management of nsclc

David R. Gandara, MDProfessor of Clinical MedicineUniversity of California Davis Cancer CenterDavis, California

Therapeutic Decision Making in Advanced NSCLC:A 2012 Perspective

This program is supported by educational grants from

clinicaloptions.com/oncologyTherapeutic Decision Making in Advanced NSCLC: A 2012 Perspective

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David R. Gandara, MD, has disclosed that he has received research grants from Bristol-Myers Squibb, Genentech, ImClone, Eli Lilly and Company, Merck, and Novartis; served as consultant for Amgen, Array, AstraZeneca, Biodesix, Boehringer-Ingelheim, Bristol-Myers Squibb, Genentech, ImClone, Merck, Novartis, Response Genetics, and sanofi-aventis.

Faculty Disclosure


Histology Maintenance

Predictive Biomarkers

Factors are interlinking and not independent

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Major Themes in Therapy of Advanced NSCLC 2012: Interrelationships Among Histology, Maintenance Therapy, and Predictive Biomarkers


Patients With the Same Diagnosis and Clinical Features (Stage IV NSCLC)

65-yr-old malesmoker,

squamous

KRAS Mt

Interpatient Heterogeneity in the Molecular Characteristics of NSCLC

In 2012: Most oncologists would agree that these patients have very different malignancies

Most oncologists would agree that these patients should receive different therapy



39-yr-old female

never-smoker,adenoca

EGFR Mt





squamous

KRAS Mt


ALK fusion

54-yr-old malenever-smoker,

adenoca





39-yr-old female

never-smoker,adenoca

EGFR Mt


squamous

KRAS Mt


CCO survey. 2012.

Nonsquamous Histology

Molecular Marker Status: EGFR Mutation Positive, ALK Fusion Negative

*Assume “standard risk” patient (no hemoptysis, no brain mets, no severe comorbidities that would alter decision making).†Assume patient has had a PR to first-line therapy and now has a PS of 0 and is asymptomatic.

Therapy Choices

Targeted therapyT0. No targeted therapyT1. BevacizumabT2. CetuximabT3. Erlotinib T4. Crizotinib

PlatinumP0. No platinumP1. CisplatinP2. Carboplatin

Nonplatinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide

Age , Yrs

Zubrod PS Smoking History

Your Treatment Recommendations

Primary Patient Desire: Response and Survival

Primary Patient Desire: QoL and Low Risk for AEs

First line* Maintenance† First line* Maintenance†

Younger than 70 0, 1 Never/former light

T0P0C0

T0P0C0

T0P0C0

T0P0C0

Younger than 70 0, 1 Former heavy/current

T0P0C0

T0P0C0

T0P0C0

T0P0C0

Younger than 70 2 Never/former light

T0P0C0

T0P0C0

T0P0C0

T0P0C0

Younger than 70 2 Former heavy/current

T0P0C0

T0P0C0

T0P0C0

T0P0C0

70 or older 0, 1 Never/former light

T0P0C0

T0P0C0

T0P0C0

T0P0C0

70 or older 0, 1 Former heavy/current

T0P0C0

T0P0C0

T0P0C0

T0P0C0

70 or older 2 Never/former light

T0P0C0

T0P0C0

T0P0C0

T0P0C0

70 or older 2 Former heavy/current

T0P0C0

T0P0C0

T0P0C0

T0P0C0


Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Algorithm for Therapy of Advanced-Stage NSCLC: 2009

*Docetaxel, paclitaxel, vinorelbine.

