Please note, these are the - PowerPoint Presentation

Slide1

Please note, these are the

actual

video-recorded proceedings from the

live

CME event and may include the use of trade names and other raw, unedited content.

Slide2

Disclosures for

Dr Langer

Advisory Committee

Abbott Laboratories, AstraZeneca Pharmaceuticals LP,

Boehringer

Ingelheim

Pharmaceuticals

Inc

, Celgene Corporation, Genentech

BioOncology

, Lilly, Merck, Pfizer

Inc

, Roche Laboratories

Inc

, Takeda Oncology

Consulting Agreements

AstraZeneca Pharmaceuticals LP, Bayer HealthCare Pharmaceuticals,

Boehringer

Ingelheim

Pharmaceuticals

Inc

, Bristol-Myers Squibb Company, Celgene Corporation, Eisai

Inc

, Genentech

BioOncology

, Lilly, Merck, Novartis, Pfizer

Inc

, Roche Laboratories

Inc

, Takeda Oncology

Contracted Research

Advantagene

Inc

,

Ariad

Pharmaceuticals

Inc

, GlaxoSmithKline,

Inovio

Pharmaceuticals

Inc

, Merck, Takeda Oncology

Data and Safety Monitoring Board

Amgen

Inc

Slide3

Disclosures for

Dr Hanna

Contracted

Research

Bristol-Myers Squibb Company, Merck

Slide4

Disclosures for

Dr Horn

Advisory Committee

AbbVie

Inc

, Genentech

BioOncology

, Merck

Consulting Agreements

AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Lilly,

Xcovery

Paid Travel

Boehringer

Ingelheim

Pharmaceuticals

Inc

Slide5

Disclosures for

Dr Sequist

Consulting Agreements

AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Genentech

BioOncology

, Merrimack Pharmaceuticals

Inc

, Pfizer

Inc

Contracted Research

AstraZeneca Pharmaceuticals LP,

Boehringer

Ingelheim

Pharmaceuticals

Inc

, Genentech

BioOncology

, Merrimack Pharmaceuticals

Inc

, Novartis

Slide6

Agenda

Introduction

–

The New Taxonomy of Metastatic Non-Small Cell Lung Cancer (

NSCLC)

 

Module 1 –

Emerging Research Data with and Potential Clinical Role of Immune Checkpoint Inhibitors in the Management of Locally Advanced NSCLC 

Module

2 –

Integration of Anti-PD-1/PD-L1 Antibodies into Current Treatment Algorithms for Patients with Metastatic NSCLC

Module

3

–

Ongoing Evaluation of Existing and Emerging Immunotherapeutic Approaches, Including Combination Strategies  

Module

4 –

Identification

and Management of Immune-Mediated and Other Toxicities Associated with Checkpoint Inhibitors; Relative Contraindications for Patients with Existing Autoimmune Disease

Slide7

Indiana University

Vanderbilt

University

University

of

Pennsylvania

Massachusetts

General Hospital Cancer

Center

Yale Cancer Institute

Memorial Sloan Kettering Cancer Center

Sarah Cannon Research Institute

In preparation for this meeting, we conducted a survey of

7

lung cancer clinical investigators:

Slide8

Agenda

Introduction – 

The

New Taxonomy of Metastatic Non-Small Cell Lung Cancer (NSCLC)

 

Module 1

–

Emerging Research Data with and Potential Clinical Role of Immune Checkpoint Inhibitors in the Management of Locally Advanced NSCLC 

Module

2

–

Integration of Anti-PD-1/PD-L1 Antibodies into Current Treatment Algorithms for Patients with Metastatic NSCLC

Module

3

–

Ongoing Evaluation of Existing and Emerging Immunotherapeutic Approaches, Including Combination Strategies  

Module

4

–

Identification

and Management of Immune-Mediated and Other Toxicities Associated with Checkpoint Inhibitors; Relative Contraindications for Patients with Existing Autoimmune Disease

Slide9

Based on available data and your own clinical experience, what genomic alterations do you feel must be ruled out prior to initiation of first-line therapy for a patient with metastatic disease?

EGFR, ALK, ROS1, BRAF V600E,

MET

exon 14

EGFR, ALK, ROS1, BRAF V600E

EGFR, ALK, ROS1, BRAF V600E,

MET

exon 14

EGFR, ALK, ROS1, BRAF V600E,

MET

exon 14

EGFR, ALK, ROS1, BRAF

V600E

EGFR, ALK, ROS1, BRAF V600E,

MET

exon 14, RET

EGFR, ALK, ROS1, BRAF V600E,

MET

exon 14, HER2

None

None

None

None

None

None

None

Nonsquamous

Squamous

Slide10

Low TPS

High TPS

TPS = PD-L1 tumor proportion score

Low

TPS = 10%;

high

TPS = 60%

No targetable mutation

Low TPS

High

TPS

EGFR mutation

ALK rearrangement

ROS1 rearrangement

Low TPS

High

TPS

BRAF V600E mutation

MET exon 14 mutation

RET rearrangement

HER2 mutation

The New Taxonomy of Metastatic

Non-Small

Cell Lung Cancer

Low

TPS

High

TPS

T790M

mutation-positive

T790M

mutation-negative

T790M

mutation-positive

T790M

mutation-negative

Low TPS

High

TPS

Low TPS

High

TPS

Low TPS

High TPS

Low TPS

High TPS

Low TPS

High TPS

Nonsquamous

Squamous

(no targetable mutation)

 Targeted treatment

Chemotherapy ± biologic

Chemotherapy + checkpoint inhibitor

Checkpoint inhibitor

Love N et al.

