Treatment Based On Molecular Factors in Lung Cancer

Başak OyanYeditepe University HospitalSection of Medical Oncology

Treatment Based On Molecular Factors in Lung Cancer

ak Oyan-Uluç, MDYeditepe University HospitalSection of Medical Oncology

Overview

• First line therapy• Chemotherapy• Chemotherapy + Bevacizumab• Chemotherapy + Cetuximab• EGFR TKIs

• Maintenance therapy

• Second line therapy

Overview

Chemotherapy + BevacizumabChemotherapy + Cetuximab

Maintenance therapy

Second line therapy

Advanced NSCLC

• 85% of NSCLC

Management strategy

• Best supportive care

• Initial chemotherapy regimens

• Refined doublet chemotherapy

• Doublet chemo. + targetted agent

Advanced NSCLC

Median survival

3-4 mo

Initial chemotherapy regimens 6-8 mo

Refined doublet chemotherapy 8-10 mo

Doublet chemo. + targetted agent 12+ mo

FIRST LINE THERAPY

- Chemotherapy

FIRST LINE THERAPY

Chemotherapy -

Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxel

Carboplatin/paclitaxel

100

80

60

40

20

00 5 10 15 20

Months

Surv

ival

(%)

No platin-3rd generation combination is superior

Median survival: 8 mo

Med PFS: 5 mo

1-y survival: 34%

RR: %20-30

Cisplatin/paclitaxelCisplatin/gemcitabineCisplatin/docetaxel

Carboplatin/paclitaxel

20 25 30

3rd generation combination is superior

Schiller, J. et al. N Engl J Med 2002;346:92-98

All recent randomized chemotherapy studies have similar results

Phase III trial: Pemetrexed/Cisplatin vsGemcitabine/Cisplatin

Noninferiority study

Prespecified subset analysis according to histology

Pemetrexed/Cisplatin vsGemcitabine/Cisplatin

Scagliotti GV et al J Clin Oncol 26:5343-51, 2008.

Prespecified subset analysis according to histology

Results: Benefit depend

All patients

No difference in OS

Nonsquamous

Cis+Pem > Cis+Gem

Possible Explanation:Pemetrexed inhibits thymidylate synthaseTS expression levels are higher in squamousHigh expression of TS correlates with reduced sensitivity to

enefit depends on histology

Nonsquamous

Cis+Pem > Cis+Gem

Squamous

Cis+Gem > Cis+Pem

Pemetrexed inhibits thymidylate synthaseare higher in squamous versus adenocarcinoma.

orrelates with reduced sensitivity to pemetrexed.

Scagliotti GV et al J Clin Oncol 26:5343-51, 2008.

Biomarkers for chemotherapy

§ Thymidylate synthase (TS)§ Increased expression predicts resistance to pemetrexed

§ Excision Repair Cross Complemetation§ Involved in nucleotide excision repair (repair cisplatin§ Conflicting results in lung cancer§ High ERCC1 levels may be predictive of reduced benefit from platinum

based chemo

§ Ribonucleotide reductase M1 (RRM1)§ Target for gemcitabine§ Overexpression is associated with reduced survival benefit with gem/cis

§ BRCA-1§ Function in DNA repair§ May be a potential predictor of cisplatin chemosensitivity§ Patients with BRCA overexpression and gem/cis

JCO 2006; 24 (suppl): 13058; Chest 2005; 127: 2741; Clin Cancer Res 2004: 10:1318; Hum Mol Gen 2004; 13: 2443

Biomarkers for chemotherapy

Increased expression predicts resistance to pemetrexed

Excision Repair Cross Complemetation-1 (ERCC1)Involved in nucleotide excision repair (repair cisplatin-DNA adducts)Conflicting results in lung cancerHigh ERCC1 levels may be predictive of reduced benefit from platinum-

Ribonucleotide reductase M1 (RRM1)

Overexpression is associated with reduced survival benefit with gem/cis

May be a potential predictor of cisplatin chemosensitivityPatients with BRCA overexpression and gem/cis à decreased survival

JCO 2006; 24 (suppl): 13058; Chest 2005; 127: 2741; Clin Cancer Res 2004: 10:1318; Hum Mol Gen 2004; 13: 2443

Molecular analysis-directed individualized therapy (MADe

Molecular analysis-directedRR: 44%Disease cont. rate: 88%Med PFS: 6.6 mo, 1-year PFS: 14% Med OS: 13.3 mo, 1-year OS: 59%

directed individualized therapy (MADe-IT)

Simon et al. JCO 2007; 25:2741

Phase 2 trial

Uncustomized (literature) RR: 20-30%Disease cont. rate: 50-60%Med PFS: 5 moMed OS: 8 mo

Immediately frozen, sectioned, laser capture microdissection

mRNA expression analysis

Gemcitabine+carboplatin

RRM1 high

Patients with previously untreated

advanced NSCLC

Phase III Molecular analysisindividualized therapy: Ongoing

RRM1 low

ERCC1 low

ERCC1 high

ERCC1 low

ERCC1 high

Gemcitabine+carboplatin

Cassidy J, et al. ESMO 2006. Abstract LBA3.

