oncologie thoracique - canceraquitaine
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Oncologie Thoracique
Dr Rémi Veillon CHU Bordeaux
Dr Sylvestre Le MoulecInstitut Bergonié
Oncologie Thoracique
Dr VEILLON RémiOncologue médical
Service des maladies respiratoires
Bordeaux, Jeudi 21 Septembre 2017
Liens d’intérêtsdepuis 2013
• Participation à des congrès (ASCO, ESMO, WCLC) :• Roche, Amgen, Lilly, Boehringer-Ingelheim, Pfizer, MSD, Bristol-Myers Squibb
• Board local d’experts ; animations ou interventions (réunions d’experts, post-congrès) :
• Boehringer-Ingelheim, Roche, Astra-Zeneca, Bristol-Myers Squibb, MSD
• Consultant• MSD
• Honoraires investigateurs dans le cadre de recherche clinique (compte recherche Accelence)
• Roche, Astra-Zeneca, Takeda, Abbvie, Merck-Serono, Bristol-Myers Squibb
Le contenu et/ou les opinions exprimées lors de cette présentation ont été réalisés en toute indépendance
Addiction Oncogénique
• EGFR• Osimertinib
• ALK :• Crizotinib
• BRAF• Dabrafenib - Trametinib
EGFR : Osimertinib• Anti EGFR de 3e génération• Efficacité sur les échappement aux anti EGFR de 1ère génération par la voie
T790M
• Etude AURA 3 : Osimertinib vs chimiothérapie (après ITK 1ère ligne)
• Efficace dès la 1ère ligne ?Mok et al. NEJM 2017 ; 376:629-640
Osimertinib : FLAURA• Adénocarcinomes bronchiques mutés EGFR, 1ère ligne
• Objectif primaire : • Survie sans progression
• Objectifs secondaires : • RO%, durée de réponse, Taux de contrôle, importance de la réponse, survie
globale, échelles symptomatiques et qualité de vie, tolérance
Osimertinib 80 mg/jN=279
Gefitinib 250 mg/j ou erlotinib 150 mg/j
N=277
RR
1:1
Age > 18 ansPS OMS 0/1Délation exon 19 ou L858RNon prétraitéMétastases cérébrales stables autorisées
Evaluation RECIST / 6 sem jusqu’à progression
Cross over possible dans le groupe contrôle si T790 M+ à progression
Ramalingam S et al., abstr. LBA2 PR
0 3 6 9 12 15 18 21 24 270
0,2
0,4
0,6
0,8
1,0
Prob
abili
té d
e SS
P
0
0,2
0,4
0,6
0,8
1,0
Prob
abili
té d
e su
rvie
glo
bale
0 3 6 9 12 15 18 21 24 27 30
279277
262239
233197
210152
178107
13978
7137
2610
42
00
279277
276263
269252
253237
243218
232200
154126
8764
2924
41
00
Temps depuis la randomisation Temps depuis la randomisation
OsimertinibITK 1G
18,9 (15,2-21,4)10,2 (9,6-11,1)
SSP médiane, mois(IC95)
HR = 0,46IC95 : 0,37-0,57
p < 0,0001
HR = 0,63IC95 : 0,45-0,88
p = 0,0068
Survie sans progression Survie globale
Patients à risque (n) Patients à risque (n)
Osimertinib : FLAURA
Ramalingam S et al., abstr. LBA2 PR
Meilleure séquence ?
Mok T. discussion abstr. LBA2 PR
ALK : Crizotinib• PROFILE 1014• Crizotinib vs chimiothérapie• 1ère ligne• Objectif primaire
• Survie sans progression• Médiane : 10,9 vs 7,0 mois
• Objectifs secondaires• RO %• SG• Tolérance• Qualité de vie
Solomon et al. NEJM 2014 ; 371 : 2167-2177
Crizotinib vs chimiothérapie (1ère ligne)
0 10 20 30 40 50 60 70
172171
144131
111100
8982
6563
3631
811
00
Mois
0
20
40
60
80
100 Suivi médian 46 mois
HR = 0,760 (IC95 : 0,548-1,053) ; p = 0,978
Surv
ie g
loba
le
Crizotinib(n = 172)
Chimiothérapie(n = 171)
Décés, n (%) 71 (41,3) 81 (47,4)
SG médiane (IC95), mois NR (45,8-NR) 47,5 (32,2-NR)
CrizotinibChimiothérapie
Patients à risque
Mok T et al., abstr. LBA50
Crizotinib vs chimiothérapie (1ère ligne)
• Impact des traitements ultérieurs sur la survie globale
Mok T et al., abstr. LBA50
0 10 20 30 40 50 60 70
5737
1433
5730
1232
5019971
4213791
335
601
253
431
30
101
0000
Mois
0
20
40
60
80
100
Surv
ie g
loba
le
Patients à risque
Crizotinib suivi par un ITK anti ALKCrizotinib suivi par un autre traitement non ITKChimiothérapie suivie par un ITK anti ALKChimiothérapie suivie par un autre traitement non ITK
BRAF
• Mutation BRAF• 2 à 3% des CBNPC
• V600E : 70% en métastatique
(Litvak et al. JTO 2014 ; 9 : 1669-1674)
• Dabrafenib seul(Planchard et al. Lancet Oncol 2016 ; 17 : 642-50)
• 1/3 de répondeurs• Survie sans progression : 5,5 mois
• Dabrafenib + Trametinib(Planchard et al. Lancet Oncol 2016 ; 17:984-99)
• 2/3 de répondeurs• Survie sans progression : 9mois
Dabrafénib + trametinib en 1ère ligne
Patient
Dim
inut
ion
max
iam
lede
puis
l’éva
luat
ion
initi
ale
(%)
Meilleure réponseconfirmée
RCRPStabilisationProgressionNon évaluable
10
0
-10
-20
-30
-40
-50
-60
-100
-70
-80
-90
Meilleur taux de réponse : 64 % (IC95 : 46-79)
La ligne grise (-30) représente le seuil de réponse partielle, selon les critères RECIST v1.1
Planchard D et al., abstr. LBA51
• Survie sans progression
0 5 10 20 2515 30 35 40
Surv
iesa
ns p
rogr
essi
on
(éva
luat
ion
inve
stig
ateu
r), %
Délai depuis la première dose, mois
20
40
60
80
100
0
Patients à risque
36 25 18 11 4 1 1 1 0
Evaluation par l’investigateur
(n = 36)
Relecture centraliséeindépendante (n = 36)
Evénements, n (%) 24 (67) 22 (61)
Médiane (IC95), mois 10,9 (7,0-16,6) 14,6 (7,0-22,1)
Survie à 6 mois (IC95), % 72 (53-84) 69 (51-82)
IC95
Numerical differences in median PFS between investigator and IRC assessments were primarily driven by censored observations for IRC (five patients who were assessed by the investigators as having PD had values for PFS close to the medians). Because no further tumour assessment scans were collected for these patients, and because the IRC did not assess these last scans as PD, the events for these patients in IRC assessment were based on the receipt of subsequent anticancer therapy.
