l immunothérapie dans le cancer bronchique post wclc 2016 · 2017. 2. 17. · l ’...

L’immunothérapie dans le cancer bronchique POST WCLC 2016

Bertrand Mennecier Pole pathologie Thoracique CHU Strasbourg

Paris 13 Janvier 2017

Liens d’intérets

• Consultant : BMS • Advisory Board : BMS, MSD • Communications rémunérées : ROCHE, AZ • Investigateur : BMS, MSD, ROCHE, AZ

Anticoprs Cible Companie Développement

Ipilimumab CTLA-4 Bristol-Myers Squibb Phase III

Tremelimumab CTLA-4 MedImmune/Astra Zeneca Phase III

BMS-936558 Nivolumab PD-1 Bristol-Myers Squibb AMM

BMS-936559 PD-L1 Bristol-Myers Squibb Phase I

MK-3575 pembrolizumab PD-1 Merck AMM

Medi-4736 PD-L1 MedImmune Phase II et III

MPDL-3280A atezolizumab PD-L1 Genentech Phase II et III

AMP-224

Fc fusion De PD-L2 GSK Phase I

Les molécules en développement dans le CBNPC

Principales Données d’efficacité en 2ème ligne et plus

Avant le WCLC

Anti-PD1 en 2eme ligne CHECKMATE-017 – Nivolumab Epidermoïdes

KEYNOTE-010 – Pembrolizumab PD-L1 >1%, toutes histologies

CHECKMATE-057 – Nivolumab Non-épidermoïdes

KEYNOTE-010 – Pembrolizumab PD-L1 >50%, toutes histologies

Atezolizumab : Essai OAK

• Atezolizumab (anti–PD-L1) Ac monoclonaj qui inhibe PD-L1/PD-1 et PD-L1/B7.1

• Améliore l’OS vs docetaxel dans les essais deja rapportés : Phase II POPLAR (mediane OS 12.6 vs 9.7 mois; HR = 0.69)

• OAK : premiere Phase III pour un anti PD-L1

Figure: Fehrenbacher Lancet 2016; Smith J Clin Oncol 2016. Barlesi F. et al. - ESMO® 2016 - Abs. LBA44

PD

PD or loss of clinical benefit

Phase III OAK design de l’étude

• Primary Endpoints (first 850 enrolled patients):

– SG sur l’ensemble de la population – SG chez les patients exprimant PD-L1 ≥ 1% TC or IC

• Secondary Endpoints : ORR, PFS, DoR, Safety

R A B D O M I Z E D

1 to 1

Stratification factors - PD-L1 expression - Histology - Prior chemotherapy

regimens

Docetaxel 75 mg/m2 q3w

Atezolizumab 1200 mg IV q3w

Barlesi et al. - ESMO® 2016 - Abs. LBA 44

Locally Advanced or Metastatic NSCLC 1–2 prior lines of chemo including at least 1 platinum based Any PD-L1 status N = 1,225 enrolled

R

Survie globale, ITT (n = 850)


Ove

rall

surv

ival

time (months) Number at risk

Atezolizumab 425 363 305 248 218 188 157 74 28 1 Docetaxel 425 336 263 195 151 123 98 51 16 0

Docetaxel N=425

Atezolizumab N=425

Median (95%CI) months

9,6 (8,6-11,2)

13,8 (11,8-15,7)

HR (95%CI) 0,73a (0,62-0,87)

Log-rank p-value = 0,0003

aStratified HR.

SG selon l’histologie

HR, 0.73a (95% CI, 0.60, 0.89) P = 0.0015b

Atezolizumab Docetaxel

Minimum follow up = 19 months

HR, 0.73a (95% CI, 0.54, 0.98) P = 0.0383b

Non-squamous Squamous

Ove

rall

Surv

ival

(%)

Months



Median 11.2 mo (95% CI, 9.3, 12.6)

Median 15.6 mo (95% CI, 13.3, 17.6)

Ove

rall

Surv

ival

(%)

Months

Median 7.7 mo (95% CI, 6.3, 8.9)

Median 8.9 mo (95% CI, 7.4, 12.8)

Atézolizumab Nivolumab Pembrolizumab

Auteur

Barlési OAK

Phase III

Brahmer Checkmate 017

Phase III

Borghaei Checkmate 057

Phase III

Herbst Keynote 010

Phase III

IHC (anticoprs) Cible

SP 142 Ventana TC (tumor cells) et TIC (T.immune)

28-8 Dako (rabbit) TC (tumor cells)

28-8 Dako (rabbit) TC

22C3 Dako (mouse) TC et stroma

Comparateur Docétaxel Docétaxel Docétaxel Docétaxel

Histologie Épidermoïdes ( 26%) Non épidermoïdes (74 %)