Gemcitabine+docetaxel

Docetaxel+vinorelbine

Docetaxel+carboplatin

Phase III Molecular analysis-directed individualized therapy: Ongoing

ERCC1 low

ERCC1 high

ERCC1 low

ERCC1 high

Gemcitabine+carboplatin

Chemotherapy: selection criteria

• Patient related• Performance status• Age• Platin contraindication based on toxicity• Side effects, patient preference

• Histology– Nonsquamous: Pemetrexed

• Biomarkers– ERCC-1 (Excision Repair Cross Complemetation): Cisplatin– RRM1 (Ribonucleotide reductase M1): Gemcitabine– Thymidylate synthase: Pemetrexed

Chemotherapy: selection criteria

Platin contraindication based on toxicitySide effects, patient preference

Nonsquamous: Pemetrexed

1 (Excision Repair Cross Complemetation): CisplatinRRM1 (Ribonucleotide reductase M1): GemcitabineThymidylate synthase: Pemetrexed

FIRST LINE THERAPY

- Chemotherapy + Bevacizumab

FIRST LINE THERAPY

Chemotherapy + Bevacizumab -

E4599: Bevacizumab Phase III Study

1st-line treatment of patients with stage IIIB with malignant

pleural effusion,stage IV, or recurrent

NSCLC(N = 878)

1st-line treatment of patients with stage IIIB with malignant

pleural effusion,stage IV, or recurrent

NSCLC(N = 878) Bevacizumab 15 mg/kg + PC

q3wk (BV/PC)× 6 (unless progression or

unacceptable toxicity)

Bevacizumab 15 mg/kg + PC q3wk (BV/PC)

× 6 (unless progression or unacceptable toxicity)

Paclitaxel 200 mg/mcarboplatin AUC 6 mg/mL/min

(PC)q3wk x 6 (unless

progression or unacceptabletoxicity)

Paclitaxel 200 mg/mcarboplatin AUC 6 mg/mL/min

(PC)q3wk x 6 (unless

progression or unacceptabletoxicity)

Exclusion criteria• Squamous cell ca• Hemoptysis• CNS metastases• History of hemorrhagic

diathesis or coagulopathy• Therapeutic anticoagulation• Major surgery within 28d• Uncontrolled hypertension

Bevacizumab Phase III Study

BV 15 mg/kg q3wk until progression or

unacceptable toxicity

BV 15 mg/kg q3wk until progression or

unacceptable toxicity

Bevacizumab 15 mg/kg + PC q3wk (BV/PC)

6 (unless progression or unacceptable toxicity)

Bevacizumab 15 mg/kg + PC q3wk (BV/PC)

6 (unless progression or unacceptable toxicity)

Paclitaxel 200 mg/m2 +carboplatin AUC 6 mg/mL/min

q3wk x 6 (unlessprogression or unacceptable

toxicity)

Paclitaxel 200 mg/m2 +carboplatin AUC 6 mg/mL/min

q3wk x 6 (unlessprogression or unacceptable

toxicity)

(No crossover permitted)(No crossover permitted)

EndpointsPrimary: Overall survival

Secondary: Response ratesProgression-free survival Toxicity

Sandler A, et al. N Engl J Med. 2006;355:2542.

Bevacizumab improves survival

• Improved median survival (HR:0.79, 95% CI 0.67-0.92)– 12.3 mo vs 10.3 mo

– In adenoca: 14.2 mo vs 10.3 mo (HR: 0.69)

• Improved response rates (35% vs. 15%)

• Improved progression-free survival (6.2 mo vs. 4.5 mo)

Bevacizumab improves survival

In adenoca: 14.2 mo vs 10.3 mo (HR:

Improved response rates (35% vs. 15%)

free survival (6.2

Sandler A, et al. N Engl J Med. 2006;355:2542.

