Transcript EGFR wild-type

Filippo de Marinis
Department of Thoracic Oncology, IEO, Milan, Italy
DEPARTMENT OF THORACIC ONCOLOGY
Carboplatino + Gemcitabina
25%
Cisplatino + Pemetrexed
23%
Docetaxel + Gemcitabina
15%
Carboplatino + Pemetrexed
12%
Cisplatino + Gemcitabina
8%
Carboplatino + Paclitaxel
8%
Altro
8%
13%
49%
52%
28%
34.0%
11%
10%
2%
Docetaxel Pemetrexed Gemcitabina Vinorelbina
Altro
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 secondline 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
•locally advanced or metastatic,
non-squamous NSCLC
• previously treated with one
platinum-based chemotherapy
• no EGFR mutation in exons 1821 tested by direct sequencing
Pemetrexed
500mg/m2, iv, d1,
with vitamin B12
and folic acid
supplement, q3w
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
OS
• Median OS showed the trend of superiority in Pemetrexed arm
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 secondline setting for EGFR wild-type advanced nonsquamous NSCLC.
• Pemetrexed should be recommended for EGFR wildtype advanced non-squamous NSCLC in second-line
treatment due to its good efficacy and tolerability.
STUDY
DRUGS
PFS ms
HR/p
V-15-32*
GEF vs DOC
2.0 vs 2.0
0.90/ p=.77
INTEREST
GEF vs DOC
1.7 vs 2.6
1.24/ p=.14
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
* UNSELECTED PTS
** Phase II trial
OS ms
HR/p
11.5 vs 14.0 1.12/ p=.330
6.4 vs 6.0
1.02/ p=.91
p=0.970
Erlotinib is dosed adequately to inhibit
WT EGFR, whereas gefitinib is not
Average plasma concentrations after 28 days
(relative to required inhibition levels)
Free-drug
concentration (ng/mL)
1,000
1,000
100
100
IC50 wild-type
EGFR
IC50 wild-type
EGFR
10
0
Erlotinib1
150mg/day
1F.
10
0
Gefitinib2
250mg/day
Hoffmann-La Roche, data on file; 2Li J, et al. J Natl Cancer Inst 2006;98:1714–23
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
PROSE: Study Design
Crossover permitted
at progression
•Cytological or
histological
diagnosis of
NSCLC
•Advanced
stage IIIB-IV
•One previous
line platinumbased therapy
non EGFR-TKIs
VERISTRAT
TESTING
Patients and
investigators
blinded to
VeriStrat
status
VeriStrat
Good
1:1
Randomization
VeriStrat
Poor
Stratified:
VeriStrat
ECOG PS
Smoking
Center
Pemetrexed
500 mg/m2
or
Docetaxel
75 mg/m2
Erlotinib
150 mg daily
•ECOG PS 0-2
• 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.
01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D
PROSE: Patient Overall Survival by Treatment Arm
Chemotherapy vs. erlotinib (for primary analysis)
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)
Presented by: Vanesa Gregorc, MD
PROSE OVERALL SURVIVAL
Incidence of VS Status
V Gregorg et al, P ASCO 2013
PFS in unselected patient and interaction analysis
Median PFS, Months (95% CI)
Median PFS, Months
4.2 (2.6 – 5.0)
2.2 (2.0 – 2.4)
HR=1.27(95%CI:.99 – 1.62)
p =0.060
4.8
2.8
2.5
1.7
01.07 PROSE Secondary Endpoint Analysis Vanesa Gregorc, MD, Ph.D
VS GOOD: UNSELECTED
VS POOR: UNSELECTED
VS GOOD: WILD TYPE
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
OS and VeriStrat classification at progression
Group
Median
Group
Median
A : VS-G to VS-G E
14.6 months
A : VS-G to VS-G CT
16.2 months
B : VS-G to VS-P E
10.0 months
B : VS-G to VS-P CT
6.3 months
C : VS-P to VS-P E
5.0 months
C : VS-P to VS-P E CT
10.2 months
HR (A vs B): 0.68 (95% CI: 0.34-1.28); log-rank p = 0.222
HR (A vs B): 0.51 (95% CI: 0.18-1.08); log-rank p = 0.079
HR (B vs C): 0.29 (95% CI: 0.04-0.37); log-rank p = 0.001
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.
MO21.01 PROSE: VeriStrat analysis of longitudinal samples Silvia Novello, MD
Grade 4 TFS
Median 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
miR-200c
miRNA
?