Proc IASLC

2017;Abstract 75. 

Slide11

Osimertinib vs

Standard

of

Care

(

SoC

) EGFR-TKI as

First-Line Therapy

in

Patients

(pts) with

EGFRm

Advanced

NSCLC: FLAURA

Ramalingam

S et al.Proc ESMO

2017;Abstract LBA2_PR.

Slide12

FLAURA data cut-off:

12

June 2017; NCT02296125

* ≥

20 years in

Japan;

†

With

central laboratory assessment performed for sensitivity;

‡

cobas

EGFR Mutation Test (Roche Molecular Systems);

§

Sites to select either gefitinib or erlotinib as the sole comparator prior to site initiation;

¶

Every

12 weeks after 18 months

WHO = World Health

Organization;

EGFR = epidermal growth factor receptor;

SoC

= standard of care;

CNS =

central nervous system;

po

= orally;

TKI

= tyrosine kinase

inhibitor; RECIST 1.1 =

Response Evaluation Criteria In Solid Tumors version 1.1;

PFS

= progression-free

survival

Patients with locally advanced or

metastatic NSCLC

Key inclusion criteria

≥18 years*

WHO performance status 0/1

Exon 19 deletion/L858R (enrollment by local

†

or central

‡

EGFR testing)

No prior systemic anticancer/EGFR

TKI therapy

Stable CNS metastases allowed

Endpoints:

Primary

endpoint

:

PFS based on investigator assessment (according to RECIST 1.1

)

Secondary

endpoints:

objective response rate, duration of response, disease control rate, depth of response, overall survival,

patient

reported outcomes,

safety

FLAURA

Double-Blind Study Design

Crossover was allowed

for patients

in the

SoC

arm, who could receive open-label osimertinib upon central

confirmation

of progression and T790M positivity

Stratification by

mutation status

(exon

19

deletion/

L858R

)

and

race

(

Asian/non-Asian

)

Randomized 1:1

Osimertinib

(

80

mg

po

qd

) (

n

=

279

)

EGFR TKI

So

C

§

;

gefitinib

(250 mg po

qd) or erlotinib

(150 mg po qd) (n = 277

)RECIST 1.1 assessment every 6

weeks¶ until objective progressive disease

Slide13

Os

im

er

t

i

n

ib

279

262

233

210

178

139

71

26

4

0

S

oC

277

239

197

152

107

78

37

10

2

0

Primary Endpoint: Progression-Free Survival

(PFS)

b

y

Investigator Assessment

18.9

10.2

P

r

ob

a

b

ili

ty

of

p

r

og

r

e

s

si

o

n

-f

r

e

e

s

u

r

vi

v

al

0.2

0.4

0.6

0.8

0.0

0

3

6

21

24

27

9 12 15 18

Time from randomisation

(months)

No. at

risk

O

simer

tinib

SoC

FLAURA data

cut-off:

12 June

2017

.

Tick marks

indicate censored

data

.

DCO

=

data

cutoff

;

HR

=

hazard

ratio

;

SoC

=

standard

of

care

342 events in 556

patients

at DCO: 62%

maturity;

osimertinib: 136 events (49%),

SoC:

206 events

(74

%)

Median PFS,

months

HR

0.46

p

<

0.0001

1.0

Slide14

All Causality Adverse Events* (≥15% of Patients)

FLAURA

data

cut-off:

12

June

2017.

Grade

3

QTc

prolongation

based

on

collected

digital

ECGs

values

were

recorded

for

3

patients

in

the

osimertinib

arm

and

2

patients

in

the

SoC

arm

*

In

the SoC arm

there

was

1 patient

with Grade missing and

1 patient

with

Grade 5

diarrhea

AE

= adverse event;

SoC = standard of care; AST =

aspartate aminotransferase; ALT = alanine aminotransferase

AEs

by

preferred

term, n

(%)

Osimertinib

(

n =

279)

SoC

(

n

=

277)

Any

grade

Grade

1

Grade

2

Grade

3

Grade

4

Any

grade

Grade 1

Grade 2

Grade 3

Grade 4

Diarrhea

161

(58)

120

(43)

35

(13)

6

(2)

0

159

(57)*

116

(42)

35

(13)

6

(2)

0

Dry

skin

88

(32)

76

(27)

11

(4)

1

(<1)

0

90

(32)

70

(25)

17

(6)

3

(1)

0

Paronychia

81

(29)

37

(13)

43

(15)

1

(<1)

0

80

(29)

46

(17)

32

(12)

2

(1)

0

Stomatitis

80

(29)

65

(23)

13

(5)

1

(<1)

1

(<1)

56

(20)

47

(17)

8

(3)

1

(<1)

0

Dermatitis

acneiform

71

(25)

61

(22)

10

(4)

0

0

134

(48)

71

(26)

50

(18)

13

(5)

0

Decreased

appetite

56

(20)

27

(10)

22

(8)

7

(3)

0

51

(18)

24

(9)

22

(8)

5

(2)

0

Pruritis

48

(17)

40

(14)

7

(3)

1

(<1)

0

43

(16)

30

(11)

13

(5)

0

0

Cough

46

(16)

34

(12)

