les cbnpc mutés ou réarrangés … · orr, percentage of patients in the fas with a confirmed...
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Les CBNPC mutés ou réarrangés de la Première à la Nième ligne
JY DOUILLARD MD PhD Professeur d’ Oncologie Médicale
En collaboration avec J. Raimbourg Cheffe de Clinique en Oncologie Médicale
Institut de Cancérologie de l’Ouest
ICO R Gauducheau Université de Nantes France
Cours Européen Interuniversitaire en Oncologie Thoracique G.O.L.F. Strasbourg 16-19 Novembre 2015
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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%
9911 patients
Barlesi F, J Clin Oncol 31, 2013 (suppl; abstr 8000)
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Distribution of EGFR mutations in lung cancer.
Ohashi K et al. JCO 2013;31:1070-1080
©2013 by American Society of Clinical Oncology
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Etude IFUM
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IFUM Objective response rate (primary endpoint) and disease
control rate (FAS)
ORR by secondary, supportive, central review: 50% (53/106)
ORR (post-hoc analysis) of patients assessed by central review with measurable disease at baselineb: 60%
Rate, % (N) 95% CI
Objective response ratea 69.8 (74/106) 60.5 – 77.7
Disease control rate 90.6 83.5 – 94.8
aInvestigator assessment (primary endpoint) b17 patients with measurable disease by investigator assessment were assessed as having no measurable disease at baseline by central review ORR, percentage of patients in the FAS with a confirmed response of CR or PR (RECIST 1.1); DCR, percentage of patients (FAS) with a best response of CR, PR or SD (SD required for ≥6 weeks)
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FASTACT-2: Phase III study of intercalated erlotinib
Wu, et al. Lancet Oncol 2013
Placebo
Erlotinib 150mg/day
Previously untreated
stage IIIB/IV NSCLC,
ECOG PS 0/1 (n=451)
R
PD
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2
(d1) + placebo (d15–28); q4wks x 6 cycles
GC-placebo (n=225)
Gemcitabine 1,250mg/m2 (d1, 8) + carboplatin AUC=5 or cisplatin 75mg/m2
(d1) + erlotinib 150mg/day (d15–28); q4wks x 6 cycles
GC-erlotinib (n=226)
PD
Study treatment Maintenance phase Screening
Erlotinib 150mg/day
1:1; stratified by stage, histology, smoking status
and chemo regimen
Primary endpoint: IRC confirmed PFS
Secondary endpoints: subgroup analyses, OS in all patients and subgroups, ORR, duration of response, TTP, NPR at 16 weeks, safety, QoL
Combining TKIs with chemotherapy
Unselected on EGFR mutation
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FASTACT-2: PFS and OS benefit with intercalated erlotinib in EGFR Mut+ disease
PFS
prob
abili
ty
OS
prob
abili
ty
0 4 8 12 16 20 24 28 32 0 4 8 12 16 20 24 28 32 36
6.9 16.8 20.6 31.4
GC-erlotinib (n=49) GC-placebo (n=48) HR=0.48 (0.27–0.84) p=0.0092
GC-erlotinib (n=49) GC-placebo (n=48) HR=0.25 (0.16–0.39) p<0.0001
1.0
Time (months) Time (months)
PFS OS
OS benefit with GC-erlotinib vs GC-placebo despite high rate of crossover (85%) from GC-placebo to second-line EGFR
TKI
0.8
0.6
0.4
0.2
0
1.0
0.8
0.6
0.4
0.2
0
Wu, et al. Lancet Oncol 2013
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NEJ005/TCOG0902/ Trial design: PFS and OS
Sugarawa et al Annals of Oncology 00: 1–7, doi:10.1093/annonc/mdv063
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Study objective • To compare first-line erlotinib+bevacizumab with erlotinib alone in patients
with EGFR-mutated NSCLC
Primary endpoint • PFS
Secondary endpoints • OS, tumour response, safety and QoL
R 1:1
PD
PD Key patient inclusion criteria • Non-squamous NSCLC • Stage IIIB/IV or recurrent • EGFR mutation-positive • No previous CT • ECOG PS 0/1 (n=150)
Erlotinib 150 mg/day alone (n=77)
Erlotinib 150 mg/day + bevacizumab 15 mg/kg
q3w (n=75)
Stratification • EGFR mutation (Del19 or L858R) • Gender, smoking status, stage
The Lancet Oncol online August 28, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70381-X
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The Lancet Oncol online August 28, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70381-X
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The Lancet Oncol online August 28, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70381-X
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EFGR TKI au-delà de la Progression
IMPRESS (Gefitinib)
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IMPRESS : y a-t-il un bénéfice à poursuivre le géfitinib en association à la chimiothérapie lors de la résistance acquise ?
