DEPARTMENT OF THORACIC ONCOLOGY

Filippo de MarinisDepartment of Thoracic Oncology, IEO, Milan, Italy

49%

28%

11% 10%2%

Docetaxel Pemetrexed Gemcitabina Vinorelbina Altro

49%

28%

11% 10%2%

Docetaxel Pemetrexed Gemcitabina Vinorelbina Altro

52%52%

8%

8%

8%

12%

15%

23%

25%

Altro

Carboplatino + Paclitaxel

Cisplatino + Gemcitabina

Carboplatino + Pemetrexed

Docetaxel + Gemcitabina

Cisplatino + Pemetrexed

Carboplatino + Gemcitabina

8%

8%

8%

12%

15%

23%

25%

Altro

Carboplatino + Paclitaxel

Cisplatino + Gemcitabina

Carboplatino + Pemetrexed

Docetaxel + Gemcitabina

Cisplatino + Pemetrexed

Carboplatino + Gemcitabina

13%13%

34.0%34.0%

C Gridelli, F de Marinis et al, data on file, 2013

ESMO GL WG, Ann Oncol 2012

Final results of CTONG 0806: a phase II trial comparing pemetrexed with gefitinib as second-

line treatment of advanced non-squamous NSCLC

patients with wild-type EGFR

Qing Zhou1, Ying Cheng2, Ming-fang Zhao3, Jin-ji Yang1, Hong-hong Yan1, Li Zhang4, Yong Song5, Jian-hua Chen6,

Wei-neng Feng7, Chong-rui Xu1, Yi-long Wu1*Chinese Thoracic Oncology Group (CTONG)

1, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China; 2, Jilin Provincial Cancer Hospital, Changchun, China; 3, Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, China; 4, Perking Union Medical Hospital, Beijing, China;5, Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China; 6, Hunan Cancer Hospital, Changsha, China; 7, The First People's Hospital of Foshan, Foshan, China;  * Corresponding author Yi-long Wu, E-mail Address: syylwu@live.cn

Study Design• A multi-center, randomized, controlled, open-label phase II trial

Pemetrexed 500mg/m2, iv, d1, with vitamin B12

and folic acid supplement, q3w

•locally advanced or metastatic, non-squamous NSCLC • previously treated with one platinum-based chemotherapy• no EGFR mutation in exons 18-21 tested by direct sequencing

PD

Gefitinib 250mg qd PD

Primary endpoint: PFS

Secondary endpoints ： 4- and 6-month PFS rate, OS, ORR, DCR, QoL, Safety

Primary endpoint: PFS

• The primary endpoint of PFS was met

Evaluted by investigators Evaluted by IRC

* IRC ： independent review committee

• Median OS showed the trend of superiority in Pemetrexed arm

OS

Conclusions

• CTONG0806 is the first trial to show significant improvement in PFS, DCR and a trend of improving OS with pemetrexed compared with gefitinib in second-line setting for EGFR wild-type advanced non-squamous NSCLC.

• Pemetrexed should be recommended for EGFR wild-type advanced non-squamous NSCLC in second-line treatment due to its good efficacy and tolerability.

STUDY DRUGS PFS ms HR/p OS ms HR/p

V-15-32* GEF vs DOC 2.0 vs 2.0 0.90/ p=.77 11.5 vs 14.0 1.12/ p=.330

INTEREST GEF vs DOC 1.7 vs 2.6 1.24/ p=.14 6.4 vs 6.0 1.02/ p=.91

ISTANA GEF vs DOC 3.3 vs 3.4 0.72/ p=.044 14.1 vs 12.2 0.87/ p=.437

CTONG 0806

GEF vs PEM 1.7 vs 5.6 0.53/p=.001 9.6 vs 12.4

0.72/p=.077

TITAN ERL vs DOC/PEM 1.4 vs 2.0 1.25/ p=.2 6.4 vs 4.5 0.85/p=.37

HORG ERL vs PEM 3.6 vs 2.9 0.92/p=.434 9.7 vs 8.2 1.19/p=528

DELTA ERL vs DOC 1.3 vs 2.9 1.45/p= 9.0 vs 10.1 0.98

TAILOR ERL vs DOC 2.4 vs 2.9 0.71/p=.02 5.4 vs 8.2 0.73/ p=0.05

NCT01565538 **

ERL vs PEM 4.1 vs 3.9 0.92/p=.68 p=0.970

* UNSELECTED PTS ** Phase II trial

Erlotinib is dosed adequately to inhibit WT EGFR, whereas gefitinib is not

1F. Hoffmann-La Roche, data on file; 2Li J, et al. J Natl Cancer Inst 2006;98:1714–23