12

(4)

0

0

42

(15)

25

(9)

16

(6)

1

(<1)

0

Constipation

42

(15)

33

(12)

9

(3)

0

0

35

(13)

28

(10)

7

(3)

0

0

AST

increased

26

(9)

18

(6)

6

(2)

2

(1)

0

68

(25)

38

(14)

18

(6)

12

(4)

0

ALT

increased

18

(6)

11

(4)

6

(2)

1

(<1)

0

75

(27)

31

(11)19 (7)21 (8)4 (1)

Median

duration of

exposure:

osimertinib

: 16.2

months (range

0.1

to

27.4),

SoC

:

11.5

months (range 0 to

26.2)

Slide15

In general, based on the results of the FLAURA study, what would be your likely first-line treatment recommendation for an otherwise healthy patient with metastatic adenocarcinoma of

the lung

with an EGFR exon 19 deletion mutation and a TPS of…

Osimertinib

Erlotinib

Osimertinib

Osimertinib

Osimertinib

or

afatinib

Osimertinib

Osimertinib

Osimertinib

Erlotinib

Osimertinib

Osimertinib

Osimertinib

or

afatinib

Osimertinib

Osimertinib

10%

60%

Slide16

Agenda

Introduction

–

The New Taxonomy of Metastatic Non-Small Cell Lung Cancer (

NSCLC)

 

Module 1 –

Emerging Research Data with and Potential Clinical Role of Immune Checkpoint Inhibitors in the Management of Locally Advanced NSCLC

 

Module

2 –

Integration of Anti-PD-1/PD-L1 Antibodies into Current Treatment Algorithms for Patients with Metastatic NSCLC

Module

3

–

Ongoing Evaluation of Existing and Emerging Immunotherapeutic Approaches, Including Combination Strategies  

Module

4 –

Identification

and Management of Immune-Mediated and Other Toxicities Associated with Checkpoint Inhibitors; Relative Contraindications for Patients with Existing Autoimmune Disease

Slide17

PACIFIC: A

Double-Blind

,

Placebo-Controlled

Phase III

Study

of

D

urvalumab

after

C

hemoradiation

Therapy

(CRT) in Patients with Stage III, Locally Advanced

, Unresectable NSCLC

Paz-Ares L et al.

Proc ESMO

2017;Abstract LBA1.

Slide18

PACIFIC:

Study

Design

Phase III, Randomized,

Double-Blind

,

Placebo-Controlled

,

Multicenter,

International

Study

 (NCT02125461

)

Patients with

S

tage

III,

locally advanced, unresectable NSCLC

who

have not progressed following definitive platinum-based

cCRT

(≥2

cycles

)

18 years or

older

WHO

PS

score 0 or

1

Estimated life expectancy

of

≥12

weeks

Archived

tissue

was

collected

All-comers

population

Placebo

10

mg/kg

q2w

k

for

up

to

12

months

N

=

237

2:1 randomization,

stratified

by age,

sex

and smoking history

N

=

713

Key secondary

endpoints

ORR

(per

BICR)

DoR

(per

BICR)

Safety and

tolerability

Patient-reported outcomes

Co-primary

endpointsPFS by BICR using RECIST

v1.1*OS

1-42

days post-cCR

T* Defined

as the

time from randomization

(which occurred

up to 6

weeks

post-cCRT) to

the first documented

event of tumor progression

or death in

the

absence of progression. cCRT

= concurrent chemoradiation therapy; WHO = World Health

Organization; PS = performance status; BICR =

blinded independent central review; RECIST = Response Evaluation Criteria In

Solid Tumors; OS = overall survival

; ORR = objective response

rate; DoR = duration

of response

Durvalumab

10 mg/kg q2wk for

up to 12 months

N = 476

Slide19

PFS

by BICR (Primary Endpoint;

ITT)

BICR =

blinded independent

central review;

ITT = intention to treat

P

FS

prob

a

b

i

li

ty

1.0

0.9

0.8

0.7

0.6

0.5

0

.4

0.3

0.2

0.1

0.0

0

3

6

21

24

27

9 12 15

18

Time

from

randomization

(months)

P

l

ace

bo

Durvalumab

No. at

risk

Du

r

v

alumab

476

377

301

264

159

86

44

21

4

1

P

la

c

ebo

237

163

106

87

52

28

15

4

3

0

Durvalumab

(

N

=

476

)

Placebo

(

N

=

237

)

Median

PFS,

months

16.8

5.6

12-month

PFS

rate

55.9%

35.3

%

18-month

PFS

rate

44.2%

27.0

%

Stratified hazard ratio,

0.52

Two-sided

P

<

0.0001

Slide20

PFS Subgroup Analysis by BICR

(ITT)

* HR not

calculated if

the subgroup has

less

than 20 events. BICR = blinded independent central review;

cCRT

= concurrent

chemoradiation

therapy; CR = complete response; PR = partial response; SD = stable

disease

Slide21

Antitumor Activity by BICR

(ITT)

* Patients

with measurable

disease at baseline,

as determined by

either of

the

2

independent

reviewers;

†

One

patient could

not be grouped

into

any

of

the best

overall

response

categories

due

to inconsistency in

the

baseline

assessment

for

measurable

disease

between the

2

independent

central reviewers.