EMT
miR-200c was identified as a suppressor of EMT
TKI
resistance
EMT= epithelial-to-mesenchymal transition
O01.05: EGFR wild-type NSCLC patients with high Presentation
miR-200c expression
Number: can
Presentation
benefit from
Title
EGFR-TKIs
– Presenting
– Jiayu
Author
Li
O01.05: EGFR wild-type NSCLC patients with high Presentation
miR-200c expression
Number: can
Presentation
benefit from
Title
EGFR-TKIs
– Presenting
– Jiayu
Author
Li
Conclusions-Part2
Conclusions-Part1
• Our study showed for the first time that miR-200c expression
• MiR-200c
regulated
EMTbiomarker
by targeting
ZEB1 in patients
might
be a potent
predictive
in EGFR–WT
NSCLC
cell lines treatment.
receiving
EGFR-TKIs
• EGFR TKIs may be a non-inferior option to second line
chemotherapy
if EGFR-WT
patients resulted
with highinmiR-200c
• Ectopic expression
of miR-200c
partial
expression
were
willingsensitivity
to chooseinorNSCLC
unablecell
to tolerant
restoration
ofnot
gefitinib
lines
chemo drugs.
• miRNAs are stable in serum or plasma, circulating miR-200c
• miR-200c
be responsible
could
become low-expression
a non-invasive, may
blood-based
NSCLCfor
gefitinib resistance through PI3K/AKT and MEK/ERK
biomarker.
pathwayclinical trials are wanted to confirm the miR-200c
• Prospective
as a predicting biomarker in EGFR-WT NSCLC patients.
O01.05: EGFR wild-type NSCLC patients with high miR-200c expression can benefit from EGFR-TKIs – Jiayu Li
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
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
LUME-Lung 1 Study Design
• 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
R
A
N
D
O
M
I
S
E
Nintedanib 200 mg BID PO, D2–21,
+ Docetaxel 75 mg/m2 IV, D1,
21-day cycles (n=655)
PD
Placebo BID PO, D2–21,
+ Docetaxel 75 mg/m2 IV, D1,
21-day cycles (n=659)
PD
1:1
N=1314
Number of docetaxel cycles not restricted
Monotherapy allowed after ≥4 cycles of combination therapy
LUME-Lung 1 met its primary endpoint: PFS (HR: 0.79 p=0.0019)
*AJCC 6th/7th edition; **Other than bevacizumab
LUME-Lung 1 Overall Survival
Probability of survival (%)
Patients with Squamous Cell Carcinoma and Sum of Longest Diameters
(SLD) of Target Lesions ≥7.5cm
Nintedanib +
docetaxel
Placebo +
docetaxel
Median, mo
7.7
6.1
HR (95% CI)
0.82 (0.65 to 1.04)
100
80
p-value
60
0.0995
Feb 2013, 328 events
40
20
0
0
No. at risk
Nintedanib
Placebo
2
4
6
166 148 124 102
159 133 102 74
8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Time (months)
77
59
59
42
43
34
29
24
25
13
22
10
18
7
17
4
13
3
9
3
7
2
5
2
3
1
2
1
1
1
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
Nintedanib +
docetaxel
Placebo +
docetaxel
Median, mo
10.9
7.9
HR (95% CI)
0.75 (0.60 to 0.92)
Probability of survival (%)
100
80
p-value
60
0.0073
Feb 2013, 345 events
46.8%
40
20.7%
20
34.3%
10.4%
0
No. at risk
Nintedanib
Placebo
0
4
8
12
206
154
167
91
119
62
92
42
16
20
24
Time (months)
73
25
51
17
35
12
28
32
36
16
5
9
1
3
199
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)
Abstract ID 2812
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
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!
Description of rebiopsies
Rebiopsy
Reasons for no rebiopsy
Site of rebiopsy
Methods for rebiopsy
done
no
inaccessible lesion
medical limit
patient refusal
nodes
lung
liver
bone
skin
other
bronchial endoscopy
per cutaneous trans thoracic pon
thoracic surgery
other
82 (82%)
18 (18%)
4 (22.2%)
13 (72.2%)
1 (5.6%)
3 (3.0%)
60 (73.2%)
2 (2.4%)
6 (7.3%)
2 (2.4%)
9 (11.0%)
41 (50.0%)
18 (22.0%)
2 (2.4%)
21 (25.6%)
MO-07: Rebiopsy– A Vergnenegre
Initial molecular profil (n=100)
EGFR mutated n=50
Post biopsy molecular profil (n=82)
EGFR mutated:
KRAS mutated:
Re biopsy done: n = 40 T790M mutation:
16
1
2
EGFR wild type: 2
small cell LC:
1
No profil available: 18
KRAS mutated n=7
KRAS mutated:
1
Re biopsy done: n = 5 No profil available: 3
KRAS wild type:
1
EGFR- KRAS wild type n=25
9
EML4ALK :
Ros1 :
1
1
KRAS mutated:
5
EGFR-KRAS wild type
EGFR mutated:
1
Her2:
1
Re biopsy done: n = 22
No profil available: 9
No biological profil n=18
EGFR mutated:
1
No profil available: 9
Re biopsy done: n = 15
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 TKI
Oligo-Progression
Local therapy +
continuation of TKI
Systemic
Progression
Systemic
PD
Targeting the
resistant gene
Systemic therapy
Chemotherapy
Chemotherapy +
TKI
TKI at 2nd PD