Fre

e-d

rug

con

cen

trat

ion

(n

g/m

L)

Erlotinib1

150mg/day

Average plasma concentrations after 28 days (relative to required inhibition levels)

1,000

100

10

0 Gefitinib2

250mg/day

1,000

100

10

0

IC50 wild-typeEGFR

IC50 wild-typeEGFR

01.07 | Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) versus Chemotherapy (CT) in

Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): Secondary Endpoint Analysis

Presenting Author: Vanesa Gregorc1

Co-Authors: Chiara Lazzari1, Silvia Novello2, Sandro Barni3, Michele Aieta4, Francesco Grossi5, Tomasso De Pas6, Filippo de Marinis7, Manlio Mencoboni8, Alessandra Bearz9, Irene Floriani10, Valter Torri10, Fred Hirsch11, Heinrich Roder12, Julia Grigorieva12, Joanna Roder12, Alessandra Bulotta1, Silvia Foti1, Mariagrazia Viganò1, Matteo Giaj Levra2, Angela Bachi1

01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D

Erlotinib150 mg daily

Erlotinib150 mg daily

Pemetrexed500 mg/m2

orDocetaxel 75 mg/m2

Pemetrexed500 mg/m2

orDocetaxel 75 mg/m2

1 : 1Randomization

Stratified:VeriStrat ECOG PS SmokingCenter

VERISTRATTESTING

Patients and investigators

blinded to VeriStrat

status

VERISTRATTESTING

Patients and investigators

blinded to VeriStrat

status

VeriStrat Good

VeriStrat Good

VeriStrat Poor

VeriStrat Poor

•Cytological or histological diagnosis of NSCLC

•Advanced stage IIIB-IV

•One previous line platinum-based therapy non EGFR-TKIs

•ECOG PS 0-2

•Cytological or histological diagnosis of NSCLC

•Advanced stage IIIB-IV

•One previous line platinum-based therapy non EGFR-TKIs

•ECOG PS 0-2

PROSE: Study Design

Crossover permittedat progression

• Objective: To prospectively evaluate the predictive utility of VeriStrat classification on the survival outcome of erlotinib vs chemotherapy in the 2nd line NSCLC setting.

• Primary Endpoint: Overall Survival ; Secondary Endpoints: PFS (CT scans 8 week interval), DCR and ORR (RECIST investigators based, no central review) .

• EGFR and K-RAS exploratory analysis performed in 190/263 (72%) and 166/263 (63%) patients, respectively.

PROSE: Patient Overall Survival by Treatment ArmChemotherapy vs. erlotinib (for primary analysis)

Presented by: Vanesa Gregorc, MD

Third-line treatment at progression: • CT arm: 41% overall (48% VS-G and 27% VS-P)• ERL arm: 52% overall (56% VS-G and 39% VS-P)

Incidence of VS Status

PROSE OVERALL SURVIVAL

V Gregorg et al, P ASCO 2013

Median PFS, Months (95% CI)

4.2 (2.6 – 5.0)

2.2 (2.0 – 2.4)

HR=1.27(95%CI:.99 – 1.62)p =0.060

Median PFS, Months

4.82.82.51.7

01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D

PFS in unselected patient and interaction analysis

VS GOOD: UNSELECTED VS GOOD: WILD TYPE

VS POOR: UNSELECTED VS POOR: WILD TYPE

Randomized Proteomic Stratified Phase III Study of Second Line Erlotinib (E) Versus Chemotherapy (CT) in Patients with Inoperable Non-Small Cell Lung Cancer (PROSE): VeriStrat Analysis of Longitudinal Samples