‡

Percentages

calculated

by Kaplan-Meier method;

¶

Placebo

was

the reference group when RR and HR were

calculated;

therefore, an RR

value

greater than

1

is

in

favor

of

durvalumab

and an

HR

value

less

than 1

is

in

favor

of

durvalumab

BICR =

blinded independent

central review;

NR = not reached; RR = relative risk

D

u

r

v

alum

a

b

(N =

443)*

Pl

aceb

o(N

= 213)*

Treatment

effect (HR)¶

Best overall response,

n (%)†

Complete

response

6

(1.4)

1 (0.5)

Partial

response

120

(27.1)

33

(15.5)

Stable

disease

233

(52.6)

119

(55.9)

Progressive

disease

73

(16.5)

59 (27.7)

Nonevaluable

10

(2.3)

1

(0.5)

Duration of

response,

months

Median

NR

13.8

0.43

Ongoing response at data

cutoff

,

%

‡

At

12

monthsAt 18 months

72.8

72.8

56.1

46.8

35

30

25

20

15

10

5

0

Durvalumab (

N

=

443

)*

Placebo (

N

=

2

1

3

)*

% patients

(95%

CI)

Objective

Response

P

<0.0

0

1

28.4

16.0

Treatment

effect

(

RR

)

¶

:

1.78

Slide22

Incidence

of

New Lesions by

BICR

(ITT)

* A

patient

may

have

had

more

than

1

new

lesion site.

†

Includes

lesions in:

abdominal wall,

biliary tract,

breast, chest wall,

kidney,

ovary,

pancreas

,

pericardium,

peritoneal fluid,

peritoneum, retroperitoneum,

skin, spleen, uterus and other

(unspecified

).

BICR

=

blinded independent

central

review

New

lesion

site*

D

u

r

v

alum

a

b

(N

=

476

)

Pl

a

cebo

(N

=

237

)

Any

new

lesion,

n

(%)

97

(20.4)

76

(32.1)

Lymph

nodes

27

(5.7)

27

(11.4)

Brain

26 (5.5)

26

(11.0)

Lung

56

(11.8)

41

(17.3)

Liver

9

(1.9)

8

(3.4)

Adrenal

3

(0.6)

5

(2.1)

Bone

8

(1.7)

6 (2.5)

Other

†

9

(1.9)

5 (2.1)

Slide23

Du

r

v

alumab

476

407

336

288

173

91

46

22

4

1

0

P

la

c

ebo

237

184

129

106

63

32

16

5

4

0

0

Time

to Distant Metastasis or Death by BICR

(ITT)

BICR =

blinded independent

central

review

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

1

3

6

9

12

1

5

1

8

21

24

27

30

P

r

obab

ili

ty

o

f

dea

th

o

r

d

i

st

an

t

m

e

t

a

st

a

s

i

s

Time

from randomization

(months)

P

la

c

ebo

Durvalumab

No. at

risk

Durvalumab

Placebo

Median

PFS,

months

23.2

14

.6

Stratified hazard ratio,

0.52

Two-sided

P

<

0.0001

Slide24

Safety Summary*

* Two

patients

randomized

to placebo received at least

1

dose

of

durvalumab

and were

considered

part

of

the

durvalumab

arm

for safety

reporting.

Safety

analysis set.

AE =

adverse event;

SAE =

serious

adverse

event

Durvalumab

(N = 475)

Placebo

(N = 234)

Any-grade all-causality AEs, n (%)

460 (96.8)

222 (94.9)

Grade 3/4

142 (29.9)

61 (26.1)

Grade 5

21

(4.4)

13 (5.6)

Leading to discontinuation

73 (15.4)

23 (9.8)

Any-grade treatment-related AEs, n (%)

322 (67.8)

125 (53.4)

SAEs

,

n

(%)

136 (28.6)

53 (22.6)

Any-grade immune-mediated AEs, n (%)

115 (24.2)

19 (8.1)

Grade 3/4

16 (3.4)

6 (2.6)

Slide25

Most Frequent

Adverse

Events

*

Event

Durvalumab

(N = 475)

Placebo (N = 234)

Any grade

Grade 3 or 4

Any grade

Grade 3 or 4

Any

event,

n

(%)

460

(96.8)

142

(29.9)

222

(94.9)

61

(26.1)

Cough

168

(35.4)

2

(0.4)

59

(25.2)

1

(0.4)

Pneumonitis/radiation

pneumonitis

†

161

(33.9)

16

(3.4)

58

(24.8)

6

(2.6)

Fatigue

113

(23.8)

1

(0.2)

48

(20.5)

3

(1.3)

Dyspnea

106

(22.3)

7

(1.5)

56

(23.9)

6

(2.6)

Diarrhea

87

(18.3)

3

(0.6)

44

(18.8)

3

(1.3)

Pyrexia

70

(14.7)

1

(0.2)

21

(9.0)

0

Decreased

appetite

68

(14.3)

1

(0.2)

30

(12.8)

2

(0.9)

Nausea

66

(13.9)

0

31

(13.2)

0

Pneumonia

62

(13.1)

21

(4.4)

18

(7.7)

9

(3.8)

Arthralgia

59

(12.4)

0

26

(11.1)

0

Pruritus

58

(12.2)

0

11

(4.7)

0

Rash

58

(12.2)

1

(0.2)

17

(7.3)

0

Upper

respiratory tract

infection

58

(12.2)

1

(0.2)

23

(9.8)

0

Constipation

56

(11.8)

1

(0.2)

20

(8.5)

0

Hypothyroidism

55

(11.6)

1

(0.2)

4

(1.7)

0

Asthenia

51

(10.7)

3

(0.6)

31

(13.2)

1

(0.4)

Back

pain

50

(10.5)

1

(0.2)

27

(11.5)

1

(0.4)

Safety

analysis set (all-causality).