Epidermoïdes (100%)

ADK (100%)

Épidermoïdes (20 %) Non épidermoïdes (80 %)

Dosage cycle

1200 mg 21 jours

3 mg/kg 15 jours

3 mg/kg 15 jours

2 mg/kg, 10 mg/kg 21 jours

N 425 vs. 425 135 vs. 137 292 vs. 290 345 vs. 346 vs. 343

MS (mois) 13,8 vs. 9,6 HR 0,73 p= 0,0003

9,2 vs 6 HR 0,44, p

WCLC 2016 immunothérapie 2eme ligne ou au delà

L’heure est au recul

KEYNOTE-010: Durable Clinical Benefit in Patients With Previously Treated, PD-L1–Expressing NSCLC Who

Completed Pembrolizumab

RS Herbst,1 EB Garon,2 D-W Kim,3 BC Cho,4 S Gadgeel,5 H Lena,6 A Gúrpide,7 J-Y Han,8 C Dubos-Arvis,9 M Majem,10 M Forster,11 I Monnet,12 S Novello,13 H Saka,14 Z Szalai,15 M Gubens,16 W-C Su,17 GM Lubiniecki,18

A Samkari,18 Y Shentu,18 GL Ferraro,18 P Baas19

1Yale School of Medicine, Yale Cancer Center, and Smilow Cancer Hospital, New Haven, CT, USA; 2David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA, USA; 3Seoul National University Hospital, Seoul, South Korea; 4Yonsei Cancer Center, Yonsei University

College of Medicine, Seoul, South Korea; 5Karmanos Cancer Institute, Detroit, MI, USA; 6Centre Hospitalier Universitaire Rennes, Rennes, France; 7Clínica Universidad de Navarra, Pamplona, Spain; 8National Cancer Center, Goyang, South Korea; 9Centre François Baclesse, Caen, France;

10Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; 11University College Hospital, London, England, UK; 12Centre Hospitalier Intercommunal Créteil, Créteil, France; 13Ospedale San Luigi Gonzaga, Orbassano, Italy; 14National Hospital Organization Nagoya Medical Center, Nagoya, Japan;

15Petz Aladár Megyei Oktató Kórház, Gyor, Hungary; 16University of California, San Francisco, San Francisco, CA, USA; 17National Cheng Kung University Hospital, Tainan, Taiwan; 18Merck & Co., Inc., Kenilworth, NJ, USA; 19The Netherlands Cancer Institute and The Academic Medical Hospital

Amsterdam, Amsterdam, Netherlands

6769: KEYNOTE-010: durable clinical benefit in patients with previously treated, PD-L1–expressing NSCLC who completed pembrolizumab – RS Herbst

KEYNOTE-010 (NCT01905657): Study Design1

aPrior therapy must have included ≥2 cycles of platinum-doublet chemotherapy. An appropriate tyrosine kinase inhibitor was required for patients whose tumors had an EGFR sensitizing mutation or an ALK translocation. bAdded after 441 patients enrolled based on KEYNOTE-001 (Garon EB et al. N Engl J Med. 2015;372:2018-28). cPatients received the maximum number of cycles permitted by the local regulatory authority. 1. Herbst RS et al. Lancet. 2016;387:1540-1550.

6769 – RS Herbst

Patients •Advanced NSCLC •Confirmed PD after ≥1 line of chemotherapya •No active brain metastases •ECOG PS 0-1 •PD-L1 TPS ≥1% •No serious autoimmune disease •No ILD or pneumonitis requiring systemic steroids

Pembrolizumab 2 mg/kg IV Q3W for 24 months

Pembrolizumab 10 mg/kg IV Q3W

for 24 months

R 1:1:1

Docetaxel 75 mg/m2 Q3W

per local guidelinesc

Stratification factors: •ECOG PS (0 vs 1) •Region (East Asia vs non-East Asia) •PD-L1 statusb (TPS ≥50% vs 1%-49%)

End points in the TPS ≥50% stratum and TPS ≥1% population

• Primary: PFS and OS • Secondary: ORR, duration of response, safety

6769 – RS Herbst

Pembrolizumab •691 allocateda •682 received treatment

• 40 ongoing • 604 discontinued – 308 progressive disease – 81 adverse events – 6 deaths – 178 physician decision – 19 withdrew consent – 12 other • 46 completed

Data cutoff date: September 30, 2016.

