Le Cancer à Petites Cellules (CPC) - SPLF · 2019. 10. 23. · Présentation clinique et bilan d’extension 9 | Page BILAN D’EXTENSION Le bilan doit inclure : - Un examen clinique,

Le Cancer à Petites Cellules (CPC)

Isabelle MONNET Centre Hospitalier Intercommunal de Créteil

Présentation clinique et bilan d’extension

•  Envahissement hilaire et médiastinal important associé –  souvent à une atteinte métastatique (foie, surrénales, cerveau, os…) –  parfois à un syndrome paranéoplasique

•  Le bilan initial: –  examen clinique complet –  biologie standard y compris LDH –  histologie (fibroscopie bronchique, ponction sous scanner, abord médiastinal) –  scanner thoracoabdominopelvien –  IRM encéphalique –  scintigraphie osseuse souvent remplacée par le TEP scanner (indispensable si

un traitement local envisagé). –  aucune place pour les marqueurs tumoraux –  EFR avec DLCO si une radiothérapie thoracique est envisagée .

70 Farago and Keane. Clinical management of SCLC

© Translational lung cancer research. All rights reserved. Transl Lung Cancer Res 2018;7(1):69-79tlcr.amegroups.com

of SCLCs express at least one neuroendocrine marker

detectable by immunohistochemistry, neuroendocrine

marker detection is not required for diagnosis (8).

Clinical staging of any solid tumor is ultimately a

question of “where is the cancer?” SCLC is typically staged

using CT scans. In addition, the use of PET scan and brain

MRI has increased the sensitivity for detection of distant

metastases (9). Two staging systems are commonly used.

The Veterans’ Administration Lung Study Group (VALSG)

introduced a two-stage classification system in the 1950s which was later revised in 1989 [(10), and reviewed in (9)].

Briefly, this system classifies SCLC as limited-stage (LS), in which the disease is confined to an area within the thorax that can be encompassed within a radiation port, and

extensive-stage (ES), in which disease cannot be classified

as limited, and may include malignant pleural or pericardial

effusions or metastases consistent with hematogenous

spread.

The International Association for the Study of Lung

Cancer (IASLC) subsequently proposed that the TNM

lung cancer staging system be used in place of the VALSG

system (11). In the TNM system, cancers are staged using

tumor (T), nodal (N), and metastatic (M) parameters. An

updated eighth edition of the TNM lung cancer staging

system is anticipated within the next year (12), and again

appears to have prognostic value (13). Although the

TNM system is more precise, for practical purposes the

VALSG system is often still used clinically, as further sub-

classification by stage rarely impacts management.

Limited stage SCLC

Approximately 30% of patients with SCLC present with

early stage disease, classified as limited stage by the VALSG system or as M0 by the TNM system. A small subset

of these patients present without clinical or pathologic

evidence of mediastinal lymph node involvement. For those

T1–T2 N0 M0 SCLCs, surgical resection is recommended

for patients with sufficient performance status (14,15). While there are no prospective studies assessing the benefit of adjuvant chemotherapy in this setting, a retrospective

series of 1,574 cases in the National Cancer Database between 2003 and 2011 indicates that overall survival (OS)

was improved among those patients who received adjuvant

chemotherapy with or without adjuvant radiation (16).

Furthermore, in a retrospective review of 82 patients

at Johns Hopkins University who underwent surgical

resection of SCLC, outcomes were improved for those who

received platinum-based neoadjuvant or adjuvant therapy

compared to non-platinum regimens (17). Thus, platinum-

based adjuvant therapy is generally recommended following

surgical resection of any early-stage, node-negative SCLC.

The vast majority of LS-SCLCs have mediastinal lymph

node involvement at the time of diagnosis. The optimal

treatment for these cancers is concurrent chemotherapy and

radiation (15). This issue remained controversial until the early 1990s. Previously, numerous randomized trials had

been conducted to assess the effect of thoracic radiotherapy

in patients with LS-SCLC, but most were not sufficiently powered to detect differences in survival. Subsequently, two

meta-analyses published in 1992 established that concurrent

chemotherapy and RT improves survival and local control

of disease compared to chemotherapy alone (18,19). In

the larger of the two studies, which included 13 trials and

2,140 patients with limited disease, with a median follow up of 43 months, the relative risk of death in the concurrent therapy group compared to the chemotherapy alone group

was 0.86, and the OS benefit at 3 years was 5.4% (19). The optimal radiation schedule for LS-SCLC remains

controversial. Turrisi et al. randomized 417 patients to receive a total of 45 Gy radiotherapy, either once-daily (1.8 Gy in 25 fractions) or twice-daily (1.5 Gy in 30 fractions) with concurrent cisplatin and etoposide (VP-16) (20). After

a median follow up of nearly 8 years, there was a significant

Figure 1 Coronal chest CT image of patient with SCLC at the

time of diagnosis. The tumor involves the left upper lobe (green

arrow) and extends into the mediastinum (green arrow head). CT,

computed tomography; SCLC, small cell lung cancer.


9 | P a g e

BILAN D’EXTENSION

Le bilan doit inclure : - Un examen clinique, - Un bilan biologique (ionogramme, bilan hépatique, LDH, NFP, bilan de coagulation), - Une fibroscopie bronchique, - Un scanner thorax et abdomen, une IRM ou un scanner cérébral et une scintigraphie osseuse, - Une TEP devrait être réalisée lorsqu’un traitement local est envisagé.

OPTION : exploration médullaire, si tous ces sites sont négatifs.

- Le bilan peut s’arrêter dès l’identification d’un premier site métastatique. L’ordre des examens sera orienté par la clinique, la pénibilité, la facilité d’accès des examens complémentaires et la fréquence des sites métastatiques (moelle, cerveau, foie, os…). Par contre, le bilan pourra être exhaustif en cas de possibilité d’inclusion dans un essai clinique.

- Lorsqu’une radiothérapie thoracique est envisagée, un bilan respiratoire associant EFR et DLCO est recommandé.

Il n’est pas nécessaire de doser un marqueur tumoral pour le diagnostic, le pronostic ou le suivi du patient. Evaluation gériatrique : la détermination du score G8 est recommandée, même si aucun score gériatrique n’est actuellement validé en cancérologie thoracique. Une évaluation gériatrique peut être proposée pour aider à la prise en charge du patient.

Figure 3 – Arbre d’aide à la décision pour le bilan d’extension des cancers bronchiques, (INCa, extrait de (3))

Intérêt du TEPscan non formellement démontré mais: •  meilleure détection des métastases •  orientation des biopsies •  meilleure ciblage de la RT


0

0,2

0,4

0,6

0,8

1

0 24 48 72 96

HR 0,87 (0,71-1,07) p=0,198

0

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0,4

0,6

0,8

1

0 24 48 72 96

HR 0,87 (0,70-1,08) p=0,192

Sur

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glob

ale

(%)

TEP 18F-FDG Scanner

Survieglobale

Surviesansprogression

Temps (mois) Temps (mois)

NombredepatientsavecTEP18FDG

320

0

20

40

60

80

100

102 3927

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GB

France

Canada

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“étude de sous groupe” non planifiée de CONVERT: •  Évaluer l’effet de la méthode de staging (scanner vs TEP) sur la SSP et la SG

des patients atteints de CBPC localisés traités par radio-chimiothérapie (n=540) •  Déterminer la valeur pronostique de paramètres métaboliques et volumétriques

du TEP au 18FDG pré-thérapeutique (n=94)

Faivre-Finn WCLC 2018 Le scanner peut être suffisant pour le staging des CBPC ?

Le TEP au 18FDG peut être utile pour guider la radiothérapie

Staging: 2 systèmes

VALSG (Veterans’ Administration Lung Study Group) •  stades localisés

–  maladie entrant dans un champ d’irradiation y compris adénopathies sus claviculaires homolatérales

•  stades disséminés ou diffus –  maladie ne pouvant pas entrer dans un champ d’irradiation ou présentant un

épanchement tumoral pleural ou péricardique tumoral, des adénopathies hilaires ou sus claviculaires controlatérales

–  ou des localisations à distance

IASLC (International Association for the Study of Lung Cancer) •  système TNM (8ème édition)

système TNM est plus précis mais VALSG plus adapté aux décisions thérapeutiques

Traitement

•  Chimiothérapie:

–  pierre angulaire du traitement quel que soit le stade –  association de référence: platine et étoposide (PE) plus efficace et mieux tolérée que les protocoles comportant des agents alkylants comme le CAV (cyclophosphamide, adriamycine, vincristine) –  supériorité confirmée par une méta analyse –  nombre optimal de cures (4 ou 6 ?) –  synergie avec la radiothérapie

•  peut êre utilisée pour les formes localisées dans les protocoles de radiochimiothérapie.

–  schéma de référence en Europe et aux États-Unis. –  au Japon un essai randomisé a montré la supériorité de l’association

cisplatine/ irinotécan sur cisplatine/étoposide en terme de taux de réponse, survie sans progression et survie globale

Traitement

•  Tentatives d’optimisation –  intensification de doses, régimes à 3 ou 4 drogues, alternance de différents

régimes sans résistances croisées, maintenance, consolidation…..

•  Le régime PE reste la référence –  importance de respecter les doses théoriques en particulier en début de

traitement –  choix du sel de platine:

•  pas de différence signicative entre cisplatine et carboplatine selon la méta analyse COCIS

•  choix selon âge, comorbidités, et différentes toxicités attendues

Traitement: formes localisées au thorax

•  30 % des patients •  le traitement est une urgence médicale car il peut être curatif •  taux de réponse de 90 %, médiane de survie 15-20 mois et

survie à 5 ans de 15 à 25 %. •  moins de 5 % des patients présentent un CPC T1-T2N0M0

–  un traitement chirurgical est alors recommandé si le performance status et le bilan fonctionnel le permettent (études rétrospectives, registres)

–  survie à 5 ans : 47 % pour les T1-T2N0, montant à 67 % si les patients avaient reçu chimiothérapie et irradiation prophylactique cérébrale (IPC)

–  la chirurgie sera donc suivie d’une chimiothérapie adjuvante à base de platine - étoposide

–  chez ces patients ayant un CPC de stade I, l’incidence des métastases cérébrales est de l’ordre de 10 %, l’intérêt de l’IPC reste discuté (RCP)

Früh Ann Oncol 2013, Yang J Clin Oncol 2016, Le Péchoux J Thorac Oncol 2017

Traitement: formes localisées au thorax la radiothérapie thoracique

•  standard thérapeutique: –  association de radio et chimiothérapie –  deux méta analyses ont démontré dès 1992 le rôle de la radiothérapie

thoracique, permettant un gain en survie de 5,4 % à 2 ans et 3 ans

•  quel timing? –  radio-chimiothérapie concomitante –  la radiothérapie doit débuter précocement, avant le 3e cycle de

chimiothérapie, permettant un gain de survie de 5 % à 2 ans par rapport à une irradiation tardive (méta-analyse)

–  absence de bénéfice à débuter l’irradiation dès la 1ère cure par rapport à la 3e cure

Traitement: formes localisées au thorax: la radiothérapie thoracique

Faivre-Finn Lancet Oncol 2017

ChimiothérapieRadiothérapie

RTthoraxaprèsrandomisationRTdébutéeàJ22cycle1•  RT3DouIMRT•  PasdeRTprophylactique

desganglions•  ProgrammeAssur.Qual.

Chimiothérapie4à6cycles•  Cisplatine25mg/m2J1-3

ou75mg/m2J1•  Etoposide100mg/m2J1-3

Facteursdestratification•  Centre•  No.decycleschimio:4-6•  PS:0,1vs2

•  Imageriecérébraleobligatoireavantlarandomisation

•  IPCpasaprès6semainesaprèsladernièreCT

Stable,RP,RC:IPC

Siprogression:pasd'IPC

Enregistremen

t-Ran

domisation

Réévalua

tion

CBPC

localisé

RT45Gy/30F/19JRTthoracique2fois/j(2/J)

J1J3 J22J24 J43J45 J64J66

RT66Gy/33F/45JRTthoracique1fois/j(1/J)

J1J3 J22J24 J43J45 J64J66

547 patients inclus survie à 2 ans idem: 56 % pour le schéma bi fractionné vs 51 % pour le mono fractionné, toxicité comparable. résultats meilleurs que les résultats historiques (47 % vs 41 %) dans l’essai importance de l’optimisation du staging et la meilleure qualité de la radiothérapie.