* Occurring

in

>11%

of patients in either

treatment arm.

Two

patients

randomized

to placebo received at least

1

dose

of

durvalumab

and

were

considered

part

of

the

durvalumab

arm

for

safety

reporting.

†

Pneumonitis/radiation

pneumonitis

was

assessed

by

investigators

with

subsequent

review

and

adjudication

by

the

study

sponsor.

In addition,

pneumonitis,

as

reported

in

the

table, is

a

grouped

term,

which

includes

acute

interstitial

pneumonitis,

interstitial

lung disease,

pneumonitis and

pulmonary

fibrosis

.

Slide26

Pneumonitis (grouped terms) or radiation pneumonitis, n (%)*

Durvalumab

(N = 475)

Placebo

(

N

=

234)

Any

grade

161

(33.9)

58

(24.8)

Grade

3/4

16

(3.4)

6

(2.6)

Grade

5

5

(1.1)

4

(1.7)

Leading

to

discontinuation

30

(6.3)

10

(4.3)

Pneumonitis or Radiation

Pneumonitis

Safety analysis set (all-causality).

*

Pneumonitis/radiation

pneumonitis was assessed by investigators with subsequent review and adjudication by the study sponsor. In addition, pneumonitis, as reported in the table, is a grouped term, which includes acute interstitial pneumonitis, interstitial lung disease,

pneumonitis

and pulmonary fibrosis

.

Two patients randomized to placebo received at least

1

dose of

durvalumab

and were considered part of the

durvalumab

arm for

safety

reporting.

Slide27

Summary

Durvalumab

demonstrated a statistically significant and robust improvement in PFS versus

placebo

(HR 0.52;

P

< 0.0001

; median improvement of >11 months) at a planned interim

analysis.

PFS improvement with

durvalumab

was observed across all

prespecified

subgroups.

Durvalumab

demonstrated a clinically meaningful benefit in ORR (28.4% vs 16.0%;

p

< 0.001

), with

durable

responses versus placebo (median

DoR

not reached vs

13.8

months

).

Patients receiving

durvalumab had a lower incidence of new lesions, including new brain

metastases, compared to patients receiving placebo.The safety profile of

durvalumab was consistent with that of other immunotherapies

and with its known safety profile as monotherapy in patients with more advanced disease;

1 no new

safety signals were identified.

The study remains blinded to OS.

1. Antonia

SJ

et al. Poster presented at the 41st

European Society for Medical Oncology Annual Meeting, Copenhagen, October

7-11

, 2016

. ORR =

overall response rate;

DoR

= duration of response

Slide28

Conclusion

Durvalumab

is a promising new therapeutic option in

patients

with

Stage

III, locally advanced,

unresectable

NSCLC

who have completed

cCRT

cCRT

=

concurrent

chemoradiation

therapy

Slide29

Nivolumab

q2wk

x 1 year

Placebo

www.clinicaltrials.gov,

NCT02768558

Eligibility (N = 660)

Unresectable

, Stage III NSCLC

Received cisplatin/etoposide concurrent with radiation therapy

Primary

Endpoints:

Overall and progression-free survival

RTOG 3505: A Phase III Study of

Nivolumab

in Locally Advanced NSCLC

R

Slide30

For a patient with

unresectable Stage IIIB

nonsquamous

disease, would you administer

durvalumab

as sequential therapy after standard platinum-based

chemoradiation

therapy

?

Not at this time but would

if it were approved 

Not at this time but would

if it were approved 

Not at this time but would

if

it were

approved

Yes

Yes

Yes

Yes

Not at this time but would

if

it were approved 

No

Not at this time but

would

if it were

approved

Yes

Yes

Yes

Yes

Asympt

,

nonbulky

Mildly

sympt

, bulky

Slide31

For a patient with

unresectable

Stage IIIB

squamous

disease, would you administer

durvalumab

as sequential therapy after standard platinum-based

chemoradiation

therapy?

Not at this time but would

if it were approved 

Not at this time but would

if it were approved 

Not at this time but

would

if

it were approved

Yes

Yes

Yes

Yes

Not at this time but would

if

it were approved 

No

Not at this time but

would

if it were

approved

Yes

Yes

Yes

Yes

Asympt

,

nonbulky

Mildly

sympt

, bulky

Slide32

For a patient with mildly symptomatic

unresectable

, bulky Stage IIIB

nonsquamous

disease, would you administer

durvalumab

as sequential therapy if the patient achieved a partial response to

chemoradiation

therapy but is experiencing…

No

No

No

No

No

No

Yes

Not at this time but would

if it were approved 

No

Not at this time but

would

if

it were approved

No

No

Yes

Yes

Mildly

sympt

pneumonitis

Asympt

pneumonitis

Slide33

For a patient with mildly symptomatic

unresectable

, bulky Stage IIIB

nonsquamous

disease, would you administer

durvalumab

as sequential therapy if the patient achieved a partial response to

chemoradiation

therapy but is experiencing…

No

No

Not at this time but would

if it were approved

Yes

Yes

Yes

Yes

No

No

No

No

Yes

No

Yes

Mildly

sympt

esophagitis

Clinically significant esophagitis

Slide34

Agenda

Introduction

–

The New Taxonomy of Metastatic Non-Small Cell Lung Cancer (

NSCLC)