AVAiL: Cisplatin/Gemcitabine

No protocol-specified crossover to bevacizumabPatients receiving angiogenesis inhibitors after progression: <%1

AVAiL: Cisplatin/Gemcitabine ±Bevacizumab

specified crossover to bevacizumabPatients receiving angiogenesis inhibitors after progression: <%1

Reck M et al. JCO 2009; 27: 1227

AVAiL trial: Significant prolongation of PFS

No increase in treatment –related deaths

RR

AVAiL trial: Significant prolongation of PFS

related deaths

RR 20% 34% 30%

Reck M et al. JCO 2009; 27: 1227

AVAiL: no significant benefit in OS (secondary endpoint)

AVAiL: no significant benefit in OS (secondary endpoint)

Reck M et al. JCO 2009; 27: 1227

Acceptable safety in patients with treated brain metastases

PASSPORT trial§ Phase II, patients with treated brain met§ No grade ≥ 2 CNS hemorrhage

ATLAS trial§ Phase III, 1st line§ Includes pts with treated brain met, peripherally

located squamous cell ca§ Chemo + beva à beva ±

§ No safety problem

Acceptable safety in patients with treated brain metastases

Phase II, patients with treated brain metNo grade ≥ 2 CNS hemorrhage

Includes pts with treated brain met, peripherally located squamous cell ca

erlotinib

Socinski et al. JCO 2009; 27: 5255Aketley et al: JCO 2008; A8043

Phase IV safety trials: SAIL & ARIES

No increased toxicity in patients:• With brain metastases• ECOG PS >1• Age ≥ 70y• On anticoagulation or antiplatelet therapy• With centrally located tumors• With tumor cavitation

Phase IV safety trials: SAIL & ARIES

No increased toxicity in patients:

On anticoagulation or antiplatelet therapyWith centrally located tumors

Fischbach et al. JCO 2009; 27: A8040Crino etla J Clin Oncol 2009; 27: A8043

Bevacizumab-Selection criteria

Patient clinical characteristics§ ECOG PS 0,1,2§ Exclusion § History of hemoptysis§ Significant cardiac dysfunction

Histology§ Non-squamous

Molecular predictors§ Not defined yet

Selection criteria

Patient clinical characteristics

Significant cardiac dysfunction

FIRST LINE THERAPY

- Chemotherapy + Cetuximab

FIRST LINE THERAPY

Chemotherapy + Cetuximab -

FLEX: Cisplatin/vinorelbine first line advanced NSCLC

FLEX: Cisplatin/vinorelbine ± Cetuximab in first line advanced NSCLC

Pirker et al. Lancet 2009; 373: 1525

FLEX: ResultsFLEX: Results

Pirker et al. Lancet 2009; 373: 1525

Results are not dependent on histology

FLEX Biomarker Analysis: Results

• Benefit from cetuximab in NSCLC independent of KRASmutation status and EGFRgene copy number

– No significant differences in PFS, RR, or OS

• First-cycle rash identified as clinical biomarker predictive of increased survival

– Any grade– HR: 0.631 (95% CI: 0.515-0.774;

P < .001)

FLEX Biomarker Analysis: Results

O’Byrne K, et al. ASCO 2009. Abstract 8007.

Cetuximab - Selection criteria

Patient clinical characteristics§ Patients ineligible for chemotherapy + bevacizumab

Biomarker§ EGFR expressing tumors by immunohistochemistry

Selection criteria

Patient clinical characteristicsPatients ineligible for chemotherapy + bevacizumab

EGFR expressing tumors by immunohistochemistry

FIRST LINE THERAPY

-EGFR TKIs

FIRST LINE THERAPY

EGFR TKIs-

Targeting EGFR Signaling PathwayTargeting EGFR Signaling PathwayForm homo- or heterodimers

after ligand binding.

Malignant transformation

• EGFR overexpression

• EGFR amplification

• EGFR mutation: leads to

ligand-independent

activation

Activation of EGFR signaling

also leads to an autocrine

loop resulting from the

formation and release of

ligands.

