PRIMARY ANALYSIS FROM OAK, A RANDOMIZED …f1e065e4-8c27-4e3f-8f48-da873f9a6f51… · PRIMARY...

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PRIMARY ANALYSIS FROM OAK, A RANDOMIZED PHASE III STUDY COMPARING ATEZOLIZUMAB WITH DOCETAXEL IN ADVANCED NSCLC Fabrice Barlesi, Keunchil Park, Fortunato Ciardiello, Joachim von Pawel, Shirish Gadgeel, Toyoaki Hida, Dariusz Kowalski, Manuel Cobo Dols, Diego Cortinovis, Joseph Leach, Jonathan Polikoff, David R. Gandara, Carlos Barrios, Daniel Chen, Pei He, Marcin Kowanetz, Marcus Ballinger, Daniel Waterkamp, Alan Sandler, Achim Rittmeyer

Presidential Symposium 2, Main Auditorium, 16:25 –18:20, Sunday 9 October 2016

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§ Consultations fees from Astra-Zeneca, Bristol-Myers Squibb, Boehringer–Ingelheim, Clovis Oncology, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, MSD, Pierre Fabre and Pfizer

DISCLOSURE SLIDE Fabrice Barlesi

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh

§ 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

BACKGROUND

1. Herbst Nature 2014. 2 Chen Immunity 2013. 3. Fehrenbacher Lancet 2016; 4. Smith J Clin Oncol 2016.

3 Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh


§ In previously treated NSCLC, atezolizumab improved OS vs docetaxel in the randomized Phase II POPLAR study (median OS 12.6 vs 9.7 mo; HR = 0.69)3,4

BACKGROUND




§ In previously treated NSCLC, atezolizumab improved OS vs docetaxel in the randomized Phase II POPLAR study (median OS 12.6 vs 9.7 mo; HR = 0.69)3,4

§ The data from OAK are the first Phase III results for a PD-L1-directed antibody

BACKGROUND



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PHASE III OAK STUDY DESIGN

Atezolizumab 1200 mg IV q3w

PD or loss of clinical benefit

Docetaxel 75 mg/m2 q3w

Locally Advanced or Metastatic NSCLC

• 1–2 prior lines of chemo including at least 1 platinum based

• Any PD-L1 status

N = 1,225 enrolleda PD

R 1:1

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

regimens

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

Secondary Endpoints: ORR, PFS, DoR, Safety aA prespecified analysis of the first 850 patients provided sufficient power to test the co-primary endpoints of OS in the ITT and TC1/2/3 or IC1/2/3 subgroup (≥ 1% PD-L1 expression). TC, tumor cells; IC, tumor-infiltrating immune cells. Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh

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BASELINE CHARACTERISTICS, ITT (N = 850)


Characteristics Atezolizumab n = 425

Docetaxel n = 425

Median age, y 63 y 64 y ≥ 65 y 45% 49% Male 61% 61% Histology Nonsquamous 74% 74% Squamous 26% 26% ECOG PS, 0 / 1 37% / 64% 38% / 62% No. of prior therapies, 1 / 2 75% / 25% 75% / 25% History of tobacco use Never 20% 17% Current / Previous 14% / 66% 16% / 67% CNS mets, Yes / No 9% / 91% 11% / 89% Known EGFR status Mutant / Wild type 10% / 75% 10% / 73%

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OVERALL SURVIVAL, ITT (N = 850)

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh aStratified HR.

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 Minimum follow up = 19 months

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OVERALL SURVIVAL, ITT (N = 850)

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh aStratified HR


55%

40%

41%

27%

18-mo OS

12-mo OS

Ove

rall

Sur

viva

l (%

)

Months


aStratified HR. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival.

HR, 0.74a (95% CI, 0.58, 0.93) P = 0.0102

OS, PD-L1 EXPRESSION ON ≥ 1% TC OR IC TC1/2/3 OR IC1/2/3; 55% OF PATIENTS

Median 10.3 mo (95% CI, 8.8, 12.0)

Median 15.7 mo (95% CI, 12.6, 18.0)

Ove

rall

Sur

viva

l (%

)


Months

Minimum follow up = 19 months


aUnstratified HR. bP values for descriptive purpose only. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival.