 

Module 1 –

Emerging Research Data with and Potential Clinical Role of Immune Checkpoint Inhibitors in the Management of Locally Advanced NSCLC 

Module

2

–

Integration

of Anti-PD-1/PD-L1 Antibodies into Current Treatment Algorithms for Patients with Metastatic

NSCLC

Module

3

–

Ongoing Evaluation of Existing and Emerging Immunotherapeutic Approaches, Including Combination Strategies  

Module

4 –

Identification

and Management of Immune-Mediated and Other Toxicities Associated with Checkpoint Inhibitors; Relative Contraindications for Patients with Existing Autoimmune Disease

Slide35

Immune

Checkpoint Inhibitors

in NSCLC

2008

Nivolumab FIH trial initiated

2012

Checkmate

017 and 057

initiated

Pembrolizumab FIH trial initiated

2015 (March)

Nivolumab FDA approved in 2

nd

line

s

q

NSCLC

2015 (Fall)

Nivolumab

approved

in

fall

for 2

nd

line

non-

sq

NSCLC

Pembrolizumab

FDA approved

in

2

nd

line NSCLC (PD-L1 > 50%)

2016 (Fall)

Pembrolizumab

FDA approved

1

st

line NSCLC

(PD-L1 > 50%)

Pembrolizumab

FDA approved in 2

nd

line NSCLC (

PD-L1

> 1%)

Atezolizumab

FDA approved 2

nd

line NSCLC

2017 (April)

Pembrolizumab

+

pemetrexed

and carboplatin

FDA approved

1

st

line NSCLC

Nivolumab

PD-1

Pembrolizumab

PD-1

Atezolizumab

PD-L1

Courtesy of

Corey Langer, MD

Slide36

PD1/PD-L1 Inhibitors

Increase

Overall Survival in 2L Advanced NSCLC

CHECKMATE 017

CHECKMATE 057

KEYNOTE-010

(TPS

≥

1

%)

OAK

Brahmer

NEJM 2015.

Borghaei

, NEJM 2015.

Herbst

Lancet 2016.

Rittmeyer

Lancet 2017.

Nivolumab

(n = 292)

Docetaxel

(n = 290)

mOS

,

mo

12.2

9.4

HR = 0.73 (96% CI: 0.59, 0.89);

P

= 0.0015

1-yr OS rate = 51%

1-yr OS rate = 39%

Treatment arm

Median

(95% CI),

mo

HR*

(95% CI)

p

-value

Pembro

2 mg/kg

14.9 (10.4-NR)

0.54 (0.38-0.77)

0.0002

Pembro

10 mg/kg

17.3 (11.8-NR)

0.50 (0.36-0.70)

<0.0001

Docetaxel

8.2 (6.4-10.7)

—

—

Time, months

Overall survival, %

2 vs 10 mg/kg

HR 1.12, 95% CI 0.77-1.62

HR, 0.73

(95% CI, 0.62, 0.87)

P

= 0.0003

Minimum follow-up = 19 months

Median 9.6

mo

(95% CI, 8.6, 11.2)

Median 13.8

mo

(95% CI, 11.8, 15.7)

Atezolizumab

Docetaxel

M

onths

Overall survival (%)

Slide37

KEYNOTE-024 Trial: First-Line

Pembro

versus Chemotherapy for PD-L1-Positive

NSCLC: PFS and OS

Brahmer

J et al.

Proc ASCO

2017;Abstract 9000.

Median OS: Not reached

(

pembro

) vs 14.5

mo

(chemo

); HR = 0.63;

p

= 0.003

Patients with PD-L1 TPS ≥50% who received first-line 

pembrolizumab

had better overall survival than those who received first-line 

chemotherapy

Median follow-up: 19 months

HR 0.54

p

< 0.001

Median

18.3

mo

8.4

mo

59.7%

38.5%

51.0%

24.6%

Time, months

PFS2, %

Pembrolizumab

n = 154

Chemotherapy n = 151

Time, months

OS,

%

Median

Not reached

14.5

mo

HR

0.63

p

=

0.003

Slide38

KEYNOTE-021: Updated Efficacy Results of First-Line

Pembro

/Carbo/

Pem

(

Pembro

/CP) vs CP

Borghaei

H

et al.

Proc ESMO

2017;Abstract

LBA49.

ORR = 56.7%

(

pembro

/CP

) vs

31.7%

(CP);

p

=

0.0029

12-mo

OS =

77% (

pembro

/CP

) vs 69% (CP

)

18-mo OS = 70%

(

p

embro

/CP

)

vs

56% (CP

)

Median

HR

Pembro

/CP (n = 60)

19.0

mo

0.54

CP (n = 63)

8.9

mo

p

=

0.0067

Progression-free survival, %

9

mo

63.2%

48.1%

12

mo

56.4%

33.9%

Time, months

Slide39

KEYNOTE-189 Phase III Trial Design

www.clinicaltrials.gov

; NCT02578680. Accessed March 2017.

Hall RD et al.

Proc ASCO

2016;Abstract TPS9104.

