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: [email protected]
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