1034 allocated to treatment

Docetaxel •343 allocated •309 received treatment

• 2 ongoing • 321 discontinued – 101 progressive disease – 51 adverse events – 1 death – 122 physician decision – 44 withdrew consent – 2 other • 20 completedb

2222 with PD-L1 results

1475 with PD-L1 TPS ≥1% 66% with ≥1% 28% with ≥50%

2699 patients screened

Disposition

47 patients received 35 cycles (2 years) of pembrolizumab •46 completed • 1 discontinued (patient withdrawal)

6769 – RS Herbst a1 patient excluded from efficacy analyses because of noncompliance with imaging guidelines for prebaseline scans. bPatients who received the maximum number of docetaxel doses permitted per local guidelines. Data cutoff date: September 30, 2016.

Baseline Characteristics

a1/4 patients with ECOG PS ≥2 during screening resolved to ≤1 by treatment assignment. Data cutoff date: September 30, 2016.

6769 – RS Herbst

Pembro 2-10 mg/kg

Q3W n = 690

Pembro 24 months

n = 47

Age, median (range), years

63 (20-88) 61 (39-86)

Male, % 62 79

Race, % White Asian Other or unknown

72 21 7

72 19 9

ECOG PS,a % 0 1

34 66

36 64

Smoking status, % Former/current Never Unknown

82 18

OS in the Total Populationa

aComparison of pembrolizumab vs docetaxel. Data are an additional 12 months of follow-up from the final analysis, bMedian time from first randomization to current DBL. Data cutoff date: September 30, 2016.

6769 – RS Herbst

Ove

rall

Surv

ival

, %

Docetaxel 75 mg/m2 (n = 343) Pembrolizumab 2 mg/kg Q3W (n = 344) Pembrolizumab 10 mg/kg Q3W (n = 346)

No. at risk Docetaxel Pembro 2 mg/kg Q3W Pembro 10 mg/kg Q3W

216 261 259

129 176 195

84 135 259

40 88 100

20 46 57

6 12 15

0 0 1

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25 30 35

Pembro 2 mg/kg Q3W

n = 344

Pembro 10 mg/kg

Q3W n = 346

Docetaxel n = 343

Events, n (%) 233 (68) 214 (62) 257 (75)

OS, median mo (95% CI)

10.5 (9.6-12.4)

13.4 (11.2-17.0)

8.6 (7.9-9.8)

HR (95% CI) 0.72 (0.60-0.86) 0.60

(0.49-0.72) —

P value (vs docetaxel) 0.00017

Confirmed Best Overall Response (RECIST v1.1) Patients Completing 24 months of Pembrolizumab (N = 47)


6769 – RS Herbst

Best Overall Response n %

Complete response 3 6

Partial response 39 83

Stable disease 5 11

Progressive disease 0 0

No assessment/Not evaluable 0 0

Median duration of response, months (range) Not reached (2+─31+)

•Objective response rate: 89% •Clinical benefit rate (CR + PR + SD ≥6 months): 100% •Median time to response: 2 months (range, 2-24 months) •72% of responses were ongoing

Change from Baseline in Tumor Size (RECIST v1.1, Central Imaging Review; N = 47)


6769 – RS Herbst

0

–10

–20

–30

–40

–50

–60

–70

–80

–90

–100

Cha

nge

from

Bas

elin

e, %

SD PR/CR


1st Treatment Duration and Time to Last Scan (RECIST v1.1, Central Imaging Review; N = 47)

6769 – RS Herbst

• Median time off therapy 3.8 (range), months (

Conclusions • With 1 year longer follow-up, the OS benefit of pembrolizumab over

docetaxel in previously treated NSCLC patients is maintained • A survival plateau above 30% beyond 2 years appears to be

developing • Most patients who complete 2 years of pembrolizumab and stop

treatment remain with response including patients with stable disease • Clinical benefit of pembrolizumab is durable after 2 years of treatment

– Majority of patients who completed 2 years of pembrolizumab were initially responders (PR and CR)

– This analysis confirmed disease progression in only 4% after stopping pembrolizumab

6769 – RS Herbst

PrésentateurCommentaires de présentationConfirmed


L’heure est aux analyses en sous groupes

Presentation Number: Presentation Title – Presenting Author

Analysis of Early Survival in Patients With Advanced Non-Squamous NSCLC Treated With

Nivolumab vs Docetaxel in CheckMate 057

Solange Peters,1 Federico Cappuzzo,2 Leora Horn,3 Luis Paz-Ares,4 Hossein Borghaei,5 Fabrice Barlesi,6 Martin Steins,7 Enriqueta Felip,8 David Spigel,9 Cécile Dorange,10 Haolan Lu,10 Diane Healey,10

Teresa Kong Sanchez,10 Prabhu Bhagavatheeswaran,10 James Novotny, Jr,10 Brian Lestini,10 Julie Brahmer11