•  quelle dose/fractionnement? phase III CONVERT

Traitement: formes localisées au thorax: la radiothérapie thoracique

Hu, WCLC 2018

CBPClocalisésEP×2

Patientssansmaladie

progressive

Irradiationduvolumerésiduelpost-chimiothérapie

(Brasexploratoire)

Irradiationduvolumeinitial

prés-chimiothérapie(Brascontrôle)

PatientsachevantRCouRP

Irradiationcérébrale

prophylactiqueEtfollow-up

Irradiationdessitesenvahispourles2bras

S1S3S5S7S9S11S13S15S17S19S21

Chimiothérapieparetoposide(100mg/m2,j1-3)etcisplatine(80mg/m2,j1)oucarboplatine(AUC=5,j1)estadministréeIVà21joursd'intervallepour4to6cycles.

RTréaliséeparfractionde1.5Gy2fois/jen30frt(=CONVERT)sur3semainespouruntotalde45Gy.

IPC est délivrée 1 fois/j pour un total de 30 Gy ou 25 Gy.

HR: 0.91, 95% CI: 0.70-1.19

SG BrasexploréN=159

BrascontrôleN=150 P

Médiane(mois)

22,1(18.2-26.0)

26,9(23.5-30.3)

0,511an 81,1% 85,3%

3ans 31,6% 36,6%

5ans 23,9% 26,1%

•  Quel volume?

Pas de différence de contrôle local ni de survie globale

Traitement: formes localisées au thorax l’Irradiation Prophylactique Cérébrale (IPC)

•  Les premiers essais randomisés ont montré que l’IPC réduit l’incidence des MC

•  La méta-analyse d’Aupérin : •  7 essais randomisés, pour démontrer l’impact de l’IPC •  diminution de l’incidence des MC à 3ans: 33% vs 59% (p=0,001) •  augmentation de la survie globale de 5,4 % à 3 ans : 20,7 % vs 15,3 %

(p = 0,01). •  patients en réponse complète après la chimiothérapie et localisés au

thorax (86%)

•  Le schéma optimal pour l’IPC est de 25 Gy en 10 fractions qui a montré sa supériorite par rapport à 36 Gy

•  Un problème majeur: la neurotoxicité potentielle –  déclin cognitif (lésions hippocampiques?) –  2 pistes: la protection de l’hippocampe pendant l’irradiation et l’utilisation

de mémantine

Traitement: formes localisées au thorax standards de traitement

Recommandations NCCN 2018, référentiels AURA 2018

•  4 à 6 cycles de chimiothérapie par platine/étoposide •  radiothérapie concomitante de type conformationnel débutant avant le 3e cycle

•  Soit 66 Gy en monofractionné (33 fractions, 45 jours) •  Soit 45 Gy en bifractionné (30 fractions, 19 jours) •  volumes à irradier: ceux persistant après les 2 premières cures de

chimiothérapie + les ganglions atteints sur le TEP initial •  le schéma séquentiel peut être une option chez les patients âgés ou PS2

•  une IPC–  chez les patients en réponse complète ou « bonne réponse » –  25 Gy en 10 fractions, moins de 75 ans?

•  surveillance chez les patients en réponse et stables: –  visite tous les 3 mois (an1-2), tous les 6 mois (an 3) puis tous les ans –  avec examen clinique, scanner thoracoabdominopelvien, IRM cérébrale

tous les 3 mois si le patient n’a pas eu d’IPC.

Traitement: formes disséminées •  70 % des patients •  traitement le plus souvent palliatif •  taux de réponse de 60%, médiane de survie 10-12 mois, survie

à 2 ans 10%, récidive quasi inéluctable •  chimiothérapie:

–  doublet de chimiothérapie PE, 4 à 6 cures –  option pour les patients PS 0-1 l’association PCDE (étoposide–platine–

cyclophosphamide− épirubicine) sous couvert de facteurs de croissance


10 | P a g e

TRAITEMENT DES CBPC DE STADES IV

Le traitement des CBPC diffus repose essentiellement sur la chimiothérapie. Il est palliatif, ne permettant qu’exceptionnellement une survie supérieure à 2 ans. Sans traitement, la survie est brève (3 à 6 mois) ; avec un traitement, la médiane de vie est autour de 10-12 mois avec une amélioration nette de la qualité de vie. 1. Chimiothérapie de première ligne

Recommandations – Chimiothérapie de 1ère ligne / Stades - cisplatine 80 à 100 mg/m² J1 - étoposide 80 à 120 mg/m² J1, J2, J3 (IV) Reprise du cycle toutes les 3 semaines, 4 à 6 cycles Après réponse partielle ou complète, l’intérêt de réaliser une chimiothérapie au-delà de 6 cycles n’est pas démontré.

OPTIONS : -«PCDE» : cisplatine 100 mg/m² J2, étoposide 100 mg/m² J1, J2, J3, cyclophosphamide 400 mg/m² J1-2-3, épirubicine 40 mg/m² J1 toutes les 4 semaines. A réserver aux patients, PS 0 ou 1, et sous couvert de FCH, 4 à 6 cycles (4). -Il est possible de remplacer le cisplatine par le carboplatine AUC 5 (Calvert (5)), notamment chez le sujet âgé ou fragile (PS > ou égal 2) (6). -Irradiation cérébrale prophylactique après imagerie cérébrale négative pour les patients de moins de 75 ans, PS 0 à 2, et en réponse objective après la chimiothérapie (7). Un délai minimum de 4 semaines doit être respecté entre la fin de la chimiothérapie et le début de la radiothérapie. Dose : fractions inférieures ou égales à 2,5 Gy pour une dose totale de 25 à 30 Gy (10 x 2,5 Gy ou 15 x 2 Gy). -Irradiation thoracique complémentaire pour les patients en PS 0-1, en réponse significative après la chimiothérapie et avec une masse tumorale extra-thoracique limitée, à discuter en RCP (8). Une étude rétrospective sur une partie des patients inclus dans cet essai suggère que le bénéfice d’une irradiation thoracique est réservée aux patients avec 3 sites métastatiques ou moins ET avec un résidu tumoral thoracique.

2. Chimiothérapie de seconde ligne et ultérieure Les patients qui rechutent après une réponse initiale sont qualifiés de :

- "hautement sensibles" si la ré-évolution survient plus de 6 mois après l'arrêt de la chimiothérapie de première ligne,

- «sensibles» entre 3 et 6 mois, - «résistants» en cas de rechute avant 3 mois, - ou "réfractaires" en cas de progression sous traitement.

Ces patients bénéficient d’une chimiothérapie de deuxième ligne, qui dépend de l’état du patient, de la réponse à la première ligne et de ses comorbidités (9,10). 2.1. Chez les patients «hautement sensibles» et «sensibles» Reprise du schéma cisplatine ou carboplatine et étoposide.

Chez les patients pour lesquels la reprise de la chimiothérapie à base de sels de platine et étoposide n’est pas appropriée, le topotecan a démontré son efficacité. Les associations CAV et carboplatine-paclitaxel peuvent aussi être utilisées.

10 | P a g e

TRAITEMENT DES CBPC DE STADES IV

Le traitement des CBPC diffus repose essentiellement sur la chimiothérapie. Il est palliatif, ne permettant qu’exceptionnellement une survie supérieure à 2 ans. Sans traitement, la survie est brève (3 à 6 mois) ; avec un traitement, la médiane de vie est autour de 10-12 mois avec une amélioration nette de la qualité de vie. 1. Chimiothérapie de première ligne

Recommandations – Chimiothérapie de 1ère ligne / Stades - cisplatine 80 à 100 mg/m² J1 - étoposide 80 à 120 mg/m² J1, J2, J3 (IV) Reprise du cycle toutes les 3 semaines, 4 à 6 cycles Après réponse partielle ou complète, l’intérêt de réaliser une chimiothérapie au-delà de 6 cycles n’est pas démontré.

OPTIONS : -«PCDE» : cisplatine 100 mg/m² J2, étoposide 100 mg/m² J1, J2, J3, cyclophosphamide 400 mg/m² J1-2-3, épirubicine 40 mg/m² J1 toutes les 4 semaines. A réserver aux patients, PS 0 ou 1, et sous couvert de FCH, 4 à 6 cycles (4). -Il est possible de remplacer le cisplatine par le carboplatine AUC 5 (Calvert (5)), notamment chez le sujet âgé ou fragile (PS > ou égal 2) (6). -Irradiation cérébrale prophylactique après imagerie cérébrale négative pour les patients de moins de 75 ans, PS 0 à 2, et en réponse objective après la chimiothérapie (7). Un délai minimum de 4 semaines doit être respecté entre la fin de la chimiothérapie et le début de la radiothérapie. Dose : fractions inférieures ou égales à 2,5 Gy pour une dose totale de 25 à 30 Gy (10 x 2,5 Gy ou 15 x 2 Gy). -Irradiation thoracique complémentaire pour les patients en PS 0-1, en réponse significative après la chimiothérapie et avec une masse tumorale extra-thoracique limitée, à discuter en RCP (8). Une étude rétrospective sur une partie des patients inclus dans cet essai suggère que le bénéfice d’une irradiation thoracique est réservée aux patients avec 3 sites métastatiques ou moins ET avec un résidu tumoral thoracique.

2. Chimiothérapie de seconde ligne et ultérieure Les patients qui rechutent après une réponse initiale sont qualifiés de :

- "hautement sensibles" si la ré-évolution survient plus de 6 mois après l'arrêt de la chimiothérapie de première ligne,

- «sensibles» entre 3 et 6 mois, - «résistants» en cas de rechute avant 3 mois, - ou "réfractaires" en cas de progression sous traitement.

Ces patients bénéficient d’une chimiothérapie de deuxième ligne, qui dépend de l’état du patient, de la réponse à la première ligne et de ses comorbidités (9,10). 2.1. Chez les patients «hautement sensibles» et «sensibles» Reprise du schéma cisplatine ou carboplatine et étoposide.

Chez les patients pour lesquels la reprise de la chimiothérapie à base de sels de platine et étoposide n’est pas appropriée, le topotecan a démontré son efficacité. Les associations CAV et carboplatine-paclitaxel peuvent aussi être utilisées.

Traitement: formes disséminées la radiothérapie thoracique Articles

www.thelancet.com Vol 385 January 3, 2015 39

radiotherapy group and 3% (95% CI 2–8) in the control group (p=0·004). The number of patients needed to treat to avoid one death was 10·6 (95% CI 6·1–42·5).

Median survival was signifi cantly diff erent between patients in whom diagnosis of extensive stage disease was on the basis of intrathoracic disease only (11·8 months), distant metastases (7·5 months), or both factors (8·3 months; p<0·0001). We recorded no signifi cant diff erences in overall survival in subgroups divided by presence of intrathoracic disease at randomisation, sex, age, response to chemo therapy, WHO performance score, or extent of disease (ie, whether extensive stage disease was diagnosed on the basis of distant metastases, volume of intrathoracic tumour, or both (fi gure 3).

Progression was less likely in the thoracic radiotherapy group than in the control group (HR=0·73, 95% CI 0·61–0·87, p=0·001; fi gure 4). Progression-free survival at 6 months was 24% (95% CI 19–30) for the thoracic radiotherapy group and 20% (95% CI 16–26) in the control group (p=0·001). Median progression-free survival was 4 months for the thoracic radiotherapy group and 3 months for the control group. In a test for interaction of factors with treatment, there was no signifi cant diff erence in the eff ect of thoracic radiotherapy on progression-free survival for presence of intrathoracic disease at random-isation (p=0·11), sex (p=0·12), age (p=0·19), response to chemotherapy (p=0·92), WHO performance score (p=0·94), and extent of disease (p=0·78).

Isolated intrathoracic progression was rarer in the thoracic radiotherapy group (n=49, 19·8%) than in the control group (n=114, 46·0%, p<0·0001). Intrathoracic progression either with or without progression elsewhere occurred in 108 (43·7%) in the thoracic radiotherapy group versus 198 (79·8%) in the control group (p<0·0001). Brain metastases occurred in 24 (9·7%) versus 13 (5·2%; p=0·09), and disease progression at other sites occurred in 149 (60·3%) versus 100 (40·3%; p<0·0001). Table 3 shows patterns of progression. We considered pro-gression occurring at diff erent organ sites within 30 days as simultaneous progression. The thorax was the fi rst site of disease progression for 103 (41·7%) patients in the thoracic radiotherapy group versus 193 (77·8%) in the control group (p=0·009).

