Histologic Distinctions in the Management of Non-Small ... · PDF fileManagement of Non-Small...

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A Collabora)ve Prac)ce Approach to Managing Pa)ents With Advanced

Non-‐Small Cell Lung Cancer Clarifying the Selec)on of Newer Treatment Op)ons

Corey Langer, MD, FACP Beth Eaby-Sandy, CRNP, OCN®

Abramson Cancer Center University of Pennsylvania

Histologic Distinctions in the Management of Non-Small Cell Lung

Cancer

Corey Langer, MD, FACP

Disclosure

Dr. Langer discloses the following:

Grant/Research: Genentech, Merck, GSK, Nektar, Daiichi-Sankyo Scientific Advisor: Novartis, Genentech, Bayer/Onyx, Abraxis, Abbott,

Biodesix, Clarient, Caris Dx, Vertex, Synta, Celgene, Boehringer-Ingelheim

DSMC: Eli Lilly, Amgen, Synta, Peregrine

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Therapeutic Implications Histologic Prism

•  Tendency over past 25 years to “lump” non-small cell lung cancer (NSCLC) histologies – Little difference in treatment outcome

• Therapeutic empiricism –  Increasing NOS designation

•  Insufficient tissue • Pathologic “laziness”

ECOG 1594: Overall Survival by Treatment Group

•  1,207 pa)ents, stage IIIB/IV (15/85%), PS 0–2, median age 63, M/F (64%/36%)

Schiller, J. H., et al. (2002). N Engl J Med, 346(2), 92-98.

Personalized Therapy

•  Previous “one size fits all” approach •  Eclipsed by “personalized” or “patient-specific”

treatment – Histology – Molecular markers

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NSCLC

•  Adenocarcinoma – Glandular pattern – Mucin positivity (50%) – CK7+/CK20- – TTF-1+ (75%)

•  Squamous cell carcinoma – Cellular keratinization – Intercellular bridges – Keratin “pearl” formation – CK7-/CK20- – TTF-1 neg – P63+ p40+ CK5/6+

Common, but not 100%

WHO

Common, but not 100%

WHO

Emergence of Histology as Determinant of Therapy

•  Sandler: Paclitaxel-carboplatin +/- bevacizumab •  Scagliotti: Gem-DDP vs. pem-DDP •  Socinski: Nab-paclitaxel–carboplatin vs.

paclitaxel-carboplatin

ECOG 4599: Phase III Trial of Bevacizumab in Non-Squamous NSCLC

Sandler, A., et al. (2006). N Engl J Med, 355, 2542-2550.

Parameter PC PCB p value

RR (%) 15 35 <.001

PFS (mo) 4.5 6.2 <.001

Median survival (mo) 10.3 12.3 p = .003 1-year survival (%) 44 51

2-year survival (%) 15 23

PC Paclitaxel 200 mg/m2 Carbopla)n AUC 6 mg/m2 q3wk Eligibility

•  Non-‐squamous NSCLC •  No Hx of hemoptysis •  No CNS metastases

Stra)fica)on variables   RT vs. no RT   Stage IIIB or IV vs. recurrent   Wt loss < 5% vs. ≥ 5%   Measurable vs. nonmeasurable

No crossover to bevacizumab permitted

RT = radiotherapy PD = progressive disease

PCB Paclitaxel x 6 cycles + bevacizumab (15 mg/kg q3wk) to PD

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ECOG 4599 Adverse Events

*Pulmonary hemorrhagic events are included in the hemorrhagic events. **p < .05

Patients, %

Event PC

(n = 441) B/PC

(n = 427) GI perforation 0 0.9 Hemorrhage* (grade 3-5)1 1.1 4.7** Pulmonary hemorrhage2 0.5 2.3 Arterial thromboembolic events 1.4 3 Hypertension (grade 3/4) 0.7 8** Neutropenia and infection Neutropenia 17 27** Infection without neutropenia 3 7 Infection with neutropenia (grade 3/4) 2 4 Febrile neutropenia 2 5**

Treatment-related deaths (actual numbers) 2 15**

1Sandler, A. B., et al. (2006). N Engl J Med, 355, 2542-2550. 2Bevacizumab prescribing information, Genentech, 2008.

Advanced Stage IIIB/IV NSCLC First-Line Subsets

•  Bevacizumab-ineligible (~60%-70%) – Squamous histology – Brain metastases – Ongoing anticoagulation – Antecedent hemoptysis – Poor PS (2+)

•  Bevacizumab-eligible (~20%-30%) – Non-squamous

•  EGFR mutants (~10%) Socinski, M., et al. (2009). J Clin Oncol, 27, 5255-5261; Reck, M., et al. (2009). J Clin Oncol, 27, 1227-1234.