1University of Lausanne, Lausanne, Switzerland; 2AUSL Romagna, Ospedale Santa Maria delle Croci, Department of Oncology and Hematology, Ravenna, Italy; 3Vanderbilt University Medical Center, Nashville, TN, USA; 4Hospital Universitario Doce de Octubre & CNIO, Madrid, Spain; 5Fox Chase Cancer Center, Philadelphia, PA, USA; 6Aix-Marseille Université,

Assistance Publique Hôpitaux de Marseille, Marseille, France; 7Thoraxklinik-Heidelberg gGmbH, Heidelberg, Germany; 8Hospital Universitari Vall d’Hebron, Barcelona, Spain; 9Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN, USA; 10Bristol-Myers Squibb, Princeton, NJ, USA;

11The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA

Abstract OA03.05 – Solange Peters


Phase 3 CheckMate 057 Study Design: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

24

Key eligibility criteria •Stage IIIB/IV NSQ NSCLC •ECOG PS 0–1 •1 prior platinum-based chemotherapy •Prior TKI therapy allowed for known ALK translocation or EGFR mutation •Prior maintenance therapy allowed

•Pretreatment tumor samples required for PD-L1 analysis

(N = 582)

Nivolumab 3 mg/kg IV Q2W until PD or unacceptable toxicity

(n = 292)

Docetaxel 75 mg/m2 IV Q3W

until PD or unacceptable toxicity

(n = 290)

• Primary endpoint – OS

• Additional endpoints – ORR – PFS – Efficacy by tumor PD-L1

expression – Safety – Quality of life R

ando

miz

e 1:

1

Randomization stratified by prior maintenance therapy and line of therapy (second-line vs third-line)

ClinicalTrials.gov number NCT01673867 NSQ = non-squamous; TKI = tyrosine kinase inhibitor


Overall Survival CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

25

Based on a February 18, 2016 database lock; minimum follow-up: 2 years Borghaei H, et al. Presented at the American Society of Clinical Oncology 2016 Annual Meeting; June 3–7, 2016; Chicago, IL, USA. Abstract 9025.

Nivolumab (n = 292)

Docetaxel (n = 290)

Events, n (%) 228 (78) 247 (85)

Median OS, mo (95% CI)

12.2 (9.7, 15.1)

9.5 (8.1, 10.7)

HR (95% CI) 0.75 (0.63, 0.91)

Number of patients at risk 194

194

148

111

112

66

81

45

18

6

233

243

171

150

128

89

97

53

46

25

6

3

0

0

0

1 Nivolumab

Docetaxel

292

290

2-year OS = 29%

2-year OS = 16%

Months

20

40

60

80

100

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

1-year OS = 51%

1-year OS = 39%

1 5

Δ12%

0

OS

(%)

Δ13% Nivolumab Docetaxel


Number of patients at risk 194

194

148

111

112

66

81

45

18

6

233

243

171

150

128

89

97

53

46

25

6

3

0

0

0

1 Nivolumab

Docetaxel

292

290

Overall Survival CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

26

Based on a February 18, 2016 database lock; minimum follow-up: 2 years Borghaei H, et al. Presented at the American Society of Clinical Oncology 2016 Annual Meeting; June 3–7, 2016; Chicago, IL, USA. Abstract 9025.

2-year OS = 29%

2-year OS = 16%

Months

20

40

60

80

100

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

Nivolumab Docetaxel

1-year OS = 51%

1-year OS = 39%

1 5

Δ12%

0

OS

(%)

Δ13%

Events

Nivolumab (n = 292)

n

Docetaxel (n = 290)

n

Difference n

0−3 months 59 44 15

3−6 months 39 48 [9]


Single Baseline Characteristics by OS (n Values) CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

• No treatment-related deaths occurred in patients with OS ≤3 months; OS ≤3 months was most commonly attributed to disease progression

• No single baseline factor reliably characterized the OS subgroups

27

Nivolumab, n Docetaxel, n

OS ≤3

mo (n=59)

OS >3 mo

(n=233)

OS ≤3 mo

(n=44)

OS >3 mo

(n=246) Prior therapy

Presentation Number: Presentation Title – Presenting Author 28

Single Baseline Characteristics by OS With Nivolumab CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

Patie

nts

with

fact

or in

O

S su

bgro

up (%

)

OS ≤3 months OS >3 months

Based on a March 18, 2015 database lock; aPercentages of patients are based on numbers of patients with quantifiable PD-L1 expression at baseline; maint. = maintenance; mets = metastases; mut. = mutation; pos. = positive; resp. = response; TX = treatment

5 sites with

lesions

Bone mets

Liver mets

Never Current/ former

0 1

Presentation Number: Presentation Title – Presenting Author 29

Proportion of Patients With Baseline Factor Alive at 3 Months With Nivolumab

CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

Based on a March 18, 2015 database lock; maint. = maintenance; mets = metastases; resp. = response; TX = treatment