DiscussionThe addition of thoracic radiotherapy to prophylactic cranial irradiation for patients with extensive stage small-cell lung cancer did not improve survival at 1 year. However, 2-year overall survival was signifi cantly improved and progression-free survival was signifi cantly greater. Further more, we report an almost 50% reduction in intrathoracic recurrences. These positive results are consistent with fi ndings from studies of patients with locally advanced non-small-cell lung cancer showing that improved local control leads to improved survival.16

As might be expected from treatment of metastatic extensive stage small-cell lung cancer, overall survival

was much the same in both groups during the fi rst 9 months, but a signifi cant diff erence in favour of the thoracic radiotherapy emerged at 2 years. 1 year survival for patients who received prophylactic cranial irradiation only was similar to that of patients who received only this treatment in an EORTC study6 (27·1% versus 27·6%), suggesting that our fi ndings are representative and applicable to patients with extensive stage small-cell lung cancer. We measured median survival and 2 year survival from the time of randomisation, which was about 4 months after the start of chemotherapy. As such, our

Number at riskThoracic radiotherapy

groupControl group

0

247

248

6

147

160

12

67

61

18

26

17

24

14

5

30

7

1

Time (months)

0

0·2

0·4

0·6

0·8

1·0

Over

all s

urvi

val

Thoracic radiotherapy groupControl group

Figure 2: Kaplan-Meier curves for overall survival

Hazard ratio (CI)*

Thoracic radiotherapy

Control

Intrathoracic disease Yes NoSex Men WomenAge (years) 36–70 71–85Response to chemotherapy CR PR Good responseWHO performance status 0 1 2Extensive disease based on Intrathoracic disease Distant metastases BothTotal

p value

0·35

0·06

0·58

0·58

1·00

0·86

195/215 29/33

122/136 102/112

170/189 54/59

12/13 153/170 59/65

65/70 136/155 23/23

9/15 172/188 43/45 224/248

Events/patients Events/patients

175/213 26/34

115/135 86/112

152/193 49/54

10/13 148/179 43/55

74/97 101/121 26/29

11/19 161/190 29/38 201/247

0·80 (0·61−1·05) 1·09 (0·54−2·18)

1·01 (0·72−1·41) 0·68 (0·46−1·00)

0·82 (0·61−1·09) 0·96 (0·58−1·60)

1·38 (0·45−4·22) 0·81 (0·60−1·10) 0·76 (0·45−1·28)

0·85 (0·55−1·32) 0·84 (0·60−1·18) 0·83 (0·39−1·78)

0·68 (0·20−2·31) 0·87 (0·66 −1·16) 0·89 (0·48−1·65) 0·84 (0·69−1·02)

10 1·5 20·5

Favours controlFavours thoracicradiotherapy

Figure 3: Overall survival at 1 year in subgroups*CI is 99% for subgroups, 95% for total. CR=complete response. PR=partial response.

Articles

www.thelancet.com Vol 385 January 3, 2015 39

radiotherapy group and 3% (95% CI 2–8) in the control group (p=0·004). The number of patients needed to treat to avoid one death was 10·6 (95% CI 6·1–42·5).

Median survival was signifi cantly diff erent between patients in whom diagnosis of extensive stage disease was on the basis of intrathoracic disease only (11·8 months), distant metastases (7·5 months), or both factors (8·3 months; p<0·0001). We recorded no signifi cant diff erences in overall survival in subgroups divided by presence of intrathoracic disease at randomisation, sex, age, response to chemo therapy, WHO performance score, or extent of disease (ie, whether extensive stage disease was diagnosed on the basis of distant metastases, volume of intrathoracic tumour, or both (fi gure 3).

Progression was less likely in the thoracic radiotherapy group than in the control group (HR=0·73, 95% CI 0·61–0·87, p=0·001; fi gure 4). Progression-free survival at 6 months was 24% (95% CI 19–30) for the thoracic radiotherapy group and 20% (95% CI 16–26) in the control group (p=0·001). Median progression-free survival was 4 months for the thoracic radiotherapy group and 3 months for the control group. In a test for interaction of factors with treatment, there was no signifi cant diff erence in the eff ect of thoracic radiotherapy on progression-free survival for presence of intrathoracic disease at random-isation (p=0·11), sex (p=0·12), age (p=0·19), response to chemotherapy (p=0·92), WHO performance score (p=0·94), and extent of disease (p=0·78).

Isolated intrathoracic progression was rarer in the thoracic radiotherapy group (n=49, 19·8%) than in the control group (n=114, 46·0%, p<0·0001). Intrathoracic progression either with or without progression elsewhere occurred in 108 (43·7%) in the thoracic radiotherapy group versus 198 (79·8%) in the control group (p<0·0001). Brain metastases occurred in 24 (9·7%) versus 13 (5·2%; p=0·09), and disease progression at other sites occurred in 149 (60·3%) versus 100 (40·3%; p<0·0001). Table 3 shows patterns of progression. We considered pro-gression occurring at diff erent organ sites within 30 days as simultaneous progression. The thorax was the fi rst site of disease progression for 103 (41·7%) patients in the thoracic radiotherapy group versus 193 (77·8%) in the control group (p=0·009).

DiscussionThe addition of thoracic radiotherapy to prophylactic cranial irradiation for patients with extensive stage small-cell lung cancer did not improve survival at 1 year. However, 2-year overall survival was signifi cantly improved and progression-free survival was signifi cantly greater. Further more, we report an almost 50% reduction in intrathoracic recurrences. These positive results are consistent with fi ndings from studies of patients with locally advanced non-small-cell lung cancer showing that improved local control leads to improved survival.16

As might be expected from treatment of metastatic extensive stage small-cell lung cancer, overall survival

was much the same in both groups during the fi rst 9 months, but a signifi cant diff erence in favour of the thoracic radiotherapy emerged at 2 years. 1 year survival for patients who received prophylactic cranial irradiation only was similar to that of patients who received only this treatment in an EORTC study6 (27·1% versus 27·6%), suggesting that our fi ndings are representative and applicable to patients with extensive stage small-cell lung cancer. We measured median survival and 2 year survival from the time of randomisation, which was about 4 months after the start of chemotherapy. As such, our

Number at riskThoracic radiotherapy

groupControl group

0

247

248

6

147

160

12

67

61

18

26

17

24

14

5

30

7

1

Time (months)

0

0·2

0·4

0·6

0·8

1·0

Over

all s

urvi

val

Thoracic radiotherapy groupControl group

Figure 2: Kaplan-Meier curves for overall survival

Hazard ratio (CI)*

Thoracic radiotherapy

Control

Intrathoracic disease Yes NoSex Men WomenAge (years) 36–70 71–85Response to chemotherapy CR PR Good responseWHO performance status 0 1 2Extensive disease based on Intrathoracic disease Distant metastases BothTotal

p value

0·35

0·06

0·58

0·58

1·00

0·86

195/215 29/33

122/136 102/112

170/189 54/59

12/13 153/170 59/65

65/70 136/155 23/23

9/15 172/188 43/45 224/248

Events/patients Events/patients

175/213 26/34

115/135 86/112

152/193 49/54

10/13 148/179 43/55

74/97 101/121 26/29

11/19 161/190 29/38 201/247

0·80 (0·61−1·05) 1·09 (0·54−2·18)

1·01 (0·72−1·41) 0·68 (0·46−1·00)

0·82 (0·61−1·09) 0·96 (0·58−1·60)

1·38 (0·45−4·22) 0·81 (0·60−1·10) 0·76 (0·45−1·28)

0·85 (0·55−1·32) 0·84 (0·60−1·18) 0·83 (0·39−1·78)

0·68 (0·20−2·31) 0·87 (0·66 −1·16) 0·89 (0·48−1·65) 0·84 (0·69−1·02)

10 1·5 20·5

Favours controlFavours thoracicradiotherapy

Figure 3: Overall survival at 1 year in subgroups*CI is 99% for subgroups, 95% for total. CR=complete response. PR=partial response.

Articles

38 www.thelancet.com Vol 385 January 3, 2015

Role of the funding sourceThe funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. The corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication.

ResultsBetween Feb 18, 2009, and Dec 21, 2012, we randomly assigned 498 patients (249 in each group; fi gure 1). The analysis was done in December, 2013; median follow-up was 24 months. 201 patients in the thoracic radiotherapy group died compared with 224 in the control group, with 231 versus 239 progression-free survival events.

The mean interval between start of chemotherapy and randomisation was 15 weeks (range 14–19); the mean interval between diagnosis and randomisation was 17 weeks (16–21). Baseline characteristics were much the same in each group (table 1). 22·9% of patients were over 70 years and 7·8% were over 75 years. The diagnosis of extensive stage disease was based on the presence of distant metastases in 378 patients (76·4%), the extent of intrathoracic disease in 34 patients (6·9%), or both factors in 83 patients (16·8%). No patients had brain, lepto meningeal, or pleural metastases. 230 (46%) of asymptomatic patients underwent a brain CT or MRI according to local policy. After completion of chemotherapy, a CT of the thorax was done for 482 (97%) patients and a brain CT or MRI in 43 (13%) of asymptomatic patients.

Chemotherapy consisted of a platinum etoposide combination for 488 (99%) patients, with seven patients receiving other platinum-based regimens. Nine patients did not receive or stopped prophylactic cranial irradiation (six had disease progression, two had deterioration of general health, and one patient refused), six in the thoracic radiotherapy group and three in the control group. In the thoracic radiotherapy group, seven patients did not receive and six did not complete thoracic radiotherapy, because of disease progression (n=5), deterioration of general condition (n=3), patient refusal (n=4), or treatment-related toxic eff ects (n=1). The mean interval between last chemotherapy and prophylactic cranial irradiation was 32 days. Prophylactic cranial irradiation was delivered as 20 Gy in fi ve fractions for 300 patients (62%), 25 Gy in ten fractions for 105 patients (22%), 30 Gy in ten fractions for 65 patients (14%), and 30 Gy in 12–15 fractions for 15 patients (3%). For 240 (88%) patients in the thoracic radiotherapy group, thoracic radiotherapy was combined with prophylactic cranial irradiation. Thoracic radio therapy was started 1 week before prophylactic cranial irradiation for fi ve (2%) patients, and thoracic radiotherapy was started for 13 patients (5%) within 7 days or less or on average 1 week after prophylactic cranial irradiation for all other patients (n=235, 98%). Grade 3 or higher toxic eff ects occurred in 26 patients in the thoracic radiotherapy group and 18 patients in the control group (p=0·28, table 2).

Overall survival at 1 year was 33% (95% CI 27–39) in the thoracic radiotherapy group versus 28% (95% CI 22–34) in the control group: the diff erence between groups was not signifi cant (HR 0·84, 95% CI 0·69–1·01, p=0·066; fi gure 2). Median overall survival was 8 months in both groups. At 18 months, survival was 16% versus 9% (p=0·03). At 2 years, survival was 13% (95% CI 9–19) in the thoracic

Thoracic radiotherapy group (n=247) Control group (n=248)

Median age (IQR, years) 63 (58–69) 63 (57–69)

Age <75 years 233 (94%) 226 (91%)

Age ≥75 years 16 (6%) 23 (9%)

Median time to diagnosis (IQR, months) 3·7 (3·2–4·4) 3·7 (3·2–4·4)

Sex

Men 135 (55%) 136 (55%)

Women 112 (45%) 112 (45%)

WHO performance score

0 97 (39%) 70 (28%)

1 121 (49%) 155 (63%)

2 29 (12%) 23 (9%)

Response after chemotherapy

Complete response 12 (5%) 13 (5%)

Partial response 180 (73%) 170 (69%)

Good response 55 (22%) 65 (26%)

Persistent intrathoracic disease 215 (87%) 219 (88%)

Data are median (IQR) or n (%). Data are unavailable for smoking status.