Authors: Alessandra Bulotta1, Chiara Lazzari1, Silvia Foti1, Mariagrazia Viganò1, Domenico Ghio2, Silvia Novello3, Sandro Barni4, Michele Aieta5, Francesco Grossi6, Tomaso De Pas7, Filippo de Marinis8, Manlio Mencoboni9, Alessandra

Bearz10, Joanna Roder11, Heinrich Roder11, Julia Grigorieva11, Irene Floriani12, Valter Torri12, Vanesa Gregorc1

Group Median

A : VS-G to VS-G E 14.6 months

B : VS-G to VS-P E 10.0 months

C : VS-P to VS-P E 5.0 months

HR (A vs B): 0.68 (95% CI: 0.34-1.28); log-rank p = 0.222

HR (B vs C): 0.29 (95% CI: 0.04-0.37); log-rank p = 0.001

Group Median

A : VS-G to VS-G CT 16.2 months

B : VS-G to VS-P CT 6.3 months

C : VS-P to VS-P E CT 10.2 months

HR (A vs B): 0.51 (95% CI: 0.18-1.08); log-rank p = 0.079

HR (B vs C): 0.70 (95% CI: 0.27-1.58); log-rank p = 0.377• Patients whose VeriStrat classification changed from VS-G to VS-P at progression had numerically worse OS

compared with those whose classification remained VS-G regardless of therapy.• These patients had significantly better survival outcomes than those whose classification remained VS-P when

treated with E.

OS and VeriStrat classification at progression

MO21.01 PROSE: VeriStrat analysis of longitudinal samples Silvia Novello, MD

Grade 4 TFS

Median TFS= 7.5 moSMedian TFS= 7.5 moS

Median TFS= 2.3 mo

F de Marinis et al, The Oncologist 2008

O01.05:

EGFR wild-type NSCLC patients with high miR-200c expression

can benefit from EGFR-TKIs

Presenting Author: Jiayu Li, Ph.D

Shanghai Pulmonary Hospital, Tongji University, Shanghai, China

Presentation Number: Presentation Title – Presenting Author

miR-200c was identified as a suppressor of EMT

O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li

EMTmiRNA

TKI resistance

miR-200c ?

EMT= epithelial-to-mesenchymal transition

Presentation Number: Presentation Title – Presenting AuthorO01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li

O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li

• MiR-200c regulated EMT by targeting ZEB1 in NSCLC cell lines

• Ectopic expression of miR-200c resulted in partial restoration of gefitinib sensitivity in NSCLC cell lines

• miR-200c low-expression may be responsible for gefitinib resistance through PI3K/AKT and MEK/ERK pathway

Conclusions-Part1Conclusions-Part2• Our study showed for the first time that miR-200c expression

might be a potent predictive biomarker in EGFR–WT patients receiving EGFR-TKIs treatment.

• EGFR TKIs may be a non-inferior option to second line chemotherapy if EGFR-WT patients with high miR-200c expression were not willing to choose or unable to tolerant chemo drugs.

• miRNAs are stable in serum or plasma, circulating miR-200c could become a non-invasive, blood-based NSCLC biomarker.

• Prospective clinical trials are wanted to confirm the miR-200c as a predicting biomarker in EGFR-WT NSCLC patients.

Authors: M Reck, S Novello, A Mellemgaard, S Orlov, R Kaiser, J Barrueco, 

B Gaschler-Markefski, J-Y Douillard, for the LUME-Lung 1 Study Group

Abstract: 3284 Presentation: O16.01

Impact of tumour burden on the overall survival analysis of the LUME-Lung 1 study: a randomized,

double-blind phase 3 trial of nintedanib (BIBF 1120) + docetaxel in NSCLC patients progressing

after first-line chemotherapy

Presenting Author: M Reck

LUME-Lung 1 Study Design

Nintedanib 200 mg BID PO, D2–21,+ Docetaxel 75 mg/m2 IV, D1,

21-day cycles (n=655)

Nintedanib 200 mg BID PO, D2–21,+ Docetaxel 75 mg/m2 IV, D1,

21-day cycles (n=655)

Placebo BID PO, D2–21,+ Docetaxel 75 mg/m2 IV, D1,

21-day cycles (n=659)

Placebo BID PO, D2–21,+ Docetaxel 75 mg/m2 IV, D1,

21-day cycles (n=659)