Planchard D et al., abstr. LBA51
Dabrafénib + trametinib en 1ère ligne
• Survie globaleSu
rvie
glob
ale
(%)
0 5 10 20 2515 30 35 40
Délai depuis la première dose, moisPatients à risque
36 32 26 19 12 3 1 1 0
20
40
60
80
100
0IC95
n = 36
Evènements, n (%) 17 (47)
Médiane (IC95), mois 24,6 (12,3-NE)
Survie à 2 ans (IC95), % 51 (33-67)
Planchard D et al., abstr. LBA51
Dabrafénib + trametinib en 1ère ligne
En bref…• OCTOMUT : efficacité des anti EGFR chez les +80ans
• Corre R. et al. Abs.#1356
• Importance de la séquence thérapeutique des mutés EGFR (suite des études Lux Lung : afatiniben 1ère ligne)
• Sequist L. et al. Abs.#1349
• Alectinib vs chimiothérapie en 3e ligne : 9,6 vs 1,4 mois (HR 0,15)• Novello S. et al. Abs.#12990
• Lorlatinib efficace même en Xème ligne• Felip Front E. et al. Abs.#1343 (ALK)• Besse B. et al. Abs.#1308 (ROS1)
• Brigatinib efficace après Crizotinib, y compris au niveau cérébral• Bazhenova L.A. et al. Abs.#1344• Felip Font E. et al. Abs.#1345
• Variants de ALK (en RNAseq) : influence sur la réponse au Crizotinib• A. Mc Leer et al. Abs.#1336
• HER2 : quel test ? (FISH, IHC, séquençage ?), efficacité modeste de l’Afatinib• Tanaka T. et al. Abs.#1339• Peters S. et al. Abs.#1355
Post ESMO 2017Oncologie thoracique
Immunothérapie
Sylvestre Le Moulec21 septembre 2017
Cellule tumorale
LymphocyteParadigme historique:
Cibler cellules Tumorales
Paradigme nouveau:Cibler cellules Immunitaires
Sylvestre Le Moulec, 21 juin 2017
Metastatic
Immunothérapie dans les CBNPC métastatiques en 2017
2nd line and beyond
1st line monotherapy
In combination
1st Line
Nivolumab withno biomarker
Pembro in PDL1 +
Atezo in PDL1 +
SCC
ADK
Pembro in PDL1 + (> 50%)
Nivo + IpiVs
Durva + Treme
IO + Ct (ahead)Other lines
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Etude Pacific
La Lettre du Cancérologue
Etude PACIFIC
Etude de phase III, internationale, randomisée en double aveugle, multicentrique
• Patients de stades III, localement avancés, non opérables, n’ayant pas progressés après au moins 2 cycles de chimiothérapie à base de sels de platine et radiothérapie
• 18 et plus
• PS 0-1
• Durée vie estimée ≥12 semaines
Pas de sélection selon statutPDL1
Durvalumab10 mg/kg toutes 2
semaines jusqu’à 12 mois (N = 476)
Placebo10 mg/kg toutes
2semaines jusqu’à 12 mois (N = 237)
2:1 randomisation,Stratification selon age, sexe, statut tabagique n
= 713
Objectifs secondaires• Proportion de patients en vie
et sans progression à 12 et 18 mois (BICR)
• Taux réponse (BICR)• Durée objectif de réponse (
BICR)• Survie à 24 mois• Sécurité et tolérance• Qualité de vie• Pharmacocinétique• Immunogenicité
Objectifs primaires• Survie sans progression selon
une relecture indépendantesen aveugle (BICR), RECIST v1.1
• Survie globale
R
1-42 jourspost-cCRT
ESMO 2017 - D’après Paz-Ares L et al., abstr. LBA1-PR, actualisé
La Lettre du Cancérologue
Etude PACIFIC
SSP (Objectif primaire en intention de traitement)
Prob
abili
téde
SSP
1,0
0,8
0,6
0,4
0,2
0,0
0 3 6 9 12 15 18 21 24 27Time from randomization (months)
Placebo
Durvalumab
Stratification, hazard ratio,0.52 (IC95 : 0,42-0,65)Two-sided p < 0,0001
476 377 301 264 159 86 44 21 4237 163 106 87 52 28 15 4 3
10
No. a risqueDurvalumab
Placebo
Durvalumab(n = 476)
Placebo(n = 237)
SSP médiane (IC95), mois 16,8 (13,0-18,1) 5,6 (4,6-7,8)
SSP à 12 mois (IC95) 55,9 % (51,0-60,4) 35,3 % (29,0-41,7)
SSP à 18 mois (IC95) 44,2 % (37,7-50,5) 27,0 % (19,9-34,5)
ESMO 2017 - D’après Paz-Ares L et al., abstr. LBA1-PR, actualisé
La Lettre du Cancérologue
Etude PACIFICTemps à décés ou métastase à distance (intention de traitement)
1,0
0,8
0,6
0,4
0,2
0,0
1 3 6 9 12 15 18 21 24 27 30
Prob
abili
ty o
f dea
th o
r dist
ant m
etas
tasis
Hazard ratio, 0.52 (IC95 : 0,39-0,69)Two-sided p < 0,0001