Table 1: Baseline characteristics

249 allocated to thoracic radiotherapy

249 allocated to no thoracic radiotherapy

247 analysed 248 analysed

498 randomly assigned

2 withdrew consent 1 withdrew consent

Figure 1: Trial profi le

Thoracic radiotherapy group (n=247) Control group (n=248)

Cough (grade 3) 0 (0·0%) 1 (0·4%)

Dysphagia (grade 3) 1 (0·4%) 0 (0·0%)

Dyspnoea (grade 3) 3 (1·2%) 4 (1·6%)

Oesophagitis (grade 3) 4 (1·6%) 0 (0·0%)

Fatigue (grade 3) 11 (4·5%) 8 (3·2%)

Fatigue (grade 4) 0 (0·0%) 1 (0·4%)

Insomnia (grade 3) 3 (1·2%) 2 (0·8%)

Nausea or vomiting (grade 3) 1 (0·4%) 0 (0·0%)

Headache (grade 3) 3 (1·2%) 2 (0·8%)

Table 2: Grade 3 and higher toxic eff ects

498 patients en réponse après CT (+IPC) RT de consolidation 30 Gy (10 fr) vs contrôle Survie à 12 mois 33% vs 28% (p=0,066) Survie à 24 mois 13% vs 3% (p=0,004) Rechutes surtout extra-cérébrales et extra-thoraciques Patients bénéficiaires:

maladie extra-thoracique limitée résidu tumoral thoracique

Slotman Lancet 2015, Lung Cancer 2017

Traitement: formes disséminées l’Irradiation Prophylactique Cérébrale (IPC): controversée

•  2 essais randomisés de phase III IPC vs observation chez des patients répondeurs à la chimiothérapie

n IPC Imagerie C à la R

MC à 1 an Survie médiane mois

Survie à 1 an

Slotman

286 Hétérogène 20 Gy en 5 fr ou 30 Gy en 12 fr

non 14,6% vs 40,4% (symptomatiques)

6,74 vs 5,42 27,1 vs 13,3% P= 0,003

Takahashi 224 Homogène 25 Gy en 10 fr

Oui (IRM) puis tous les

3 mois

32,9% vs 59% (p<0,0001)

11,6 vs 13,7 48,4 vs 53,6%

Key Differences in the RandomizedTrials of PCI in ES-SCLC

The divergent OS outcomes in the EORTC11 andJapanese12 trials in ES-SCLC are likely explained byimportant differences in CNS staging and surveillance(Fig. 1).13 The EORTC trial did not require CNS imagingbefore randomization, and subsequent imaging wasacquired only for neurologic symptoms. The Japanesetrial mandated CNS imaging before randomization and at3, 6, 9, 12, 18, and 24 months in both arms. Therefore,whereas the EORTC trial included an arm of PCI omis-sion, the Japanese trial included PCI omission with activeMRI surveillance.

The differences in CNS staging may have beenconsequential. BMs at diagnosis in SCLC are identifiablein approximately 10% of patients using computedtomography and up to 25% using more sensitive brainMRI.14 BMs can also become evident after initial therapy;one retrospective analysis reported new BMs inone-third of patients after initial therapy and beforeplanned PCI.15 Thus, the literature indicates that ameaningful but unquantified number of patients in theEORTC trial would have had asymptomatic BMs atenrollment and, in reality, these patients were random-ized to early therapeutic (rather than prophylactic)radiation versus observation of BMs until the time ofneurologic symptoms.

It could be reasonably argued that the inclusion ofpatients with macroscopic BMs in the EORTC trial mightnot have altered the impact of radiation, given thatmultiple trials excluding patients with SCLC have failedto show an OS advantage with whole-brain radiation(WBRT) for BMs.16–21 A strong counterargument, how-ever, is that PCI has historically been justified by theperception of an OS advantage with brain radiationspecific to the SCLC histologic type and not seen, forexample, in NSCLC.22–24 Under this premise, it is rationalto expect that the benefits of treating subclinical BMs

present in an unknown percentage of patients (i.e., PCI)would, in fact, be magnified in an enriched subset whereall patients have BM.

The active MRI surveillance in the Japanese trial, ascompared with the reactive imaging for neurologicsymptoms in the EORTC trial, likely influenced thetiming and percentage of patients eligible for salvagetherapy. In the Japanese trial, of the patients in the activesurveillance alone arm in whom BMs developed, 83%received salvage brain radiation. In the EORTC trial, ofthe patients in the observation arm in whom BMsdeveloped, 59% received salvage radiation. Thus, aremarkable 41% with symptomatic BMs in the observa-tion arm of the EORTC trial did not receive radiation.Although it is not possible to know all the factors un-derlying decisions to offer salvage treatment, it is plau-sible that delayed identification of BMs in the EORTCtrial may have compromised performance status andreduced the percentage of patients eligible for salvagetherapy, with a resulting decrement in OS. This possi-bility is further supported by the observation that pa-tients in the PCI omission arm of the EORTC trialreceived less salvage chemotherapy, whereas the oppo-site was true in the Japanese trial.

In addition to CNS staging and surveillance, a thirdconsideration would be for potential differences in theefficacy of therapies in Japanese and Western pop-ulations. For example, irinotecan-platinum significantlyimproved OS over that with etoposide-platinum in aJapanese ES-SCLC trial,25 whereas OS differences wereeither smaller or not observed in subsequent Westerntrials,26–29 with speculation that pharmacogenomicsmight underlie the differences.28,29 As a result,irinotecan-platinum was delivered in 38% of patients inthe Japanese PCI trial12 but not mentioned in the earlierEORTC trial.30 The impact of these chemotherapeuticdifferences on the efficacy of PCI is unknown31,32;however, this example highlights the interest in

Figure 1. Overall survival in randomized trials of prophylactic cranial irradiation in extensive-stage SCLC. EORTC, EuropeanOrganization for Research and Treatment of Cancer; MRI, magnetic resonance imaging. Adapted with permission fromSlotman et al.11 and Takahashi et al.12

December 2017 PCI vs Active MRI Surveillance for SCLC 1747

largely precluded by the selection and indication biasesthat drive PCI delivery.53,54

Overall, many of the criticisms of the EORTC trial11

regarding suboptimal CNS staging and surveillance thatinformed the design of the Japanese trial in ES-SCLC12

would also appear to apply to the pre-MRI meta-analysis data supporting PCI in LS-SCLC (Table 1).Currently, there are no randomized data assessing PCIversus active MRI surveillance in LS-SCLC, and in thecontext of this modern comparison the potential impactof PCI on survival is unknown.

QoL, Cognition, and theRisk-Benefit Assessment

If the reduction in BMs with PCI was associated withimproved QoL and sustained cognition, there would beclinical justification for delivery in all patients with SCLCeven without an OS advantage. Unfortunately, PCI hasbeen associated with measurable declines in cognitivefunction and QoL in contemporary trials, with effectsthat appear comparable to those of WBRT for BM.Indeed, approximately 40% of patients with LS-SCLC donot receive PCI, primarily because of concerns overtoxicity.55,56

A pooled analysis of the Radiation Therapy OncologyGroup (RTOG) 0212 and 0214 trials57 reportedinferior performance on cognitive testing and a morethan threefold increase in patient-reported cognitivedysfunction with PCI at both 6 and 12 months(Fig. 2). RTOG 0214 reported a significant decline in

performance on the Hopkins Verbal Learning Test at 3, 6,and 12 months with PCI versus with observation.58

RTOG 0212 demonstrated increased cognitive toxicitywith higher PCI dose, and the Intergroup and RTOG 0212trials observed greater declines in QoL and cognitionafter PCI with older patient age.59,60 Recognition of thecognitive sequelae of PCI has led to the ongoing coop-erative randomized phase II/III trial NRG CC003, whichis evaluating PCI with and without hippocampal avoid-ance techniques (ClinicalTrials.gov identifierNCT02635009). The primary end point of the phase IIIcomponent of this trial is to determine whether hippo-campal avoidance PCI can reduce the incidence ofcognitive deterioration on the Hopkins Verbal LearningTest at 6 months versus with standard PCI.

The EORTC randomized trial of PCI versus observa-tion for ES-SCLC prospectively evaluated patient-reported QoL.61 Because of a median OS of only 6months and poor compliance with questionnaires overtime, the analysis was primarily limited to short-termQoL assessment. Inferior QoL scores with PCI wereobserved during the first 3 months for all prespecifiedend points, with the differences reaching significance forfatigue and hair loss and trends for global health,cognitive, emotional, and role functioning. Severe re-ductions in QoL (!20 points on a 100-point scale) weremore common with PCI in all domains. Exploratory an-alyses demonstrated significant reductions in QoL scoreswith PCI for nausea and vomiting, appetite, constipation,future uncertainty, headaches, motor dysfunction, and

Figure 2. Tested and self-reported cognitive decline with and without prophylactic cranial irradiation (PCI). Thin verticalbars represent the 95% confidence intervals. Adapted with permission from the pooled analysis of the RTOG 0212 and 0214trials reported by Gondi et al.57

December 2017 PCI vs Active MRI Surveillance for SCLC 1749

Slotman N Engl J Med 2007, Takahashi Lancet 2017, Rusthoven J Thorac Oncol 2017)

Traitement: formes disséminées faut il irradier les sites métastatiques?

Randomized Phase II Study Comparing Prophylactic Cranial Irradiation Alone To Prophylactic Cranial Irradiation And Consolidative Extra-Cranial Irradiation For Extensive Disease Small Cell Lung Cancer (ED-SCLC): NRG Oncology RTOG 0937

Elizabeth M Gore, MD1, Chen Hu, PhD2,11, Alexander Y Sun, MD3, Daniel F Grimm, MS4, Suresh S Ramalingam, MD5, Neal E Dunlap, MD6, Kristin A Higgins, MD5, Maria Werner-Wasik, MD7, Aaron M Allen, MD8, Puneeth Iyengar, MD, PhD9, Gregory M M Videtic, MD10, Russell K Hales, MD11, Ronald C McGarry, MD12, James J Urbanic, MD13, Anthony T Pu, MD14, Candice A Johnstone, MD1, Volker W Stieber, MD15, Rebecca Paulus, BS2, and Jeffrey D Bradley, MD16

1Froedtert and the Medical College of Wisconsin, Milwaukee, WI2NRG Oncology Statistics and Data Management Center, Philadelphia, PA3University Health Network-Princess Margaret Hospital, Toronto, ON4Zablocki Veterans Administration Medical Center, Milwaukee, WI5Emory University/Winship Cancer Institute, Atlanta, GA6James Graham Brown Cancer Center, University of Louisville, Louisville, KY7Thomas Jefferson University Hospital, Philadelphia, PA8Rabin Medical Center, Petah Tikva, Israel9UT Southwestern Medical Center, Dallas, TX10Cleveland Clinic Foundation, Cleveland, OH11Johns Hopkins University, Baltimore, MD12University of Kentucky, Lexington, KY13UC San Diego Moores Cancer Center, La Jolla, CA14Sutter Cancer Research Consortium, Sacramento, CA

Corresponding Author: Elizabeth Gore, MD, Professor of Radiation Oncology, Medical College of Wisconsin, 9200 W. Wisconsin Avenue, Milwaukee, WI 53226, Office: 414-805-4465, Fax: 414-805-4354, [email protected]. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Conflicts of interest: Dr. Hu reports grants from National Cancer Institute (NCI), during the conduct of the study. Dr. Ramalingam reports serving on Advisory Boards for Amgen, Astra Zeneca, Abbvie, BMS, Lilly, Celgene, Genentech, and Novartis, outside the submitted work. Ms. Paulus reports grants from National Cancer Institute (NCI) during the conduct of the study.

HHS Public AccessAuthor manuscriptJ Thorac Oncol. Author manuscript; available in PMC 2018 October 01.

Published in final edited form as:J Thorac Oncol. 2017 October ; 12(10): 1561–1570. doi:10.1016/j.jtho.2017.06.015.

Author Manuscript

Author Manuscript

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IPC vs IPS + radiothérapie de consolidation thoracique et extra-thoracique Patients en réponse après CT avec 1–4 métastases extra-cérébrales IPC: 25GY/10 fractions. cRT: was 45GY/15 fractions. 97 patients en 5 ans: 11 inéligible, 42 PCI seule vs 44 PCI+cRT. Survie à 1 an non différente:

60.1% [95% CI: 41.2–74.7%] pour PCI et 50.8% [95% CI:34.0– 65.3%] pour PCI+cRT (p=0.21). Temps jusqu’à progression en faveur de IPC + RT : HR=0.53 (95% CI: 0.32–0.87, p=0.01).

Figure 2. Overall Survival

Gore et al. Page 13

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Gore et al. Page 16

Table 2

Failure Patterns

PCI(n=32)n (%)

PCI and ConsolidativeRT

(n=31)n (%)

First failure at site of disease present at diagnosis 25 (78.1%) 13 (41.9%)

Locoregional disease as first failure 20 (62.5%) 8 (25.8%)

First failure brain 0 (0.0%) 6 (19.4%)

Failure at any time at new site 10 (31.3%) 19 (61.3%)

J Thorac Oncol. Author manuscript; available in PMC 2018 October 01.

Traitement: formes disséminées standard de traitement


•  4 à 6 cycles de chimiothérapie par platine/étoposide •  radiothérapie thoracique de consolidation

–  pour les répondeurs (avec résidu thoracique et moins de 3 sites métastatiques) et bon état général (PS 0-1)

–  30 Gy en 15 fractions –  à discuter en RCP

•  IPC en option à discuter (RCP) –  vs surveillance IRM et traitement à l’apparition de MC–  chez les patients en réponse complète ou « bonne réponse » –  25 Gy en 10 fractions, moins de 75 ans?

•  surveillance chez les patients en réponse et stables: –  visite tous les 2 mois (an1), tous les 3-4 mois (an 2-3) puis tous les 6 mois (an

4-5) puis tous les ans –  avec examen clinique, scanner thoracoabdominopelvien, IRM cérébrale tous les

3 mois si le patient n’a pas eu d’IPC.