Molecular Clinical (PS)

Progression

Clinical

Histologic

Second

line

First line

Ma

inte

na

nce

Bevacizumab or erlotinib or pemetrexed

Pemetrexed or erlotinib Erlotinib Based on previous

therapy

Chemotherapy by algorithm

Based on previous therapy

Based on previous therapy Based on previous therapy

End of first-line chemotherapy

Platinum/pemetrexed (or other*) ± bevacizumab

Platinum/pemetrexed (or other*)

Platinum/gemcitabine (or other*)

Bevacizumab eligible

Bevacizumab ineligible

Single-agent chemotherapy

SquamousNonsquamousErlotinib

EGFR mutation positive Good PS POOR PS

Proposed Treatment Algorithm


Advanced-Stage NSCLC & PS 0-1

EFGR mutation and ALK negative and nonsquamous

histology

EFGR mutation and ALK negative and squamous

histology

Bevacizumab appropriate

Bevacizumab inappropriate

EGFR mutation positive

Erlotinib or gefitinibfirst line

Consider crizotinib first or second line

ELM4-ALK positive

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.

Proposed Treatment Algorithm for Advanced NSCLC: First-line Therapy 2012

Consider carboplatin/paclitaxel +

bevacizumab or

cisplatin/pemetrexed± bevacizumab

Considercisplatin or carboplatin

combined with docetaxel or

gemcitabine or paclitaxel

orcisplatin/vinorelbine

± cetuximab


combined with pemetrexed, docetaxel

or gemcitabine or paclitaxel


± cetuximab


Molecular

Advanced-Stage NSCLC & PS 0-1


histology


histology






ELM4-ALK positive

Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.



bevacizumab or

cisplatin/pemetrexed± bevacizumab





± cetuximab





± cetuximab

Histology: Clinical


Histology Maintenance Therapy






Observation: Differential efficacy of pemetrexed in squamous vs nonsquamous subtypes of NSCLC

JMDB: Pemetrexed/cisplatin vs gemcitabine/cisplatin in first-line therapy of advanced NSCLC[1]

JMEI: Pemetrexed vs docetaxel in second-line therapy of advanced NSCLC[2]

JMEN: Pemetrexed vs placebo as maintenance therapy of NSCLC[3]

1. Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.2. Otani S, et al. Gan To Kagaku Ryoho. 2012;39:59-62.3. Greenhalgh J, et al. Health Technol Assess. 2010;14(suppl 2):33-39.

Hypothesis: Treatment of NSCLC Should Be Histology Based


No difference in overall PFS or survival between study arms

Cis/Pem improves survival over CG in non-SCCA (HR: 0.81; P = .005)

Cis/Gem improves survival over CP in SCCA (HR: 1.23; P = .05)

Scagliotti GV, et al. J Clin Oncol. 2008;26:3543-3551.

JMDB Trial: Cisplatin/Pemetrexed vs Cisplatin/Gemcitabine in Advanced NSCLC

0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0

Survival Time (Mos) in All Patients

Su

rviv

al

Pro

bab

ilit

y

CPCG

CP vs CG

Median (95% CI)10.3 (9.8-11.2)10.3 (9.6-10.9)

Adjusted HR (95% CI)0.94 (0.84-1.05)

0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0

Survival Time (Mos) in All PatientsWith Nonsquamous Histology

Su

rviv

al

Pro

bab

ilit

y

CPCG

CP vs CG

Median (95% CI) 11.8 (10.4-13.2)10.4 (9.6-11.2)

Adjusted HR (95% CI)0.81 (0.70-0.94)

0 6 12 18 24 300.10.20.30.40.50.60.70.80.91.0

Survival Time (Mos) in All Patients

Su

rviv

al

Pro

bab

ilit

yCPCG

CP vs CG

Median (95% CI) 9.4 (8.4-10.2)10.8 (9.5-12.1)

Adjusted HR (95% CI)1.23 (1.00-1.51)


SWOG Database Analysis of Taxane/Vinca- Based Therapy in Adv NSCLC by Histology N = 741

S9806, S0003, and CDDP/vin arm of S9308

No difference in any efficacy outcome by histology

Histology N (%)

OS PFS

Median, Mos Adjusted HR* Median, Mos Adjusted HR*

Adeno 424 (57) 8.5 1.00 (referent) 4.3 1.00 (referent)

SCCA 128 (17) 8.4 0.987 (P = .89)† 4.5 0.986 (P = .89)‡

Large cell 82 (11) 7.9 0.974 (P = .83) 4.2 1.03 (P = .81)

NSCLC, NOS 107 (14) 9.6 0.971 (P = .79) 5.0 0.87 (P = .20)

*HR from Cox proportional hazards model with adenocarcinoma as referent, adjusted for sex. †HR for SCCA vs all others combined, OS: 0.995 (95% CI: 0.82-1.21; P = .96). ‡HR for SCCA vs all others combined, PFS: 1.01 (95% CI: 0.83-1.22; P = .94)

Chansky K, et al. IASLC WCLC 2009. Abstract B2.7


Scagliotti G, et al. J Thorac Oncol. 2009;4:1568-1571.