Time from randomization (months)
Placebo
Durvalumab
No. a risqueDurvalumab
Placebo476 407 336 288 173 91 46 22 4 1 0237 184 129 106 63 32 16 5 4 0 0
Durvalumab Placebo
Temps médian (IC95),mois 23,2 (23,2-non atteint) 14,6 (10,6-18,6)
ESMO 2017 - D’après Paz-Ares L et al., abstr. LBA1-PR, actualisé
Neoadjuvant
Adjuvant Metastatic1L 2LPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Checkmate 153Poursuite Nivo ?
Etude OAKTMB et PDL 1 NEG
Questions PratiquesHPD et Prédiction RP
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Checkmate 153Poursuite Nivo ?
La Lettre du Cancérologue ESMO 2017 - D. Spigel 297O actualisé D’après et al., abstr. 1
CheckMate 153 : Poursuite vs 1 an de traitement par nivolumabSurvie sans progression depuis la randomisation en fonction de la réponse
0 3 6 9 12 15 18 21 240
20
40
60
80
100
Poursuite
1 an de traitement
5349
4529
4126
3920
2814
1711
73
21
00
Temps post-randomisation (mois)
SSP
(%)
Réponse complète/ partielle
Médiane, mois(IC95)
Poursuite Non atteint
1 an de traitement 10,6 (4,8-NA)
HR = 0,45 ; IC95 : 0,24-0,85
0 3 6 9 12 15 18 21 240
20
40
60
80
100
Poursuite
1 an de traitement
2338
1521
1217
1013
77
55
32
10
00
Temps post-randomisation (mois)
SSP
(%)
Maladie stable
Médiane, mois(IC95)
Poursuite Non atteint(5,6-NA)
1 an de traitement 9,6 (4,5-12,6)HR = 0,44 ; IC95 : 0,17-1,09
Patients à risque (n)
La Lettre du Cancérologue ESMO 2017 - D. Spigel 297O actualisé D’après et al., abstr. 1
CheckMate 153 : pousuite vs 1 an de traitement Survie sans progression après randomisation
0 3 6 9 12 15 18 21 240
20
40
60
80
100
poursuite1 an de traitement
7687
6050
5343
4933
3521
2216
105
31
00
Temps après randomisation (mois)
SSP
(%)
Médiane, mois(IC95)
SSP, %
À 6 mois À 1 an
poursuite NR (NR) 80 65
1 an de traitement 10,3 (6,4-15,2) 60 40
HR = 0,42 ; IC95 : 0,25-0,71
Patients à risque (n)
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Etude OAKTMB et PDL 1 NEG
28
Atezolizumab1200 mg IV q3w
PD or loss of clinical benefit
Docetaxel 75 mg/m2 q3w
Locally Advanced or Metastatic NSCLC
• 1–2 prior lines of chemo including at least 1 platinum based
• Any PD-L1 status
N = 1,225 enrolledaPD
R 1:1
Stratification factors• PD-L1 expression• Histology • Prior chemotherapy
regimens
Primary Endpoints (first 850 enrolled patients):
• OS in the ITT population• OS in patients with PD-L1 expression on ≥ 1% TC or IC
Secondary Endpoints: ORR, PFS, DoR, Safety
aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression). TC, tumor cells; IC, tumor-infiltrating immune cells. Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh
OAK background: study design
Blood-Based Biomarkers for Cancer Immunotherapy: Tumor Mutational Burden in Blood (bTMB) is Associated With Improved Atezolizumab Efficacy in 2L+ NSCLC (POPLAR and OAK)
David R. Gandara,1 Marcin Kowanetz,2 Tony Mok,3 Achim Rittmeyer,4 Louis Fehrenbacher,5
David Fabrizio,6 Geoff Otto,6 Christine Malboeuf,6 Daniel Lieber,6 Sarah M. Paul,2 Lukas Amler,2
Todd Riehl,2 Erica Schleifman,2 Yan Li, 2 Craig Cummings,2 Priti S. Hegde,2 Wei Zou,2 Alan Sandler,2
Marcus Ballinger,2 David S. Shames2
1 UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 2 Genentech, Inc., South San Francisco, CA, USA; 3 Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 4 Lungenfachklinik Immenhausen, Immenhausen, Germany; 5 Kaiser Permanente Medical Center, Vallejo, CA, USA; 6 Foundation Medicine Inc., Cambridge, MA, USA
Gadgeel S, et al. SP142 vs 22c3 PD-L1 Expression in OAK a PD-L1 expression was evaluated by immunohistochemistry (IHC) using the VENTANA SP142 assay; TC3 or IC3, ≥50% of TC or ≥10% of IC express PD-L1. BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; TC, tumor cell.