Traitement de 2ème ligne et au delà

D’après Greillier , Rev Mal Respir 2017

•  La probabilité de réponse au traitement de 2ème ligne dépend: –  de la réponse au traitement initial –  du délai écoulé depuis la fin de la CT de 1ère ligne

•  patients hautement sensibles (rechute plus de 6 mois après la fin de la 1ère ligne) •  sensibles (entre 3 et 6 mois) •  résistants (moins de 3 mois) •  réfractaires (progression sous traitement de 1ère ligne)

•  Le seul traitement ayant actuellement l’AMM en 2ème ligne en France est le Topotécan même si son efficacité est faible

phase n Réponse% Surviemédianemois

TopoPOvsSP III 141 7vs0 6,4vs3,4*

TopoIVvsCAV III 211 24,3vs18,3 6,2vs6,1

TopoPOvsIV III 304 18,3vs21,9 8,2vs8,7

TopoIVvsAmrubicine III 637 16,9vs31,1 7,8vs7,7

Traitement de 2ème ligne et au delà

Kondo, Oncology 2018, recommandations NCCN 2018, référentiels AURA 2018

•  Recommandations actuelles: –  reprendre platine/étoposide chez les patients hautement sensibles ou

sensibles –  topotécan dans les autres cas, les associations CAV et paclitaxel

carboplatine étant des alternatives.

Clinical Study

Oncology 2018;94:223–232

A Phase II Study of Irinotecan for Patients with Previously Treated Small-Cell Lung CancerRie Kondo

a Satoshi Watanabe a Satoshi Shoji

a Kosuke Ichikawa a

Tetsuya Abe a Junko Baba

b Junta Tanaka a Hiroki Tsukada

c Masaki Terada d

Kazuhiro Sato e Yoshie Maruyama

f Masato Makino g Akira Hirata

h Hiroshi Tanaka

i Toshiyuki Koya a Hirohisa Yoshizawa

j Toshiaki Kikuchi a

a Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical

and Dental Sciences, Niigata, Japan; b Department of Respiratory Medicine, Nishi-Niigata Chuo National Hospital, Niigata, Japan; c Department of Respiratory Medicine, Niigata City General Hospital, Niigata, Japan; d Department of Respiratory Medicine, Saiseikai Niigata Daini Hospital, Niigata, Japan; e Department of Respiratory Medicine, Nagaoka Red Cross Hospital, Nagaoka, Japan; f Department of Internal Medicine, Tsubame Rosai Hospital, Tsubame, Japan; g Department of Internal Medicine, Niigata Prefectural Shibata Hospital, Shibata, Japan; h Department of Respiratory Medicine, Tsuruoka Municipal Shonai Hospital, Tsuruoka, Japan; i Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan; j Department of Respiratory Medicine, Niigata Medical Center, Niigata, Japan

Received: July 28, 2017Accepted after revision: January 3, 2018Published online: February 14, 2018

Dr. Satoshi WatanabeDepartment of Respiratory Medicine and Infectious DiseasesNiigata University Graduate School of Medical and Dental Sciences1-757 Asahimachidori, Chuoku, Niigata 951-8510 (Japan)E-Mail satoshi7 @ med.niigata-u.ac.jp

© 2018 S. Karger AG, Basel

E-Mail [email protected]/ocl

DOI: 10.1159/000486622

KeywordsSmall-cell lung cancer · Irinotecan · Phase II study · Refractory relapse · Sensitive relapse

AbstractObjective: Chemotherapy with irinotecan plus cisplatin has shown promise in chemo-naïve small-cell lung cancer (SCLC) patients. However, irinotecan treatment for relapsed or re-fractory SCLC has not been adequately evaluated. This phase II study evaluated the appropriate treatment schedule of iri-notecan as a single agent. This study was designed to deter-mine the antitumor activity, toxicity, and survival in previ-ously treated SCLC patients. Methods: Previously treated SCLC patients with at least one platinum-based regimen re-ceived irinotecan (100 mg/m2) on days 1 and 8, every 3 weeks, until disease progression. The assessment of the re-

sponse rate was the primary endpoint. Results: Thirty pa-tients were enrolled, with an objective response rate of 41.3% (95% confidence interval [CI] 25.5–59.3), and a disease control rate of 69%. Median progression-free and overall sur-vival was 4.1 months (95% CI, 2.2–5.4) and 10.4 months (95% CI, 8.1–14), respectively. The grade 3/4 hematological toxici-ties were neutropenia (36.7%), thrombocytopenia (3.3%), anemia (13.3%), and febrile neutropenia (6.6%). There were no grade 4 nonhematological toxicities. Frequent grade 3 nonhematological toxicities included diarrhea (10%), an-orexia (6.6%), and hyponatremia (6.6%). Conclusions: This phase II study showed a high objective response rate and long survival. Irinotecan monotherapy schedule used was well tolerated, and could be an active treatment option for these patients. © 2018 S. Karger AG, Basel

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193.

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3 - 4

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10:

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Irinotecan for Relapsed SCLC 227Oncology 2018;94:223–232DOI: 10.1159/000486622

The median PFS of the elderly patients (age ≥70) was 3.7 months (95% CI, 1.3–5.6) compared with 4.2 months (95% CI, 1.2–6.8) in patients younger than 70 years old (p = 0.782). Therefore, there was no significant difference in PFS between these two age groups. The MST of the el-

derly patients was 9.7 months (95% CI, 7.9–12.5), and that of the patients younger than 70 years old was 11.0 months (95% CI, 5.7–15.6; p = 0.323) (Fig. 2c, d). There-fore, there was no significant difference in MST between these two age groups.

100

80

60

40

20

00 5

Median PFS: 4.1 months(95% CI: 2.2–5.4)

Median OS: 10.4 months(95% CI: 8.1–14)

10Time, monthsa

PFS,

%

15 20 25

100

80

60

40

20

00 2010 30

Time, monthsb

OS,

%

40 50 60

100

80

60

40

20

00 5

Median PFSSensitive: 5.2 months (95% CI: 3.0–6.8)Refractory: 2.1 months (95% CI: 0.56–4.9)p < 0.05

10Time, monthsa

PFS,

%

15 20 25

100

80

60

40

20

00

Median OSSensitive: 11.6 months (95% CI: 8.3–21.6)Refractory: 7.7 months (95% CI: 1.3–14)p < 0.05

Time, monthsb

OS,

%

20 40 60

100

80

60

40

20

00 5

Median PFS<70 y.o. 4.2 months (95% CI: 1.2–6.8)≥70 y.o. 3.7 months (95% CI: 1.3–5.6)p = 0.782

10Time, monthsc

PFS,

%

15 20 25

100

80

60

40

20

00

Median OS<70 y.o. 11.0 months (95% CI: 5.7–15.6)≥70 y.o. 9.7 months (95% CI: 7.9–12.5)p = 0.323

Time, monthsd

OS,

%

20 40 60

Fig. 1. Kaplan-Meier analysis of progression-free survival (PFS) (a) and overall survival (OS) (b) for the intent-to-treat (ITT) population (n = 30).

Fig. 2. Subgroup analysis of survival according to treatment-free interval and age. OS, overall survival; PFS, pro-gression-free survival.

Dow

nloa

ded

by:

INSE

RM

DIS

C IS

T

193.

54.1

10.3

3 - 4

/29/

2018

10:

59:2

6 AM

30 patients CPC 2ème ligne RO: 41%

Les nouveaux traitements: l’immunothérapie rationnel

•  Charge mutationnelle élevée – 8,8 mutations/mégabytes

•  Mais expression de PDL1 généralement faible (environ 30% des patients >1%)

•  Syndromes paranéoplasiques immunomédiés de bon pronostic – Lambert Eaton

Les nouveaux traitements: l’immunothérapie

indication drogue N RO SSP (mois) MS (mois) 1ère ligne Phase III Phase III Impower 133

platine/étoposide + Ipilimumab (à partir de cycle 3 + maintenance) vs placebo + platine/etoposide Carboplatine/étoposide + atézolizumab vs Carboplatine/étoposide + placébo

1132

403

-

60% vs 64%

4,6 vs 4,4 (HR : 0,85)

5,2 vs 4,3* (HR: 0,77)

11 vs 10,9 (HR 0,94)

12,2 vs 10,3* (HR: 0,7)

Maintenance Phase II

pembrolizumab

45

-

1,4 PDL1+ 5,5 vs 1,3

9,6

Rechute Checkmate 032 Phase I/II Keynote 028 Phase Ib multicohorte Keynote 158 (abstr) Phase II Multicohorte

Nivo 3 mg/kg Nivo 1 mg/kg + ipilimumab 1 mg/kg Nivo 1 mg/kg + ipilimumab 3 mg/kg Nivo 3 mg/kg + ipilimumab 1 mg/kg Pembrolizumab Pembrolizumab

98 3 61 54

24 (PDL1>1%) PDL1+=32% des pts

107 dont 42 (PDL1+)

10% 33% 23% 19%

33,3% Durée 19m

18,7% 35,7%

1,4

2,6 1,4

1,9 - -

4,4

7,7 6

9,7 -

15

principaux essais d’immunothérapie publiés

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med nejm.org 1

The authors’ full names, academic de-grees, and affiliations are listed in the Appendix. Address reprint requests to Dr. Horn at Vanderbilt University Medical Cen-ter, 2220 Pierce Ave., 777 PRB, Nashville, TN 37232, or at leora . horn@ vumc . org.

* A complete list of investigators in the IMpower133 Study Group is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on September 25, 2018, at NEJM.org.

DOI: 10.1056/NEJMoa1809064Copyright © 2018 Massachusetts Medical Society.

BACKGROUNDEnhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)–programmed death 1 (PD-1) signaling has shown promise in the treat-ment of extensive-stage small-cell lung cancer. Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.

METHODSWe conducted this double-blind, placebo-controlled, phase 3 trial to evaluate atezo-lizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment. Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezoliz-umab or placebo for four 21-day cycles (induction phase), followed by a mainte-nance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors, version 1.1, or no additional clinical benefit. The two primary end points were investigator-assessed progression-free survival and overall survival in the intention-to-treat population.

RESULTSA total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% confidence interval [CI], 0.54 to 0.91; P = 0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P = 0.02). The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the indi-vidual agents, with no new findings observed.

CONCLUSIONSThe addition of atezolizumab to chemotherapy in the first-line treatment of exten-sive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by F. Hoffmann–La Roche/Genentech; IMpower133 ClinicalTrials.gov number, NCT02763579.)

A BS TR AC T

First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer

L. Horn, A.S. Mansfield, A. Szczęsna, L. Havel, M. Krzakowski, M.J. Hochmair, F. Huemer, G. Losonczy, M.L. Johnson, M. Nishio, M. Reck, T. Mok, S. Lam,

D.S. Shames, J. Liu, B. Ding, A. Lopez-Chavez, F. Kabbinavar, W. Lin, A. Sandler, and S.V. Liu, for the IMpower133 Study Group*

Original Article

The New England Journal of Medicine Downloaded from nejm.org at INSERM DISC DOC on September 25, 2018. For personal use only. No other uses without permission.

Copyright © 2018 Massachusetts Medical Society. All rights reserved.

Les nouveaux traitements: l’immunothérapie 1ère ligne

Horn, N Engl J Med, sept 2018

MaintenanceInduction(4cyclesde21jours)Patientsavec

(N=403):•  CBPCavancémesurable

(RECISTv1.1)•  ECOGPS0ou1•  Pasdetraitement

systémiqueantérieur•  Métastasescérébrales

asymptomatiquestraitéesautorisées

Stratification:•  Sexe(HvsF)•  ECOGPS(0vs1)•  Métastasescérébrales

(ouivsnon)

Survie

Objectifsprimaires:•  Survieglobale

•  SSPdéterminéeparlesinvestigateurs

Objectifssecondaires:•  Tauxderéponseobjective

•  Duréederéponse•  Tolérance

Irradiationpancérébraleprophylactiqueautoriséeselonleshabitudes

Carboplatine:AUC5mg/mL/minIV,J1Etoposide:100mg/m2IV,J1–3

Traitementjusqu’à

progressionouperte

debénéficecliniquePlacebo

Atezolizumab

R1:1

Atezolizumab(1200mgIV,J1)+carboplatine+etoposide

Placebo+carboplatine+etoposide

Éssai IMPOWER 133











A BS TR AC T




Original Article





Éssai IMPOWER 133


First-Line Atezolizumab in Extensive-Stage SCLC

analysis of tumor mutational burden; 351 of the samples (93.8%) yielded high-quality data for analysis of tumor mutational burden. An explor-atory analysis showed a consistent overall sur-vival and progression-free survival benefit above and below the prespecified cutoffs of 10 and 16 mutations per megabase (Fig. 2C, and Fig. S2 in the Supplementary Appendix).