Essai randomisé
Objectives
Cisplatine 75 mg/m2
+ pemetrexed 500 mg/m2
(≤ 6 cycles) +
Géfitinib 250 mg
Cisplatine 75 mg/m2 i.v.
+ pemetrexed
500 mg/m2 i.v. (≤ 6 cycles)
+ Placebo 250 mg
1:1 randomisationb n = 133
n = 132
Principal • Survie sans
progression
Secondaire • Survie globale • Réponse objective • Tolérance • Qualité de vie
Exploratoire • Biomarqueurs
• Âge ≥ 18 ans • (≥ 20 ans au Japon) • WHO PS 0-1
• CBNPC confirmé histologiquement
• Stade IIIB/IV • Mutation EGFR • Pas de chimiothérapie
antérieure • Réponse objective
≥ 4 mois ou stabilisation > 6 mois avec géfitinib en première ligne
• Résistance acquise (RECIST)a < 4 semaines avant randomisation
Patients Objectifs
Lancet Oncol 2015 Published Online July 7, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00121-7
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Géfitinib (n = 133)
Placebo (n = 132)
SG médiane, mois 14,8 17,2 Nbre d’évts, n (%) 50 (37,6) 37 (28,0)
HR (IC95) = 1,62 (1,05-2,52) ; p = 0,029
1,0
0,8
0,6
0,4
0,2
0,0 0 2 8 10 16 18 22 26
Prob
abili
té d
e SG
Patients à risque Géfitinib Placebo
133 132
111 119
64 76
43 55
19 27
8
10
2 4
0 0
4 7
0 2
Géfitinib (n = 133) Placebo (n = 132)
4 6 12 14 20 24
125 129
88 94
27 39
12 16
ESMO 2014 – D'après Mok T et al., abstract LBA2-PR, actualisé
IMPRESS : y a-t-il un bénéfice à poursuivre le géfitinib en association à la chimiothérapie lors de la résistance acquise ?
Survie globale (données immatures à 33 % d’événements attendus)
Durée après randomisation (mois)
Lancet Oncol 2015 Published Online July 7, 2015 http://dx.doi.org/10.1016/S1470-2045(15)00121-7
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EFGR TKI au-delà de la Progression
ASPIRATION (Erlotinib)
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ASPIRATION : poursuite de l’EGFR TKI au-delà de la progression RECIST
Essai de phase II ouvert conduit en population asiatique
D’après Park K et al. ESMO 2014 Abstract 12230, actualisé
Erlotinib
Progression RECIST 1
Progression selon
l’investigateur SSP 1
SSP 2
Erlotinib Patients ≥ 18 ans CBNPC stade IV EGFR
mut+
• Critères d’inclusion : patients ≥ 18 ans avec CBNPC de stade IV porteur de mutation des exons 18-21 mutations (sauf T790M), ECOG PS 0-2
• Critères d’exclusion : mutation T790M, traitement antérieur par chimiothérapie ou TKI de l’EGFR, co-morbidités non contrôlées, traitement par warfarin
• Objectif principal : SSP1 (temps jusqu’à la progression RECIST ou le décès)
• Objectifs secondaires : – SSP2 (temps jusqu’à arrêt de l’erlotinib suite à la progression définie par l’investigateur en cas de
poursuite de l’erlotinib au delà de la progression RECIST) – Survie globale/ taux de réponse/ taux de contrôle de la maladie/tolérance
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ASPIRATION : poursuite de l’EGFR TKI au-delà de la progression RECIST
Le bénéfice de survie sans progression à la poursuite de l’erlotinib post progression RECIST (93 patients) était de 3,1 mois
Le profil de tolérance était similaire dans les deux groupes
D’après Park K et al. ESMO 2014 Abstract 12230, actualisé
Surv
ie s
ans
prog
ress
ion
Mois
1,0
0
0,8
0,6
0,4
0,2
0,0 10 20 30
SSP1 SSP2
11,0 mois 14,1 mois
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EGFR TKI chez les EGFR mutant: 2nd/ 3rd lignes
Mok t et al J Clin Oncol 2013, 31: 1081-1088
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AFATINIB (GIOTRIF®)
(DACOMITINIB)
ITK de 2ème Génération
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Afatinib 40 mg/db
Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2
IV q21d, up to 6 cycles
Stage IIIB (wet)/IV lung adenocarcinoma, with EGFR mutation in tumour (central lab testing; Therascreen® EGFR29a RGQ PCR)
Gemcitabine + Cisplatin 1000 mg/m2 D1, D8 + 75 mg/m2
IV q21d, up to 6 cycles
LUX-Lung 31 * (n=354l; Global trial)
LUX-Lung 62 (n=364; Asian Pts)
Randomisation 2:1 Stratified by EGFR mutation (Del19/L858R/
other)
* 72% Asiatique dans Lux-Lung 3
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PFS
(pro
babi
lity)
1.0
0.8
0.6
0.4
0.2
0.0
Months 0
Afatinib LUX-Lung 3 Cis/pem LUX-Lung 3
3 6 9 12 15 18 21 24 27
No. at risk: Afatinib (LL3) 230 180 151 120 77 50 31 10 3 0 Cis/pem (LL3) 115 72 41 21 11 7 3 2 0 0
Afatinib LUX-Lung 6 Cis/gem LUX-Lung 6
Afatinib (LL6) 242 208 166 126 89 60 35 12 4 0 Cis/gem (LL6) 122 70 25 8 1 0 0 0 0 0
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% d’effets secondaires de grade 3 et 4.D’après l’étude de Maemondo et al, l’étude Eurtac et l’étude Lux lung 3 [3,5,9].