EGFR Tyrosine kinase inhibitors (EGFR TKI): The Story so far

1994 Discovery of EGFR TKI

2001 IDEAL (Ph II) –>Efficacy of gefitinib in 2nd

2002 Japanese approval of gefitinib

2003 US approval of gefitinib

2004 ISEL (Ph III)—> No survival benefit with gefitinib

US approval of erlotinib in 2nd

2005 Label restrictions of gefitinib

2006-07 Gefitinib ≅ Docetaxel in 2nd line

2008 IPASS à Superior efficacy of gefitinib in 1st line in EGFR muta (+) pts

2009 EU approval of Gefitinib

EGFR Tyrosine kinase inhibitors (EGFR TKI): The Story so far

>Efficacy of gefitinib in 2nd-3rd line

Japanese approval of gefitinib

> No survival benefit with gefitinib

US approval of erlotinib in 2nd-3rd line

Label restrictions of gefitinib

Docetaxel in 2nd line

Superior efficacy of gefitinib in 1st line in EGFR

EU approval of Gefitinib in 1st line in EGFR muta (+) pts

1994

2009

Who responds to erlotinib/gefitinib?

• Clinical characteristics– Female– Non-smoker/former light smoker– East Asian race– Adenocarcinoma

• Molecular factors– EGFR overexpression– EGFR amplification (increased gene copy #)– EGFR activating mutation– K-ras mutation

Who responds to erlotinib/gefitinib?

smoker/former light smoker

EGFR amplification (increased gene copy #)EGFR activating mutation

John T et al. Oncogene 2009; 28: S14

Molecular predictors

EGFR overexpression by IHC• Prevalence

– Squamous-cell carcinoma: 55-– Adenocarcinoma: 35-60%– Large-cell carcinoma: 20-60%

• Association with response to EGFR TKIs (controversial)• Conflicting results in predicting survival with EGFR TKIs• Correlated with poor prognosis

EGFR amplification (FISH)• Prevelance: 40-45%• Amplified: Increased response, PFS, OS• Correlates with poor prognosis

Molecular predictors

-100%

Association with response to EGFR TKIs (controversial)Conflicting results in predicting survival with EGFR TKIsCorrelated with poor prognosis

Amplified: Increased response, PFS, OSCorrelates with poor prognosis

John T et al. Oncogene 2009; 28: S14

EGFR gene mutations• Affect ATP-binding cleft of EGFR

• Prevalence– Caucasian: 5-10%– Asian: 20-40%

• More common in:– Female– Never smoker– East Asian race– Adenocarcinoma

• Most common drug sensitive mutations (85– Deletion in exon 19 (del 746-A750)– Point mutation at exon 21 (L858R)

EGFR gene mutationsbinding cleft of EGFR à constitutive TK activity

Most common drug sensitive mutations (85-90%)A750)

Point mutation at exon 21 (L858R)Oncogene 2009; 28: S14-S23

EGFR mutations as biomarkers

• High response rates to TKIs– ORR as high as 80% in pts with mutations vs. ≤10% in

muta (-) pts

• Increased PFS (9-13 mo)

• Increased OS (17.5-18.5 mo)

• Correlates with favorable prognosis

EGFR mutations as biomarkers

High response rates to TKIsORR as high as 80% in pts with mutations vs. ≤10% in

13 mo)

18.5 mo)

Correlates with favorable prognosisJohn T et al. Oncogene 2009; 28: S14

Frequency of EGFR mutations in different NSCLC patient subgroups

Total (%) Non

All 19SmokersNon-smokers

1154

Non-adenocarcinoma Adenocarcinoma

3 42

Male Female

1646

*Large cell carcinoma: up to 11% have EGFR mutation

Frequency of EGFR mutations in different NSCLC patient subgroups

Non-east Asian (%) East Asian (%)

10 304

351760

1*16

4 49

1-820-30

2258

Clin cancer Res 12 (4 suppl): 4416sNEJM 2009; 361: 958

*Large cell carcinoma: up to 11% have EGFR mutation

IPASS Phase III Study: FirstGefitinib vs CP in Advanced

Untreated Asian patients* with stage IIIb/IV

NCSLC and PS 0-2,Adenocarcinoma

Nonsmoker/former light smoker

(N = 1217)Paclitaxel 200 mg/m

§ Primary endpoint: PFS

§ Secondary endpoints: OS, ORR, QoL, disease

§ Biomarker analysis: EGFR mutation, expression, and gene copy number

§ Non-inferiority trial

*Never smokers or ex-light smokers.†≤ 6 cycles.