• The majority of patients with these factors were alive >3 months

OS ≤3 months OS >3 months

5 sites with

lesions

Bone mets

Liver mets

Never Current/ former

0 1


Conclusions CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLC

• Nivolumab is a standard of care as second-line treatment for advanced squamous and non-squamous NSCLC across all PD-L1 expression levels

• While enhanced clinical activity with nivolumab correlates with increasing tumor PD-L1 expression in this patient population, nivolumab-treated patients with low or no PD-L1 expression have a comparable probability of response, more durable responses, comparable OS, and fewer treatment-related AEs vs those treated with docetaxel

• The absolute difference in death events in the first 3 months of treatment was n = 15 – Exploratory post hoc multivariate analysis suggested that patients with poorer prognostic factors

and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher risk of death on nivolumab vs docetaxel

– The majority of patients with these factors were alive >3 months in the nivolumab arm

• Additional biomarker research is ongoing to help identify patients with advanced NSCLC who may derive the most clinical benefit from nivolumab

31

Gadgeel et al., WCLC 2016

OAK, a randomized Ph III study of atezolizumab vs docetaxel in patients with advanced NSCLC:

results from subgroup analyses

Gadgeel et al., WCLC 2016

Shirish M. Gadgeel,1 Fortunato Ciardiello,2 Achim Rittmeyer,3 Fabrice Barlesi,4 Diego Cortinovis,5 Carlos Barrios,6 Toyoaki Hida,7 Keunchil Park,8 Dariusz Kowalski,9 Manuel Cobo Dols,10 Joseph Leach,11

Christina Matheny,12 Pei He,12 Marcin Kowanetz,12 Daniel S. Chen,12 Daniel Waterkamp,12 Marcus Ballinger,12 Alan Sandler,12 David R. Gandara,13 Joachim von Pawel14

1 Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA; 2 Seconda Università degli Studi di Napoli, Napoli, Italy; 3 Lungenfachklinik Immenhausen, Immenhausen, Germany; 4 Aix Marseille University; Assistance Publique Hôpitaux de Marseille, Marseille, France;

5 Medical Oncology Unit, AOU San Gerardo, Monza, Italy; 6 PUCRS School of Medicine, Porto Alegre, Brazil; 7 Aichi Cancer Center Hospital, Nagoya, Japan; 8 Sungkyunkwan University School of Medicine, Seoul, South Korea;

9 Oncology Centre, Institute M. Sklodowska - Curie, Warsaw, Polandomg; 10 Medical Oncology Section, Hospital Regional Universitario Carlos Haya, Málaga, Spain; 11 PRA Health Sciences, Raleigh, NC, USA; 12 Genentech, Inc., South San Francisco, CA, USA;

13 UC Davis Comprehensive Cancer Center, Sacramento, CA, USA; 14 Asklepios-Fachkliniken München-Gauting, Gauting, Germany

Gadgeel et al., WCLC 2016 Gadgeel et al., WCLC 2016

Phase III OAK study design

Atezolizumab (anti–PD-L1) is an engineered mAb that inhibits the PD-L1/PD-1 and PD-L1/B7.1 interactions to restore anti-tumor T-cell activity and enhance T-cell priming1,2

aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression). bPD-L1 expression assessed with VENTANA SP142 IHC assay 1. Herbst Nature 2014. 2. Chen Immunity 2013. 3. Barlesi et al. ESMO 2016 LBA44

Atezolizumab 1200 mg IV q3w

PD or loss of clinical benefit

Docetaxel 75 mg/m2 q3w

Locally Advanced or Metastatic NSCLC3

•N = 1225 enrolleda •1–2 prior lines of chemo including ≥ 1 platinum-based •Any PD-L1 statusb

•Stratification factors: PD-L1 expression, histology, prior chemotherapy regimens

PD

R 1:1

Primary Endpoints (first 850 enrolled patients) •OS in the ITT population •OS in patients with PD-L1 expression on ≥ 1% TC or IC

Secondary Endpoints ORR, PFS, DoR, Safety

OAK study design

Gadgeel et al., WCLC 2016 aStratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for other subgroups. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival. Barlesi et al. ESMO 2016 LBA44

Overall survival, ITT (n = 850) and PD-L1 subgroups

Atezolizumab

Docetaxel

Median 9.6 mo (95% CI, 8.6, 11.2)

Median 13.8 mo (95% CI, 11.8, 15.7)

Ove

rall

Sur

viva

l (%

)

Months

HR, 0.73a (95% CI, 0.62, 0.87)