PASSPORT Study: Bevacizumab in Patients With Treated Brain Metastasis

Socinski, M., et al. (2009). J Clin Oncol. 27, 5255-5261.

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Median Survival (mo) 3 age cut-points

Age Cohort < 45 yr 45-59 yr ≥ 60 yr Women control 5.8 12.5 13.8 Women + BEV 16.8 15.5 12.8 Men control 3.4 9.5 8.5 Men + BEV 12.6 12.3 11.0

Wakelee, H., et al. (2012). Lung Cancer, 76, 410-415.

Conclusion: The only group that failed to have a conclusive benefit was women over 60.

Median Survival by Sex and Age With or Without Bevacizumab on E4599

Overall Survival in the Pooled Population of E4599 and POINT-BREAK

Unadjusted Kaplan-Meier estimates for OS among patients (A) < 75 years and (B) ≥ 75 years receiving PC + bevacizumab in the pooled population of E4599 and PointBreak relative to patients receiving PC alone in E4599

Langer, C., et al.,15th World Conference on Lung Cancer (WCLC), Sydney, 2013.

Pemetrexed and Histology: The Scagliotti Study

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Study Design

Gemcitabine 1250 mg/m2 days 1 + 8 Cispla)n 75 mg/m2 day 1

Stage IIIB/IV NSCLC

PS 0 -‐ 1

No prior chemo

Randomiza)on: gender, PS, stage, histo vs cyto dx, brain mets

Pemetrexed 500 mg/m2 + Cispla)n 75 mg/m2 day 1

Primary objec)ve: Overall survival

15% Non-‐inferiority margin (HR 1.17)

N = 1,700 pa)ents, power 80%

B12, folate, and dexamethasone given in both arms

Scagliotti, G. V., et al. (2008). J Clin Oncol, 26(21), 3543-3551.

Overall Survival: All Patients Cisplatin + Gemcitabine vs. Cisplatin + Pemetrexed

1.176 was non-inferiority margin Scagliotti, G. V., et al. (2008). J Clin Oncol, 26, 3543-3551.

months

Overall Survival in Patients With Nonsquamous Histology

Scagliotti, G. V., et al. (2008). J Clin Oncol, 26, 3543-3551. months

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What Op)ons Exist for NSCLC With Squamous Histology?

•  Gemcitabine •  Nab-paclitaxel •  Cetuximab •  Necitumumab •  Ipilimumab

Overall Survival in Patients With Squamous Cell Carcinoma

months Scagliotti, G. V., et al. (2008). J Clin Oncol, 26, 3543-3551.

Abstract 7511 Phase III Trial: Nab-paclitaxel–Carbo vs Carbo-Paclitaxel

Chemo-naive NSCLC

IIIB/IV

ECOG PS 0-1

Baseline peripheral neuropathy ≥ grade 2

N = 1,050

Nab-paclitaxel 100 mg/m2 d1, 8, 15 Carbo AUC 6 d1 No premeds

Paclitaxel 200 mg/m2 d1 Carbo AUC 6 d1 Premeds: dex, antihistamines

RANDOM I ZED

•  Stratification factors: stage IIIb vs. IV, age < 70 or ≥ 70, gender, histology (SCC vs. non-SCC), geography •  Primary endpoint: ORR •  Secondary endpoint: PFS, OS, DCR, safety (NCI CTCAE v3)

Socinski, M., et al. (2011). ASCO Abstract 7551; Socinski, M., et al. (2012). J Clin Oncol, 30, 2055-2062.

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Res

pons

e R

ate

(%)

Objective Responses by Histology*

p < .001 RR =1.680

p =.808 RR=1.034

* Not a pre-specified subgroup analysis

41%

26% 24% 25%

0

10

20

30

40

50 Ab-‐P/C P/C

Interac)on p value for histology: .036

Squamous Histology

Non-Squamous Histology


PFS: ITT Population

Prop

ortio

n N

ot P

rogr

esse

d

Months

Pt at risk Ab-P P

521 531

330 321

167 162

86 75

38 48

23 19

10 10

4 4

0 2

0 1

0 0

Ab-P/carboplatin (N=521) paclitaxel/carboplatin (N=531)

0 3 6 9 12 15 18 21 24 27 30 33 0.00

0.25

0.50

0.75

1.00 Ab-P/ Carbo

Paclitaxel/ Carbo HR

P value

N/Events 521/297 531/312

Median PFS (mo)*

6.3 5.8 0.902 0.214

95% CI 5.6-7.0 5.6-6.7 0.767-1.060

* PFS based on independent assessment

Overall Survival: ITT Population

Prob

abili

ty o

f Sur

viva

l

Months

Pt at risk Ab-P Pac

521 531

469 470

381 389

313 308

246 243

200 191

163 148

98 89

23 24

0 5

0 1

Ab-P/carboplatin (N=521) Paclitaxel/carboplatin (N=531)

