keynote-407: phase 3 study of carboplatin-paclitaxel/nab

KEYNOTE-407: Phase 3 Study of Carboplatin-Paclitaxel/Nab-Paclitaxel With or Without Pembrolizumab for Metastatic Squamous NSCLC

1Hospital Universitario 12 de Octubre, Madrid, Spain; 2Leningrad Regional Clinical Hospital, St. Petersburg, Russia; 3Wollongong Hospital, Wollongong, NSW, Australia; 4Kartal Research and Training Hospital, Istanbul, Turkey; 5Centre Hospitalier Universitaire de Toulouse, Toulouse, France; 6Universitätskinikum Tübingen, Tuebingen, Germany; 7Ankara University, Ankara, Turkey; 8Országos Korányi TBC és Pulmonológiai Intézet, Budapest, Hungary; 9Oncology Center, Medica Sur Hospital, Mexico City, Mexico; 10Sendai Kousei Hospital, Sendai, Japan; 11Cancer Hospital of Jilin Province, Changchun, China; 12University of Turin, Orbassano, Italy; 13Albert Einstein College of Medicine, Bronx, NY, USA; 14Merck & Co., Inc., Kenilworth, NJ, USA; 15Maria Skłodowska-Curie Institute of Oncology, Warsaw, Poland

Luis Paz-Ares,1 Alexander Luft,2 Ali Tafreshi,3 Mahmut Gümüş,4 Julien Mazières,5Barbara Hermes,6 Filiz Çay Senler,7 Andrea Fülöp,8 Jeronimo Rodriguez Cid,9Shunichi Sugawara,10 Ying Cheng,11 Silvia Novello,12 Balazs Halmos,13 Yue Shentu,14

Xiaodong Li,14 Gregory M Lubiniecki,14 Bilal Piperdi,14 Dariusz Kowalski15

Pembrolizumab and First-Line Treatment of Metastatic NSCLC • Pembrolizumab: anti–PD-1 monoclonal antibody with antitumor activity

against lung cancer and several other tumors, as well as a favorable

safety profile

• As monotherapy: significantly improves OS over platinum-doublet

chemotherapy for metastatic NSCLC with PD-L1 TPS ≥50%, with a benefit

observed for both squamous and nonsquamous histology1

• In combination with pemetrexed and platinum: significantly improves OS

over pemetrexed and platinum alone and has a manageable safety profile

for metastatic nonsquamous NSCLC, irrespective of PD-L1 TPS2

• Evaluation of pembrolizumab plus chemotherapy in metastatic squamous

NSCLC is a logical next step

1. Reck M et al. N Engl J Med 2016;375:1823-33.

2. Gandhi L et al. N Engl J Med 2018;378:2078-92.

KEYNOTE-407 Study Design (NCT02775435)

Key Eligibility Criteria

• Untreated stage IV NSCLC with squamous histology

• ECOG PS 0 or 1

• Provision of a sample for PD-L1 assessment

• No symptomatic brain metastases

• No pneumonitis requiring systemic steroids

Pembrolizumab 200 mg Q3W +Carboplatin AUC 6 Q3W +

Paclitaxel 200 mg/m2 Q3W OR nab-Paclitaxel 100 mg/m2 Q1W

for 4 cycles (each 3 wk)

Placebo (normal saline) Q3W +Carboplatin AUC 6 Q3W +

Paclitaxel 200 mg/m2 Q3W OR nab-Paclitaxel 100 mg/m2 Q1W

for 4 cycles (each 3 wk)

R (1:1)

Pembrolizumab 200 mg Q3W

for up to 31 cycles

Placebo (normal saline) Q3W

for up to 31 cycles

Stratification Factors

• PD-L1 expression (TPSa <1% vs ≥1%)

• Choice of taxane(paclitaxel vs nab-paclitaxel)

• Geographic region(east Asia vs rest of world)

Optional Crossoverb

Pembrolizumab200 mg Q3W

for up to 35 cyclesPDb

BICR, blinded independent central radiologic review. aPercentage of tumor cells with membranous PD-L1 staining assessed using the PD-L1 IHC 22C3 pharmDx assay.bPatients could crossover during combination therapy or monotherapy. To be eligible for crossover, PD must have been verified by BICR and all safety criteria had to be met.