IPASS Phase III Study: First-line in Advanced NSCLC

Gefitinib 250 mg/day (n = 609)

Carboplatin AUC 5-6 +Paclitaxel 200 mg/m2 3 every wks†

(n = 608)

Mok TS et al. NEJM 2009; 361: 947

Secondary endpoints: OS, ORR, QoL, disease-related symptoms, safety, tolerability

mutation, expression, and gene copy number

Progression-free survival in ITT

Med survival: 18.6 mo. in gefitinib arm, 17.3 mo in CP arm

free survival in ITT population

Mok TS et al. NEJM 2009; 361: 947

Gefitinib

CP

Med survival: 18.6 mo. in gefitinib arm, 17.3 mo in CP arm

IPASS: PFS according to EGFR mutation status

§ Treatment by EGFR mutation status interaction test, P < .0001

§ EGFR mutas (+): In 59.7% of analysed tumors

according to EGFR mutation status

Treatment by EGFR mutation status interaction test, P < .0001

EGFR mutas (+): In 59.7% of analysed tumorsMok TS et al. NEJM 2009; 361: 947

IPASS: OS by EGFR mutation status

Represent just 1/3 of patients who have tissue available

IPASS: OS by EGFR mutation status

Represent just 1/3 of patients who have tissue available

IPASS Ph III Study: ORR

OR

R (%

)

OR: 2.75P = .0001

OR: 0.94P = .0013

OR: 1.79P = .0243

10

30

50

70

80

Positive

60

40

20

Negative HighEGFR Mutation EGFR

Number

71.2

47.3

1.1

23.5

58.9

44.8

0

IPASS Ph III Study: ORR

Fukuoka M, et al. ASCO 2009. Abstract 8006.

= .0243OR: 0.80P = .5580

OR: 1.49P = .1093

OR: 1.44P = .4146

Low Positive Negative

EGFR Gene Copy Number

EGFR Expression

44.8

22.226.3

51.541.8

3426.1

GefitinibCP

Implications of IPASS

• EGFR mutation is proven as an important predictive marker for EGFR TKI

• 1st line therapy– Pts with EGFR mutation: Gefitinib– Pts with wild type EGFR: Chemotherapy

• Gefitinib is well tolerated, offering superior quality of life compared to chemotherapy

Implications of IPASS

EGFR mutation is proven as an important marker for EGFR TKI.

: GefitinibPts with wild type EGFR: Chemotherapy

Gefitinib is well tolerated, offering superior life compared to chemotherapy

Not all EGFR mutations have similar impact• Phase II, prospective, 1st line, Asian, stage IIIB/IV• Gefitinib• 68% female, %88 non-smoker/former smoker, %91 adenocarcinoma

% RR (%)

All pts 100 50.9

EGFR mutant 61.1 69

Del 19/L858R 78.2 84.2

Del 19 36.4 95

L858R 41.8 73.9

Other mutation 21.8 16.7

Wild 38.9 20

Not performed 56.3

P .001

Not all EGFR mutations have similar impactPhase II, prospective, 1st line, Asian, stage IIIB/IV

smoker/former smoker, %91 adenocarcinoma

Yang CH et al. JCO 2008;26:2745

DCR (%) Med TTF Med OS

82.1 5.5 22.4

87.3 8 24

95.3 8.9 24

95 8.9 24

95.7 9.1 NR

58.3 2.1 6.7

68.6 3.4 12.9

93.8 5.6 NR

.002 .0001

K-ras Mutation

• Codon 12 & 13 mutations

• Frequency: 20-30%

• More in smokers (92%, current or former)• In nonsmokers: 15%• Uncommon in squamous cell carcinoma

• EGFR and k-ras mutations are mutually exclusive

• Resistance to EGFR TKIs (negative predictor for EGFR TKI)– RR <1%

ras Mutation

More in smokers (92%, current or former)

Uncommon in squamous cell carcinoma

ras mutations are mutually exclusive

Resistance to EGFR TKIs (negative predictor for EGFR

EML4-ALK mutant tumor

• Frequency: ≤ 5

• Not overlapping with EGFR mutation & kmutationà distinct subtype

• Resistant to treatment with EGFR TKI

• No difference in response to chemotherapy

ALK mutant tumor

Not overlapping with EGFR mutation & k-ras distinct subtype

Resistant to treatment with EGFR TKI

No difference in response to chemotherapy

Shaw et al. JCO 2009; 27: 4247

Implication of EML4• Not frequent in general population

– EGFR muta 10% vs EML4-ALK muta 5%

• In pts with clinical characteristics asso. with EGFR mutation– EGFR muta 20-35 % vs EML4-ALK muta 13%

• Not give EGFR TKI based on clinical characteristics asso. with EGFR mutation

• Do we need to test for EML4-ALK routinely?