Histology Not a Predictor of Survival From Antimicrotubule or Gem.-Based Therapy

0 6 12 18 24 360

0.2

0.4

0.6

0.8

1.0

OS (Mos)

Pro

po

rtio

n S

urv

ivin

g

30

All Patients (N = 607)

AdenoOther

Large cellSquamous

0 6 12 18 24 360

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g

30

PC Patients (n = 201)

AdenoOther

Large cellSquamous

OS (Mos)

0 6 12 18 24 360

0.2

0.4

0.6

0.8

1.0

OS (Mos)

Pro

po

rtio

n S

urv

ivin

g

30

VC Patients (n = 201)

AdenoOther

Large cellSquamous

0 6 12 18 24 360

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n S

urv

ivin

g

30

GC Patients (n = 205)

AdenoOther

Large cellSquamous

OS (Mos)


Histology Will Be Suboptimal for Selecting Chemotherapy (or Targeted Therapy) Histologic subtyping groups tumors based on microscopic

pattern recognition by a pathologist (using 1800s’ technology)

At best, histology = “crude molecular selection”

Molecular ProfilingMolecular ProfilingVan LeeuwenHoek


Squamous

Small Cell

Adenocarcinoma

Normal lu

ng

TS

SCLC: highest TS Squamous: high TS Adeno: low TSBhattacharjee A, et al. Proc Natl Acad Sci U S A.

2001;98:13790-13795.

Thymidylate Synthase Expression in Lung Cancer


TS mRNA Results by Histology (N = 1671):Squamous vs Adenocarcinoma

Biomarker NSCLC: Total (N = 1671)

NSCLC: SCCA (n = 316)

NSCLC: AC (n = 649)

SCCA vs AC P Value

TS Median 2.71 4.1 2.5 < .001*

Range 0.14-68.0 0.14-59.3 0.39-68.0 *Mann-Whitney test

TS (Reference < 2.33 for Pemetrexed)

% Below Reference Level

NSCLC: total 41.3

NSCLC: adenoca 45.7

NSCLC: SCCA 25.9

Gandara DR, et al. ASCO 2010. Abstract. 7513.

1412

10

TS 8

6

420

AC SCCA




Factors are Interlinking and not independent




Platinum-based doublet chemotherapy:4 cycles of “induction”

eg, cisplatin + agent “A”

Platinum-based doublet chemotherapy:4 cycles of “induction”

eg, cisplatin + agent “A”

Same agent “A” until PD or toxicity

Different agent “C” until PD or toxicity

Continuation maintenanceContinuation maintenance

Switch maintenanceSwitch maintenance

Maintenance Therapy Terminology:“A Rose by Any Other Name”?