P = 0.0003


425

363

305

248

218 188

157 74 28 1

425

336

263

195

151

123 98 51 16 0

No. at risk

Atezolizumab

Docetaxel

0.2 2

Subgroup

TC1/2/3 or IC1/2/3a

TC0 and IC0

ITTa

TC3 or IC3

TC2/3 or IC2/3

Median OS, mo

n = 425 n = 425

9.6

8.9

10.3

10.8

8.9

13.8

12.6

15.7

16.3

20.5 0.41

0.67

0.74

0.75

0.73

0.2 1 2

In favor of docetaxel

Hazard Ratioa

In favor of atezolizumab

Docetaxel Atezolizumab OS HR

Gadgeel et al., WCLC 2016 *TC1/2/3 or IC1/2/3 includes TC3 or IC3 1. Lukas et al. WCLC 2016. Poster P2.03b–014

Efficacy in CNS mets subgroup

• Although the incidence of new CNS lesions is similar between arms, the time to development of new CNS lesions is longer in patients treated with atezolizumab1

• No additional toxicities with atezolizumab were observed in patients with CNS mets1

In favor of docetaxel Hazard Ratio


No CNS mets

CNS mets

0.75 0.97

0.54 0.61

0.73 0.93

0.2 1 2

ITT

PFS HR OS HR

No CNS mets

CNS mets

Doc (n = 47)

Doc (n = 378)

Atezo (n = 38)

Atezo (n = 387)

TC0 and IC0 TC1/2/3 or IC1/2/3* TC3 or IC3

PD-L1 expression

Gadgeel et al., WCLC 2016 *TC1/2/3 or IC1/2/3 includes TC3 or IC3

Efficacy in tobacco use subgroup

Never Current / previous n = 84 72 341 353 425 425

ITT

6%

18% 16%

13% 13% 14%

OR

R (%

)

0.71 1.3

0.74 0.87

0.73 0.93

Never

Current/previous



ITT

PFS HR OS HR

0.2 1 2

Never

Doc (n = 72)

Doc (n = 353)

Atezo (n = 341)

Atezo (n = 84)

Current/previous


PD-L1 expression

• PD-L1 expression was slightly higher in the current/previous vs never group

• Overall survival advantage seen with atezolizumab irrespective of tobacco use


Gadgeel et al., WCLC 2016 *TC1/2/3 or IC1/2/3 includes TC3 or IC3 1. Borghaei et al NEJM 2016.

Efficacy in EGFR subgroups

• Lack of improved efficacy relative to docetaxel similar to other in-pathway agents1

n = 318 310 42 43 425 425

Wild type Mutant ITT

15%

11%

5%

28%

13% 14%


OR

R (%

)

Wild type

341 353

0.69 0.92

1.24 1.21

0.73 0.93

PFS HR OS HR

Mutant



ITT

0.2 1 2

Wild type

Mutant

Doc (n = 43)

Doc (n = 310)

Atezo (n = 42)

Atezo (n = 318)


PD-L1 expression

Gadgeel et al., WCLC 2016 aOS and PFS were not estimable in the ≥ 85 year patient subgroup (n = 2)

Efficacy in subgroups by age

84 72 341 353 425

0.2 1 2.5

75–84 yearsa

ITT



OS HR

0.80 0.93

0.63 0.98

0.73 0.93

PFS HR

65–74 years

< 65 years

0.79 0.93

n (%)

453 (53%)

850 (100%)

307 (36%)

88 (10%)

Gadgeel et al., WCLC 2016 Gadgeel et al., WCLC 2016

Conclusion

• OAK subgroup analysis demonstrated broad clinically-relevant efficacy with atezolizumab – OS benefit observed regardless of PD-L1 expression levels as measured

by IHC or gene expression – OS benefit observed in both histology subgroups across PD-L1

expression levels – OS improvement observed in subgroups including all age ranges,

never smokers and patients with baseline brain metastases – Lack of improved efficacy relative to docetaxel in EGFR mutant patients

similar to other in-pathway agents


L’arrivée de nouvelles molécules

Durvalumab in ≥3rd-line locally advanced or metastatic, EGFR/ALK wild-type NSCLC: results from the Phase 2 ATLANTIC study Marina Chiara Garassino1, Johan Vansteenkiste2, Joo-Hang Kim3, Hervé Lena4, Julien Mazières5, John Powderly6, Phillip Dennis7, Yifan Huang7, Catherine Wadsworth8, Naiyer Rizvi9 1Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 2University Hospitals KU Leuven, Leuven, Belgium; 3CHA Bundang Medical Center, CHA University, Gyeonggi-do, Republic of Korea; 4CHU Rennes - Hôpital Pontchaillou, Rennes, France; 5CHU de Toulouse - Hôpital Larrey, Toulouse, France; 6Carolina BioOncology Institute, Huntersville, NC, USA; 7AstraZeneca, Gaithersburg, MD, USA; 8AstraZeneca, Alderley Park, UK; 9Columbia University Medical Center, New York, NY, USA