Limited overlap between bTMB ≥16 and PD-L1 expressiona (OAK BEP)
• Non-significant overlap between the bTMB ≥16 and TC3 or IC3 subgroups (Fisher exact test, P = 0.62)
• 19.2% of tumors with bTMB ≥16 were also TC3 or IC3
• 29.1% of tumors with TC3 or IC3 also had bTMB ≥16
PFS HR (95% CI)
OS HR (95% CI)
bTMB ≥16 0.64 (0.46, 0.91)
0.64 (0.44,0.93)
TC3 or IC3 0.62 (0.41, 0.93)
0.44 (0.27, 0.71)
bTMB ≥16 and TC3 or IC3
0.38 (0.17, 0.85)
0.23 (0.09, 0.58)
DR. Gandara. et al, bTMB in OAK and POPLAR
Clinical efficacy of atezolizumab in pd-l1 selected subgroups defined by sp142 and 22c3 ihc assays in 2L+ NSCLC: results from the randomized oak trial Shirish Gadgeel,1 Marcin Kowanetz,2 Wei Zou,2 Fred R. Hirsch,3 Keith Kerr,4 David R. Gandara,5
Fabrice Barlesi,6 Keunchil Park,7 Mark McCleland,2 Hartmut Koeppen,2 Marcus Ballinger,2
Alan Sandler,2 Priti S. Hegde,2 Achim Rittmeyer8
1University of Michigan, Ann Arbor, MI, USA; 2Genentech, Inc., South San Francisco, CA, USA; 3University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 4Aberdeen Royal Infirmary/Aberdeen University Medical School, Aberdeen, UK; 5UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 6 Aix Marseille Universite, Assistance Publique Hôpitaux de Marseille, Marseille, France; 7 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 8 Lungenfachklinik Immenhausen, Immenhausen, Germany.
• OS benefit observed in PD-L1 negative populations as defined by either assay
SP142 assay: TC0 and IC0, PD-L1 expression on <1% TC and IC.22C3 assay: TPS <1%, PD-L1 expression on <1% TC. Dx-, no or low PD-L1 expression.
Overall Survival in PD-L1 Negative Subgroups in OAK BEP
OS HR (95% CI)
SP142 Dx-(N = 150)
0.55 (0.37, 0.80)
22C3 Dx-(N = 218)
0.61 (0.45, 0.84)
+ Censored
Atezolizumab
Docetaxel
SP142 TC0 and IC0
Months
+ Censored
Atezolizumab
Docetaxel
22C3 TPS < 1%
Ove
rall
Surv
ival
(%)
Months
Ove
rall
Surv
ival
(%)
Gadgeel S, et al. 22C3 vs SP142 in OAK
• Patients without PD-L1 expression, as defined by both IHC assays, continue to show improved survival with atezolizumab compared with docetaxel
IC, tumor infiltrating immune cell; TC, tumor cell; TPS, tumor proportion score.
Overall Survival in Subgroup Defined PD-L1–Negative by Both Assays
TC0 and IC0 TPS < 1%
SP142 22C3and
+ CensoredDocetaxel (N = 60)
Atezolizumab (N = 55)
OS HR, 0.63 (95% CI: 0.41, 0.97) P = 0.0347
Ove
rall
Surv
ival
(%)
Months
Gadgeel S, et al. 22C3 vs SP142 in OAK
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Questions PratiquesHPD et Prédiction RP
Roberto Ferrara1*, Caroline Caramella2, Matthieu Texier3, Clarisse Audigier-Valette4, Laurent Tessonnier5, Laura Mezquita1, Jihene Lahmar1, Julien Mazieres6, Gerard Zalcman7, Solenn Brosseau7, Virginie Westeel8, Sylvestre Le Moulec9, Laura Leroy9, Boris Duchemann10, Rémi Veillon11,
David Planchard1, Marie-Eve Boucher1, Serge Koscielny3, Jean Charles Soria12, Benjamin Besse1.1 Medical Oncology Department, Gustave Roussy, Villejuif, France, 2 Radiology Department, Gustave Roussy, Villejuif, France, 3 Biostatistics and Epidemiology Department, Gustave
Roussy, Villejuif, France, 4 Pneumology Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France, 5 Nuclear Medicine Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France, 6 Thoracic Oncology Department, Centre Hospitalier Universitaire de Toulouse, Toulouse, France, 7 Thoracic Oncology Department, Hôpital Bichat-Claude Bernard,
Université Paris-Diderot, Paris, France, 8 Pneumology Department, Centre Hospitalier Universitaire de Besançon, Besançon, France, 9 Medical Oncology Department, Institute Bergonié, Bordeaux, France, 10 Medical Oncology Department, Hôpital Avicenne, Bobigny, France, 11 Medical Oncology Department, Centre Hospitalier Universitaire de Bordeaux-Hôpital Haut-
Lévêque, Pessac, France,8 Drug Development Department (DITEP), Gustave Roussy and Paris Sud University, Villejuif, France
HYPERPROGRESSIVE DISEASE (HPD) IS FREQUENT IN NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH ANTI PD-1/PD-L1 MONOCLONAL
ANTIBODIES (IO) AND PREDICTS POOR SURVIVAL
Hyperprogressive disease (HPD) is an “atypical” & rapid phenomenon in IO treated NSCLC
AIM OF THIS STUDY: To assess the prevalence, the prognostic
value of HPD and the correlation with clinical features
in a large multicentric cohort of IO treated advanced NSCLC patients.