0 3 6 9 12 15 18 21 24 27 30 33 0.00

0.25

0.50

0.75

1.00

0 0

Ab-P/Carbo

Paclitaxel/ Carbo HR P value

N/Events 521/360 531/384

Median OS (mo) 12.1 11.2 0.922 0.271

95% CI 10.8-12.9 10.3-12.6 0.797-1.066

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Secondary Endpoint: OS

Median OS (mo) Events / N HR ab-P/C P/C

744 / 1052

86 / 149 521 / 724 127 / 165 589 / 789 155 / 263 639 / 896 105 / 156 343 / 450 401 / 602 142 / 218 602 / 834

0.922 0.950 1.019 0.622 0.894 0.995 0.999 0.583 0.890 0.950 0.896 0.917

12.1 16.7 11.0 12.7 11.4 16.8 11.4 19.9 10.7 13.1 12.4 12.0

11.2 17.2 11.1 9.8

10.0 16.0 11.3 10.4 9.5

13.0 13.6 11.0

Favors ab-P/C


Paclitaxel + Carboplatin Show Significant Benefit in Pts ≥ 70 y/o With Advanced NSCLC

Phase III study in 451 patients 70-89 yo •  Arm A: Carboplatin AUC 6 every 4 weeks + paclitaxel 90 mg/m² (d1,8,15) Q 4wk vs •  Arm B: Single agent gemcitabine 1150 mg/m² or vinorelbine 30 mg/m², d1, d8

Conclusions: Paclitaxel + carboplatin provides a significantly longer survival in elderly patients with advanced NSCLC than current standard single-agent therapy, with acceptable toxicity

Parameter Arm A

Carbo + Pacl Arm B

Gem + Vin Median OS, mo 10.4 6.2 1 yr OS % 44 25 Median PFS, mo 6.3 3.2 Grade 3-4 hematologic tox 54.1% 17.9%

Quoix, et al. (2010). J Clin Oncol, 28(suppl), ASCO abstract; Quoix, et al. (2011). Lancet, 378, 1079-1088.

Chemotherapy-‐naive advanced NSCLC

Vinorelbine 25 mg/m2 d1,8

+ cispla)n 80 mg/m2 d1 q3wk

Phase III FLEX: Vinorelbine/Cisplatin ± Cetuximab in 1st-Line Advanced NSCLC

Primary endpoint: OS

Secondary endpoints: PFS, ORR, DCR, QoL, safety

n=557

n=568

Cetuximab 400 mg/m2 d1 wk1, then 250 mg/m2 qwk

+ vinorelbine 25 mg/m2 d1,8

+ cispla)n 80 mg/m2 d1 q3wk

RANDOMIZE

Up to 6 cycles of chemotherapy; patients not progressing continue on cetuximab maintenance

Pirker, R. et al. (2008). ASCO, oral presentation and abstract 3; Pirker, R., et al. (2009). Lancet, 373(9674), 1525.

Stra)fied by   IIIB or IV   ECOG PS 0,1

or 2

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*Including: large cell, adenosquamous, and undifferentiated carcinoma

Characteristic CT + Cetuximab (n=557)

CT (n=568)

Male/female, % 69/31 71/29 Median age, years (range) ≥ 65 years, %

59 (18–78) 31

60 (20–83) 32

ECOG PS, % 0 1 2

24 60 17

21 60 18

Stage, % IIIB wet IV

6 94

6 94

Histology, % Adenocarcinoma Squamous cell carcinoma Other*

46 34 20

49 33 18

Never smoker, % 22 22

Ethnicity, % Caucasian Asian Other

84 11 5

85 10 5

FLEX Patient baseline characteristics


FLEX Overall Survival

Months Pa)ents at risk CT + Cetuximab 557 383 251 155 53 3 CT 568 383 225 134 48 0

Overall Survival (%

)

p value = stratified log-rank test (2-sided)

Median OS 1-year survival

▬ CT + Cetuximab (n=557) 11.3 months 47 %

▬ CT (n=568) 10.1 months 42 %

HR=0.871 (95% CI 0.762–0.996), p=.044


Median OS (months)

CT + Cetuximab CT HR [95% CI] p value

All (n=1125) 11.3 10.1 0.871 [0.762–0.996]

.044

Caucasian (n=946)

Adenoca. (n=413)

SCC (n=347)

10.5 9.1 0.803 [0.694–0.928]

.003

12.0 10.3 0.815 [0.649–1.023]

.077

10.2 8.9 0.794 [0.626–1.007]

.057

Asian (n=121) 17.6 20.4 1.179 [0.730–1.905]

.499


FLEX: OS by Subgroups Ethnic Origin and Histology (ITT)

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High and Low EGFR Expression Low EGFR expression IHC score < 200

High EGFR expression IHC score ≥ 200

IHC score=270 IHC score=30 IHC score=0*

IHC, immunohistochemistry; *IHC score=7 for tumor overall

O’Byrne, K., et al. (2010). JTO, 12(suppl), S558 (LBOA1).

