Oncologie Thoracique - Canceraquitaine

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.



• 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)



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


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)



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


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)


Neoadjuvant

Adjuvant Metastatic1L 2LPreventive?


Surgery

Locally advanced

Checkmate 153Poursuite Nivo ?

Etude OAKTMB et PDL 1 NEG

Questions PratiquesHPD et Prédiction RP

Neoadjuvant



Surgery

Locally advanced


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


SSP

(%)

Maladie stable


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

(%)


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


Neoadjuvant



Surgery

Locally advanced


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


Neoadjuvant



Surgery

Locally advanced


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



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



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


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)



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


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)


Neoadjuvant

Adjuvant Metastatic1L 2LPreventive?


Surgery

Locally advanced




Neoadjuvant



Surgery

Locally advanced


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


SSP

(%)

Réponse complète/ partielle


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


SSP

(%)

Maladie stable


Poursuite Non atteint(5,6-NA)

1 an de traitement 9,6 (4,5-12,6)HR = 0,44 ; IC95 : 0,17-1,09


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

(%)


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


Neoadjuvant



Surgery

Locally advanced


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

(%)


• 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


Neoadjuvant



Surgery

Locally advanced


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

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