PD
HPD
Time
TumorVolume
Delta TGR: TGR IO – TGR pre-IO
HPD: deltaTGR >50%
Scan before IO
Scan before IO Scan IO start
Scan IO start
Scan during IO
Scan during IO
Typical & atypical
response patterns to IO
HPD is a frequent phenomenon and it can occur in ~16% of IO treated NSCLC patients
Und
er t
reat
men
t per
cent
chan
ge
in t
um
or
volu
me
per
month
-100
0
100
200
300
400
500
Prebaseline percent change in tumor volume per month
-100 0 100 200 300 400 500
Statut delta TGR <50%delta TGR>=50% (Hyperprogressor)
TGR pre-IO (%)
TGR
-IO (%
)
Blue = HPD
Black = Not- HPD
1 spot= 1 patient
PATIENTS CHARACTERISTICS N=242 (%)
Age≥ 65 years 118 (49%)
Smoking historyNon-smoker 18 (7%)Former 101 (42%)Current 123 (51%)
HistologyNon-squamous 172 (71%)Squamous 70 (29%)
PD-L1 statusPDL-1 negative 26 (11%)PDL-1 positive 30 (12%)Unknown 186 (77%)
Stage (advanceddisease)
IVA or IVB 204 (85%)N° met sites IO baseline
> 2 108 (45%)Performance status
0-1 217 (90%)IO Line
≥ 2 (range 2-7) 238 (98%)IO drug type
PD-1 inhibitor 235 (97%)PD-L1 inhibitor 7 (3%)
Mono or combo
Monotherapy 232 (96%)Molecular Status
EGFR mutation 6 (2,5%)ALK t 4 (1 5%)
TRG VARIATION N=242 (%)
Delta TGR ≤ 0 (regressing/stable tumors)
155 (64%)
Delta TGR > 0 (not regressing tumors) 87 (36%)
Delta TGR ≤ 50% 202 (84%)
Delta TGR > 50% (HPD) 40 (16%)
Response by deltaTGR
Typical and atypical response
patterns to IO
DELETERIOUS EFFECT OF IO
16%
45%
1.2%
15%
39%
HPD correlates with > 2 metastatic sites and predicts poor overall survival
CONCLUSIONS:
In this cohort, 40 patients (16%) experienced HPD.
HPD correlated with >2 metastatic sites before IO.
HPD is a negative prognostic factor in IO treated advanced NSCLC.
OVERALL SURVIVALCorrelation between HPD status and clinical characteristics
Patients characteristics
not-HPD
N=202
HPDN=40
TotalN=242
p-value(chi²)
Age 0.69
≥ 65 101 (50%) 17 (43%) 118 (49%)
< 65 101 (50%) 23 (58%) 124 (51%)
Smoking history 0.97Non-smoker 15 (7%) 3 (8%) 18 (7%)
Former 84 (42%) 17 (44%) 101 (42%)
Current 104 (51%) 19 (49%) 123 (51%)
Histology 0.80
Adenocarcinoma 125 (62%) 27 (68%) 152 (63%)
NSCLC- other 17 (8%) 3 (8%) 20 (8%)
Squamous 60 (30%) 10 (25%) 70 (29%)
PD-L1 status 0.16
PDL-1 negative 21 (43%) 5 (71%) 26 (46%)
PDL-1 positive 28 (57%) 2 (29%) 30 (54%)
Unknown 153 33 186Stage group 0.89
III (A or B) 32 (16%) 6 (15%) 38 (16%)
IV (A or B) 170 (84%) 34 (85%) 204 (84%)
N° of met sites (baseline IO)
0.03
IDO-1 and PD-L1 predict response to immunotherapy in advanced Non Small Cell Lung Cancer: an NGS and multiplex IHC analysis
Post ESMO 2017Oncologie thoracique
Immunothérapie
Sylvestre Le Moulec21 septembre 2017
Cellule tumorale
LymphocyteParadigme historique:
Cibler cellules Tumorales
Paradigme nouveau:Cibler cellules Immunitaires
Sylvestre Le Moulec, 21 septembre 2017
Metastatic
Immunothérapie dans les CBNPC métastatiques en 2017
2nd line and beyond
1st line monotherapy
In combination
1st Line
Nivolumab withno biomarker
Pembro in PDL1 +
Atezo in PDL1 +
SCC
ADK
Pembro in PDL1 + (> 50%)
Nivo + IpiVs
Durva + Treme
IO + Ct (ahead)Other lines
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Etude Pacific
La Lettre du CancérologueLa Lettre du Cancérologue
Etude PACIFIC
Etude de phase III, internationale, randomisée en double aveugle, multicentrique
• Patients de stades III, localement avancés, non opérables, n’ayant pas progressés après au moins 2 cycles de chimiothérapie à base de sels de platine et radiothérapie
• 18 et plus
• PS 0-1
• Durée vie estimée ≥12 semaines
Pas de sélection selon statutPDL1
Durvalumab10 mg/kg toutes 2 semaines jusqu’à12 mois (N = 476)
Placebo10 mg/kg toutes
2semaines jusqu’à12 mois (N = 237)
2:1 randomisation,Stratification selonage, sexe, statut
tabagique n = 713
Objectifs secondaires• Proportion de patients en
vie et sans progression à 12 et 18 mois (BICR)
• Taux réponse (BICR)• Durée objectif de réponse (
BICR)• Survie à 24 mois• Sécurité et tolérance• Qualité de vie• Pharmacocinétique• Immunogenicité
Objectifs primaires• Survie sans progression
selon une relectureindépendantes en aveugle(BICR), RECIST v1.1
• Survie globale
R
1-42 jourspost-cCRT
ESMO 2017 - D’après Paz-Ares L et al., abstr. LBA1-PR, actualisé
La Lettre du CancérologueLa Lettre du Cancérologue
Etude PACIFIC
SSP (Objectif primaire en intention de traitement)Pr
obab
ilité
de S
SP
1,0
0,8
0,6
0,4
0,2
0,0
0 3 6 9 12 15 18 21 24 27Time from randomization (months)
Placebo
Durvalumab
