department of thoracic/head & neck
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Department of Thoracic/Head & Neck Medical Oncology
Mutational Analysis in NSCLC Adenocarcinoma to Guide Therapy
Anne S. Tsao, M.D.Associate Professor
The University of Texas
MD ANDERSON
CANCER CENTER
Director, Mesothelioma Program
Director, Thoracic Chemo-XRT Program
BackgroundEpidemiology
HistologyMolecular Profiling
Outline: NSCLC
EGFR mutantsIPASS
EURTAC LUX LUNG 3
EML 4 ALK, ROS 1
CrizotinibUpcoming agents
Lung Cancer
• During 2013, ~228,190 new cases and ~159,480 deaths are expected in the United States
• Second most common cancer and leading cause of cancer death
American Cancer Society. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer Society; 2013; Siegel. CA Cancer J Clin. 61(4):212.
Stage at Diagnosis
Localized(stage I/II)
15%
Distant(stage IV)
56%
Regional(stage III)
22%
5-Year Relative Survival Rateby Stage at Diagnosis
Su
rviv
al (
%)
Localized DistantRegional
53%
24%
4%0
10
2030
40
50
60
70
80
90100
2004 WHO Classification of Lung TumorsNSCLC (87%) SCLC (13%)
Adenocarcinoma (45%) SCC (33%) LCC (9%)
Combined SCLC
Mixed subtype
Acinar
Papillary
BACNonmucinous
MucinousMixed
Solid
Papillary
Clear cell
Small cell
Basaloid
LCNEC Combined LCNEC
Clear cell
Basaloid
Lymphoepithelioma-like
LCC with rhabdoid phenotype
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.
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.
Lung Cancer Mutation ConsortiumOrganization
• 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 #O16.01Kris 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 #O16.01Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506
NO MUTATION DETECTED
EML4-ALK9%
BRAF 2%PIK3CA 2%
MET AMPMEK1NRAS
AKT1
KRAS23%
EGFR 18%
Lung Cancer Mutation ConsortiumIncidence of Mutations Detected (n=516)
A driver mutation was found in 54% (280/516) oftumors completely tested (CI 50-59%)
HER 2
Johnson et al on behalf of LCMC investigators, WLCC July 2011 Abstract #O16.01Kris 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 2% BRAF mutations– 18% EGFR mutations 2% PIK3CA mutations– 9% EML4-ALK
• 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 #O16.01Kris et al. on behalf of LCMC investigators, ASCO June 2011 Abstract #CRA7506
BackgroundEpidemiology
HistologyMolecular Profiling
Outline: NSCLC
EGFR mutantsIPASS
EURTAC LUX LUNG 3
EML 4 ALK, ROS 1
CrizotinibUpcoming agents
NSCLC PATIENT
Non-SCC
Neuroendocrine
Platinum-etoposide; Switch
Maintenance: pemetrexed,
erlotinib
Adenocarcinoma
EGFR mutation EGFR wild-type
EGFR TKI1st or 2nd lineMaintenance
(IPASS, BR.21, SATURN)
EML 4 ALK or ROS 1
crizotinib
Platinum-doublet-bevacizumabPlatinum-pemetrexed + bevacizumabNon-platinum or platinum based doubletSwitch Maintenance: pemetrexed, erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)
SCC
Avoid pemetrexed or bevacizumab
Consider 2nd line EGFR TKI or maintenance
erlotinib (BR.21, SATURN)
Tsao Algorithm: Histology and Molecular Profiling
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.
12-00 12-02
Patient with EGFR mutation deletion exon 19
Newly diagnosed3-16-07
3 months of erlotinib6-18-07
Patient with L858 EGFR mutation
EGFR T790M: Frequently Found inTumor 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 lightex-smoker* withadenocarcinoma
histology
PS 0-2
Stage IIIB or IVchemotherapy-naïve
NSCLCN=1217
RANDOMIZE
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 tolerabilityExploratory: biomarkers – EGFR mutation, gene copy number, and protein expression
Mok. N Engl J Med. 2009;361:947.
*Never smoker=smoked <100 cigarettes in lifetime; light ex-smoker=stopped ≥15 years ago and smoked ≤10 pack-years.