Pembrolizumab

200 mg +

pemetrexed

500 mg/m

2

+ cisplatin 75 mg/m

2

or

carboplatin AUC 5

q3wk x 4 cycles*

Placebo +

pemetrexed

500 mg/m

2

+ cisplatin 75 mg/m

2

or carboplatin AUC 5

q3wk x 4 cycles*

R

Estimated accrual (n = 570)

Stage IV

nonsquamous

NSCLC

No sensitizing EGFR mutation or ALK translocation

Treatment naïve

* Followed by pembrolizumab 200 mg or placebo with pemetrexed 500 mg/m

2

q3wk up to 35 cycles

2:1

Stratification: PD-L1 TPS <1% vs ≥1%, smoking status, cisplatin versus carboplatin

Slide40

CheckMate

026: Phase III Study Design

www.clinicaltrials.gov

; NCT02041533. Accessed November 9, 2016;

Socinski

MA et al.

Proc ESMO

2016;Abstract LBA7_PR.

R

Stage IV or recurrent NSCLC

No prior

tx

for advanced disease

No EGFR/ALK mutations

≥1% PD-L1 expression

Nivolumab

3 mg/kg IV q2wk

(n = 271)

Disease progression or unacceptable toxicity

1:1

*

Squamous

: gemcitabine 1,250 mg/m

2

+ cisplatin 75 mg/m

2

; gemcitabine 1,000 mg/m

2

+ carboplatin AUC 5; paclitaxel 200 mg/m

2

+ carboplatin AUC 6;

Nonsquamous

:

pemetrexed

500 mg/m

2

+ cisplatin 75 mg/m

2

;

pemetrexed

500 mg/m

2

+ carboplatin AUC 6; option for

pemetrexed

maintenance therapy

Chemotherapy*

(n = 270)

Disease progression

Crossover to

nivolumab

Slide41

CheckMate

026: Efficacy and Safety of First-Line

Nivolumub

versus Chemotherapy for PD-L1-Positive NSCLC

In patients with ≥5% PD-L1 expression (n = 423),

nivolumab

did not improve OS (HR, 1.02;

p

= 0.25) or ORR.

Safety results of

nivolumab

were consistent with the known profile.

Fewer Grade 3-4 AEs with

nivolumab

than with chemotherapy.

Socinski

M et al.

Proc ESMO

2016;Abstract LBA7_PR.

Slide42

In general, which first-line treatment regimen would you most likely recommend for

an

asymptomatic

patient with metastatic

nonsquamous

lung cancer and no identified targetable mutations with a PD-L1 TPS of…

Carbo/

pem

/

pembro

Carboplatin/

pemetrexed

Carbo/

pem

/

pembro

Carboplatin/

pemetrexed

Carbo/

pem

/

bev

Cis/

pem

/

bev

Carbo/

pem/pembro

Carbo/pem/

pembro

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

10%

60%

Slide43

A 65-year-old patient presents with

significant respiratory distress

and highly symptomatic metastatic

nonsquamous

lung cancer

with no identified targetable mutations. What would be your most likely treatment recommendation if the patient had a PD-L1 TPS of…

Carbo/

pem

/

pembro

Carboplatin/

pemetrexed

Carbo/

pem

/

pembro

Carbo/

pem

/

pembro

Carbo/

pem

/

pembro

Carboplatin/

pemetrexed

Carbo/

pem/pembro

Carbo/pem

/pembro

Pembrolizumab

Carbo/

pem/

pembro

Carbo/pem

/

pembro

Carbo/

pem

/

pembro

Pembrolizumab

Pembrolizumab

10%

60%

Slide44

In general, which first-line treatment regimen would you most likely recommend for

an otherwise healthy

patient with metastatic

squamous

cell lung cancer and a PD-L1 TPS of…

Carboplatin/gemcitabine

Carboplatin/

nab

paclitaxel

Carboplatin/

nab

paclitaxel

Carboplatin/gemcitabine

Carboplatin/gemcitabine 

Carboplatin/gemcitabine

Carboplatin/

nab

paclitaxel 

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

 

Pembrolizumab

Pembrolizumab

10%

60%

Slide45

Pembrolizumab

Palliative care assessment to discuss goals of care

Carboplatin/

nab

paclitaxel

Hospice

Pembrolizumab

 

Pembrolizumab

Carboplatin/

nab

paclitaxel 

Cost and reimbursement issues aside, in general, which first-line treatment regimen would you most likely recommend for

a very elderly (age 87), frail

patient with metastatic

squamous

cell lung cancer and a PD-L1

TPS of 10%

?

Slide46

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

 

Pembrolizumab

Pembrolizumab

A 65-year-old patient presents with significant respiratory distress and highly symptomatic metastatic

squamous cell cancer of the lung

and a PD-L1

TPS of 60%

. What would be your most likely treatment recommendation?

Slide47

Are anti-PD-1/PD-L1 antibodies effective in patients with brain metastases? Have you observed any meaningful clinical responses to anti-PD-1/PD-L1 antibodies in a patient with brain metastases?

Yes,

as

effective as with

systemic

mets

Yes,

as

effective as with

systemic

mets

Yes,

less

effective than with

systemic

mets

 

Yes,

as

effective as

with

systemic

mets

Yes, as effective as with

systemic

mets

Yes,

as

effective as

with

systemic

mets

Yes, as effective as with

systemic

mets

Yes

Yes

No

No

Yes

Yes

No

Effective in brain

mets

?

Seen response?