Stratification, hazard ratio,0.52 (IC95 : 0,42-0,65)Two-sided p < 0,0001
476 377 301 264 159 86 44 21 4237 163 106 87 52 28 15 4 3
10
No. a risqueDurvalumab
Placebo
Durvalumab(n = 476)
Placebo(n = 237)
SSP médiane (IC95), mois 16,8 (13,0-18,1) 5,6 (4,6-7,8)
SSP à 12 mois (IC95) 55,9 % (51,0-60,4) 35,3 % (29,0-41,7)
SSP à 18 mois (IC95) 44,2 % (37,7-50,5) 27,0 % (19,9-34,5)
ESMO 2017 - D’après Paz-Ares L et al., abstr. LBA1-PR, actualisé
La Lettre du CancérologueLa Lettre du Cancérologue
Etude PACIFIC
Temps à décés ou métastase à distance (intention de traitement)
1,0
0,8
0,6
0,4
0,2
0,0
1 3 6 9 12 15 18 21 24 27 30
Pro
babi
lity
of d
eath
or d
ista
nt m
etas
tasi
s
Hazard ratio, 0.52 (IC95 : 0,39-0,69)Two-sided p < 0,0001
Time from randomization (months)
Placebo
Durvalumab
No. a risqueDurvalumab
Placebo476 407 336 288 173 91 46 22 4 1 0237 184 129 106 63 32 16 5 4 0 0
Durvalumab Placebo
Temps médian (IC95),mois
23,2 (23,2-nonatteint) 14,6 (10,6-18,6)
ESMO 2017 - D’après Paz-Ares L et al., abstr. LBA1-PR, actualisé
Neoadjuvant
Adjuvant Metastatic1L 2LPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Checkmate 153Poursuite Nivo ?
Etude OAKTMB et PDL 1 NEG
Questions PratiquesHPD et Prédiction RP
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Checkmate 153Poursuite Nivo ?
La Lettre du CancérologueLa Lettre du Cancérologue ESMO 2017 - D. Spigel 297O actualisé D’après et al., abstr. 1
CheckMate 153 : Poursuite vs 1 an de traitement par nivolumab
Survie sans progression depuis la randomisation en fonction de la réponse
0 3 6 9 12 15 18 21 240
20
40
60
80
100
Poursuite
1 an de traitement
5349
4529
4126
3920
2814
1711
73
21
00
Temps post-randomisation (mois)
SSP
(%)
Réponse complète/ partielle
Médiane, mois(IC95)
Poursuite Non atteint
1 an de traitement 10,6 (4,8-NA)
HR = 0,45 ; IC95 : 0,24-0,85
0 3 6 9 12 15 18 21 240
20
40
60
80
100
Poursuite
1 an de traitement
2338
1521
1217
1013
77
55
32
10
00
Temps post-randomisation (mois)
SSP
(%)
Maladie stable
Médiane, mois(IC95)
Poursuite Non atteint(5,6-NA)
1 an de traitement 9,6 (4,5-12,6)HR = 0,44 ; IC95 : 0,17-1,09
Patients à risque (n)
La Lettre du CancérologueLa Lettre du Cancérologue ESMO 2017 - D. Spigel 297O actualisé D’après et al., abstr. 1
CheckMate 153 : pousuite vs 1 an de traitement
Survie sans progression après randomisation
0 3 6 9 12 15 18 21 240
20
40
60
80
100
poursuite1 an de traitement
7687
6050
5343
4933
3521
2216
105
31
00
Temps après randomisation (mois)
SSP
(%)
Médiane, mois(IC95)
SSP, %
À 6 mois À 1 an
poursuite NR (NR) 80 65
1 an de traitement 10,3 (6,4-15,2) 60 40
HR = 0,42 ; IC95 : 0,25-0,71
Patients à risque (n)
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Etude OAKTMB et PDL 1 NEG
Atezolizumab1200 mg IV q3w
PD or loss of clinical benefit
Docetaxel 75 mg/m2 q3w
Locally Advanced or Metastatic NSCLC
• 1–2 prior lines of chemo including at least 1 platinum based
• Any PD-L1 status
N = 1,225 enrolledaPD
R 1:1
Stratification factors• PD-L1 expression• Histology • Prior chemotherapy
regimens
Primary Endpoints (first 850 enrolled patients):
• OS in the ITT population• OS in patients with PD-L1 expression on ≥ 1% TC or IC
Secondary Endpoints: ORR, PFS, DoR, Safety
aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression). TC, tumor cells; IC, tumor-infiltrating immune cells. Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh
OAK background: study design
BLOOD-BASED BIOMARKERS FOR CANCER IMMUNOTHERAPY: TUMOR MUTATIONAL BURDEN IN BLOOD (bTMB) IS ASSOCIATED WITH IMPROVED ATEZOLIZUMAB EFFICACY IN 2L+ NSCLC (POPLAR AND OAK)
David R. Gandara,1 Marcin Kowanetz,2 Tony Mok,3 Achim Rittmeyer,4 Louis Fehrenbacher,5
David Fabrizio,6 Geoff Otto,6 Christine Malboeuf,6 Daniel Lieber,6 Sarah M. Paul,2 Lukas Amler,2
Todd Riehl,2 Erica Schleifman,2 Yan Li, 2 Craig Cummings,2 Priti S. Hegde,2 Wei Zou,2 Alan Sandler,2
Marcus Ballinger,2 David S. Shames2
1 UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 2 Genentech, Inc., South San Francisco, CA, USA; 3 Chinese University of Hong Kong, Hong Kong, People’s Republic of China; 4 Lungenfachklinik Immenhausen, Immenhausen, Germany; 5 Kaiser Permanente Medical Center, Vallejo, CA, USA; 6 Foundation Medicine Inc., Cambridge, MA, USA
a PD-L1 expression was evaluated by immunohistochemistry (IHC) using the VENTANA SP142 assay; TC3 or IC3, ≥50% of TC or ≥10% of IC express PD-L1. BEP, biomarker-evaluable population; IC, tumor-infiltrating immune cell; TC, tumor cell.