Months

HR, 0.75a (95% CI, 0.59, 0.96) P = 0.0205b

Median 8.9 mo (95% CI, 7.7, 11.5)

Median 12.6 mo (95% CI, 9.6, 15.2)

OS, PD-L1 EXPRESSION ON < 1% TC AND IC TC0 AND IC0; 45% OF PATIENTS

Ove

rall

Sur

viva

l (%

)


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OS, PD-L1 EXPRESSION ON ≥ 50% TC OR ≥ 10% IC TC3 OR IC3; 16% OF PATIENTS

Median 8.9 mo (95% CI, 5.6, 11.6)

Median 20.5 mo (95% CI, 17.5, NE)


aUnstratified HR. bP values for descriptive purpose only. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival.

HR, 0.41a (95% CI, 0.27, 0.64) P < 0.0001b

Months

Ove

rall

Sur

viva

l (%

)



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OS BY PD-L1 EXPRESSION

0.2 2

In favor of docetaxel

Hazard Ratioa In favor of

atezolizumab

Subgroup

Median OS, mo Atezolizumab Docetaxel

n = 425 n = 425

0.2 1 2

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

TC0 and IC0

ITTa

TC3 or IC3 TC2/3 or IC2/3

13.8 9.6

12.6 8.9 15.7 10.3 16.3 10.8 20.5 8.9

0.41

0.67 0.74

0.75

0.73

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh aStratified HR for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for subgroups. TC, tumor cells; IC, tumor-infiltrating immune cells; OS, overall survival.

0% 20% 40% 60% 80% 100%

16%

31%

55%

100%

45%

On-study Prevalence

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OS BY HISTOLOGY

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

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

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


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

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


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

Non-squamous Squamous

Ove

rall

Sur

viva

l (%

)

Months

Ove

rall

Sur

viva

l (%

)

Months


aUnstratified HRs. bP values for descriptive purpose only. Histology information from eCRF. OS, overall survival.


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OS IN SELECTED SUBGROUPS


0.2 2

0.64 n (%) Subgroup

330 (39%) 520 (61%)

Female

Median OS, mo Atezolizumab Docetaxel

n = 425 n = 425 16.2 11.2 12.6 9.2

13.2 10.5 14.1 9.2

17.6 15.2 10.6 7.6

12.8 9.1 15.2 12.0

16.3 12.6 13.2 9.3

17.2 10.5 13.8 11.3

10.5 16.2 15.3 9.5

13.8 9.6

Male

453 (53%) 397 (47%)

< 65 years ≥ 65 years

315 (37%) 535 (63%)

ECOG PS 0 ECOG PS 1

640 (75%) 210 (25%)

1 prior therapy 2 prior therapies

156 (18%) 694 (82%)

Never smokers Current/previous smokers

59 (7%) 203 (24%)

KRAS mutant KRAS wildtype

85 (10%) 628 (74%)

EGFR mutant EGFR wildtype

850 (100%) ITT

0.79

0.80 0.66

0.78 0.68

0.2 1 2

0.71 0.80

0.71 0.74

0.71 0.83

1.24 0.69

0.73

HRa

In favor of docetaxel Hazard Ratio

In favor of atezolizumab

85 (10%) 765 (90%)

CNS mets No CNS mets

20.1 11.9 13.0 9.4

0.54 0.75

aStratified HR for ITT. Unstratified HR for subgroups. OS, overall survival.

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SUBSEQUENT THERAPIES

Category Atezolizumab Docetaxel

ITT n = 425 n = 425

Any non-protocol therapy 49% 45%

Chemotherapy 41% 31%

Targeted therapy 15% 16%

Immunotherapy 5% 17%

Nivolumab 4% 14%

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh No crossover from docetaxel to atezolizumab allowed.

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SUBSEQUENT THERAPIES

Category Atezolizumab Docetaxel

ITT n = 425 n = 425

Any non-protocol therapy 49% 45%

Chemotherapy 41% 31%

Targeted therapy 15% 16%

Immunotherapy 5% 17%

Nivolumab 4% 14%

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh No crossover from docetaxel to atezolizumab allowed.