FLEX H Score Elevated Cohort (> 200)

Arm C225 Control Number 178 176 OR% 44* 28 PFS (mo) 5.0 4.4 Med survival (mo) 12** 9.6 1 yr OS% 50 37 2 yr OS% 24 15

* p = .002 **HR = 0.73, p = .011


Elevated Cohort (> 200) Breakdown by Histology

C225 Control Adenocarcinoma * MS (mo) 20.2 13.3 Arm 65 52 Squamous cell ca** MS (mo) 11.2 8.9 1 yr OS % 45 25

*HR = 0.72 **HR = 0.62


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Perspectives on First-Line Therapy Based on Histology

•  Based on E4599 and Scagliotti trials, use of Pemetrexed and Bevacizumab is limited to NON-squamous histology

•  Standard cytotoxic platform for Adenocarcinoma – Platinum plus either pemetrexed or taxane

•  Standard platform for Squamous cell carcinoma – Platinum plus either gemcitabine or taxane

Histologic Distinctions in the Treatment of NSCLC: Conclusions

•  Prognosis is generally inferior in squamous vs. non-squamous NSCLC

•  Gemcitabine appears superior to pemetrexed in the first-line setting in squamous NSCLC (in combination with cisplatin), while pemetrexed appears superior in non-squamous cell carcinoma

•  It is NOT safe to use bevacizumab in squamous NSCLC patients, its use should be limited to patients with non-squamous histology

Molecular Distinctions in the Management of

Non-Small Cell Lung Cancer

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Molecular Determinants of Treatment in NSCLC

•  EGFR mutation •  EML4/ALK •  ROS-1 •  KRAS (?) •  BRAF •  cMET •  ERCC1 and RRM1

Ac)onable

Possibly Ac)onable

An Evolving View of Adenocarcinoma Emergence of Molecular Markers

KRAS

2000

Pending

EGFR BRAF

PIK3CA

EML4-‐ALK

ROS1 HER2

2013

Lung Cancer Mutation Consortium Patients and Study Plan

1000 patients Stage IV ECOG PS 0-2 Lung Adenocarcinoma Sufficient Tissue (Paraffin) Informed Consent

Central Confirmation of Adenocarcinoma Diagnosis (1 slide)

Mutational Analysis CLIA-Certified lab at LCMC site: KRAS, EGFR, EML4-ALK, BRAF, HER2, PIK3CA, NRAS, MEK1, AKT1, MET amplification

Use Data to Select Therapy (Erlotinib with EGFR mutation)

Report to Physician

Report to LCMC Virtual Database

Recommend Clinical Trial of Agent Specific for Target NCI’s Lung Cancer Mutation Consortium (LCMC)

Kris, M. G., et al. (2011). J Clin Oncol, 29(18 suppl), Abstract CRA7506.

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Incidence of Muta)ons Detected

Muta)on found in 54% (280/516) of tumors completely tested (CI 50-‐59%)

Johnson et al on behalf of LCMC inves)gators, WLCC July 2011 Abstract O16.01. Kris et al on behalf of LCMC inves)gators, ASCO June 2011 Abstract #CRA7506.

Biomarkers (BM) France: Results Biomarkers Assessment (n=9911)

EGFR act mut 9.5% EGFR res mut

0.8%

HER2 mut 0.9%

KRAS mut 27%

BRAF mut 1.7%

PI3K mut 2.6%

ALK rearrangement

3.7%

UKN/Other 53.8%

Results expressed in % on available analyses

Barlesi , F., et al. (2013). J Clin Oncol, 31(suppl), abstract 8000.

Results: Biomarkers by Smoking Status (n=9911*)

33.2

3.1 9.6

1.8 9.7 3.6

3.8

35.2

Never smokers

EGFR activ EGFR resist KRAS BRAF ALK PI3K HER2 UNK

4.2 0.3 31.7

1.6 3.5 1.7 0.2

56.8

Smokers

* Including 2664 with full clinical data available at the time of this analysis.

Barlesi , F., et al. (2013). J Clin Oncol, 31(suppl), abstract 8000.

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Detecting EGFR Mutations in NSCLC

•  NSCLC patients with the somatic activation mutation of EGFR are hyper-responsive to EGFR TKIs

•  Most common NSCLC-associated EGFR mutations: – In-frame deletion in exon 19 (E746-A750del) – Point mutation in exon 21 (L858R)

•  These account for 85-90% of EGFR mutations •  Most other mutations, especially those on exon 20,

are associated with resistance to EGFR TKIs

Yu, et al. (2008). Molecular Markers Meeting, Abstract No 64.