Agent/Control Arm N PFS Salvage Treatment,

%

OS

Fidias[1] DocetaxelDelayed docetaxel

309 5.7 mos HR: 0.632.7 mos P = .001

63 12.3 HR: 0.809.7 P = .085

Ciuleanu[2] PemetrexedPlacebo

663 4.0 mos HR: 0.502.6 mos P < .0001

67 13.4 HR: 0.7910.6 P = .012

Cappuzzo[3] ErlotinibPlacebo

889 12.3 wks HR: 0.7111.1 wks P < .0001

72 12.0 HR: 0.8111.0 P = .0088

Miller[4] Erlotinib + bevacizumabPlacebo + bevacizumab

768 4.8 mos HR: 0.723.8 mos P = .001

55.5 15.9 HR: 0.9013.9 P = .2686

Perol[5] ErlotinibObservation

310 2.9 mos HR: 0.821.9 mos P = .002

81.9 NA HR: .91NA

Zhang[6] GefitinibPlacebo

296 4.8 mos HR: 0.422.6 mos P < .0001

58.8 18.7 HR: .8416.9 P = .2608

1. Fidias P, et al. J Clin Oncol. 2010;28:5116-5123. 2. Ciuleanu T, et al. Lancet. 2009;374:1432-1440.3. Cappuzzo F, et al. Lancet Oncol. 2010;11:521-529. 4. Miller VA, et al. ASCO 2009. Abstract LBA8002.5. Perol M, et al. ASCO 2010. Abstract 7507. 6. Zhang L, et al. ASCO 2011. Abstract LBA7511.

Summary of “Switch Maintenance” Trials


Study Yr Induction Therapy Maintenance Therapy Median PFS, Mos

Median OS, Mos

Main Grade 3/4 Toxicities

Brodowicz[1] 2006 Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4

Gemcitabine 1250 mg/m2 on Days 1,8

BSC

6.6

5.0(P < .001)

13.0

11.0

Maintenance Gem: ANC 14.9%, Plts 1.7%; blood transfusion: 20% gemcitabine vs 6.3% BSC

Belani[2] 2010 Gemcitabine 1000 mg/m2 on Days 1, 8 + carboplatin AUC 5 on Day 1 x 4

Gemcitabine 1000 mg/m2

on Days 1,8

BSC

7.4

7.7(P = .575)

8.0

9.3(P = .838)

ANC: 15% chemo, 2% BSC; Plts: 9% chemo, 4% BSC; fatigue: 5% chemo, 2% BSC

Perol[3] 2010 Gemcitabine 1250 mg/m2 on Days 1, 8 + cisplatin 80 mg/m2 on Day 1 x 4

Gemcitabine 1000 mg/m2 on Days 1,8

BSC

3.8

1.9(P < .0001)

NR

NR

At least 1 grade 3/4 AE: chemotherapy 27.9%, observation 2.6%

Paz Ares[4] 2011 Pemetrexed 500 mg/m2 on Day 1 + cisplatin 75 mg/m2 on Days 1 x 4

Pemetrexed 500 mg/m2 on Day 1

BSC

4.1

2.8(P

= .00006)

NR

NR

Fatigue: 4.2% pem, 0.6% BSC; Anemia: 4.5%, 0.6% BSC; ANC: 3.6% pem, 0 BSC

1. Brodowicz T, et al. Lung Cancer. 2006;52:155-163. 2. Belani CP, et al. ASCO 2010. Abstract 7506.3. Perol M, et al. ASCO 2010. Abstract 7507. 4. Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.

Continuation Maintenance Trials


Pemetrexed: median 3.9 mos (3.0-4.2)Placebo: median 2.6 mos (2.2-2.9)Log-rank P = .0002Unadjusted HR: 0.64 (0.51-0.81)

Pem + BSC

Paz-Ares LG, et al. ASCO 2011. Abstract CRA7510.

PARAMOUNT: Continuation Pemetrexed Maintenance

Su

rviv

al P

rob

abil

ity

Mos

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15

Placebo + BSC

Independently Reviewed PFS From Maintenance


“Maintenance Therapy”: Options After Platinum-Based Therapy With Non-PD

R4 (~ 6) cycles chemo stop Watch and wait

Continue same chemo “Continuation maintenance”

RDifferent chemo or another drug Early second-line therapy

R4 (~ 6) cycles chemo stop Watch and wait

Different chemo or another drug “Switch maintenance”

4 (~ 6) cycles chemo Stop Watch and wait

Options: bevacizumab, cetuximab, pemetrexed

Options: docetaxel, pemetrexed, erlotinib/gefitinib

Who decided that 4 cycles of therapy is optimal?

Gandara DR. Best of ASCO 2011.

Watch & Wait vs Maintenance/ Consolidation/Sequencing


The big question about maintenance therapy is WHO to treat and WHEN to treat

How do these trials relate to the patients I am treating in my office?