0 4 8 12 16 20 24Time From Randomization (Months)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
bab
ilit
y o
f P
FS
Gefitinib EGFR M+ (N=132)Gefitinib EGFR M– (N=91)Carboplatin/paclitaxel EGFR M+ (N=129)Carboplatin/paclitaxel EGFR M– (N=85)
HR <1 implies a lower risk of progression in the M+ group compared with the M– group.
IPASS: PFS by EGFR Mutation Status Within Treatment Arms
Gefitinib, HR=0.19; P<0.0001Carboplatin/paclitaxel, HR=0.78; P=0.1103
Adapted with permission from Mok. N Engl J Med. 2009;361:947; Mok. ESMO. 2008 (abstr LBA2).
M=mutation.
IPASS: PFS and OS by EGFR Mutation Status
1.0
0.8
0.6
0.4
0.2
0.0
0 4 8 12 16 20 24
Mos
Gefitinib EGFR M+Gefitinib EGFR M-C/P EGFR M+C/P EGFR M-
OS (2010)PFS (2008)
1.0
0.8
0.6
0.4
0.2
0.0
0 4 8 12 16 20 24
Mos
28 32 36 40 44 48 52
Mutation +
Mutation -
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
*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).
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 MIZE
Erlotinib 150 mg/day
Platinum-based doublet chemotherapy
q3w × 4 cycles*
PD
PD
ResponseErlotinib
N=86Chemotherapy
N=87
ORR 58% 15%
DCR 79% 66%
PD 7% 13%
Inevaluable 14% 22%
Response and PFS in ITT
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 EGFR-mutation 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
Yang et al. ASCO 2012 Abstract LBA7500
Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation (+) => 345 randomized
[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.
BackgroundEpidemiology
HistologyMolecular Profiling
Outline: NSCLC
EGFR mutantsIPASS
EURTAC LUX LUNG 3
EML 4 ALK, ROS 1
CrizotinibUpcoming agents
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.
EML4-ALK Fusion Gene
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
Crino et al. ASCO 2011 Abstract 7514
Phase II crizotinib in ALK-positive NSCLC
Crino et al. ASCO 2011 Abstract 7514
Best responseORR 51.1% SD 34%DCR week 6 85%
week 12 74%PD 7.5%
Tumor response
Crizotinib was FDA approved for usein pre-treated EML4 ALK patients.
ALK Inhibitor Efficacy in EML4-ALK NSCLC
Baseline 2 months of PF-02341066Kwak 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):863-870, 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-crizotinibpre-crizotinib post-crizotinib (56 days)post-crizotinib (56 days)
pre-crizotinibpre-crizotinib post-crizotinib (12 weeks)post-crizotinib (12 weeks)
Bergethon et al. JCO 2012Davies 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
NSCLC PATIENT
Non-SCC
Neuroendocrine
Platinum-etoposide; Switch
Maintenance: pemetrexed,
erlotinib
Adenocarcinoma
EGFR mutation EGFR wild-type
EGFR TKI1st or 2nd lineMaintenance
(IPASS, BR.21, SATURN)
EML 4 ALK or ROS1
crizotinib
Platinum-doublet-bevacizumabPlatinum-pemetrexed + bevacizumabNon-platinum or platinum based doubletSwitch Maintenance: pemetrexed, erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)
SCC
Avoid pemetrexed or bevacizumab
Consider 2nd line EGFR TKI or maintenance
erlotinib (BR.21, SATURN)
Tsao Algorithm: Histology and Molecular Profiling
Adenocarcinoma
EGFR mutation
EGFR TKI
Resistance – rebiopsyT790M – irreversible EGFR
TKIMET upregulation – Met
inhibitor
EML 4 ALK or ROS1 mutant
crizotinib
BRAF mutation
Resistance – rebiopsyHsp90 inhibitor
novel agent targeting ALK resistance mutation
BRAF inhibitor
Resistance – rebiopsyNovel agent
Platinum-doublet-bevacizumabPlatinum-pemetrexed + bevacizumabNon-platinum or platinum based doubletSwitch Maintenance: pemetrexed, erlotinib
(E4599, AVAiL, Pointbreak, SATURN, JMEN)
PI3K mutant
PI3K inhibitor
Resistance – rebiopsyNovel agent
Potential Future of NSCLC - Molecular Profiling
Met +
Met inhibition
Resistance – rebiopsyNovel agent
KRAS mutant
MEK inhibitor combination
Resistance – rebiopsyNovel Agent
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