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– Afatinib significantly prolonged survival in overall EGFR-mutant population
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Yang et al. J Clin Oncol 2014; 32 (suppl 5; abstr 8004^)
OS (Del19) OS (L858R) 1.0
0.8
0.6
0.4
0.2
0
Est
imat
ed O
S p
roba
bilit
y
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
1.0
0.8
0.6
0.4
0.2
0
Est
imat
ed O
S p
roba
bilit
y
Time (months)
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
236 230 223 217 202 192 173 160 145 131 117 90 50 38 22 6 1 0
119 113 103 95 87 72 63 55 51 43 38 27 14 9 1 1 0 0
Afatinib
CT
No of patients
183 181 167 154 141 128 111 91 80 70 64 51 27 20 11 3 0 0
93 86 82 78 75 69 61 55 50 40 32 25 20 14 9 4 1 0
Afatinib
CT
No of patients
Afatinib (n=236)
CT (n=119)
Median, months 31.7 20.7
HR (95%CI) p-value
0.59 (0.45, 0.77) 0.0001
Median, months 22.1 26.9
HR (95%CI) p-value
1.25 (0.92, 1.71) 0.1600
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Randomization
1:1
Oral afatinib once daily Oral gefitinib once daily
Patients with: • Adenocarcinoma of the lung • Presence of EGFR mutation (del 19 and/or L858R) in the tumour tissue • Stage IIIb/IV • No prior treatment with chemotherapy for advanced/metastatic disease • No prior treatment with EGFR inhibitors • ECOG PS 0–1
n=264
Co-primary endpoint: PFS, DCR at 12 months
A randomized, open-label, Phase IIb trial of afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive advanced
adenocarcinoma of the lung
LUX-Lung 7: http://clinicaltrials.gov/ct2/show/NCT01466660?term=1200.123&rank=1
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Impact des EGFR TKI de 2nd génération
• Chez les patients mutés pré-traités, les EGFR TKI de 2nd génération n’ont pas montré d’effet convaincant
• Raisons de cet échec:
– Forte fixation à l’EGFR Sauvage – Associée à une toxicité majorée – Impossibilité d’utiliser des doses ayant une action sur la mutation
T790M
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•
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•
•
•
•
• •
– –
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Relative frequency of acquired resistance mechanisms
Yu H A et al. Clin Cancer Res 2013;19:2240-2247
Other mutations tested but not found: PIK3CA, AKT1, Braf, Kras, Nras,MEK1, ERBB2
amplification
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A Phase I/II, open-label, multicentre study to assess the safety, tolerability, pharmacokinetics and anti-tumour activity of ascending doses of AZD9291 in patients with advanced NSCLC who have progressed following prior therapy with an EGFR-TKI agent
*cobas® EGFR Mutation Test (Roche Molecular Systems). Tissue and plasma samples will be collected so as to understand: a) the utility of multiple sample types for the identification of T790M+ tumours, b) the molecular evolution of the disease
T790M+
PART 1 Escalation and expansion cohorts
T790M+ T790M+
ESCALATION Not preselected by T790M status (rolling six design)
EXPANSION Enrolment by local testing followed by central confirmation* of T790M status or by central testing alone
NCT01802632, www.clinicaltrials.gov Ranson M et al. Presentation MO21.12, WCLC congress, Sydney, 2013
T790M+ T790M+
EGFRm+, EGFR mutation-positive; EGFR-TKI, EGFR tyrosine kinase inhibitor; MTD, maximum tolerated dose; NSCLC, non-small cell lung cancer;
PK, pharmacokinetics; RP2D, recommended Phase II dose; T790M+, T790M mutation-positive; T790M-, T790M mutation-negative
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Original Article AZD9291 in EGFR Inhibitor–Resistant Non–Small-
Cell Lung Cancer
Pasi A. Jänne, M.D., Ph.D., James Chih-Hsin Yang, M.D., Ph.D., Dong-Wan Kim, M.D., Ph.D., David Planchard, M.D., Ph.D., Yuichiro Ohe, M.D., Suresh
S. Ramalingam, M.D., Myung-Ju Ahn, M.D., Ph.D., Sang-We Kim, M.D., Ph.D., Wu-Chou Su, M.D., Leora Horn, M.D., Daniel Haggstrom, M.D.,
Enriqueta Felip, M.D., Ph.D., Joo-Hang Kim, M.D., Ph.D., Paul Frewer, M.Sc., Mireille Cantarini, M.D., Kathryn H. Brown, Ph.D., Paul A. Dickinson, Ph.D., Serban Ghiorghiu, M.D., and Malcolm Ranson, M.B.,
Ch.B., Ph.D.