End points

• Primary: PFS (RECIST v1.1, BICR) and OS

• Secondary: ORR and DOR (RECIST v1.1, BICR), safety

Statistical Considerations

• First analysis of PFS and OS• Planned to occur after ~332 PFS events

observed• Statistical methods

– Difference in OS and PFS: stratified log-rank test

• Data cutoff date: Apr 3, 2018– External DMC meeting: May 21, 2018– Patients with a PFS event: 349– Superiority thresholds (one-sided): 0.008 for PFS,

0.0029 for OS– Median follow-upa: 7.8 months (range, 0.1-19.1)

All interim analyses reviewed by external, independent data monitoring committee. aDefined as the time from randomization to the date of death or data cut-off, whichever occurred first.

Second Interim Analysis• Planned enrollment: 560 patients– Actual enrollment: 559 patients

• Study has at least 90% power for PFS and 85% power for OS with a target HR of 0.70

• Protocol specified 3 interim analyses (IA) before the final analysis

• Overall alpha for study: strictly controlled at one-sided 2.5% using the graphical method of Mauer and Bretz

Analysis End Points Planned Timing

IA1 ORR ~200 patients followed for ~28 wk

IA2 PFS and OS ~332 PFS events

IA3 PFS and OS ~415 PFS events

Final OS ~361 deaths

Disposition of Study Treatment at IA2

aAn additional 21 patients received other subsequent therapy (7.5% of ITT, 10.1% excluding those still on therapy. Data cutoff date: Apr 3, 2018.

559 patients randomly allocated

Pembrolizumab + Chemotherapy• 278 allocated• 278 treated

Placebo + Chemotherapy• 281 allocated• 280 treated

• 121 ongoing• 157 discontinued– 86 radiographic PD– 48 AEs– 13 clinical PD– 5 consent withdrawal– 5 physician decision– 0 lost to follow-up

• 72 ongoing• 208 discontinued– 140 radiographic PD– 25 AEs– 26 clinical PD– 9 consent withdrawal– 6 physician decision– 2 lost to follow-up

Crossovera

75 in-study pembro+

14 off-study anti–PD-(L)1=

31.7% of ITT

42.8% excluding those still on therapy

≥1 subsequent therapy• 15.8% of ITT• 28.0% excluding

those still on therapy

Baseline Characteristics at IA2

Data cutoff date: Apr 3, 2018.

Pembro + Chemo(N = 278)

Placebo + Chemo (N = 281)

Age, median (range), years 65.0 (29-87) 65.0 (36-88)

Men 220 (79.1%) 235 (83.6%)

ECOG PS 1 205 (73.7%) 191 (68.0%)

Stable brain metastases 20 (7.2%) 24 (8.5%)

Former/current smoker 256 (92.1%) 262 (93.2%)

Enrolled in east Asia 54 (19.4%) 52 (18.5%)

PD-L1 TPS ≥1% 176 (63.3%) 177 (63.0%)

Paclitaxel chosen as taxane 169 (60.8%) 167 (59.4%)

Prior thoracic radiation 17 (6.1%) 22 (7.8%)

Prior (neo)adjuvant therapy 5 (1.8%) 8 (2.8%)

Frequency of PD-L1 TPS Categories

Not evaluable refers to specimens with an inadequate number of tumor cells or no tumor cells seen; these patients were included in the PD-L1 TPS <1% group for randomization stratification but excluded from analyses of efficacy by TPS. Data cutoff date: Apr 3, 2018.

34.2%37.1%

26.3%

2.5%

35.2% 37.0%

26.0%

1.8%05

101520253035404550

<1% 1-49% ≥50% Not evaluable

Freq

uenc

y, %

Pembro + Chemo

Placebo + Chemo

0 3 6 9 1 2 1 5 1 8 2 10

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th s

OS

, %

N o . a t R is k278 256 188 124 17281 246 175 93 16

6245

00

24

Overall Survival at IA2, ITT


Median (95% CI)15.9 mo (13.2-NE)11.3 mo (9.5-14.8)

Events HR (95% CI) PPembro + Chemo 30.6% 0.64

(0.49-0.85)0.0008

Placebo + Chemo 42.7%

Overall Survival at IA2 in Key Subgroups


0.64 (0.49-0.85)

Region of enrollment

ECOG PS

0.1 10.5

SubgroupNo. of Deaths/No. of Patients Hazard Ratio (95% CI)

Pembro + ChemoBetter

Placebo + ChemoBetter

Overall 205/559

<65 yrs 88/254 0.52 (0.34-0.80)³65 yrs 117/305 0.74 (0.51-1.07)

Male 167/455 0.69 (0.51-0.94)Female 38/104 0.42 (0.22-0.81)

0 48/163 0.54 (0.29-0.98)1 157/396 0.66 (0.48-0.90)

East Asia 34/106 0.44 (0.22-0.89)Rest of world 171/453 0.69 (0.51-0.93)