If 6 cycles of platinum chemotherapy are given, are the maintenance data still relevant?

If a patient achieves no response (SD) and remains symptomatic, is subsequent therapy “maintenance” or “early second-line therapy”?

If a patient achieves response and becomes asymptomatic, is “maintenance therapy” always better than “watch and wait”?

What about the underlying molecular profile of the individual patient?

In the emerging era of personalized therapy, these decisions should be made on an individual basis: “One size does not fit all”

Gandara DR. Best of ASCO 2011.

Issues to Consider Regarding Maintenance Therapy


Histology Maintenance








Looking Forward to 2015:Moving From Empiric to Individualized

From “One Size Fits All” to “Tailored” and “Individualized” Therapy



Tailored and individualized therapy

Empiric therapy

Gandara DR, et al. Clin Lung Cancer. 2009;10:148-150.

Transition From Empiric to Tailored and Transition From Empiric to Tailored and Individualized Cancer TherapyIndividualized Cancer Therapy



39-yr-old femaleNever-Smoker,

Adenoca

EGFR Mt



CCO survey. 2012.



*Assume “standard risk” patient (no hemoptysis, no brain mets, no severe co-morbidities that would alter decision-making)**Assume patient has had a partial response to first-line therapy and now has a performance score of 0 and is asymptomatic

Therapy choices



Non-platinum chemotherapyC1. PaclitaxelC2. DocetaxelC3. GemcitabineC4. VinorelbineC5. PemetrexedC6. Etoposide

Age (years)



Primary patient desire: Response and Survival

Primary patient desire: QOL and Low-Risk for AEs

First line* Maintenance** First line* Maintenance**

< 70 0,1 Never/Former LightT0P0C0

T0P0C0

T0P0C0

T0P0C0

< 70 0,1 Former Heavy/CurrentT0P0C0

T0P0C0

T0P0C0

T0P0C0

< 70 2 Never/Former LightT0P0C0

T0P0C0

T0P0C0

T0P0C0

< 70 2 Former Heavy/CurrentT0P0C0

T0P0C0

T0P0C0

T0P0C0

≥ 70 0,1 Never/Former LightT0P0C0

T0P0C0

T0P0C0

T0P0C0

≥ 70 0,1 Former Heavy/CurrentT0P0C0

T0P0C0

T0P0C0

T0P0C0

≥ 70 2 Never/Former LightT0P0C0

T0P0C0

T0P0C0

T0P0C0

≥ 70 2 Former Heavy/CurrentT0P0C0

T0P0C0

T0P0C0

T0P0C0


CCO survey. 2012.



Therapy choices




Age (years)





First line* Maintenance** First line* Maintenance**


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


T3P0C0

T3P0C0

T3P0C0


Lynch TJ, et al. N Engl J Med. 2004;350:2129-2139.

EGFR Mutations and Responsiveness to Gefitinib in NSCLCPatient No.

Sex Age at Beginning of Gefitinib Therapy, Yr

Pathological Type

Previous Regimens,

n

Smoking Status

Duration of Therapy,

Mos

OS, Mos EGFR Mutation

Response

1 F 70 BAC 3 Never 15.6 18.8 Yes Major; improved lung lesions

2 M 66 BAC 0 Never > 14.0 > 14.0 Yes Major; improved bilateral lung

lesions

3 M 64 Adeno 2 Never 9.6 12.9 Yes Partial; improved lung lesions and soft-tissue mass

4 F 81 Adeno 1 Former > 13.3 > 21.4 Yes Minor; improved pleural disease

5 F 45 Adeno 2 Never > 14.7 > 14.7 Yes Partial; improved liver lesions

6 M 32 BAC 3 Never > 7.8 > 7.8 Yes Major; improved lung lesions

7 F 62 Adeno 1 Former > 4.3 > 4.3 Yes Partial; improved liver and lung

lesions

8 F 58 Adeno 1 Former 11.7 17.9 Yes Partial; improved liver lesions

9 F 42 BAC 2 Never > 33.5 > 33.5 No Partial; improved lung nodules


Trial/Patient Group

N

Median PFS, Mos OS, Mos

Gefitinib Erlotinib

Chemo HR(95% CI)