– NO. Because EGFR mutation frequency is higher and they are mutually exclusive

– YES IN THE FUTURE (When ALK targetted therapies become available)• PF-02341066: RR: 65%, Disease control rate: 83%

Implication of EML4-ALK

ALK muta 5%

In pts with clinical characteristics asso. with EGFR mutationALK muta 13%

Not give EGFR TKI based on clinical characteristics asso. with EGFR

ALK routinely?

NO. Because EGFR mutation frequency is higher and they are mutually

YES IN THE FUTURE (When ALK targetted therapies become available)02341066: RR: 65%, Disease control rate: 83%

Does treatment sequence matter?Does treatment sequence matter?

Mok TS et al. NEJM 2009; 361: 947

Rosell et al. NEJM 2009; 361: 958

EGFR TKI selection criteria

• Molecular marker– EGFR mutation

• Clinical features– If mutation analysis unavailable– To select patients for mutation analysis

• EGFR mutant: Must receive EGFR TKI, preferentially at 1st line, at least in 2nd line

EGFR TKI selection criteria

If mutation analysis unavailableTo select patients for mutation analysis

EGFR mutant: Must receive EGFR TKI, preferentially at 1st line, at least in 2nd line

MAINTENANCE THERAPYMAINTENANCE THERAPY

Maintenance strategies1. Continue with the original chemotherapy

• No OS benefit if give >4-6 cycles of original chemotherapy

2. Continue part of the current regimen (Bevacizumab, Cetuximab)

3. Sequential non-cross resistant therapy• Docetaxel à Increased PFS, similar OS• Pemetrexed• EGFR TKI• EGFR TKI+bevacizumab

Maintenance strategiesContinue with the original chemotherapy

6 cycles of original chemotherapy

Continue part of the current regimen (Bevacizumab,

cross resistant therapyIncreased PFS, similar OS

Stop chemotherapy, continue targetted therapy

Stage IIIB/IV NSCLCStage IIIB/IV NSCLC

Chemotherapy upto 6 cycles +Bevacizumab or Cetuximab

Chemotherapy upto 6 cycles +Bevacizumab or Cetuximab

Chemotherapy upto 6 cyclesChemotherapy upto 6 cycles

No control arm of chemotherapy + targetted therapy without maintanence

Impact of maintenance on survival is unknown

E4599, AVAiL, FLEX

Stop chemotherapy, continue targetted therapy

Bevacizumab or cetuximab until progression or

unacceptable toxicity

Bevacizumab or cetuximab until progression or

unacceptable toxicityChemotherapy upto 6 cycles +

Bevacizumab or CetuximabChemotherapy upto 6 cycles +

Bevacizumab or Cetuximab

Chemotherapy upto 6 cyclesChemotherapy upto 6 cycles

Sandler A, et al. N Engl J Med. 2006;355:2542. Manegold et al: Ann Oncol 2008;19:viii (ESMO 2008)Pirker et al. Lancet 2009; 373: 1525

No control arm of chemotherapy + targetted therapy without maintanence

Impact of maintenance on survival is unknown

Maintenance Pemetrexed vs.

Primary endpoint: progression-free survival

Secondary endpoints: overall survival, objective response rate, safety

Maintenance Pemetrexed vs.Placebo

free survival

Secondary endpoints: overall survival, objective response rate, safety

Ciuleanu et al Lancet 2009; 374: 1432

Maintenance Pemetrexed vs.

Better PFS4.3 vs 2.6 mo

HR: 0.50 (95%CI: 0.42-0.61)P<0.0001

Postprogression therapy in placebo arm: 67% , received pemetexed: 19%

Maintenance Pemetrexed vs.Placebo

Ciuleanu et al Lancet 2009; 374: 1432

Better OS 13.4 vs 10.6 mo

HR: 0.79 (95%CI:0.65-0.95)P=0.012

Postprogression therapy in placebo arm: 67% , received pemetexed: 19%

Efficacy by histology

A significant treatment-by-histology interaction with both PFS (

Efficacy by histology

histology interaction with both PFS (P= .036) and OS (P= .033)

Ciuleanu et al Lancet 2009; 374: 1432

SATURN Phase III Study: Erlotinib vs PMaintenance in Advanced NSCLC

Patients withstage IIIb/IV NSCLC,

PS 0-1, and nonprogression after prior platinum-based

chemo

(N = 889)

Stratified by EGFR IHC (pos vs neg vs indeterminate), stage, PS,

previous regimen, smoking history, region

§ Primary endpoint: PFS (all patients and in patients with

§ Secondary endpoints: OS (all patients and in patients with safety, TTP, biomarker analyses, QoL

SATURN Phase III Study: Erlotinib vs Placebo as Maintenance in Advanced NSCLC

Erlotinib 150 mg/day (n = 438)

Placebo (n = 451)

Stratified by EGFR IHC (pos vs neg vs indeterminate), stage, PS,

previous regimen, smoking history,

Cappuzzo F, et al. ASCO 2009. Abstract 8001.