N=1314

RANDOMISE

RANDOMISE

• Stage IIIB/IV*or recurrent NSCLC

• Failed 1st-line chemotherapy

• Any histology• ECOG PS 0 or 1• No prior

docetaxel or VEGF/VEGFR inhibitors**

• No active brain metastases

1:1

PDPD

PDPD

Number of docetaxel cycles not restricted Monotherapy allowed after ≥4 cycles of combination therapy

*AJCC 6th/7th edition; **Other than bevacizumab

LUME-Lung 1 met its primary endpoint: PFS (HR: 0.79 p=0.0019)

LUME-Lung 1 Overall SurvivalPatients with Squamous Cell Carcinoma and Sum of Longest Diameters

(SLD) of Target Lesions ≥7.5cm

100

80

60

40

20

0

166 148 124 102 77 59 43 29 25 22 18 17 13 9 7 5 3 2 1159 133 102 74 59 42 34 24 13 10 7 4 3 3 2 2 1 1 1

No. at riskNintedanib

Placebo

Time (months)

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 7.7 6.1

HR (95% CI) 0.82 (0.65 to 1.04)

p-value 0.0995

Pro

bab

ility

of

surv

ival

(%

)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Feb 2013, 328 events

HR interaction analysis revealed values <1 at SLD values around 7.5 cm; consequently, an SLD ≥7.5 cm was chosen as the cut-point for further in-depth analyses in patients with squamous cell carcinoma.

LUME Lung 1 Overall Survival: Patients with Adenocarcinoma Histology and Time Since Start of 1st Line Therapy < 9months

No. at riskNintedanib

Placebo

46.8%

34.3%

20.7%

10.4%

206 167 119 92 73 51 35 16 9 3 199154 91 62 42 25 17 12 5 1

Nintedanib + docetaxel

Placebo + docetaxel

Median, mo 10.9 7.9

HR (95% CI) 0.75 (0.60 to 0.92)

p-value 0.0073

Feb 2013, 345 events

100

80

60

40

20

00 4 8 12 16 20 24 28 32 36

Pro

bab

ility

of

surv

ival

(%

)

Time (months)

Summary

• LUME-Lung 1 met its primary endpoint: PFS (HR: 0.79 p=0.0019)

• A significant improvement in OS was demonstrated in patients with adenocarcinoma (OS; HR: 0.83 p=0.0359 median 12.6 vs 10.3 months)

• Patients with a poor prognosis had the highest OS benefit:

– adenocarcinoma histology and time since start of 1st line therapy <9 months (HR: 0.75 p=0.0073 median OS 10.9 vs 7.9 months)

– adenocarcinoma histology with PD as best response to 1st line treatment (HR: 0.62 p=0.0246 median OS 9.8 vs 6.3 months)

– squamous cell histology with a high tumour burden showed a trend towards improved OS (SLD ≥7.5 cm; HR=0.82 p=0.0995 median OS 7.7 vs 6.1 months)

• Nintedanib plus docetaxel had a manageable safety profile with no unexpected safety findings

• Further investigations are warranted to identify molecular and clinical markers for nintedanib benefit in NSCLC including the effects of high tumour burden (squamous) and tumour dynamics (adenocarcinoma)

Analysis of Patient-Reported Outcomes

from the LUME-Lung 1 Trial: A Randomized, Double-Blind, Placebo-Controlled Phase III Study in Second-Line Advanced Non-Small

Cell Lung Cancer (NSCLC) Patients

Silvia Novello,1 Rolf Kaiser,2 Anders Mellemgaard,3 Jean-Yves Douillard,4 Sergei

Orlov,5 Maciej Krzakowski,6 Joachim von Pawel,7 Maya Gottfried,8 Igor

Bondarenko,9 Meilin Liao,10 José Barrueco,11 Birgit Gaschler-Markefski,2 Ingolf

Griebsch,2 Martin Reck,12 for the LUME-Lung 1 Study Group

Abstract ID 2812

Longitudinal model estimate of differences in cough, dyspnea and pain

(adenocarcinoma patients)

Longitudinal model analysis of differences in mean global health status and functional scales (adenocarcinoma patients)