Gefitinib Erlotinib

Chemo

Selected by Clinical Factors

I-PASS[1] East Asian, light/nonsmoker,

adeno

261 10.7 6.0 0.35 (0.23-0.52)

21.6 21.9

First-SIGNAL[2] Korean, nonsmoker, adeno

42 8.4 6.7 0.613 (0.31-1.22)

30.6 26.5

Selected by Molecular Parameter

NEJ002[3] Japan, EGFR mutant

194 10.4 5.5 0.35(0.25-0.50)

28.0 23.6

WJTOG3405[4] Japan, EGFR mutant

172 9.2 6.3 0.48 (0.33-0.71)

30.9 NR

OPTIMAL[5] China, EGFR mutant

154 13.1 4.6 0.16 (0.1-0.26)

NR NR

Spain[6] Spain, EGFR mutant

217 14.0 27.0

1. Fukuoka M, et al. J Clin Oncol. 2011;29:2866-2874. 2. Lee JS, et al. WCLC 2009. Abstract PRS.4. 3. Maemondo M, et al. N Engl J Med. 2010;362: 2380-2388. 4. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 5. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 6. Rosell R, et al. N Engl J Med. 361:958-967.

EGFR TKIs vs Chemotherapy as First-line Therapy


Carboplatin + Paclitaxel

Gefitinib

Primary EndpointPFS (noninferiority)

Secondary EndpointsObjective response rateOS Quality of lifeDisease-related symptoms Safety and tolerability

ExploratoryBiomarkers

–EGFR mutation–EGFR gene copy number–EGFR protein expression

Patients Chemo naive 18 yrs of age or

older Adenocarcinoma

histology Never or ex-light

smokers* Life expectancy

≥ 12 wks WHO PS 0-2 Measurable stage

IIIB/IV disease

Conducted in China, Japan, Thailand, Taiwan, Indonesia, Malaysia, Philippines, Hong Kong, and Singapore

94% never-smokers; ~ 80% femaleMok TS, et al. N Engl J Med. 2009;361:947-957.

IPASS: Importance of EGFR Mutation on Patient Outcome—Gefitinib vs Chemo


EGFR Mutation Positive EGFR Mutation Negative

Treatment by subgroup interaction test, P < .0001

HR: 0.48 (95% CI: 0.36-0.64; P < .0001)

Gefitinib events , n (%) 97 (73.5)C/P events, n (%) 111 (86.0)

Gefitinib (n = 132)Carboplatin/paclitaxel (n = 129)

HR: 2.85 (95% CI: 2.05-3.98; P < .0001)

Gefitinib events, n (%) 88 (96.7)C/P events, n (%) 70 (82.4)

0 4 8 12 16 20 240

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

of

PF

S

0 4 8 12 16 20 240

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

of

PF

S

Gefitinib (n = 91)Carboplatin/paclitaxel (n = 85)

Mos Mos

Clinical characteristics are insufficient for selection of first-line EGFR TKI therapy

Front-line EGFR TKI should be restricted to EGFR mutation–positive patients

Mok TS, et al. N Engl J Med. 2009;361:947-957.

IPASS: PFS in EGFR Mutation–Positive and –Negative Patients


Mos

Su

rviv

al D

istr

ibu

tio

n F

un

ctio

n

1.00

0 6 12 18 24 30

0.75

0.50

0.25

0

ErlotinibPlacebo

HR: 0.73 (95% CI: 0.61-0.86*; P < .001†)4.7 mos

6.7 mos

BR.21 results not explained by EGFR mutation alone BR.21 survival primarily the results of increased SD and increased disease control rate This represents largely a “cytostatic effect” in patients with

EGFR wild-type cancers This disease control rate effect may also be true for

cetuximab in NSCLC (FLEX and S0342 trials)

Shepherd FA, et al. N Engl J Med. 2005;353:123-132.

