clin Cancer Res. 2006;12:6494-6501.
T790M blocks erlotinib binding and leads to a
resistant phenotype
Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008
IPASS: Phase III Trial of Gefitinib vs
Carboplatin/Paclitaxel in Selected Patients
With Advanced NSCLC
Never or light
ex-smoker* with
adenocarcinoma
histology
PS 0-2
Stage IIIB or IV
chemotherapy-naïve
NSCLC
N=1217
R
A
N
D
O
M
I
Z
E
Gefitinib (250 mg/day)
Offered carboplatin/paclitaxel
on progression
Carboplatin (AUC 5 or 6) +
Paclitaxel (200 mg/m2)
3 times weekly up to 6 cycles
Primary endpoint: PFS (noninferiority)
Secondary endpoints: ORR, OS, QOL, disease-related symptoms, safety, and
tolerability
Exploratory: biomarkers – EGFR mutation, gene copy number, and protein
expression
*Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped ≥15
years ago and smoked ≤10 pack-years.
Mok. N Engl J Med. 2009;361:947.
IPASS: PFS by EGFR Mutation Status
Within Treatment Arms
1.0
Gefitinib EGFR M+ (N=132)
Gefitinib EGFR M– (N=91)
Carboplatin/paclitaxel EGFR M+ (N=129)
Carboplatin/paclitaxel EGFR M– (N=85)
Probability of PFS
0.8
Gefitinib, HR=0.19; P<0.0001
Carboplatin/paclitaxel, HR=0.78; P=0.1103
0.6
0.4
0.2
0.0
0
4
8
12
16
Time From Randomization (Months)
20
24
HR <1 implies a lower risk of progression in the M+ group
compared with the M– group.
M=mutation.
Adapted with permission from Mok. N Engl J Med. 2009;361:947; Mok. ESMO. 2008 (abstr LBA2).
IPASS: PFS and OS by EGFR Mutation Status
OS (2010)
1.0
1.0
Gefitinib EGFR M+
Gefitinib EGFR MC/P EGFR M+
C/P EGFR M-
0.8
Probability of Survival
Probability of Progression-Free Survival
PFS (2008)
0.6
0.4
0.2
0.0
0.8
Mutation +
0.6
0.4
0.2
Mutation -
0.0
0
4
8
12
Mos
16
20
24
0
4
8
12 16 20 24 28 32 36 40 44 48 52
Mos
Reproduced with permission from Fukuoka. J Clin Oncol. 2011;29(21):2866. Reproduced with
permission from Yang. ESMO. 2010 (LBA2).
EURTAC: Phase III Study of Erlotinib vs
Chemotherapy in Patients with EGFR Mutations
•
•
•
•
Eligibility:
Chemo naїve
Stage IIIB/IV
NSCLC
EGFR exon 19
deletion or exon 21
L858R mutation
ECOG PS 0-2
(n=174)
R
A
N
D
O
M
I
Z
E
Erlotinib 150 mg/day
PD
Platinum-based
doublet chemotherapy
q3w × 4 cycles*
PD
*Cisplatin/docetaxel,
cisplatin/gemcitabine, carboplatin/docetaxel, or
carboplatin/gemcitabine.
• Primary endpoint: PFS
• Secondary endpoints: ORR, OS, site of progression,
safety, and QOL
• Stratification: mutation type and ECOG PS
Rosell. ASCO. 2011 (abstr 7503).
Response and PFS in ITT
Response
Erlotinib
N=86
Chemotherapy
N=87
ORR
58%
15%
DCR
79%
66%
PD
7%
13%
Inevaluable
14%
22%
Rosell et al. ASCO 2011 Abstract 7503
OS in ITT
Rosell et al. ASCO 2011 Abstract 7503
Summary EURTAC
• EURTAC is the first Caucasian front-line EGFR
TKI vs chemotherapy study performed in EGFRmutation positive patients.
• The PFS (HR 0.37) was consistent with prior
studies and favored the erlotinib arm with no
new safety signals.
• OS remains immature with high level of
crossover.