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PROGRESSION-FREE SURVIVAL

0.4

In favor of docetaxel

Hazard Ratioa

In favor of atezolizumab

Subgroup

Median PFS, mo Atezolizumab Docetaxel

n = 425 n = 425

0.4 1 2

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

TC0 and IC0

ITTa

TC3 or IC3 TC2/3 or IC2/3

2.8 4.0

2.6 4.0 2.8 4.1 4.1 3.6 4.2 3.3

0.63 0.76

1.00

0.95 Pro

gres

sion

-Fre

e S

urvi

val (

%)

Months

ITT PFS HR, 0.95a (95% CI, 0.82, 1.10) P = 0.4928b


Investigator-assessed PFS per RECIST v1.1. aStratified HRs for ITT and TC1/2/3 or IC1/2/3. Unstratified HR for subgroups. bP values for descriptive purpose only. TC, tumor cells; IC, tumor-infiltrating immune cells.


Median 4.0 mo (95% CI, 3.3, 4.2)

Median 2.8 mo (95% CI, 2.6, 3.0)

0.91

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ORR AND DOR

31

22 18

8

14 11 13

16 11

13

0

10

20

30

40

50

OR

R (%

)

TC3 or IC3 TC1/2/3 or IC1/2/3

TC0 and IC0

TC2/3 or IC2/3

ITT850


Duration of Response Atezolizumab Docetaxel

ITT n = 58 n = 57 Ongoing response 52% 18% Median (mo) 16.3 6.2 TC1/2/3 or IC1/2/3 n = 43 n = 36 Ongoing response 47% 11% Median (mo) 16.0 6.2 TC0 and IC0 n = 14 n = 21 Ongoing response 71% 29% Median (mo) NE 6.2

Objective Response Rate


Confirmed investigator-assessed ORR per RECIST v1.1. DOR, duration of response; NE, not estimable; ORR, objective response rate. TC, tumor cells; IC, tumor-infiltrating immune cells.

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SAFETY SUMMARY Atezolizumab

n = 609 Docetaxel

n = 578 Median treatment duration 3.4 moa 2.1 mo

Patients treated ≥ 12 months 20.5% 2.4% All Grade AEs, any cause Treatment-related AEs

94% 64%

96% 86%

Grade 3–4 AEs, any cause Treatment-related Grade 3–4 AEs

37% 15%

54% 43%

Grade 5 AEs, any cause Treatment-related Grade 5 AEs

2% 0%

2% 0.2%b

AEs leading to treatment withdrawal 8% 19%

AEs leading to dose modification, delay or interruption 25% 36%

Barlesi et al, Atezolizumab Phase III OAK Study. http://tago.ca/9Hh a39% of patients receiving atezolizumab were treated beyond progression bRespiratory tract infection.

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IMMUNE-MEDIATED AES


Atezolizumab n = 609

Selected immune-mediated AEs All Grade Grade 3–4

Pneumonitis 1.0% 0.7%

Hepatitis 0.3% 0.3%

Colitis 0.3% 0%

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ALL CAUSE AES >5% DIFFERENCE BETWEEN ARMS

Mor

e Fr

eque

nt W

ith

Doc

etax

el

Mor

e Fr

eque

nt W

ith

Ate

zoliz

umab

Docetaxel Atezolizumab

40% 30% 20% 10% 0 10% 20% 30% 40%

Grade 3-4 AEs Grade 1-2 AEs

Grade 3-4 AEs Grade 1-2 AEs

Myalgia

Stomatitis

Pruritus Musculoskeletal pain

Nausea

Fatigue Alopecia Diarrhea Anemia

Neutropenia

Peripheral neuropathy Peripheral edema

Dysgeusia Febrile neutropenia


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CONCLUSIONS

§ OAK data represent the first Phase 3 results for a PD–L1-directed antibody

§ Atezolizumab improved OS in all patients: median 13.8 vs 9.6 mo; HR 0.73

§ OS benefit was seen regardless of PD-L1 expression levels (HR 0.75 in <1% PD-L1 expression population; 0.41 in ≥50% TC or ≥10% IC expression population)

§ OS benefit was consistent across subgroups, including histology (HR 0.73 for both), patients with CNS mets (HR 0.54) and never smokers (HR 0.71)

§ Atezolizumab was well tolerated with a favorable safety profile compared to docetaxel. No new safety signals were identified. The rate of immune-mediated AEs was low


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ACKNOWLEDGMENTS

The patients and their families All OAK study investigators and their study teams


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