PL04a.03: Durvalumab in ≥3rd-line locally advanced or metastatic, EGFR/ALK wild-type NSCLC: results from the Phase 2 ATLANTIC study – Marina Chiara Garassino

Durvalumab is a selective, high-affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD801

Tumour cell

Immune cell

T cell

PD-L1

PD-1 PD-L1 PD-1

CD80 CD80

TCR MHC

PD-L1

Tumour antigen

CD80

CD28

TCR MHC

Inhibition Inhibition

Inhibition Inhibition

Inhibition

Durvalumab

Durvalumab blocks PD-L1 binding to PD-1 and CD80

–

Durvalumab

–

–

MHC, major histocompatibility complex; PD-1, programmed cell dealth-1; PD-L1, programmed cell death ligand-1; TCR, T-cell receptor 1. Stewart R, et al. Cancer Immunol Res 2015;3:1052–62

Activation Activation

Activation Activation

ATLANTIC (NCT02087423) is a Phase 2, open-label, single-arm trial

*PD-L1 expression levels assessed by immunohistochemistry (VENTANA PD-L1 [SP263] Assay); †ORR by independent central review (RECIST v1.1) CT, chemotherapy; DCR, disease control rate; DoR, duration of response

Primary endpoint: •ORR†

Secondary endpoints: •DoR, PFS, DCR, OS •Safety •PK •Immunogenicity

Durvalumab i.v. 10 mg/kg q2w up to 12 months

• NSCLC patients (Stage IIIB/IV)

• ≥2 prior systemic treatment regimens including 1 platinum-based CT

• Recent (≤3 months) tumour biopsy and archived tumour tissue block for PD-L1 testing N=1980 screened

Cohort 1 (n=111) EGFR mutation/ALK alteration PD-L1 high (≥25% tumour cells)

Cohort 2 (n=265) EGFR/ALK wild-type

PD-L1 high (≥25% tumour cells) and PD-L1 low/negative

Cohort 3 (n=68) EGFR/ALK wild-type

PD-L1 high (≥90% tumour cells)

Protocol amendment restricted

selection to pts with PD-L1 high tumours*

Cohorts were independent; Cohorts 2 and 3 enrolled sequentially

Baseline characteristics for Cohorts 2 and 3

Characteristic Cohort 2 (n=265)

Cohort 3 (n=68)

Median age, years 62.0 61.0 Male, % 61.1 57.4 White / Asian, % 80.0 / 19.2 61.8 / 35.3 WHO PS 0 / 1, % 32.5 / 67.2 27.9 / 72.1 Squamous / Non-squamous, % 20.8 / 79.2 29.4 / 70.6 Never smoker, % 14.7 13.2 Current or former smoker, % 84.9 86.8 Number of prior regimens, %

2 40.0 60.3 3 26.4 26.5 ≥4 33.6 13.2

Mean number of prior regimens 3.2 2.6

PS, performance status; WHO, World Health Organisation

PD-L1 expression status

Treated patients, % Cohort 2 (n=265)

Cohort 3 (n=68)

Low/negative (

Antitumour activity in Cohorts 2 and 3 (full analysis set*)

Endpoint

Cohort 2 Cohort 3

PD-L1 low/neg (

Median PFS (95% CI) PD-L1 ≥90% (n=67): 2.4 (1.8–5.5)

Progression-free survival in Cohorts 2 and 3 (full analysis set)

*Number of patients at risk is per Independent Central Review and therefore smaller than the total number of patients in the full analysis set

Cohort 2 Cohort 3

Median PFS (95% CI) PD-L1 ≥25% (n=149): 3.3 (1.9–3.7) PD-L1

Overall survival in Cohorts 2 and 3 (full analysis set)

*Median follow up for OS was 9.4 months (PD-L1 ≥25%); 9.3 months (PD-L1

Safety summary (safety analysis set)

Adverse event, n (%) Cohort 2 (n=265) Cohort 3

(n=68) Median actual duration of exposure (range), weeks 16.1 (1–62) 24.1 (2–52)

Treatment-related AEs 157 (59.2) 46 (67.6)

Grade ≥3 treatment-related AEs 22 (8.3) 12 (17.6) Treatment-related AEs leading to death 0 0

Treatment-related SAEs 14 (5.3) 8 (11.8) Treatment-related AEs leading to discontinuation 8 (3.0) 1 (1.5)

Treatment-related AESIs 80 (30.2) 32 (47.1)

Immune-mediated AEs* 27 (10.2) 14 (20.6)