Confirmed Objective Response Rate and Durations of Response

Investigator-assessed confirmed objective response rates and median duration of response were similar in the two groups (Table 2, and Table S5 in the Supplementary Appendix). In total, five patients (2.5%) in the atezolizumab group and two patients (1.0%) in the placebo group had a complete response.

SafetyThe population that could be evaluated for safety included 198 patients who received at least 1 dose of atezolizumab and 196 patients who received placebo. The median duration of treatment with atezolizumab was 4.7 months (range, 0 to 21), and the median number of atezolizumab doses received was 7 (range, 1 to 30). The median number of doses of chemotherapy was the same in the two groups (median, 4 doses of carbopla-tin and 12 doses of etoposide). The median dose intensity and total cumulative dose of chemo-therapy were similar in the two groups (Table S6 in the Supplementary Appendix).

Adverse events related to any component of the trial regimen occurred in 188 patients (94.9%) in the atezolizumab group and in 181 patients (92.3%) in the placebo group. The most common grade 3 or 4 adverse events related to the trial regimen were neutropenia, anemia, and decreased neutrophil count (Table 3).

Deaths related to the trial regimen occurred in 3 patients (1.5%) in the atezolizumab group (death was due to neutropenia in 1 patient, pneumonia in 1 patient, and an unspecified cause in 1 patient) and in 3 patients (1.5%) in the placebo group (death was due to pneumonia in 1 patient, septic shock in 1 patient, and car-diopulmonary failure in 1 patient). Immune-related adverse events occurred in 79 patients (39.9%) in the atezolizumab group and in 48

Figure 2 (facing page). Overall Survival and Investigator-Assessed Progression-free Survival in the Intention-to-Treat Population.

Panel A shows the Kaplan–Meier estimates of overall survival, and Panel B the Kaplan–Meier estimates of investigator-assessed progression-free survival. Tick marks indicate censored data. Panel C shows a sub-group analysis of overall survival according to baseline characteristics. Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with higher scores reflecting greater disability. Tumor mutational burden was assessed with the use of a blood-based assay.

VariableAtezolizumab Group

(N = 201)Placebo Group

(N = 202)

Objective confirmed response† 121 (60.2 [53.1–67.0]) 130 (64.4 [57.3–71.0])

Complete response — no. (% [95% CI]) 5 (2.5 [0.8–5.7]) 2 (1.0 [0.1–3.5])

Partial response — no. (% [95% CI]) 116 (57.7 [50.6–64.6]) 128 (63.4 [56.3–70.0])

Median duration of response (range) — mo‡ 4.2 (1.4§–19.5) 3.9 (2.0–16.1§)

Ongoing response at data cutoff — no./total no. (%) 18/121 (14.9) 7/130 (5.4)

Stable disease — no. (% [95% CI]) 42 (20.9 [15.5–27.2]) 43 (21.3 [15.9–27.6])

Progressive disease — no. (% [95% CI]) 22 (10.9 [7.0–16.1]) 14 (6.9 [3.8–11.4])

* The date of data cutoff was April 24, 2018.† The objective confirmed response rate was assessed in patients in the intention-to-treat population who had measur-

able disease at baseline. Objective response was defined as confirmed complete response or partial response as deter-mined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1.

‡ Duration of response was assessed in patients who had an objective confirmed response and was defined as the time from the first occurrence of a documented objective response to the time of disease progression as determined by the investigator (according to RECIST) or death from any cause, whichever occurred first.

§ Data for the lower range of the response in the atezolizumab group and the upper range of the response in the placebo group are censored.

Table 2. Response Rate, Duration of Response, and Disease Progression.*



patients Atezo+CTn:198

Placebo+CTn:196

Avec>1EIgrade3-4

198(100)133(67,2)

189(96,4)125(63,8)

EIliésautt 188(94,9) 181(92,3)

EIimmuno-médiés 79(39,9) 48(24,5)

EIavecarrêtdett 22(11,1) 6(3,1)

EIavecarrêtd’Atezoouplacebo

21(10,6) 5(2,6)

DCliésautt 3(1,5) 3(1,5)











A BS TR AC T




Original Article





Éssai IMPOWER 133



Patie

nts

Who

Sur

vive

d (%

)

100

80

90

70

60

40

30

10

50

20

00 1 2 3 4 5 24

24

232221

Months

B Progression-free Survival

C Overall Survival According to Baseline Characteristics

A Overall Survival

No. at RiskAtezolizumabPlacebo

201202

191194

187189

182186

180183

174171

6

159160

7

142146

8

130131

9

121114

10

10896

22

19

33

20

12

18

53

17

118

16

2113

15

3321

14

4627

13

5836

12

7459

11

9281

Atezolizumab

Placebo

Patie

nts

Who

Sur

vive

d w

ithou

tD

isea

se P

rogr

essi

on (%

)

100

80

90

70

60

40

30

10

50

20

00 1 2 3 4 5 232221

Months

Stratified hazard ratio for disease progression or death,0.77 (95% CI, 0.62–0.96)

P=0.02


201202

190193

178184

158167

147147

9880

6

5844

7

4830

8

4125

9

3223

10

2916

1

19

2

20

1

18

2

17

33

16

33

15

115

14

126

13

159

12

219

11

2615

AtezolizumabPlacebo

12.6% (95% CI, 7.9–17.4)5.4% (95% CI, 2.1–8.6)

30.9% (95% CI, 24.3–37.5)22.4% (95% CI, 16.6–28.2)

Atezolizumab

at 6 mo at 12 mo

Placebo

1.0 2.5

Placebo BetterAtezolizumab Better

SexMaleFemale

Age<65 yr≥65 yr

ECOG score01

Brain metastasesYesNo

Liver metastasesYesNo

Tumor mutational burden<10 mutations/Mb≥10 mutations/Mb<16 mutations/Mb≥16 mutations/Mb

Intention-to-treatpopulation

No. of Patients (%) Hazard Ratio for Death (95% CI)Subgroup

0.70 (0.54–0.91)0.63 (0.35–1.15)0.71 (0.52–0.98)0.68 (0.47–0.97)0.70 (0.45–1.07)

0.64 (0.45–0.90)0.81 (0.55–1.20)

0.68 (0.52–0.89)1.07 (0.47–2.43)

0.79 (0.49–1.27)0.68 (0.50–0.93)

0.53 (0.36–0.77)0.92 (0.64–1.32)

0.74 (0.54–1.02)

0.1

0.65 (0.42–1.00)261 (65)142 (35)

217 (54)186 (46)

140 (35)263 (65)

35 (9)368 (91)

149 (37)254 (63)

139 (34)212 (53)271 (67) 80 (20)

403 (100)

Median Overall Survival (mo)

10.99.5

11.59.6

12.49.3

9.710.4

7.811.2

9.211.29.9

11.910.3

12.312.5

12.112.5

16.611.4

8.512.6

9.316.8

11.814.612.517.812.3

Atezolizumab Placebo

Rate of Progression-free Survival

Median in the atezolizumab group,5.2 mo (95% CI, 4.4–5.6)

Median in theplacebo group,

4.3 mo(95% CI, 4.2–4.5)

Stratified hazard ratio for death, 0.70 (95% CI, 0.54–0.91)P=0.007

AtezolizumabPlacebo

51.7% (95% CI, 44.4–59.0)38.2% (95% CI, 31.2–45.3)

Rate of Overall Survival at 12 Mo


Median in the placebo group,10.3 mo (95% CI, 9.3–11.3)



Atezolizumab+CP/ET(N=201)

Placebo+CP/ET(N=202)

SG(événements),n(%) 104(51,7) 134(66,3)

SGmédiane,mois(95%CI)

12,3(10,8-15,9)

10,3(9,3–11,3)

HR(IC95%) 0.70(0.54-0,91)p=0,0069

Suivimédian,mois 13,9

ATEZO/CARBO/ETOPOSIDE nouveau standard?



Patie

nts

Who

Sur

vive

d (%

)

100

80

90

70

60

40

30

10

50

20

00 1 2 3 4 5 24

24

232221

Months

B Progression-free Survival

C Overall Survival According to Baseline Characteristics

A Overall Survival


201202

191194

187189

182186

180183

174171

6

159160

7

142146

8

130131

9

121114

10

10896

22

19

33

20

12

18

53

17

118

16

2113

15

3321

14

4627

13

5836

12

7459

11

9281

Atezolizumab

Placebo

Patie

nts

Who

Sur

vive

d w

ithou

tD

isea

se P

rogr

essi

on (%

)

100

80

90

70

60

40

30

10

50

20

00 1 2 3 4 5 232221

Months

Stratified hazard ratio for disease progression or death,0.77 (95% CI, 0.62–0.96)

P=0.02


201202

190193

178184

158167

147147

9880

6

5844

7

4830

8

4125

9

3223

10

2916

1

19

2

20

1

18

2

17

33

16

33

15

115

14

126

13

159

12

219

11

2615

AtezolizumabPlacebo

12.6% (95% CI, 7.9–17.4)5.4% (95% CI, 2.1–8.6)

30.9% (95% CI, 24.3–37.5)22.4% (95% CI, 16.6–28.2)

Atezolizumab

at 6 mo at 12 mo

Placebo

1.0 2.5

Placebo BetterAtezolizumab Better

SexMaleFemale

Age<65 yr≥65 yr

ECOG score01

Brain metastasesYesNo

Liver metastasesYesNo

Tumor mutational burden<10 mutations/Mb≥10 mutations/Mb<16 mutations/Mb≥16 mutations/Mb

Intention-to-treatpopulation

No. of Patients (%) Hazard Ratio for Death (95% CI)Subgroup

0.70 (0.54–0.91)0.63 (0.35–1.15)0.71 (0.52–0.98)0.68 (0.47–0.97)0.70 (0.45–1.07)

0.64 (0.45–0.90)0.81 (0.55–1.20)

0.68 (0.52–0.89)1.07 (0.47–2.43)

0.79 (0.49–1.27)0.68 (0.50–0.93)

0.53 (0.36–0.77)0.92 (0.64–1.32)

0.74 (0.54–1.02)

0.1

0.65 (0.42–1.00)261 (65)142 (35)

217 (54)186 (46)

140 (35)263 (65)

35 (9)368 (91)

149 (37)254 (63)

139 (34)212 (53)271 (67) 80 (20)

403 (100)

Median Overall Survival (mo)

10.99.5

11.59.6

12.49.3

9.710.4

7.811.2

9.211.29.9

11.910.3

12.312.5

12.112.5

16.611.4

8.512.6

9.316.8

11.814.612.517.812.3

Atezolizumab Placebo

Rate of Progression-free Survival


Median in theplacebo group,

4.3 mo(95% CI, 4.2–4.5)

Stratified hazard ratio for death, 0.70 (95% CI, 0.54–0.91)P=0.007

AtezolizumabPlacebo

51.7% (95% CI, 44.4–59.0)38.2% (95% CI, 31.2–45.3)

Rate of Overall Survival at 12 Mo


Median in the placebo group,10.3 mo (95% CI, 9.3–11.3)



Les nouveaux traitements: l’immunothérapie 2ème ligne et +

Articles

890 www.thelancet.com/oncology Vol 17 July 2016

76 (78%) patients in the nivolumab 3 mg/kg cohort, 44 (72%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and 42 (78%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort had disease pro-gression or died; median progression-free survival was 1·4 months (95% CI 1·4–1·9), 2·6 months (1·4–4·1), and 1·4 months (1·3–2·2), respectively. 1-year progression-free survival was 11% (95% CI 5–19) in the nivolumab 3 mg/kg cohort and 19% (9–32) for the

nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort (fi gure 3B). The nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort had not met the 1-year milestone for progression-free survival at the time of database lock. Two (67%) of three patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had died and one (33%) had a progression event. Nine patients crossed over from the nivolumab 3 mg/kg cohort to the combination cohorts after progression (one to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg and eight to nivolumab 3 mg/kg plus ipilimumab 1 mg/kg); eight of these patients had further disease progression and one patient in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort withdrew consent and therefore response could not be determined.

PD-L1 expression was assessable in 148 (69%) of 216 patient samples, of which 39 (27%) were provided as fresh biopsies and 109 (74%) were archived specimens. 25 (17%) had 1% or greater PD-L1 expression, and seven (5%) had 5% or greater PD-L1 expression (table 1; appendix p 21). In a pre-planned exploratory analysis of the nivolumab 3 mg/kg, nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohorts, tumour responses occurred in patients irrespective of PD-L1 expression (appendix pp 15–18).