*From Cox regression model.†From 2-sided log-rank test.

BR.21 (Erlotinib vs Placebo): OS


Cytotoxic vs Cytostatic Effects of EGFR TKIs (Erlotinib) in NSCLC Cytotoxic effects (apoptosis) primarily seen in EGFR Mt+ cancers (objective response)

Cytostatic effects (growth arrest) predominate in EGFR wild-type cancers (RECIST SD; disease control rate)

Gandara DR ,et al. Clin Lung Cancer. 2009;10:148-150. Gandara DR ,et al. J Thoracic Oncol. 2010;5:1933-1938. Jänne PA ,et al. Clin Cancer Res. 2006;12:4416s-4420s.

A549 H1666 H32550

5

10

20

25

30

Per

cen

t A

po

pto

sis

15

ControlGefitinib



ALK fusion

54-yr-old malenever-smoker,

adenoca



CCO survey. 2012.


Molecular Marker Status: EGFR Mutation Negative, ALK Fusion Positive

Therapy choices




Age (years)





First line Maintenance** First line Maintenance*


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


T4P0C0

T4P0C0

T4P0C0


EML4-ALK frequency:~ 4% (64/1709)

Primarily in adenocarcinoma More common in younger patients More common in never-smokers

(~ 20%)

EML4-ALK frequency:~ 4% (64/1709)

Primarily in adenocarcinoma More common in younger patients More common in never-smokers

(~ 20%)

Soda M, et al. Nature. 2007;448:561-566.

EML4-ALK Translocations in NSCLC

EML4

EML4-ALK variant 1

ALK1 1058 1620

10591

1 496 981HELP

TM

Kinase

WDBasic

496


ALK-Positive NSCLC and Impact of ALK Inhibition

ALK Rearrangement in NSCLC

Rarely overlaps with EGFR and KRAS mutations

Clinical testing

– Break-apart FISH assay (FDA-approved test)

– IHC

– RT-PCR

Activity of ALK Inhibitor Crizotinib in Patients With Advanced ALK-FISH–

Positive NSCLC (N = 82)

Shaw AT, et al. ASCO 2011. Abstract 7507.Shaw AT, et al. ASCO 2011. Abstract 7507.



squamous

KRAS Mt




CCO survey. 2012.

Squamous Histology

Molecular Marker Status: EGFR Mutation Negative, ALK Fusion Negative

Therapy choices




Age (years)





First line Maintenance* First line Maintenance*


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


T2P0C0

T2P2C1

T2P0C0


Advanced-Stage NSCLC and PS 0-1


histology


histology






ELM4-ALK positive

Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.Adapted from Gandara DR, et al. Clin Lung Cancer. 2009;10:392-394.



bevacizumab Or

cisplatin/pemetrexed± Bevacizumab





± cetuximab

Consider cisplatin or carboplatin




± cetuximab


Cetuximab + Cisplatin + Vinorelbine

(n = 550)

Cisplatin + Vinorelbine(n = 550)

Stage IIIB or IV EGFR positive

Survival

Eligibility criteria: EGFR-expressing, advanced-stage NSCLC; no previous CT

Primary endpoint: median OS (845 events needed)

Secondary endpoints: survival rate (1 and 2 yrs), PFS rate (6 and 12 mos), response rate, safety, QoL

Sample size: 1100 in 170 centers in EU, Latin America, Asia

R

Pirker R, et al. Lancet. 2009;373:1525-1531. Pirker R, et al. WCLC 2011. Abstract O-01.06.