6 FEB 2002 11 FEB 2002

NSCLC Pt Treated with an EGFR Inhibitor

IPASS Study Design

Gefitinib (250 mg/day)

N=609

Carboplatin (AUC 5 or 6) / paclitaxel (200 mg/m2) 3 weekly#

n=608

1:1 randomization

Never smokers = <100 cigarettes in lifetime; light ex-smokers = stopped ≥15 years ago and smoked ≤10 pack-years; #limited to a maximum of 6 cycles; carboplatin / paclitaxel was offered to gefitinib patients upon progression PS = performance status; EGFR = epidermal growth factor receptor.

Pa)ents • Chemonaive

• Age ≥ 18 years

• Adenocarcinoma histology • Never or light ex-‐smokers*

• Life expectancy ≥ 12 weeks

• PS 0-‐2

• Measurable stage IIIB / IV disease

Primary •  Progression-‐free survival (non-‐inferiority)

Secondary •  Objec)ve response rate •  Overall survival •  Quality of life •  Disease-‐related symptoms •  Safety and tolerability

Exploratory •  Biomarkers

•  EGFR muta)on •  EGFR-‐gene-‐copy number •  EGFR protein expression

• 

Endpoints

Mok, et al. (2009). N Engl J Med, 361, 947-957.

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Progression-Free Survival in ITT Population

609 453 (74.4%)

608 497 (81.7%)

N Events

HR (95% CI) = 0.741 (0.651, 0.845) p<0.0001

Gefitinib

Primary Cox analysis with covariates HR <1 implies a lower risk of progression on gefitinib

Carboplatin / paclitaxel

Carboplatin / paclitaxel

Gefitinib

Median PFS (months) 4 months progression-free 6 months progression-free 12 months progression-free

5.7 61% 48% 25%

5.8 74% 48% 7%

609 212 76 24 5 0 608 118 22 3 1 0

363 412

0 4 8 12 16 20 24 Months

0.0

0.2

0.4

0.6

0.8

1.0 Probability of PFS0

At risk :


Progression-Free Survival in EGFR Mutation Positive and Negative Patients (n=437)

EGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, p < .0001

HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001 No. events gefitinib, 97 (73.5%) No. events C / P, 111 (86.0%)

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

ITT population – Mutation rate ~60% Cox analysis with covariates

HR (95% CI) = 2.85 (2.05, 3.98) p<0.0001 No. events gefitinib , 88 (96.7%) No. events C / P, 70 (82.4%)

0 4 8 12 16 20 24 0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of p

rogr

essi

on-fr

ee s

urvi

val

0 4 8 12 16 20 24 0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of p

rogr

essi

on-fr

ee s

urvi

val

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

Months Months


Objective Response Rate in EGFR Mutation Positive and Negative Patients

Gefitinib Carboplatin / paclitaxel

EGFR M+ odds ratio (95% CI) = 2.75 (1.65, 4.60), p=0.0001

EGFR M- odds ratio (95% CI) = 0.04 (0.01, 0.27), p=0.0013

Overall response rate (%)

(n=132) (n=129) (n=91) (n=85)

Odds ratio >1 implies greater chance of response on gefitinib

71.2%

47.3%

1.1%

23.5%


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Impact on QOL


Gefitinib vs Chemotherapy in EGFR Mutated Tumors: A Prospective Study

Maemondo, et al. (2010). N Engl J Med, 362(25), 2380-2388.

Gefitinib

N=160

CBDCA + PAC n=169

Randomization balanced for institution, sex, stage

Pa)ents NSCLC with sensi)ve EGFR muta)ons • Stage IIIB , IV

• No prior chemo

• PS 0-‐1

• Age 20-‐75 y/o

Primary •  Progression-‐free survival

Secondary • Overall survival •  Objec)ve response rate • Safety and tolerability •  Quality of life

• 

Endpoints

Efficacy

Gefitinib Chemotherapy p value

N 98 100

Response rate 73.7% 30.7% <0.001

Median PFS 10.8 m 5.4 m <0.001

Median OS (mo) 30.5 23.8 0.31

Maemondo, et al. (2010). N Engl J Med, 362(25), 2380-2388.