Primary endpoint: PFS (all patients and in patients with EGFR IHC-positive tumors)

Secondary endpoints: OS (all patients and in patients with EGFR IHC-positive tumors),

Treat until disease

progression

SATURN: Results

PFS benefit with erlotinib observed regardless of histology, gender, race, or smoking history− adenocarcinoma histology: HR 0.60− squamous histology: HR 0.76

SATURN: Results

PFS benefit with erlotinib observed regardless of histology, gender, race, or smoking history

Cappuzzo F, et al. ASCO 2009. Abstract 8001.

Cappuzzo F, et al. ASCO 2009. Abstract 8001

SATURN Ph III: Strong PFS

EGFR mutation status: Only marker significantly predictive of differential erlotinib effect (interaction P < .001)

Cappuzzo F, et al. ASCO 2009. Abstract 8001, Brugger W, et al. ASCO 2009. Abstract 8020.

SATURN Ph III: Strong PFS in pts with Mut EGFR

EGFR mutation status: Only marker significantly predictive of differential erlotinib effect

Med PFS: 44.6 vs 13 wk

ATLAS Ph III Trial: Maintenance Following Bev in Advanced NSCLC:

• Primary endpoint: PFS

• Secondary endpoints: OS, safety, biomarker analysis

• Trial stopped early; met endpoint of improved PFS

Previously untreated pts with

stage IIIB or IV NSCLC

(N = 1160)

Pts without progression randomized and stratified by sex,

smoking history, ECOG PS (0 vs ≥1), chemotherapy regimen

(n = 743)

4 cycles of first-line platinum-based

chemotherapy* + bevacizumab

Trial: Bev ± Erlotinib as Maintenance Following Bev in Advanced NSCLC:

Secondary endpoints: OS, safety, biomarker analysis

Trial stopped early; met endpoint of improved PFS

Miller VA, et al. ASCO 2009. Abstract LBA8002.

Bevacizumab 15 mg/kg + Erlotinib 150 mg

(n = 370)

Bevacizumab 15 mg/kg + Placebo(n = 373)

Pts without progression randomized and stratified by sex,

smoking history, ECOG PS (0 vs ≥1), chemotherapy regimen

Disease progression

ATLAS: Maintenance Bev

• Originally designed to only include nonsquamous NSCLC – After study initiation, trial amended to include other tumor types

(peripheral or extrathoracic squamous cell carcinomas; treated brain metastases)

PFS benefit with erlotinib : in nearly all patient subgroupsgender, smoking history or PS)

Maintenance Bev ± Erlotinib

riginally designed to only include nonsquamous NSCLC After study initiation, trial amended to include other tumor types (peripheral or extrathoracic squamous cell carcinomas; treated brain

Miller VA, et al. ASCO 2009. Abstract LBA8002.

in nearly all patient subgroups (age, gender, smoking history or PS)

Drawback in maintenance trials

• Trials supporting sequential therapy all permitted 2nd line therapy, but this was not uniformly applied

• Sequential therapy > 2nd line therapy at progression

???

Drawback in maintenance trials

Trials supporting sequential therapy all permitted 2nd line therapy, but this was not uniformly applied

2nd line therapy at progression

Summary of Maintenance Therapies

• Continue bevacizumab or cetuximab if benefiting from them– Impact of maintenance not clear

• Selection criteria– Pemetrexed: Non-squamous– Erlotinib: Benefit not dependent on histology & molecular marker

• EGFR mutation status: Only marker significantly predictive of differential erlotinib effect

• If not on bevacizumab or cetuximab , should you change to pemetrexed or erlotinib? – individualized decision– Close follow-up can be an

option

Summary of Maintenance Therapies

Continue bevacizumab or cetuximab if benefiting from them

PFS benefit OS benefit

Docetaxel + -

Pemetrexed + +

Erlotinib + +

Erlotinib+Bevacizumab + NR

Erlotinib: Benefit not dependent on histology & molecular markerEGFR mutation status: Only marker significantly predictive of differential erlotinib