FLEX: Chemotherapy ± Cetuximab in First-line Therapy of Advanced NSCLC



FLEX: Response and OS by IHC Score

6Mos

0

2040

OS

(%

)

60

P = .36

CT + cetuximabCT

Treatment interaction test P = .040

P = .002

O’Byrne et al. JPO 20120,12 (suppl), S558 (LBOAI)

Interaction P = .044

CT + cetuximabCT

FLEX: Response Rate by EGFR Expression Levels(IHC Score)

Low EGFR Expression (< 200), n = 776 (69%)

High EGFR Expression (≥200), n = 345 (31%)

28.1

44.4

0 12 18 24 30

80100

Low EGFR High EGFR

HR: 0.99 (95% CI: 0.84-1.16)

HR: 0.73 (95% CI: 0.58-0.93)

Predictive Value of High EGFR for Survival Benefit With CT + Cetuximab

Mos

29.6 32.6


Pts at Risk, n

CT 69 42 2 017 7CT + cetuximab 75 52 10 032 19

OS

(%

)

Mos

0

20

40

60

80

100

180 6 12 24 30

SurvivalMedian, Mos 1 Yr, %

11.2 44

8.9 25


FLEX Survival: High EGFR ExpressionSquamous Cell Carcinoma (N = 144)

HR: 0.62 (95% CI: 0.43-0.88)

▬ CT▬ CT + cetuximab


ClinicalTrials.gov. NCT00946712. PI: R. Herbst

Marker testing

Marker +

Marker -

Chemo

Chemo/Cetux

Chemo

Chemo/Cetux

Stratify Randomize

M+

M+

M-

M-

Chemotherapy: Paclitaxel/Carboplatin

Primary endpoints: OS for entire studyPFS for EGFR FISH

Integrated: EGFR IHC score

S0819: Chemotherapy ± Cetuximab and Predictive Biomarker Validation EGFR FISH


MET AMP

Gene Event Type Frequency, %

FGFR1 Amplification 20-25

FGFR2 Mutation 5

PIK3CA Mutation 9

PTEN Mutation deletion 18

CCND1 Amplification 8

CDKN2A Deletion/mutation 45

PDGFRA Amplification mutation

9

EGFR Amplification 10

MCL1 Amplification 10

BRAF Mutation 3

DDR2 Mutation 4

ERBB2 Amplification 2

Emerging “Druggable” Targets in NSCLC-Squamous SubtypeLung Cancer Molecular Lung Cancer Molecular

ConsortiumConsortium Lung AdenocarcinomasLung Adenocarcinomas

Mutations found in 54% (280/516)

Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01

Hammerman P, et al. IASLC WCLC 2011. Abstract PRS.1

Potential “Druggable” Molecular Targets?

No MutationDetected KRAS

22%

EGFR17%

NRAS

DoubleMutants 3%

AKT1

BRAF 2%

MEK1

HER2PIK3CA 2%

EML4-ALK7%


CASTLE Network

CASTLE BiospecimensSerumRNA/DNA

Biorepository

Genomics/Proteomics/Clinical Outcomes

Core Biopsy

Biorepository

ResponseDXTM

ERCC1 gene expressionRRM1 gene expressionKRAS mutation analysisEGFR amplificationTS expression

EGFR-TKI:a) candidate

orb) contraindicated

RNA DNA

Plasma

Submissions SubmissionVeriStrat ®

clinical

research

ALCMI (Addario Lung Cancer Medical Institute)

Moving Toward 2015: CASTLE Network


Lung Cancer Therapy: 2012 Looking Forward to 2015 We are making progress

– Histology

– Maintenance therapy

– Predictive biomarkers

Progress requires continuing change

– “Culture change”

– Requirement for more tumor tissue (molecular profiling)

– “Ungroup” NSCLC into individual patients (personalized therapy)

Reality: the transition to rationally selected and personalized therapy is challenging

– In every challenge, there are opportunities

– We must take advantage of each of these opportunities if we are to advance the care and cure of patients with lung cancer

Go Online for More CCO Coverage of Advanced Lung Cancer!

clinicaloptions.com/oncology

Interactive Decision Support Tool: With just a few clicks through pulldown menus, this Interactive Decision Support Tool allows users to enter their patients’ specific characteristics along with the treatment options they would likely choose and then provides expert insight from 5 lung cancer experts regarding optimal choices for first-line and maintenance therapy for advanced NSCLC.

http://www.clinicaloptions.com/oncology

management of nsclc

Documents

therapeutic

clin lung

egfr mutation

large cell

adenoca alk

adenoca egfr

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