Department of Thoracic/Head & Neck

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


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


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




Outline: NSCLC

EGFR mutantsIPASS

EURTAC LUX LUNG 3

EML 4 ALK, ROS 1


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


Phase III Lung LUX-3 Trial

1269 screened, 452 EGFR mutation (+) => 345 randomized

[TITLE]


ORR favored afatinib


PFS favored afatinib


PFS Independent Review Subgroup Analysis


PFS Common Mutants (Del 19/L858R)


QOL: EORTC QLQ C-30


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.


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

EGFR mutantsIPASS

EURTAC LUX LUNG 3

EML 4 ALK, ROS 1


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



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



PI3K mutant

PI3K inhibitor


Potential Future of NSCLC - Molecular Profiling

Met +

Met inhibition


KRAS mutant

MEK inhibitor combination

Resistance – rebiopsyNovel Agent

Date post:	04-Feb-2016
Category:	Documents
Upload:	oria
View:	30 times
Download:	0 times

Department of Thoracic/Head & Neck

Documents