Limited overlap between bTMB ≥16 and PD-L1 expressiona (OAK BEP)
• Non-significant overlap between the bTMB ≥16 and TC3 or IC3 subgroups (Fisher exact test, P = 0.62)
• 19.2% of tumors with bTMB ≥16 were also TC3 or IC3
• 29.1% of tumors with TC3 or IC3 also had bTMB ≥16
PFS HR (95% CI)
OS HR (95% CI)
bTMB ≥16 0.64 (0.46, 0.91)
0.64 (0.44,0.93)
TC3 or IC3 0.62 (0.41, 0.93)
0.44 (0.27, 0.71)
bTMB ≥16 and TC3 or IC3
0.38 (0.17, 0.85)
0.23 (0.09, 0.58)
DR. Gandara. et al, bTMB in OAK and POPLAR
CLINICAL EFFICACY OF ATEZOLIZUMAB IN PD-L1 SELECTED SUBGROUPS DEFINED BY SP142 AND 22C3 IHC ASSAYS IN 2L+ NSCLC: RESULTS FROM THE RANDOMIZED OAK TRIAL Shirish Gadgeel,1 Marcin Kowanetz,2 Wei Zou,2 Fred R. Hirsch,3 Keith Kerr,4 David R. Gandara,5
Fabrice Barlesi,6 Keunchil Park,7 Mark McCleland,2 Hartmut Koeppen,2 Marcus Ballinger,2
Alan Sandler,2 Priti S. Hegde,2 Achim Rittmeyer8
1University of Michigan, Ann Arbor, MI, USA; 2Genentech, Inc., South San Francisco, CA, USA; 3University of Colorado Anschutz Medical Campus, Aurora, CO, USA; 4Aberdeen Royal Infirmary/Aberdeen University Medical School, Aberdeen, UK; 5UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 6 Aix Marseille Universite, Assistance Publique Hôpitaux de Marseille, Marseille, France; 7 Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 8 Lungenfachklinik Immenhausen, Immenhausen, Germany.
• OS benefit observed in PD-L1 negative populations as defined by either assay
SP142 assay: TC0 and IC0, PD-L1 expression on <1% TC and IC.22C3 assay: TPS <1%, PD-L1 expression on <1% TC. Dx-, no or low PD-L1 expression.
Overall Survival in PD-L1 Negative Subgroups in OAK BEP
OS HR (95% CI)
SP142 Dx-(N = 150)
0.55 (0.37, 0.80)
22C3 Dx-(N = 218)
0.61 (0.45, 0.84)
+ Censored
Atezolizumab
Docetaxel
SP142 TC0 and IC0
Months
+ Censored
Atezolizumab
Docetaxel
22C3 TPS < 1%
Ove
rall
Surv
ival
(%)
Months
Ove
rall
Surv
ival
(%)
Gadgeel S, et al. 22C3 vs SP142 in OAK
• Patients without PD-L1 expression, as defined by both IHC assays, continue to show improved survival with atezolizumab compared with docetaxel
IC, tumor infiltrating immune cell; TC, tumor cell; TPS, tumor proportion score.
Overall Survival in Subgroup Defined PD-L1–Negative by Both Assays
TC0 and IC0 TPS < 1%
SP142 22C3and
+ CensoredDocetaxel (N = 60)
Atezolizumab (N = 55)
OS HR, 0.63 (95% CI: 0.41, 0.97) P = 0.0347
Ove
rall
Surv
ival
(%)
Months
Gadgeel S, et al. 22C3 vs SP142 in OAK
Neoadjuvant
Adjuvant MetastaticPreventive?
Defining the Optimal Timing for Checkpoint Blockade During Disease Evolution ?