[TITLE]
Yang et al. ASCO 2012 Abstract LBA7500
Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation (+) => 345 randomized
Yang et al. ASCO 2012 Abstract LBA7500
[TITLE]
Yang et al. ASCO 2012 Abstract LBA7500
ORR favored afatinib
Yang et al. ASCO 2012 Abstract LBA7500
PFS favored afatinib
Yang et al. ASCO 2012 Abstract LBA7500
PFS Independent Review Subgroup Analysis
Yang et al. ASCO 2012 Abstract LBA7500
PFS Common Mutants (Del 19/L858R)
Yang et al. ASCO 2012 Abstract LBA7500
QOL: EORTC QLQ C-30
Yang et al. ASCO 2012 Abstract LBA7500
Summary LUNG LUX-3
• Front-line afatinib improved QOL, RR, DCR, and median PFS over
cisplatin-pemetrexed in both the overall EGFR mutation population
and in the common EGFR mutation (del19/L858) patients.
• Subgroup analysis showed benefit across most of the subgroups.
• No new safety signals with diarrhea and rash as the most frequent
AEs.
• On July 12, 2013, the FDA approved afatinib for front-line treatment of
metastatic NSCLC with EGFR exon 19 deletions or exon 21 (L858R)
as detected by an FDA-approved test.
Yang et al. ASCO 2012 Abstract LBA7500
Front-line EGFR TKI
• EGFR TKI monotherapy in NSCLC patients with sensitive
EGFR mutations improves PFS over chemotherapy.
• However, EGFR TKI monotherapy should not be given to
patients without EGFR mutations, i.e. EGFR wild-type (WT).
EGFR WT patients need front-line chemotherapy.
• It is unclear which EGFR TKI should be used front-line.
• It is unclear whether EGFR TKI + chemo or chemo then
maintenance erlotinib would improve survival for EGFR
mutation patients.
– CALGB 30406 frontline study (ASCO 2010)
– FAST - ACT (intercalating EGFR TKI with chemo) – await results. There are concerns
over combining erlotinib-chemo as erlotinib arrests the cancer cells in the G1
checkpoint and chemo usually works best in the mitotic phase.
– SATURN – showed that EGFR mutation patients had significant survival improvement
with maintenance erlotinib after 4 cycles of chemo.
Outline: NSCLC
Background
Epidemiology
Histology
Molecular Profiling
EGFR mutants
IPASS
EURTAC
LUX LUNG 3
EML 4 ALK,
ROS 1
Crizotinib
Upcoming agents
EML4-ALK Fusion Gene
ALK – anaplastic lymphoma kinase
EML 4 – echinoderm microtubule associated protein like 4
• Found Primarily in adenocarcinoma patients who are never- or light former
smokers, EGFR and KRAS WT, and younger


All adenocarcinomas: 9% EML4-ALK
If EGFR WT, Caucasian never-smoker, adenocarcinoma: ~10-20%
EML4-ALK
•EML4-ALK-positive tumors are a distinct entity among lung
adenocarcinomas and usually do not respond to EGFR TKIs.
•EML 4 ALK is a negative prognostic factor
 ALK (+) NSCLC treated with 2nd/3rd line crizotinib have longer OS than
those who are not treated with crizotinib.
Koivunen et al. CCR 14 (13): 2008; Shaw et al. ASCO 2011 Abstract 7507; Kris et al. on behalf of
LCMC investigators, ASCO June 2011 Abstract #CRA7506
Phase II crizotinib in ALK-positive NSCLC
Crino et al. ASCO 2011 Abstract 7514
Tumor response
Best response
ORR
SD
DCR
week 6
week 12
PD
51.1%
34%
85%
74%
7.5%
Crizotinib was FDA approved for use
in pre-treated EML4 ALK patients.
Crino et al. ASCO 2011 Abstract 7514
ALK Inhibitor Efficacy in EML4-ALK
NSCLC
Baseline
2 months of PF-02341066
Kwak EL. J Clin Oncol 2009;27(suppl):Abstract 3509
Crizotinib – ASCO 2010 Plenary
•
Treatment with crizotinib resulted in impressive clinical
activity in patients with ALK-positive advanced NSCLC
•
•
•
•
ORR: 57%
DCR at 8 weeks: 87%
PFS probability at 6 months: 72%
Crizotinib was well tolerated
Most frequent AEs: mild/moderate GI events and mild
visual disturbances
•
For patients with ALK-positive NSCLC, crizotinib may offer
a potential new standard of care.