Conclusions

• In second-line NSCLC patients, no significant differences in cough, dyspnea or pain were observed in patients receiving nintedanib + docetaxel compared with placebo + docetaxel– there were trends towards improvements in TTD for global health

status/QoL in patients with adenocarcinoma, and for pain in adenocarcinoma patients with a time since start of first-line therapy <9 months

– QoL scores for nausea and vomiting, appetite loss and diarrhea were worsened in patients who received nintedanib + docetaxel compared with those who received placebo + docetaxel

• Overall, PFS was improved in all patients with nintedanib + docetaxel compared with placebo + docetaxel and OS was significantly improved in patients with adenocarcinoma;1 this analysis demonstrates that these improvements were achieved without substantial alterations in self-reported QoL

ABSTRACT ID NUMBER: 1045

FEASIBILITY AND CLINICAL IMPACT OF RE-BIOPSY IN ADVANCED NON SMALL CELL LUNG CANCER: A

PROSPECTIVE MULTICENTRIC STUDY IN REAL WORLD SETTING (GFPC study 12-01)

PRESENTER: Professor Alain VERGNENEGRE

C Dujon (Le Chesnay, France), C Chouaid (Saint Antoine, France), P Do (Caen, France), I Monnet (Creteil, France), A Madroszyk (Marseille Calmette, France), H Le Caer (Draguignan, France), JB Auliac (Mantes la Jolie, France), H Berard (Toulon HIA, France), P Thomas (Gap, France), H Lena

(Rennes, France), G Robinet (Brest, France), N Baize (Angers, France), A Bizieux-Thaminy (La Roche sur Yon, France), G Fraboulet (Cercy Pontoise, France), C Locher (Meaux, France), J Le

Treut (Aix-en-Provence, France), S Hominal (Pringy, France), A Vergnenegre (Limoges, France) MO-07: Rebiopsy– A Vergnenegre

THE RE-BIOPSY IS MANDATORY!THE RE-BIOPSY IS MANDATORY!

Rebiopsy done 82 (82%)no 18 (18%)

Reasons for no rebiopsy inaccessible lesion 4 (22.2%)

medical limit 13 (72.2%)patient refusal 1 (5.6%)

Site of rebiopsy nodes 3 (3.0%)lung 60 (73.2%)liver 2 (2.4%)bone 6 (7.3%)skin 2 (2.4%)other 9 (11.0%)

Methods for rebiopsy bronchial endoscopy 41 (50.0%)per cutaneous trans thoracic pon 18 (22.0%)thoracic surgery 2 (2.4%)other 21 (25.6%)

Description of rebiopsies

MO-07: Rebiopsy– A Vergnenegre

Initial molecular profil (n=100) Post biopsy molecular profil (n=82)

EGFR mutated n=50

Re biopsy done: n = 40

EGFR mutated: 16 EGFR wild type: 2

KRAS mutated: 1 small cell LC: 1

T790M mutation: 2 No profil available: 18

KRAS mutated n=7Re biopsy done: n = 5

KRAS mutated: 1 KRAS wild type: 1

No profil available: 3

EGFR- KRAS wild type n=25

Re biopsy done: n = 22

EGFR-KRAS wild type 9

EGFR mutated: 1 EML4ALK : 1

Her2: 1 Ros1 : 1

No profil available: 9

No biological profil n=18

Re biopsy done: n = 15

EGFR mutated: 1 KRAS mutated: 5

No profil available: 9

In this prospective multicentric study, in case of progression, rebiopsy had a good acceptability rate (99%), a fisability of 82% and a clinical impact (new oncologic driver, histologic change or biological change) in 19,5%.

Abstract 1045: Rebiopsy– A Vergnenegre

NSCLC EGFR Mut+ve responder to TKINSCLC EGFR Mut+ve responder to TKI

Oligo-ProgressionOligo-Progression Systemic Systemic ProgressionProgression

Local therapy + Local therapy + continuation continuation

of TKIof TKISystemic therapySystemic therapy

Targeting the Targeting the resistant generesistant gene ChemotherapyChemotherapy Chemotherapy + Chemotherapy +

TKITKI

TKI at 2TKI at 2ndnd PD PD

SystemicSystemic PDPD