Surgery
Locally advanced
Questions PratiquesHPD et Prédiction RP
Roberto Ferrara1*, Caroline Caramella2, Matthieu Texier3, Clarisse Audigier-Valette4, Laurent Tessonnier5, Laura Mezquita1, Jihene Lahmar1, Julien Mazieres6, Gerard Zalcman7, Solenn Brosseau7, Virginie Westeel8, Sylvestre Le Moulec9, Laura Leroy9, Boris Duchemann10, Rémi Veillon11,
David Planchard1, Marie-Eve Boucher1, Serge Koscielny3, Jean Charles Soria12, Benjamin Besse1.1 Medical Oncology Department, Gustave Roussy, Villejuif, France, 2 Radiology Department, Gustave Roussy, Villejuif, France, 3 Biostatistics and Epidemiology Department, Gustave
Roussy, Villejuif, France, 4 Pneumology Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France, 5 Nuclear Medicine Department, Centre Hospitalier Toulon Sainte-Musse, Toulon, France, 6 Thoracic Oncology Department, Centre Hospitalier Universitaire de Toulouse, Toulouse, France, 7 Thoracic Oncology Department, Hôpital Bichat-Claude Bernard,
Université Paris-Diderot, Paris, France, 8 Pneumology Department, Centre Hospitalier Universitaire de Besançon, Besançon, France, 9 Medical Oncology Department, Institute Bergonié, Bordeaux, France, 10 Medical Oncology Department, Hôpital Avicenne, Bobigny, France, 11 Medical Oncology Department, Centre Hospitalier Universitaire de Bordeaux-Hôpital Haut-
Lévêque, Pessac, France,8 Drug Development Department (DITEP), Gustave Roussy and Paris Sud University, Villejuif, France
HYPERPROGRESSIVE DISEASE (HPD) IS FREQUENT IN NON-SMALL CELL LUNG CANCER (NSCLC) PATIENTS TREATED WITH ANTI PD-1/PD-L1 MONOCLONAL
ANTIBODIES (IO) AND PREDICTS POOR SURVIVAL
Hyperprogressive disease (HPD) is an “atypical” & rapid phenomenon in IO treated NSCLC
AIM OF THIS STUDY: To assess the prevalence, the prognostic
value of HPD and the correlation with clinical features
in a large multicentric cohort of IO treated advanced NSCLC patients.
PD
HPD
Time
TumorVolume
Delta TGR: TGR IO – TGR pre-IO
HPD: deltaTGR >50%
Scan before IO
Scan before IO Scan IO start
Scan IO start
Scan during IO
Scan during IO
Typical & atypical
response patterns to IO
HPD is a frequent phenomenon and it can occur in ~16% of IO treated NSCLC patients
Und
er t
reat
men
t per
cent
chan
ge
in t
um
or
volu
me
per
month
-100
0
100
200
300
400
500
Prebaseline percent change in tumor volume per month
-100 0 100 200 300 400 500
Statut delta TGR <50%delta TGR>=50% (Hyperprogressor)
TGR pre-IO (%)
TGR
-IO (%
)
Blue = HPD
Black = Not- HPD
1 spot= 1 patient
PATIENTS CHARACTERISTICS N=242 (%)
Age≥ 65 years 118 (49%)
Smoking historyNon-smoker 18 (7%)Former 101 (42%)Current 123 (51%)
HistologyNon-squamous 172 (71%)Squamous 70 (29%)
PD-L1 statusPDL-1 negative 26 (11%)PDL-1 positive 30 (12%)Unknown 186 (77%)
Stage (advanceddisease)
IVA or IVB 204 (85%)N° met sites IO baseline
> 2 108 (45%)Performance status
0-1 217 (90%)IO Line
≥ 2 (range 2-7) 238 (98%)IO drug type
PD-1 inhibitor 235 (97%)PD-L1 inhibitor 7 (3%)
Mono or combo
Monotherapy 232 (96%)Molecular Status
EGFR mutation 6 (2,5%)ALK t 4 (1 5%)
TRG VARIATION N=242 (%)
Delta TGR ≤ 0 (regressing/stable tumors)
155 (64%)
Delta TGR > 0 (not regressing tumors) 87 (36%)
Delta TGR ≤ 50% 202 (84%)
Delta TGR > 50% (HPD) 40 (16%)
Response by deltaTGR
Typical and atypical response
patterns to IO
DELETERIOUS EFFECT OF IO
16%
45%
1.2%
15%
39%
HPD correlates with > 2 metastatic sites and predicts poor overall survival
CONCLUSIONS:
In this cohort, 40 patients (16%) experienced HPD.
HPD correlated with >2 metastatic sites before IO.
HPD is a negative prognostic factor in IO treated advanced NSCLC.
OVERALL SURVIVALCorrelation between HPD status and clinical characteristics
Patients characteristics
not-HPD
N=202
HPDN=40
TotalN=242
p-value(chi²)
Age 0.69
≥ 65 101 (50%) 17 (43%) 118 (49%)
< 65 101 (50%) 23 (58%) 124 (51%)
Smoking history 0.97Non-smoker 15 (7%) 3 (8%) 18 (7%)
Former 84 (42%) 17 (44%) 101 (42%)
Current 104 (51%) 19 (49%) 123 (51%)
Histology 0.80
Adenocarcinoma 125 (62%) 27 (68%) 152 (63%)
NSCLC- other 17 (8%) 3 (8%) 20 (8%)
Squamous 60 (30%) 10 (25%) 70 (29%)
PD-L1 status 0.16
PDL-1 negative 21 (43%) 5 (71%) 26 (46%)
PDL-1 positive 28 (57%) 2 (29%) 30 (54%)
Unknown 153 33 186Stage group 0.89
III (A or B) 32 (16%) 6 (15%) 38 (16%)
IV (A or B) 170 (84%) 34 (85%) 204 (84%)
N° of met sites (baseline IO)
0.03
IDO-1 and PD-L1 predict response to immunotherapy in advanced Non Small Cell Lung Cancer: an NGS and multiplex IHC analysis