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The 7503—EURTAC Trial: Erlotinib in First-Line Therapy

Primary endpoint •  Progression-free survival (PFS)

–  interim analysis planned at 88 events Secondary endpoints •  Objective response rate •  Overall survival (OS) •  Location of progression •  Safety •  EGFR mutation analysis in serum •  Quality of life

*Cisplatin 75mg/m2 d1 / docetaxel 75mg/m2 d1; cisplatin 75mg/m2 d1 / gemcitabine 1250mg/m2 d1,8; carboplatin AUC6 d1 / docetaxel 75mg/m2 d1; carboplatin AUC5 d1 / gemcitabine 1000mg/m2 d1,8

Patients - Chemonaive - Stage IIIB/IV NSCLC -EGFR exon 19 deletion or exon 21 L858R mutation - PS 0–2 (n=174)

R

Platinum-based doublet chemotherapy q3wk x 4 cycles*

PD

Erlotinib 150 mg/day PD

Stratification •  Mutation type •  ECOG PS (0 vs 1 vs 2)

*1,139 patients screened

Rosell, R., et al. (2012). Lancet Oncol, 13, 239-246.

Best Response Erlo)nib N=86

Chemotherapy N=87

ORR 58% 13%

Stable disease 79% 66%

Progressive disease 7% 11%

No response assessment 14% 19%

Response and PFS in the ITT


Overall Survival


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Randomized Studies of First Line EGFR TKI in Patients With EGFR Mutation (Through 2012)

Author Study N (EGFR mut +) RR Median PFS

(months)

Mok et al IPASS 261 71.2% vs 47.3 9.8 vs 6.4

Lee et al First-‐SIGNAL 42 84.6% vs 37.5% 8.4 vs 6.7

Mitsudomi et al WJTOG 3405 177 62.1% vs 32.2% 9.2 vs 6.3

Maemondo et al NEJGSG002 230 73.7% vs 30.7% 10.8 vs 5.4

Zhou et al OPTIMAL 154 83% vs 36% 13.1 vs 4.6

Rosell et al EURTAC 154 54.5% vs 10.5% 9.2 vs 5.4

1018 Mok, et al. (2009). N Engl J Med, 361, 947-957; Lee, et al. (2009). Proc IASL WCLC; Mitsudomi, et al. (2010). Lancet Oncol, 11, 121-128; Maemondo, et al. (2010). N Engl J Med, 362, 2380-2388; Zhou, et al. (2010). ESMO; Rosell, R., et al. (2012). Lancet Oncol, 13, 239-246.

Afatinib in EGFR Mutated NSCLC

•  N=129 patients •  Median PFS 10.1m •  Median OS 24.8 m

Yang, et al. (2012). Lancet Oncol, 13, 539-548.

LUX-Lung 3: Afatinib in Treatment-Naive Adenocarcinoma With EGFR Mutation • Randomized, open-label phase III trial with 2:1 randomization • Afatinib 40 mg/d vs chemo; pem [500 mg/m2] –DDP [75 mg/m2] • Projected: 2,200 screened for 330 enrolled • Actual: 1,269 patients screened; 345 were randomized • Demographics: 72% East Asian, 68% never-smokers; 65% female; Exon 19

deletions (49%) and L858R point mutations (40%) • Toxicities: rash, diarrhea, mucositis, xeroderma

Conclusions: • Afatinib superior to state-of-the-art chemo in EGFR mut (+) NSCLC wrt OR%,

PFS, and QoL (PROs) • Led to FDA approval in this setting on 8/13

Arm Afatinib Pem-DDP p value HR

OR % (independent eval) 56% 23% < .001 PFS (mo) 11.1 6.9 < .001 0.58 PFS (mo) Exon 19 del, pt mut exon 21 13.6 6.9 < .001 0.47

Sequist, L. V., et al. (2013). J Clin Oncol, 31(27), 3327-3334; Yang et al ASCO 2012. .

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Why Is LUX-Lung 3 Important? •  Largest trial in the first-line EGFR mutant setting (at the time) •  1st to use a 2nd generation irreversible EGFR TKI •  State-of-the-art comparator (pem-DDP) •  Global trial •  Registration trial

What are the outstanding questions? •  Survival data? •  How does afatinib stack up against 1st gen EGFR TKIs? With

respect to toxicity, OR% PFS? •  Can we predict who is more likely to benefit? Proteomics? •  Appropriate approach in more obscure mutations?

Randomized Studies of First-Line EGFR TKI in Patients With EGFR Mutations

Author Study N (EGFR

mut +)

RR Median PFS

(mo)







Yang et al LUX-‐Lung 3 345 56% vs 23% 13.6 vs 6.9

1363 Mok, et al. (2009). N Engl J Med, 361, 947-957; Lee, et al. (2009). Proc IASL WCLC; Mitsudomi, et al. (2010). Lancet Oncol, 11, 121-128; Maemondo, et al. (2010). N Engl J Med, 362, 2380-2388; Zhou, et al. (2010). ESMO; Rosell, R., et al. (2012). Lancet Oncol, 13, 239-246.