Grade 3 or 4 treatment-related adverse events occurred in 13 (13%) of 98 patients in the nivolumab 3 mg/kg cohort, 18 (30%) of 61 patients in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and ten (19%) of 54 patients in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort (table 3); no patients in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort had a grade 3 or 4 treatment-related adverse event (appendix p 23). The most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (none vs 5 [8%] vs none) and diarrhoea (none vs 3 [5%] vs 1 [2%]). Four (4%) patients in the nivolumab 3 mg/kg cohort, two (67%) in the nivolumab 1 mg/kg plus ipilimumab 1 mg/kg cohort, 18 (30%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and eight (15%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort had dose delays due to treatment-related adverse events (appendix p 26). All-causality adverse events and serious adverse events are shown in the appendix (pp 27–30). Excluding malignant neoplasm, the most frequent serious adverse events were dyspnoea, experienced by fi ve (5%) patients in the nivolumab 3 mg/kg cohort, two (3%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and four (7%) in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort, and diarrhoea, experienced by two (2%) patients in the nivolumab 3 mg/kg cohort, four (7%) in the nivolumab 1 mg/kg plus ipilimumab 3 mg/kg cohort, and two (4%) patients in the nivolumab 3 mg/kg plus ipilimumab 1 mg/kg cohort. 17 patients discontinued treatment because of treatment-related adverse events: six (6%) patients in the Figure 3: Kaplan-Meier curves of overall survival (A) and progression-free survival (B)

A

Number at riskNivolumab 3 mg/kg

Nivolumab 1 mg/kg plusipilimumab 3 mg/kg


Number of censored patientsNivolumab 3 mg/kg



0 3 6 9 12 15 18 21 2724

9861

55

00

0

5342

37

62

3

3632

25

112

4

2522

20

207

5

1121

12

307

10

1015

1

3012

19

106

0

3020

20

42

0

3423

20

31

0

3524

20

00

0

3825

20

0

10

20

30

40

50

60

70

80

90

100

Over

all s

urvi

val (

%)

Nivolumab 3 mg/kgNivolumab 1 mg/kg plus ipilimumab 3 mg/kgNivolumab 3 mg/kg plus ipilimumab 1 mg/kg

B

Number at riskNivolumab 3 mg/kg



Number of censored patientsNivolumab 3 mg/kg



0 3 6 9 12 15 18 21 24

9861

54

00

0

1724

14

125

4

615

3

175

11

59

0

1710

12

43

0

1814

12

30

0

1917

12

30

0

1917

12

00

0

2217

12

00

0

2217

12

Time since start of treatment (months)

0

10

20

30

40

50

60

70

80

90

100

Prog

ress

ion-

free s

urvi

val (

%)

versus -sensitive disease. Other limitations include the small numberof patients and substantial patient selection as a result of the lowPD-L1 positivity rate seen in SCLC. Regardless, the objective re-sponses seen were robust and durable, consistent with the presumedmechanism of action of anti–PD-1 antibodies.13

In summary, pembrolizumab demonstrated a favorable safetyprofile and promising durable clinical activity in pretreated patientswith PD-L1–positive extensive-stage SCLC. Building on this initialsafety and clinical efficacy signal, multiple trials were initiated with theaims to (1) better define biomarkers tomore accurately define patientswith SCLCwho are likely to respond to pembrolizumabmonotherapy(KEYNOTE-158; ClinicalTrials.gov identifier: NCT02628067) and (2)increase the efficacy of monotherapy by moving treatmentwith pembrolizumab to the front-line and maintenance settings,as well as to combinations with chemotherapy, radiotherapy,and other immune-modulating agents (ie, ClinicalTrials.govidentifiers: NCT02359019, NCT02551432, NCT02934503, andNCT02402920).

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTSOF INTEREST

Disclosures provided by the authors are available with this article atjco.org.

AUTHOR CONTRIBUTIONS

Conception and design: Patrick A. OttProvision of study materials or patients: Patrick A. Ott, Dong-Wan KimCollection and assembly of data: Patrick A. Ott, Sandrine Hiret, AnneMorosky, Bilal Piperdi, Janice M. MehnertData analysis and interpretation: Patrick A. Ott, Elena Elez, Dong-WanKim, Sanatan Saraf, Bilal Piperdi, Janice M. MehnertManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authors

REFERENCES

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2. Alvarado-Luna G, Morales-Espinosa D: Treat-ment for small cell lung cancer: Where are we now?A review. Transl Lung Cancer Res 5:26-38, 2016

3. Hurwitz JL, McCoy F, Scullin P, et al: Newadvances in the second-line treatment of small-celllung cancer. Oncologist 14:986-994, 2009

4. Rossi A, Di MM, Chiodini P, et al: Carboplatin-or cisplatin-based chemotherapy in first-line treat-ment of small-cell lung cancer: The COCIS meta-analysis of individual patient data. J Clin Oncol 30:1692-1698, 2012

5. National Comprehensive Cancer Network:Guidelines: Small-cell lung cancer, 2016. 2016

6. FruhM, De Ruysscher D, Popat S, et al: Small-cell lung cancer (SCLC): ESMO Clinical PracticeGuidelines for diagnosis, treatment and follow-up.Ann Oncol 24(suppl 6):vi99-vi105, 2013

7. Okuma HS, Horinouchi H, Kitahara S, et al:Comparison of amrubicin and weekly cisplatin/etoposide/irinotecan in patients with relapsed small-cell lung cancer. Clin Lung Cancer 18:234-240, 2017

8. Bronte G, Rizzo S, La Paglia L, et al: Drivermutations and differential sensitivity to targetedtherapies: A new approach to the treatment of lungadenocarcinoma. Cancer Treat Rev 36:S21-S29,2010

9. Luo SY, LamDCL: Oncogenic drivermutationsin lung cancer. Transl Respir Med 1:6, 2013

10. Sul J, Blumenthal GM, Jiang X, et al: US Food andDrug Administration approval summary: Pembrolizumabfor the treatment of patients with metastatic non–small-cell lung cancer whose tumors express programmeddeath-ligand 1. Oncologist 21:643-650, 2016

11. Spranger S, Spaapen RM, Zha Y, et al: Up-regulation of PD-L1, IDO, and T(regs) in the mela-noma tumor microenvironment is driven by CD8(+)T cells. Sci Transl Med 5:200ra116, 2013

12. Taube JM, Anders RA, Young GD, et al:Colocalization of inflammatory response with B7-h1expression in human melanocytic lesions supportsan adaptive resistance mechanism of immune es-cape. Sci Transl Med 4:127ra37, 2012

13. Sharma P, Allison JP: The future of immunecheckpoint therapy. Science 348:56-61, 2015

14. Garon EB, Rizvi NA, Hui R, et al: Pem-brolizumab for the treatment of non–small-cell lungcancer. N Engl J Med 372:2018-2028, 2015

15. Herbst RS, Baas P, Kim DW, et al: Pem-brolizumab versus docetaxel for previously treated,PD-L1-positive, advanced non–small-cell lung cancer(KEYNOTE-010): A randomised controlled trial. Lan-cet 387:1540-1550, 2016

16. Topalian SL, Hodi FS, Brahmer JR, et al: Safety,activity, and immunecorrelates of anti-PD-1 antibody incancer. N Engl J Med 366:2443-2454, 2012

17. Larkin J, Chiarion-Sileni V, Gonzalez R, et al:Combined nivolumab and ipilimumab or monotherapyin untreatedmelanoma. N Engl JMed 373:23-34, 2015

18. Dolled-Filhart M, Roach C, Toland G, et al:Development of a companion diagnostic for pem-brolizumab in non–small-cell lung cancer using im-munohistochemistry for programmed death ligand-1.Arch Pathol Lab Med 140:1243-1249, 2016

19. Robert C, Schachter J, Long GV, et al: Pem-brolizumab versus ipilimumab in advanced mela-noma. N Engl J Med 372:2521-2532, 2015

0 4 8

28.6% 23.8%

12 16 20 24

20

40

60

80

100

Time (months)

Prog

ress

ion-

Free

Surv

ival

(%)

26824No. at risk: 024 2569 2

A

66.0% 37.7%

0 4 8 12 16 20 24

No. at risk:

20

40

60

80

100

Time (months)

Over

all S

urvi

val (

%)

4141724 048 491420 6 4

B

Fig 3. Survival of patients with small-cell lung cancer in KEYNOTE-028: (A) progression-free survival; (B) overall survival. Percentages are the proportion of patients withsurvival at that time point.

3828 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY

Ott et al

Downloaded from ascopubs.org by Institut National de la Sant et de la Recherche Mdicale on May 13, 2018 from 193.054.110.033Copyright © 2018 American Society of Clinical Oncology. All rights reserved.

Antonia, Lancet Oncol 2016, Ott, J Clin Oncol 2017

Checkmate 032 Keynote 028


•  Étude CheckMate 032 : nivolumab ± ipilimumab

CBPC,en2eligneouultérieureaprès1religneàbasedeselsdeplatine,IHC,PD-L1,tousrésultats

Nivolumab3mg/kgtousles14joursjusqu’àprogressionoutoxicité

Nivolumab3mg/kg

tousles14j(n=98)

Nivolumab3mg/kgtousles14joursjusqu’àprogressionoutoxicité

R3:2

Objectif principal : taux de RO (RECIST)

Cohorte non randomisée Cohorte randomisée

Nivolumab1mg/kg+ipilimumab3mg/kg

tousles21j4cycles(n=61)

Nivolumab1mg/kg+ipilimumab3mg/kg

tousles21j4cycles(n=95)

Nivolumab3mg/kgtousles14j(n=147)

Hellmann, ASCO 2017



12

21 11

23

Nivolumab

Nivolumab + ipilimumab

Nivolumab

Nivolumab + ipilimumab

147 95 98 61

Cohorte non randomisée Cohorte randomisée

0

10

20

30

40

Rép

onse

obj

ectiv

e (%

)

Hellmann, ASCO 2017



0 3 6 9 12 15 18 21 24 27 30 33 36 39

98 61

56 43

39 33

35 28

26 24

21 21

17 19

12 16

7 14

7 7

6 3

4 1

4 1

0 0

0

20

40

60

80

100

Mois

Surv

ie g

loba

le (%

) Nivolumab Nivolumab + ipilimumab

82 47

4,1 (3,0-6,8) 7,8 (3,6-14,2)

19,6 20,2

Evts (n) SG médiane, mois (IC95)

Suivi minimum (mois)

40 %

27 %

14 %

26 %

Patient(e)s (n)

Hellmann, ASCO 2017



Hellmann, Cancer Cell 2018

46.2%, respectively) than in patients with low (4.8% and 22.2%,respectively) or medium (6.8% and 16.0%, respectively) tumormutational burden (Figure 2). Within all tumor mutational burdentertiles, the objective response rates were higher among patientstreated with nivolumab plus ipilimumab than among those treatedwith nivolumab monotherapy (Figure 2). Similar associations wereseen when tumor mutational burden was grouped by medians orquartile boundaries (Figures S5A and S5B).We also examined how the association between objective

response and tumor mutational burden in SCLC comparedwith the similar association in NSCLC. The receiver operatingcharacteristics curves of the associations between tumor muta-tional burden and objective response to nivolumab were similar

in patients with SCLC and NSCLC, suggesting that tumor muta-tional burden is a predictor of response to nivolumab in bothpatient populations (Figures S5C and S5D).Tumor mutational burden was higher among patients with a

complete or partial response to either monotherapy or combina-tion therapy than among those with stable disease or progres-sive disease (Figure 3).Inboth treatmentgroups,estimated1-yearprogression-freesur-

vival rates were higher in the high tumor mutational burden group(21.2% and 30.0% for nivolumab monotherapy and nivolumabplus ipilimumab, respectively) compared with the low (not calcu-lable and 6.2%, respectively) or medium (3.1%and 8.0%, respec-tively) tumor mutational burden groups (Figure 4). Similar trends

Table 1. Baseline Characteristics

Characteristic

Nivolumab Nivolumab Plus Ipilimumab

All Treated

(n = 245)

Tumor-Mutational-Burden-

Evaluable (n = 133)

All Treated

(n = 156)

Tumor-Mutational-Burden-

Evaluable (n = 78)

Age (years), median (range) 63 (29–83) 63 (29–83) 65 (37–91) 65 (37–80)

Age R75 years, no. (%) 23 (9) 11 (8) 17 (11) 11 (14)

Male, no. (%) 147 (60) 79 (59) 95 (61) 52 (67)

Smoking status, no. (%)

Current/former smoker 230 (94) 126 (95) 147 (94) 73 (94)

Never smoker 13 (5) 6 (5) 8 (5) 5 (6)

Unknown 2 (1) 1 (1) 1 (1) 0

ECOGa performance status score, no. (%)

0 73 (30) 42 (32) 49 (31) 23 (29)

1 171 (70) 91 (68) 106 (68) 54 (69)

2 1 (<1) 0 0 0

Unknown 0 0 1 (0.6) 1 (1.3)

Tumor PD-L1 expression, no. (%)

R1% 24 (10) 17 (13) 19 (12) 8 (10)

<1% 149 (61) 89 (67) 90 (58) 51 (65)

Unknown 72 (29) 27 (20) 47 (30) 19 (24)

Study cohort, no. (%)

Nonrandomized 98 (40) 50 (38) 61 (39) 25 (32)

Randomized 147 (60) 83 (62) 95 (61) 53 (68)aECOG denotes Eastern Cooperative Oncology Group.