Paclitaxel 140/336 0.67 (0.48-0.93)Nab-paclitaxel 65/223 0.59 (0.36-0.98)

Age

Sex

Choice of taxane

0 3 6 9 1 2 1 5 1 8 2 1

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n t h s

OS

, %

N o . a t R is k

7 3 6 6 5 3 2 8 3

7 3 6 0 4 2 2 1 5

1 5

9

0

0

0

2

0 3 6 9 1 2 1 5 1 8 2 1

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n t h s

OS

, %

N o . a t R is k

1 0 3 9 5 6 8 5 0 9

1 0 4 9 0 6 6 3 7 6

2 5

2 1

0

0

1

0

0 3 6 9 1 2 1 5 1 8 2 1

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n t h s

OS

, %

N o . a t R is k

9 5 8 8 6 2 4 1 5

9 9 9 2 6 3 3 2 4

2 0

1 4

0

0

1

1

Overall Survival at IA2 by PD-L1 TPS


TPS 1-49% TPS ≥50%TPS <1%Events HR (95% CI)

Pembro + Chemo 30.5% 0.61 (0.38-0.98)Placebo + Chemo 44.4%

Events HR (95% CI)30.1% 0.57 (0.36-0.90)43.3%

Events HR (95% CI)31.5% 0.64 (0.37-1.10)41.1%

Median (95% CI)NR (11.3 mo-NE)NR (7.4 mo-NE)

Median (95% CI)14.0 mo (12.8-NE)11.6 mo (8.9-17.2)

Median (95% CI)15.9 mo (13.1-NE)10.2 mo (8.6-13.8)

0 3 6 9 1 2 1 5 1 8 2 10

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th s

PF

S,

%

N o . a t R is k278 223 142 57 5281 190 90 26 4

2312

00

00

Progression-Free Survival at IA2, ITT(RECIST v1.1, BICR)

BICR, blinded, independent central review. Data cutoff date: Apr 3, 2018.

Median (95% CI)6.4 mo (6.2-8.3)4.8 mo (4.3-5.7)

Events HR (95% CI) PPembro + Chemo 54.7% 0.56

(0.45-0.70)<0.0001

Placebo + Chemo 70.1%

0 3 6 9 1 2 1 5 1 8 2 1

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n t h s

PF

S,

%

N o . a t R is k

9 5 7 8 4 8 1 6 0

9 9 7 1 3 5 1 1 1

5

6

0

0

0

0

0 3 6 9 1 2 1 5 1 8 2 1

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n t h s

PF

S,

%

N o . a t R is k

7 3 6 0 4 1 1 2 0

7 3 3 8 1 3 5 2

4

2

0

0

0

0

0 3 6 9 1 2 1 5 1 8 2 1

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n t h s

PF

S,

%

N o . a t R is k

1 0 3 7 9 4 9 2 6 5

1 0 4 7 9 4 0 8 1

1 3

4

0

0

0

0

Progression-Free Survival by PD-L1 TPS(RECIST v1.1, BICR)

BICR, blinded, independent central review. Data cutoff date: Apr 3, 2018.

TPS 1-49% TPS ≥50%TPS <1%Events HR (95% CI)

Pembro + Chemo 57.9% 0.68 (0.47-0.98)Placebo + Chemo 67.7%

Events HR (95% CI)52.4% 0.56 (0.39-0.80)70.2%

Events HR (95% CI)53.4% 0.37 (0.24-0.58)75.3%

Median (95% CI)8.0 mo (6.1-10.3)4.2 mo (2.8-4.6)

Median (95% CI)7.2 mo (6.0-11.4)5.2 mo (4.2-6.2)

Median (95% CI)6.3 mo (6.1-6.5)5.3 mo (4.4-6.2)

Objective Response Rate at IA1 (RECIST v1.1 by BICR)

Best Response

Pembro +Chemo

(N = 101)

Placebo + Chemo

(N = 103)

Complete response 0 2 (1.9%)

Partial response 59 (58.4%) 34 (33.0%)

Stable disease 26 (25.7%) 36 (35.0%)

Progressive disease 7 (6.9%) 16 (15.5%)

Not evaluablea 4 (4.0%) 5 (4.9%)

Not assessedb 5 (5.0%) 10 (9.7%)

aPatients who had ≥1 post-baseline imaging assessment, none of which were evaluable per RECIST v1.1 by BICR. bPatients who did not have ≥1 post-baseline imaging assessment.

Includes confirmed responses only. Data cutoff date: Oct 27, 2017.