Author Study N (EGFR

mut +)

RR Median PFS

(mo)







Yang et al LUX-‐Lung 3 345 56% vs 23% 13.6 vs 6.9

Wu et al LUX-‐Lung 6 364 67% vs 23% 11.0 vs 5.6

1727

Randomized Studies of First-‐Line EGFR TKI in Pa)ents With EGFR Muta)ons

Mok, et al. (2009). N Engl J Med, 361, 947-957; Lee, et al. (2009). Proc IASL WCLC; Mitsudomi, et al. (2010). Lancet Oncol, 11, 121-128; Maemondo, et al. (2010). N Engl J Med, 362, 2380-2388; Zhou, et al. (2010). ESMO; Rosell, R., et al. (2012). Lancet Oncol, 13, 239-246.

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Author Study Agent

N (EGFR

mut +) RR

Median PFS

(mo) OS (mo)

Mok et al IPASS Gef 261 71.2% vs 47.3 9.8 vs 6.4 21.6 vs 21.9

Lee et al First-‐SIGNAL Gef 42 84.6% vs 37.5% 8.4 vs 6.7 27.2 vs 25.6

Mitsudomi et al WJTOG 3405 Gef 177 62.1% vs 32.2% 9.2 vs 6.3 35.5 vs 38.8

Maemondo et al NEJGSG002 Gef 230 73.7% vs 30.7% 10.8 vs 5.4 30.0 vs 23.6

Zhou et al OPTIMAL Erl 154 83% vs 36% 13.1 vs 4.6 22.6 vs 28.8

Rosell et al EURTAC Erl 154 54.5% vs 10.5% 9.2 vs 5.4 19.3 vs 19.5

Yang et al LUX-‐Lung 3 Afat 345 56% vs 23% 13.6 vs 6.9 HR 1.12

Wu et al LUX-‐Lung 8 Afat 364 67% vs 23% 11.0 vs 5.6 HR 0.95

Crossover to an EGFR TKI in the control group nullifies any chance of an OS benefit

Randomized Studies of First Line EGFR TKI in Patients with EGFR Mutations

Mok, et al. (2009). N Engl J Med, 361, 947-957; Lee, et al. (2009). Proc IASL WCLC; Mitsudomi, et al. (2010). Lancet Oncol, 11, 121-128; Maemondo, et al. (2010). N Engl J Med, 362, 2380-2388; Zhou, et al. (2010). ESMO; Rosell, R., et al. (2012). Lancet Oncol, 13, 239-246.

Resistance to EGFR TKI •  Regardless of extent of initial response, resistance to

TKI develops invariably due to –  T790 mutation (~ 50% to 60%) –  MET amplification (~ 5% to 20%) –  Conversion to SCLC (< 5%)

•  EGFR mutated tumors might progress rapidly upon withdrawal of TKI

•  Role of continuation of TKI beyond progression is under evaluation

•  Afatinib: Targets T790 mutation, and we have seen promising activity for the afatinib/C225 combination in pts with acquired resistance

Sequist, L., et al. (2011). Sci Transl Med, 3(75), 75ra26; Pao, W., et al. (2005). PLoS Med, 2(3), e73.

•  141 pts were screened for ALK fusions, 13% positive

•  F=M, young, non-smokers, usually adenocarcinoma

•  No overlap between EGFR and Kras mutants

•  Refractory to EGFR TKIs •  Typical chemo responses

(not increased as with EGFR mutations)

•  3% to 8% of general NSCLC population Signet-ring cells

Shaw, A. T., et al. (2009). J Clin Oncol, 27(26), 4247-‐4253.

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Pre-Treatment Crizotinib x 12 weeks

Response to Crizotinib (ALK Inhibitor)

Crino et al. ASCO 2011 Abstract 7514

Clinical Activity of the Oral ALK Inhibitor, Crizotinib (PF-02341066), in Patients With ALK-positive NSCLC

Key entry criteria • Positive for ALK by central laboratory

• 1 prior chemotherapy (platinum based)

Crizotinib 250 mg BID (n=159) administered on a continuous dosing schedule

Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 (n=159) infused on day 1 of a 21-day cycle

RANDOMIZE

PROFILE 1007

Key entry criteria • Positive for ALK by central laboratory

• Chemo-naive

PROFILE 1006 N=318

Current crizotinib clinical trials

Crizotinib 250 mg BID (n=159) administered on a continuous dosing schedule

Pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 (n=159) infused on day 1 of a 21-day cycle

RANDOMIZE

N=400 PROFILE 1007-NCT00932893; PROFILE 1005-NCT00932451. Bang Y et al. J Clin Oncol. 2010;28(18s). Abstract 3. Shaw, et al. (2013). N Engl J Med, 368, 2385-2394.

