department of thoracic/head & neck
DESCRIPTION
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. Department of Thoracic/Head & Neck. MD ANDERSON. Medical Oncology. CANCER CENTER. - PowerPoint PPT PresentationTRANSCRIPT
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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
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BackgroundEpidemiology
HistologyMolecular Profiling
Outline: NSCLC
EGFR mutantsIPASS
EURTAC LUX LUNG 3
EML 4 ALK, ROS 1
CrizotinibUpcoming agents
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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
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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.
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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
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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
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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
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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
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BackgroundEpidemiology
HistologyMolecular Profiling
Outline: NSCLC
EGFR mutantsIPASS
EURTAC LUX LUNG 3
EML 4 ALK, ROS 1
CrizotinibUpcoming agents
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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
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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.
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12-00 12-02
Patient with EGFR mutation deletion exon 19
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Newly diagnosed3-16-07
3 months of erlotinib6-18-07
Patient with L858 EGFR mutation
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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.
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T790M blocks erlotinib binding and leads to a resistant phenotype
Michalczyk et al. Bioorganic & Medicinal Chemistry 16 (7): 3482; April 2008
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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.
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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.
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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).
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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
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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
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OS in ITT
Rosell et al. ASCO 2011 Abstract 7503
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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.
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[TITLE]
Yang et al. ASCO 2012 Abstract LBA7500
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Yang et al. ASCO 2012 Abstract LBA7500
Phase III Lung LUX-3 Trial
1269 screened, 452 EGFR mutation (+) => 345 randomized
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[TITLE]
Yang et al. ASCO 2012 Abstract LBA7500
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ORR favored afatinib
Yang et al. ASCO 2012 Abstract LBA7500
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PFS favored afatinib
Yang et al. ASCO 2012 Abstract LBA7500
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PFS Independent Review Subgroup Analysis
Yang et al. ASCO 2012 Abstract LBA7500
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PFS Common Mutants (Del 19/L858R)
Yang et al. ASCO 2012 Abstract LBA7500
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QOL: EORTC QLQ C-30
Yang et al. ASCO 2012 Abstract LBA7500
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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
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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.
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BackgroundEpidemiology
HistologyMolecular Profiling
Outline: NSCLC
EGFR mutantsIPASS
EURTAC LUX LUNG 3
EML 4 ALK, ROS 1
CrizotinibUpcoming agents
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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
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Crino et al. ASCO 2011 Abstract 7514
Phase II crizotinib in ALK-positive NSCLC
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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.
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ALK Inhibitor Efficacy in EML4-ALK NSCLC
Baseline 2 months of PF-02341066Kwak EL. J Clin Oncol 2009;27(suppl):Abstract 3509
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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.
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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
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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
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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
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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
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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
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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
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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