SECOND LINE THERAPYSECOND LINE THERAPY

Standards

• Docetaxel– Better than BSC, vinorelbine, ifosfamide

• Pemetrexed• Erlotinib

• Similar benefit• Less toxicity with pemetrexed and erlotinib

Standards

Better than BSC, vinorelbine, ifosfamide

Less toxicity with pemetrexed and erlotinib

ORR. %7-10

Med. PFS: 2-3 mo

Med OS: 8 mo

Gefitinib250 mg/day

Docetaxel75 mg/m2 every

3 weeks

1:1 randomization

INTEREST: Ph III Gefitinib vs. docetaxel in pts

Noninferiority trial

Patients• Age ≥18 years

• Life expectancy≥ 8 weeks

• Progressive or recurrent disease following CT

• Considered candidates for further CT with docetaxel

• 1 or 2 CT regimens(≥1 platinum)

• PS 0-2

Gefitinib in not inferior to docetaxel (RR, PFS, OS)

Gefitinib250 mg/day

Docetaxelevery

3 weeks

1:1 randomization

INTEREST: Ph III Gefitinib vs. docetaxel in pts

Primary• Overall survival(co-primary analysesa of non-inferiority in all patients and superiority in patients with high EGFR gene copy number)

Secondary• Progression-free survival• Objective response rate• Quality of life• Disease related symptoms• Safety and tolerability

Exploratory• Biomarkers

Endpoints

JY Douillard et al. JCO 2009

Kim et al. Lancet 2008; 372: 1809

Gefitinib in not inferior to docetaxel (RR, PFS, OS)

PFS: According to EGFR mutation status

EGFR mutant

Gefitinib better

PFS: According to EGFR mutation status

EGFR wild type

Trend in favor of docetaxelJY Douillard et al. JCO 2009

JY Douillard et al. JCO 2009

Selection criteria of 2nd line chemotherapy

• In unselected population: – Docetaxel ≅ Pemetrexed

• Prior therapy: Most important – Use non-cross resistant therapy

• Histology:– Pemetrexed: Non-squamous

• Molecular factors– EGFR mutant: EGFR TKI if not used in 1st line– EGFR wild: EGFR TKI is still a choice

Selection criteria of 2nd line chemotherapy

In unselected population: Pemetrexed ≅ Erlotinib (efficacy)

Prior therapy: Most important cross resistant therapy

squamous

EGFR mutant: EGFR TKI if not used in 1st lineEGFR wild: EGFR TKI is still a choice

ConclusionsConclusions

İKİN

Cİ B

ASAM

AK

Platin bazlı kombinasyon

İDAM

E T

ED

AVİ

Erlotinib Birinci basamakta EGFR TKI almadıysa

Erlotinib/Gefitinib Bİ

RİN

Cİ B

ASAM

AK Pemetrekset+cis

Skuamöz olmayan

EGFR MUTASYON (+) EGFR

Erlotinib EGFR Mutas (+)/ -/?

Dosetaksel

Önceki tedaviler, ECOG PS, histoloji

Sis/vinorelbin+ Setuksimab

Kemoterapi+ bevacizumab • Skuamöz

olmayan • Hemoptizi

yok

Diğer kemoterapi Karbo/Pacli Sis/gemsitabin Sis/Dosetaksel vb.

EGFR MUTASYON (-)/Bilinmeyen

Setuksimab

Bevacizumab Pemetrekset x4 Skuamöz olmayan

Pemetrekset Skuamöz olmayan

Erlotinib EGFR +/-/?

tedaviler, ECOG PS, histoloji bakı larak karar verilir.

Not all NSCLC is the same: Distinct subtypes

Etiology– Never-smoker– Smoker

Histologically– Adenocarcinoma (including BAC)– Squamous– Other

Molecularly– EGFR mutant – EGFR wild type

• EML4-ALK mutant• K-ras mutant• EML4-ALK and k-ras wild

Not all NSCLC is the same: Distinct subtypes

Adenocarcinoma (including BAC)

Individualized therapy

Two factors already relevant• Etiology • Histology

Two factors that will increasingly direct• Genetic profile• Biologic markers

Individualized therapy

already relevant to choice of treatment

increasingly direct treatment

Barriers to individualized treatment

• Limited avalability of tissue

• Delay of several weeks before obtaining mutational status

• Limited # of labs

• EGFR status may change during the course of disease

• Cost of tests and therapies

Barriers to individualized treatment

Limited avalability of tissue

Delay of several weeks before obtaining mutational

EGFR status may change during the course of disease

Cost of tests and therapies

Thank youThank you