ROS1 is an oncogene homologous to ALK
and LTK within the Insulin Receptor
Superfamily
• v-ros initially discovered
as the oncogene in the
avian sarcoma RNA tumor
virus, UR2
• Expression restricted to
epithelial cells
•
Normally expressed in
kidney, small intestine,
lungs, heart and male
reproductive organs
• Orphan receptor with no
known ligands
Bergethon et al. J Clin Oncol. 2012;30(8):863870, Doebele. IASLC Targeted Therapy 2012
Screening for ROS1 gene fusions reveals
~1% incidence in NSCLC
•
RT-PCR (Li et al. PLoS One 2011)
– 2/202 (1%) East Asian Never Smokers with
adenocarcinoma
– assaying for SLC34A2- or CD74-ROS1 fusions
• 2/2 CD74-ROS1
•
FISH (Bergethon et al. JCO 2012)
– 18/1073 (1.7%)
– 6/18 confirmed by RT-PCR
• 5 CD74-ROS1
• 1 SLC34A2-ROS1
•
FISH (Davies et al., accepted AACR 2012)
– 5/428 (1.2%) surgically resected
– 5/5 confirmed by RT-PCR
• 2 CD74-ROS1
• 2 SLC34A2-ROS1
• 1 SDC4-ROS1
– 1/48 patients screened at U. of Colorado
• SDC4-ROS1
Doebele. IASLC Targeted Therapy 2012
Clinical tumor responses in ROS1+
NSCLC treated with crizotinib
pre-crizotinib
post-crizotinib (12 weeks)
pre-crizotinib
post-crizotinib (56 days)
Bergethon et al. JCO 2012
Davies et al. AACR 2012
Doebele IASLC Targeted Therapy 2012
ROS1
• ROS1 gene fusions involved in multiple cancer types
• Incidence across multiple studies in NSCLC is
approximately 1%
– ROS1 mutant patients are younger and more likely to
be never smokers with higher grade adenocarcinoma
histology
• Clinical responses are seen in ROS1 mutant patients
with crizotinib
• Ongoing clinical trial for ROS1 NSCLC patients using
crizotinib
Bergethon et al. J Clin Oncol. 2012;30(8):863-870,
Doebele. IASLC Targeted Therapy 2012
2nd generation ALK inhibitors
Agent
Company
Status
Ceritinib (LDK378)
Novartis
FDA breakthrough
designation 3-15-13
Alectinib
(RO5424802/CH5424802 )
Roche/Chugai
FDA breakthrough
designation 9-23-13
AP26113
Ariad
Phase I/II
X-396
Xcovery
Phase I/II
PF-06463922
Pfizer
Planned clinical trial
NMS-E628
Nerviano
Planned phase I/II
ASP-3026
Astellas
Planned clinical trial
TSR-011
Tesaro
Planned clinical trial
CEP-37440
Teva
Planned clinical trial
Tsao Algorithm: Histology and Molecular Profiling
NSCLC PATIENT
SCC
Non-SCC
Neuroendocrine
Platinumetoposide;
Switch
Maintenance:
pemetrexed,
erlotinib
EGFR TKI
1st or 2nd line
Maintenance
(IPASS, BR.21,
SATURN)
Adenocarcinoma
EGFR mutation
Avoid pemetrexed
or bevacizumab
EGFR wild-type
EML 4 ALK or ROS1
Consider 2nd line EGFR
TKI or maintenance
erlotinib
(BR.21, SATURN)
crizotinib
Platinum-doublet-bevacizumab
Platinum-pemetrexed + bevacizumab
Non-platinum or platinum based doublet
Switch Maintenance: pemetrexed, erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)
Potential Future of NSCLC - Molecular Profiling
Adenocarcinoma
EGFR mutation
Met +
BRAF mutation
EGFR TKI
KRAS mutant
PI3K mutant
EML 4 ALK or ROS1 mutant
BRAF inhibitor
Resistance – rebiopsy
T790M – irreversible EGFR
TKI
MET upregulation – Met
inhibitor
PI3K inhibitor
Met inhibition
crizotinib
Resistance – rebiopsy
Novel agent
Resistance – rebiopsy
Hsp90 inhibitor
novel agent targeting ALK
resistance mutation
MEK inhibitor
combination
Resistance – rebiopsy
Novel agent
Resistance – rebiopsy
Novel agent
Resistance – rebiopsy
Novel Agent
Platinum-doublet-bevacizumab
Platinum-pemetrexed + bevacizumab
Non-platinum or platinum based doublet
Switch Maintenance: pemetrexed, erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)