Figure 2. Objective Response Rate byTumor Mutational Burden TertileSee also Figure S5 and Tables S2 and S3.

Cancer Cell 33, 1–9, May 14, 2018 3

Please cite this article in press as: Hellmann et al., Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipili-mumab in Small-Cell Lung Cancer, Cancer Cell (2018), https://doi.org/10.1016/j.ccell.2018.04.001

et al., 2016; Hellmann et al., 2016). In a nonrandomized cohortof patients with advanced SCLC treated in CheckMate 032,the estimated 2-year overall survival rate was 14% withnivolumab monotherapy (n = 98) and 26% with nivolumab plusipilimumab (n = 61) (Hellmann et al., 2017). These results led tothe inclusion of nivolumab with or without ipilimumab in theNational Comprehensive Cancer Network guidelines as a rec-ommended therapy for second-line or later treatment of SCLC(National Comprehensive Cancer Network, 2017). In addition,the trial was expanded to include a randomized cohort ofpatients with SCLC treated with nivolumab with or withoutipilimumab (Hellmann et al., 2017).

The identification of predictors of response to immune check-point blockade in SCLC has been elusive. Unlike in some othercancers, including non-small-cell lung cancer (NSCLC) (Recket al., 2016), tumor PD ligand 1 (PD-L1) expression is uncommonin SCLC (!18%), and responses to nivolumabmonotherapy or incombination with ipilimumab have been observed regardless ofPD-L1 expression (Antonia et al., 2016). Given the initial signalsof benefit with the combination of nivolumab and ipilimumab inSCLC but the potential for greater toxicity compared withnivolumabmonotherapy, determining the predictors of responseto monotherapy and/or combination therapy is critical (Antoniaet al., 2016).

SCLC is characterized by high somatic mutational burden(George et al., 2015; Peifer et al., 2012; Rudin et al., 2012) due tothe nearly universal association of SCLCwith smoking (Alexandrovet al., 2013; Byers and Rudin, 2015); mutations can affect diversepathways, includingDNA repair mechanisms (Gazdar et al., 2017).Data in other solid tumors, including urothelial carcinoma, mela-noma, and NSCLC, have shown an association between hightumormutational burden and improved efficacy of immune check-point blockade monotherapy (Carbone et al., 2017; Galsky et al.,2017; Le et al., 2017; Rizvi et al., 2015; Rosenberg et al., 2016;Snyder et al., 2014); however, this has not previously been exam-ined in patients with SCLC or in patients treated with dual check-point blockade. We hypothesized that tumor mutational burdencould be associated with efficacy of nivolumab alone and incombination with ipilimumab in previously treated SCLC.

Figure 1. Flow Diagram of AnalyzedPatientsSee also Figures S1–S4, Table S1.

RESULTS

Patients and Tumor MutationalBurdenOf all treated patients (n = 401), 245received nivolumab 3 mg/kg every2 weeks and 156 received nivolumabplus ipilimumab (1 mg/kg plus 3 mg/kgevery 3 weeks for four cycles, followedby nivolumab 3 mg/kg every 2 weeks) inthe pooled nonrandomized or random-ized SCLC cohorts of CheckMate 032(Figures 1 and S1). Of all treated patients,61% had sufficient paired tumor and

whole blood samples to attempt whole exome sequencing(WES). WES was successful in 86% of these patients such thatoverall 211 (53%) of all treated patients were evaluable for effi-cacy analyses by tumor mutational burden (Figure 1). Baselinepatient characteristics were similar between tumor-mutational-burden-evaluable patients and all treated patients across treat-ment groups (Table 1). Clinical outcomes, including overall sur-vival, progression-free survival, and objective response rate,also were similar between tumor-mutational-burden-evaluableand all treated patients (Figure S2 and Table S1). Overall, thetumor-mutational-burden-evaluable patients were representa-tive of the total trial population.Tumor mutational burden was defined as the total number of

somatic missense mutations, and patients were divided into ter-tiles, as done previously (Carbone et al., 2017). Tertile boundarieswere defined as: low, 0 to <143 mutations; medium, 143 to 247mutations; and high,R248 mutations. The distribution of patientsby tumor mutational burden was similar between those receivingnivolumab or nivolumab plus ipilimumab (Figure S3A), similar tothe distribution seen in an independent previous report (Georgeet al., 2015) of patients with SCLC (Figure S3B), and similar tothat of patients with NSCLC treated with nivolumab in the Check-Mate 026 study (Carbone et al., 2017) but with a narrower range(Figure S3B). Tumor mutational burden estimated byWES closelycorrelatedwith the estimate after in silico filtering to the 315 genesin the FoundationOne next-generation sequencing genomicprofile (Frampton et al., 2013) (Figure S4).PD-L1 expression R1% was uncommon overall, but was

evenly distributed between the mutational burden high andmedium/low tertiles. There was no association between PD-L1expression and tumor mutational burden (Table S2) or betweenPD-L1 expression and objective response rate in the non-randomized population (Table S3).

Association of Tumor Mutational Burden and ClinicalOutcomesWithin both the nivolumab monotherapy and nivolumab plusipilimumab treatment groups, objective response rateswere higherin those patients with high tumor mutational burden (21.3% and

2 Cancer Cell 33, 1–9, May 14, 2018

Please cite this article in press as: Hellmann et al., Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipili-mumab in Small-Cell Lung Cancer, Cancer Cell (2018), https://doi.org/10.1016/j.ccell.2018.04.001

Réponse et survie selon la charge mutationnelle


KEYNOTE-158 (NTC02628067): Phase 2 Multicohort Study of Pembrolizumab for Advanced Solid Tumors

Patients

• Unresectable and/or metastatic SCLC • Progression on or intolerance to standard therapy • ECOG PS 0 or 1 • ≥1 measurable lesion • Evaluable tumor sample for biomarker assessments • No autoimmune disease or noninfections pneumonitis

Pembrolizumab 200 mg IV Q3W

Treat for 2 yearsa or until progression,b

Intolerable toxicity, or study withdrawal

Survival follow-up

Primary endpointc: ORR (RECIST v1.1, central review) Secondary endpoints: PFS, OS, duration of response, safety Exploratory endpoints: Efficacy in biomarker subgroups Response assessed every 9 weeks year 1; every 12 weeks thereafter

Chung, ASCO 2018


Sur

vie

glob

ale,

%

Temps (mois)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24

33 32

27 23

22 20

20 14

16 13

1 0

0 0

No. à risque PD-L1-positif PD-L1-negatif

9 7

PD-L1-positif PD-L1-negatif

N 42 50

Nb d’évts (%)

23 (55) 38 (76)

Médiane SSP, mo (IC95%)

14,9 (5,6-NR) 5,9 (3,3-10,1)

66,0% 48,3%

53,1% 30,7%

Keynote 158: survie globale selon le statut PDL1

Chung, ASCO 2018


•  Pas de place pour ipilimumab + chimio •  Atezolizumab + carbo/étoposide: nouveau standard en L1 pour les CPC diffus?

•  Bénefice des anti PD1/PDL1probablement pour un petit sous groupe de patients •  Facteurs prédictifs?

–  Expression PDL1? Non dans Checkmate 032, oui dans les Keynote –  Charge mutationnelle? Oui dans Checkmate 032

« PD-1–directed agents alone or in combination with anti-CTLA-4 anti bodies may provide clinically meaningful benefit in patients with SCLC »

Ed book ASCO 2018

•  Nivolumab + Ipilimumab figure dans les reférentiels NCCN pour les CPC PS 0-2 rechutant moins de 6 mois après l’arrêt du traitement initial

principaux essais d’immunothérapie publiés: conclusion


études détails phase CPC localisés

STIMULI NCT02402920

Maintenance par nivo/ipi vs observation (EC) Platine/etoposide/RT + ou – pembro (EC)

IIR I

CPC diffus naïfs REACTION KEYNOTE 604 CASPIAN MCC-18914 NCT02402920

Platine/etoposide +/- pembro (après 2 cures) (EC) Platine/etoposide +/- pembro (EC) Platine/etoposide + durva +/- treme vs platine/etoposide (RF) Platine/etoposide suivi de RT thoracique +/- nivo/ipi (RF) Platine/etoposide suivi de RT thoracique +/- pembro (EC)

II III III I/II I

CPC diffus maintenance Checkmate 451

Nivo vs nivo/ipi vs placebo (EC)

III

CPC diffus prétraités AFT 17 Checkmate 331 IFCT-1603 MISP-MK3475 PembroPlus CA001-030 NCT 02937818 Winship 3112-15 M16-300 AAAQ 8257

Pembro vs topotecan (RF) Nivo vs Topotecan ou amrubicine (RF) Atezo vs topotecan ou carboplatine/etoposide (RF) Pembro + paclitaxel (RF) Pembro + irinotecan (RF) BMS-986012 +/- nivo (RF) Durva + treme vs AZD1775 + carboplatine (EC) Treme + durva +/- RT (EC) Nivo + ROVA-T +/- ipi (EC) SGI-110 suivi de durva + treme (EC)

II III II II

I/II I/II II II I I

Nivo= nivolumab, ipi= ipilimumab, pembro= pembrolizumab, atezo= atezolizumab, RT= radiothérapie, EC= en cours de recrutement, RF= recrutement fermé

essais d’immunothérapie dont les résultats sont en attente

Pakkala, J Thorac Dis 2018

Les nouveaux traitements: traitement ciblé

•  La DLL3 (delta-like protein 3) est une nouvelle cible pour le traitement des tumeurs neuroendocrines

•  protéïne impliquée dans la voie de signalisation NOTCH et exprimée dans plus de 80% des CPC

•  Rovalpituzumab tesirine (Rova-T) : anticorps conjugué ciblant la DLL3

•  Dans une étude de phase I, les patients ayant un CPC exprimant DLL3 dans plus de 50% des cellules tumorales avaient une meilleure réponse (38% vs 0%)

•  toxicités de grade 3 les plus fréquentes : •  thrombopénie (11%) •  épanchements pleuraux (8%) •  augmentation de la lipase (7%)

Les nouveaux traitements: traitement ciblé: Rova-T

23% pts réfractaires

Carbone ASCO 2018

Les nouveaux traitements: traitement ciblé: Rova-T

2 phases III •  maintenance versus placébo après chimiothérapie d’induction (étude MERU) •  2ème ligne vs topotécan chez les patients en rechute (étude TAHOE). essais associant immunothérapie et Rova-T

Carbone ASCO 2018

Les autres nouveaux traitements •  Les anti-angiogéniques:

–  bevacizumab, thalidomide, vandétanib, sunitinib –  cisplatine − VP16 vs cisplatine − VP16 + bevacizumab (204 patients, L1)

•  survie sans progression (6,7 m vs 5,7 m, p = 0,030) •  pas d’amélioration de la survie globale (9,8 m vs 8,9 m)

–  méta-analyse de 7 essais randomisés: •  1322 patients chimio + antiangiogénique •  pas d’amélioration de la réponse, de la survie sans progression ni de la survie globale. •  un sous-groupe utilisant le bévacizumab a améliore la survie sans progression

•  Les inhibiteurs de PARP –  Olaparib: échec en maintenance, plusieurs études en cours –  Véliparib: en association avec la chimio amélioration de la SSP mais pas

de la survie

•  Inhibiteur d’AURA kinase: alisertib •  Lurbinectedine:

–  Phase I + doxorubicine prometteuse –  Phase III (étude Atlantis) en cours Carbone ASCO 2018

CONCLUSION

•  Des questions non résolues: – Place de l’IPC dans les formes disséminées? – Pour quels patients la radiothérapie thoracique

dans les formes disséminées?

•  De nouvelles options thérapeutiques – Chimio/atézo en 1ère ligne? –  Immuno en 2ème ligne?

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