0

10

20

30

40

50

60

70

80

90

100

Pembro +Chemo

Placebo +Chemo

OR

R, %

(95%

CI)

58.4%

(48.2-68.1)

35.0%

(25.8-45.0)

P = 0.0004

Best Response

Pembro +Chemo

(N = 278)

Placebo + Chemo

(N = 281)

Complete response 4 (1.4%) 6 (2.1%)

Partial response 157 (56.5%) 102 (36.3%)

Stable disease 78 (28.1%) 104 (37.0%)

Progressive disease 17 (6.1%) 39 (13.9%)

Not evaluablea 6 (2.2%) 7 (2.5%)

Not assessedb 16 (5.8%) 23 (8.2%)

aPatients who had ≥1 post-baseline imaging assessment, none of which were evaluable per RECIST v1.1 by BICR. bPatients who did not have ≥1 post-baseline imaging assessment.

Includes confirmed responses only. No alpha allocated to comparison of ORR at IA2. Data cutoff date: Apr 3, 2018.

0

10

20

30

40

50

60

70

80

90

100

Pembro +Chemo

Placebo +Chemo

OR

R, %

(95%

CI) 57.9%

(51.9-63.8)

38.4%

(32.7-44.4)

Objective Response Rate at IA2 (RECIST v1.1 by BICR)

0 3 6 9 1 2 1 5 1 80

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

M o n th s

On

go

ing

Re

sp

on

se

, %

N o . a t R is k161 120 65 27 0108 69 25 10 1

53

00

Duration of Response at IA2(RECIST v1.1, BICR)

Includes confirmed responses only. Data cutoff date for initial response: Apr 3, 2018.

Median (range)7.7 mo (1.1+ to 14.7+)4.8 mo (1.3+ to 15.8+)

Exposure to Study Treatment at IA2


Pembro + Chemo N = 278

Placebo + ChemoN = 280

Treatment duration, mean (SD) 6.3 mo (4.1) 4.7 mo (3.5)

Treatment cycles

Mean (SD) 9.3 (5.8) 7.3 (5.0)

Median (range) 8 (1-27) 6 (1-27)

4 doses of carboplatin, n (%) 219 (78.8%) 205 (73.2%)

4 doses of paclitaxel, n (%) 133/169 (78.7%) 119/167 (71.3%)

5-11 doses of nab-paclitaxel, n (%) 72/109 (66.1%) 73/113 (64.6%)

12 doses of nab-paclitaxel, n (%) 25/109 (22.9%) 24/113 (21.2%)

≥5 doses of pembrolizumab or placebo, n (%) 214 (77.0%) 189 (67.5%)

Summary of Adverse Events at IA2

aIncludes patients who discontinued pembrolizumab or placebo, carboplatin, and taxane for an adverse event at any time and patients who discontinued pembrolizumab or placebo for an adverse event after completing 4 cycles of carboplatin and taxane. bBoth deaths were due to pneumonitis. Data cutoff date: Apr 3, 2018.

Pembro + ChemoN = 278

Placebo + ChemoN = 280

All cause AEs 273 (98.2%) 274 (97.9%)Grade 3-5 194 (69.8%) 191 (68.2%)Led to death 23 (8.3%) 18 (6.4%)

Treatment-related 10 (3.6%) 6 (2.1%)Led to discontinuation

All treatmenta 37 (13.3%) 18 (6.4%)Any treatment 65 (23.4%) 33 (11.8%)

Immune mediated AEs and infusion reactions 80 (28.8%) 24 (8.6%)Grade 3-5 30 (10.8%) 9 (3.2%)Led to deathb 1 (0.4%) 1 (0.4%)

Adverse Events (All Cause): Frequency ≥20% at IA2

05

1015202530354045505560

Freq

uenc

y, %


Nause

a

Anemia

Fatigu

e

Consti

patio

n

Diarrhe

a

↓ App

etite

Neutro

penia

Thrombo

cyto-

penia

Neurop

athy

perip

heral

Asthen

ia

1-2Grade

3-5Pembro + Chemo

Placebo + Chemo

Alopec

ia

53.251.8

46.0

36.4 37.8

32.935.6

32.1 30.6

23.2

29.9

23.2 24.5

29.3

23.021.8 22.725.7

21.621.1 20.5 20.5

Arthral

gia

14.316.1

Immune-Mediated Adverse Events and Infusion Reactions at IA2

0123456789

10

Freq

uenc

y, %


Pneum

onitis

Hypoth

yroid-ism

Nephri

tis

Severe

skin

reacti

ons

Colitis

Hypop

hysit

is

Thyroi

ditis

Hypert

hyroi

d-ism

Hepati

tis

1-2Grade

3-5Pembro + Chemo

Placebo + Chemo

Infus

ion

reacti

ons

7.9

1.8

7.2

0.7

6.5

2.1

2.9

2.12.5

1.41.8

0

1.8

0.41.1

0

1.10.7 0.7

0

Summary and Conclusions• Pembrolizumab plus chemotherapy significantly improved OS (HR 0.64) over

chemotherapy alone– Benefit was observed irrespective of PD-L1 TPS: HR 0.61 for TPS <1%, 0.57 for TPS 1-49%,

and 0.64 for TPS ≥50%

• PFS (HR 0.56) and ORR (P = 0.0004) were also improved with pembrolizumab plus chemotherapy and responses were more durable