Infusion reaction AEs 4 (1.5) 3 (4.4) *AESIs that required the use of systemic steroids, other immunosuppressives and/or endocrine therapy and with no clear alternate aetiology AE, adverse event; AESI, adverse event of special interest; SAE, serious adverse event

Immune-mediated AEs by grouped term* (safety analysis set)

Adverse event (grouped term), n (%)

Cohort 2 (n=265)

Cohort 3 (n=68)

Any immune-mediated AE 27 (10.2) 14 (20.6) Hypothyroidism 13 (4.9) 8 (11.8) Hyperthyroidism 4 (1.5) 3 (4.4) Pneumonitis 5 (1.9) 2 (2.9) Dermatitis 3 (1.1) 0 Rash 1 (0.4) 2 (2.9) Select hepatic events 1 (0.4) 2 (2.9) Adrenal insufficiency 2 (0.8) 0 Colitis 1 (0.4) 1 (1.5) Diarrhoea 1 (0.4) 1 (1.5) Hypophysitis 0 1 (1.5)

*AESIs that required the use of systemic steroids, other immunosuppressives and/or endocrine therapy and with no clear alternate aetiology

Conclusions

• Durvalumab was active and led to durable responses in a heavily pretreated metastatic NSCLC population (mean of 3 prior regimens) – Higher PD-L1 expression appeared to be associated with higher response rate – 1-year OS was 48% in patients with PD-L1 ≥25% and 51% in those with PD-L1 ≥90%

• Most AEs were low grade and imAEs were manageable

• Results are consistent with other anti-PD-1/PD-L1 therapies in metastatic NSCLC

• Ongoing Phase 3 studies will clarify the role of durvalumab in NSCLC:

– MYSTIC and NEPTUNE: 1L durvalumab ± tremelimumab vs SoC in metastatic NSCLC – ARCTIC: 3L durvalumab ± tremelimumab vs SoC in metastatic NSCLC – PACIFIC: durvalumab monotherapy following chemoradiation in Stage III NSCLC

1L, first-line; 3L, third-line; imAE, immune-mediated adverse event; SoC, standard of care


CONCLUSION

•Arrivée de nouvelles molécules •Réponses sur

–La sélection des patients à ne pas traiter –La possibilité d’arrêter une immunothérapie sans

provoquer de reprise évolutive –Les analyses en sous groupes pour les patients

qui bénéficient ou non de l’atezolizumab

52

L’immunothérapie dans le cancer bronchique �POST WCLC 2016Liens d’intéretsDiapositive numéro 3Principales Données d’efficacité�en 2ème ligne et plusAnti-PD1 en 2eme ligneAtezolizumab : Essai OAKPhase III OAK design de l’étudeSurvie globale, ITT (n = 850)SG selon l’histologieImmunothérapie vs. docetaxel en 2ème ligne dans le CBNPC métastatique (essais de phase III) fin 2016WCLC 2016 immunothérapie 2eme ligne ou au delàDiapositive numéro 13Diapositive numéro 14Diapositive numéro 15Diapositive numéro 16Diapositive numéro 17Diapositive numéro 18Diapositive numéro 19Diapositive numéro 20Diapositive numéro 21WCLC 2016 immunothérapie 2eme ligne ou au delàAnalysis of Early Survival in Patients With Advanced Non-Squamous NSCLC Treated With Nivolumab vs Docetaxel in �CheckMate 057 Phase 3 CheckMate 057 Study Design: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLCOverall Survival�CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLCOverall Survival�CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLCSingle Baseline Characteristics by OS (n Values)�CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLCDiapositive numéro 28Diapositive numéro 29Conclusions�CheckMate 057: Nivolumab vs Docetaxel in Previously Treated NSQ NSCLCDiapositive numéro 32Phase III OAK study designOverall survival, ITT (n = 850) and PD-L1 subgroupsEfficacy in CNS mets subgroupEfficacy in tobacco use subgroupEfficacy in EGFR subgroupsEfficacy in subgroups by ageConclusion WCLC 2016 immunothérapie 2eme ligne ou au delàDiapositive numéro 41Durvalumab is a selective, high-affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD801ATLANTIC (NCT02087423) is a Phase 2, open-label, single-arm trial�Baseline characteristics for Cohorts 2 and 3 �PD-L1 expression status�Antitumour activity in Cohorts 2 and 3 (full analysis set*)�Progression-free survival in Cohorts 2 and 3 (full analysis set)�Overall survival in Cohorts 2 and 3 (full analysis set)�Safety summary (safety analysis set)�Immune-mediated AEs by grouped term* (safety analysis set)�Conclusions�CONCLUSION

l immunothérapie dans le cancer bronchique post wclc 2016 · 2017. 2. 17. · l ’...

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