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Primary Endpoint: PFS by Independent Radiologic Review (ITT Population)

Shaw, et al. (2013). N Engl J Med, 368, 2385-2394.

PFS Subgroup Analysis


aRECIST v1.1; bITT population; cas-treated population

Improved Response Rate

65.3

19.5 OR

R (%

)

ORR ratio: 3.4 (95% CI: 2.5 to 4.7); P<0.0001

Crizotinib (n=173)

Chemotherapy (n=174) 80

60

40

20

0 Treatment

65.7

29.3

6.9

Crizotinib (n=172) Pemetrexed (n=99) Docetaxel (n=72)

Treatment

80

60

40

20

0

Shaw et al. ESMO 2012.

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Interim Analysis of OS


Patient Reported Outcomes Symptoms and Quality of Life


Crizotinib Adverse Events in PROFILE 1007

*AEs reported in 15% or more of patients in either treatment group


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Summary of PROFILE 1007 Compared to single-agent chemotherapy, crizotinib:

•  Prolongs progression-free survival

•  Improves response rate

•  Improves symptoms and quality of life

Side effects are generally mild and manageable

•  Monitor liver function tests

•  Treat GI side effects

First and Second Generation ALK TKIs in Clinical Development

Name Company Status Comments

Crizotinib Pfizer 1st and 2nd line registration trials are ongoing. 2nd line trial is completed

Accelerated approval granted August 26, 2011 Regular approval granted November 20, 2013

LDK378* Novartis Phase I dose escalation Phase II

Activity observed at 400 mg. Enrolling in the US and Europe.

AF802 Chugai Phase I/II in Japan and starting in US

Activity observed in crizotinib-naive pts

AP26113* Ariad Phase I ongoing Some activity against EGFR T790M. Enrolling in the US.

ASP3026 Astellos Phase I Similar to TAE684. Enrolling in Japan.

CEP-28122 Cephalon Preclinical

NMS-E628 Nerviano Preclinical

X276/396 Xcovery Preclinical

*Activity seen in crizotinib exposed patients

ALK Inhibitors: RR%

Compound Company Phase No. ALKI naive ALKI exposed Crizotinib Pfizer I/II/III 261 60% NA LDK 378* Novartis I/II 130 60% 57%

CH5424802* Chugai I/II 46 94% NA AP 26113* Ariad I/II 21 50% 73%

TSR011 Tesaro I/II NA NA NA

Outstanding Questions • Do different ALK fusions lead to variable response? • Can we heighten repsonse and PFS up front with combinatorial Tx?

•  HSP 90, MEKI, mTORI • Can we overcome resistance?

Shaw, et al. (2013). N Engl J Med, 368, 2385-2394; Shaw, et al. (2013). ASCO, Abstract 8010; Nakagawa, et al. (2013). ASCO A-8033. Camidge et al. (2013). ASCO A-8031. Tesaro, European Cancer Congress 2013.

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Advances in Recurrent and Metastatic NSCLC: Past 25 yr

Endpoint 2nd Gen Era

< 1990 3rd Gen Era 1990-2000

Bev Era 2000-2005

Targeted Era [>2005]

Overall response 15% 25% 35% 35%-60% Time to progression 2 mo 4 mo 6 mo 7-12 mo

Median survival 6 mo 8-10 mo 12-14 mo 15+ mo

1-yr survival 15%-20% 30% 40%-50% 50%-60%

2-yr survival < 5% 10%-15% 20% 25%-50%

First-‐Line Therapy in NSCLC

NSCLC

1st line

EGFR mt +

Gefi)nib or Erlo)nib or Afa)nib

small molecule inhibitors of EGFR;

EGFR nega)ve or unknown

Nonsquamous

Pla)num double-‐based therapy, Cispla)n or Carbopla)n plus

pemetrexed, taxane, gemcitabine or vinorelbine

Bevacizumab-‐eligible

Pla)num doublet with bevacizumab

Con)nua)on or Switch

maintenance

Squamous Pla)num /gemcitabine;

Pla)num/taxane

Clinical Trial

Azzoli, C. G., et al. (2009). J Clin Oncol, 27(36), 6251-6266.

Alk+ or Ros1

Crizo)nib

Molecular Therapy for Advanced NSCLC: Conclusions

•  Clear role for first line EGFR TKI in patients harboring EGFR mutations (10%-15%)

•  Crizotinib highly active in patients with EML4/ALK translocation (4%-7%), now approved by FDA (independent of line of treatment); also active in ROS-1 positive patients

•  Dabrafenib has activity in BRAF V600 mutants •  MET, KRAS, and other molecular targets may prove

“actionable” in the near future •  Ongoing studies with PD1 MAb and Ipilimumab will

establish their role, if any, in advanced NSCLC

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