• AE frequency and severity were mostly similar between arms– Observed events consistent with known safety profiles of pembrolizumab and chemotherapy,

with no new safety signals identified– Rates of discontinuation due to AEs were higher in the pembrolizumab plus chemotherapy

arm, but generally low overall– Immune-mediated AEs were more frequent in the pembrolizumab arm, with frequency and

severity consistent with those observed for pembrolizumab monotherapy

• Data suggest pembrolizumab plus carboplatin and paclitaxel or nab-paclitaxel should become a new standard-of-care for first-line treatment of metastatic squamous NSCLC, irrespective of PD-L1 expression

AcknowledgementsPATIENTS AND THEIR FAMILIESInvestigators and site personnel from 166 sites in 17 countries

Australia: Houghton B, Hui R, Jennens R, Tafreshi A; Canada: Aucoin N, Castonguay V, de Angelis F, Robinson A, Roy J, Snow S, Wilson J; China: Cao L, Cheng Y, Gao H, Guo Y, Han Z, Hu C, Hu J, Huang M, Li X, Liu J, Ma Z, Sun H, Wang D, Wang Z, Wu L, Yu S, Zhang H, Zhang L, Zhou J; France: Corre R, Cousin S, Doucet L, Dourthe LM, Hiret S, Mazieres J, Moro-Sibilot D, Quantin X, Scherpereel A, Thiberbill L; Germany: Engel-Riedel W, Gruening W, Hermes B, Kokowski K, Kollmeier J, Spaeth-Schwalbe E; Hungary: Balint B, Csoszi T, Fulop A, Horvath I, Medgyasszay B, Tehenes S; Italy: Berardi R, de Argento E, Gianni L, Minotti V, Novello S, Rocco D, Soto Para H; Japan: Akamatsu H, Aoe K, Atagi S, Fukuhara T, Hirashima T, Horinouchi H, Hosomi Y, Ichiki M, Imamura F, Kaji R, Kasahara K, Kato T, Kishi K, Kubota K, Kurata T, Nakahara Y, Nishio M, Nogami N, Ohashi K, Okada M, Okamoto I, Saka H, Satouchi M, Sugawara S, TakahasiT, Tanaka H, Tokito T, Udagawa H, Yokoyama T; Mexico: de la Mora Jimenez E, Macedo Perez E, Rodriguez Cid J; Netherlands: BiesmaB, Custers F, Van den Heuvel MM; Poland: Kalinka-Warzocha E, Karaszerska B, Kowlaski D, Ramlau R; Russia: Kuzina L, Laktionov K, Luft A, Mukhametshina G, Vladmirov V; South Korea: Kang JH, Kim BS, Lee GW, Lee KH, Lee SS, Min YJ; Spain: Campos B, Felip E, Majem M, Massuti B, Ortega A, Paz-Ares L, Provencio M, Trigo J, Vicente D; Thailand: Dechaphunkul A, Korphaisarn K, Prasongsook N, Reungwetwattana T, Sriuranpong V; Turkey: Cay Senler F, Cicin I, Erman M, Gumus M, Gunduz S, Harputluoglu H, Ozkan M, Oztop I, Turna H, Yavuz S; US: Costin D, Dragnev K, Duviver H, Garon E, Gerstner G, Graham M, Gralla R, Guarino M, Halmos B, HatterlseyAnderes E, Jaslowski A, Jotte R, Kendall SD, Kloecker G, Mekhail T, Mohentash M, Parchman A, Rao S, Reddy S, Robert F, Rybkin I, Santos E, Saylors G, Sleckman B, Socoteanu M, Stampleman L, Stevenson J, Walsh W, Waterhouse D, Wrangle J

Merck & Co., Inc. (Kenilworth, NJ): Nabeegha Shinwari (study support); Melanie Leiby (medical writing support)

Copies of this presentation, available at https://tinyurl.com/ycvaeo9v, are for personal use only and may not be reproduced without permission from ASCO® and the author of this presentation.

keynote-407: phase 3 study of carboplatin-paclitaxel/nab

Documents