N Engl J Med Volume 372(18):1689-1699
April 30, 2015
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Best Percentage Change in Target-Lesion Size.
Jänne PA et al. N Engl J Med 2015;372:1689-1699
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Progression-free Survival According to Status with Respect to EGFR T790M.
Jänne PA et al. N Engl J Med 2015;372:1689-1699
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AZ9291-OSIMERTINIB-TAGRISSO
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Original Article Rociletinib in EGFR-Mutated Non–Small-Cell Lung
Cancer
Lecia V. Sequist, M.D., M.P.H., Jean-Charles Soria, M.D., Ph.D., Jonathan W. Goldman, M.D., Heather A. Wakelee, M.D., Shirish M. Gadgeel, M.D.,
Andrea Varga, M.D., Vassiliki Papadimitrakopoulou, M.D., Benjamin J. Solomon, M.B., B.S., Ph.D., Geoffrey R. Oxnard, M.D., Rafal
Dziadziuszko, M.D., Ph.D., Dara L. Aisner, M.D., Ph.D., Robert C. Doebele, M.D., Ph.D., Cathy Galasso, R.N., O.C.N., C.C.R.P., Edward B.
Garon, M.D., Rebecca S. Heist, M.D., M.P.H., Jennifer Logan, N.P., Joel W. Neal, M.D., Ph.D., Melody A. Mendenhall, M.P.-C., Suzanne Nichols, R.N., Zofia Piotrowska, M.D., Antoinette J. Wozniak, M.D., Mitch Raponi, Ph.D., Chris A. Karlovich, Ph.D., Sarah Jaw-Tsai, Ph.D., Jeffrey Isaacson, Ph.D., Darrin Despain, M.S., Shannon L. Matheny, Ph.D., Lindsey Rolfe, M.B., Ch.B., Andrew R. Allen, M.D., Ph.D., and D. Ross Camidge, M.D., Ph.D. N Engl J Med
Volume 372(18):1700-1709 April 30, 2015
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Best Response to Rociletinib.
Sequist LV et al. N Engl J Med 2015;372:1700-1709
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Treatment-Related Adverse Events in the 92 Patients Receiving Therapeutic Doses of Rociletinib, According to Event Grade.
Sequist LV et al. N Engl J Med 2015;372:1700-1709
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D’après Shaw AT et al . Principales protéines de fusion ALK dans le CBNPC. Les variants EML4-ALK, dont plus d’une vingtaine ont été identifiés, sont les plus fréquentes des protéines de fusion.
ALK: 5% des CBNPC, ROS1: 1%, RET: < 0.5%
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N Engl J Med 2013.
• Phase III Crizotinib vs. Pemetrexed ou Docetaxel, 347 patients, 2nd ligne. • Objectif Principal: PFS (Cross-over possible)
ORR: 65 vs. 20%
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• Phase III Crizotinib vs. Pemetrexed/Platine, 343 patients, 1ère ligne. • Objectif Principal: PFS (Cross-over possible)
ORR: 74 vs. 45%
N Engl J Med 371;23, 2014
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J Clin Oncol 33. 2015
• Etude monobras: 31 patients, • 30 pré-traités,
• 24 à base de Pemetrexed ORR: 80%
PFS: 9.1m, PFS 1 an: 44%
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