Slide48

FDA-Approved Anti-PD-1/PD-L1 Checkpoint Inhibitors for Second- or Later-Line Metastatic NSCLC

Agent

FDA approval

Pivotal

studies

Indication

Pembrolizumab

(q3wk)

10-2-2015

KEYNOTE-001

KEYNOTE-010

Metastatic

nonsquamous

and squamous cell

NSCLC with disease progression on or after

platinum-containing

chemo in pts

whose tumors express PD-L1 (TPS ≥1%)

Nivolumab

(q2wk)

3-4-2015

10-9-2015

CheckMate-017

CheckMate-057

Metastatic

squamous cell

NSCLC with disease progression on or after

platinum-containing

chemo

Metastatic

nonsquamous

NSCLC with disease progression on or after

platinum-containing

chemo

Atezolizumab

(q3wk)

10-18-2016

OAK

POPLAR

Metastatic

nonsquamous

and squamous cell

NSCLC with disease progression on or after

platinum-containing

chemo

Garon

EB et al.

N

Engl

J Med

2015;372:2018-28.

Herbst

RS et al.

Lancet

2016;387(10027):1540-50.

Pembrolizumab

package insert, October 2016.

Brahmer

J et al.

N

Engl

J Med

2015;373(2):123-35.

Borghaei

H et al.

N

Engl

J Med

2015;373(17):1627-39.

Nivolumab

package insert, October 2016.

Rittmeyer

A et al.

Lancet

2017;389:255-65.

Slide49

A patient with metastatic

nonsquamous

lung cancer with no identified targetable mutations receives first-line carboplatin/paclitaxel/bevacizumab and experiences

asymptomatic

disease progression. What would you most likely recommend for this patient if he/she had a PD-L1 TPS of…

Atezolizumab

Nivolumab

or

atezolizumab

Atezolizumab

Nivolumab

or

atezolizumab

Atezolizumab

Nivolumab

Atezolizumab

Pembrolizumab

Nivo

,

pembro

or

atezo

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Atezolizumab

<1%

1

0%

Slide50

A patient with metastatic

squamous

cell lung cancer receives first-line carboplatin/paclitaxel and experiences

asymptomatic

disease progression. What would you most likely recommend for this patient if he/she had a PD-L1 TPS of…

Atezolizumab

Nivolumab

or

atezolizumab

Atezolizumab

Nivolumab

or

atezolizumab

Atezolizumab

Nivolumab

Atezolizumab

Pembrolizumab

Nivo

,

pembro

or

atezo

Pembrolizumab

Pembrolizumab

Pembrolizumab

Pembrolizumab

Atezolizumab

<1%

1

0%

Slide51

ORRs based on EGFR and ALK status

Gainor

JF et al.

Clin

Cancer Res

2016;22(18):4585-93.

Objective Response to Anti-PD-1/Anti-PD-L1 Antibodies by Mutation Status: A Retrospective Analysis

EGFR-mutant or ALK-positive

EGFR WT/ALK-negative

ORR

P

= 0.053

Slide52

Checkpoint Inhibitors in Metastatic EGFR-Mutated

NSCLC — A Meta-Analysis

Lee CK et al.

J

Thorac

Oncol

2017;12(2):

403-7

.

Study

Weight

Hazard ratio

EGFR wild-type

CheckMate

057

26.0%

0.66

KEYNOTE-010

52.0%

0.66

POPLAR

11.0%

0.70

Subtotal

89.0%

0.66

EGFR mutant

CheckMate

057

6.0%

1.18

KEYNOTE-010

3.8%

0.88

POPLAR

1.1%

0.99

Subtotal

11.0%

1.05

Total

100.0%

0.70

0.5

0.7

1

1.5

2

Favors PD-1/PD-L1

inhibitor

Favors docetaxel

Hazard ratio

Slide53

In general, when do you believe checkpoint inhibitors should be introduced into the treatment of

metastatic

EGFR-mutant NSCLC

with

a

TPS of…

After

targeted

tx

and

2 lines of

chemo

After

targeted

tx

and

2 lines of chemo

After

targeted

tx

and

1 line of

chemo

Never or only after all other options are

exhausted

After targeted

tx

and 1 line of

chemo

After

targeted

tx and

1 line of chemo

After targeted tx

and 1 line of chemo

After targeted

tx but before chemo

After

targeted

tx

and

2 lines of

chemo

After

targeted

tx

and

1 line of

chemo

Never or only after all other options are

exhausted

After targeted

tx

and 1 line of

chemo

Would consider pembro

in 1st line in asymptomatic ptsAfter targeted tx

and 1 line of chemo<50% >50%

Slide54

In general, when do you believe checkpoint inhibitors should be introduced into the treatment of ALK-rearranged NSCLC with a TPS of…

After

targeted

tx

and

1 line of

chemo

After

targeted

tx

and

2 lines of

chemo

After

targeted

tx

and

1 line of

chemo

Never or only after all other options are

exhausted

After targeted

tx

and 1 line of

chemo

After

targeted

tx

and

1 line of

chemo

After targeted

tx and 1 line of chemo

After

targeted tx but before

chemo

After targeted

tx

and

2 lines of

chemo

After

targeted

tx

and

1 line of

chemo

Never or only after all other options are

exhausted

After targeted

tx

and 1 line of

chemo

Would consider

pembro

in 1st line in asymptomatic pts

After targeted tx and 1 line of chemo<50%

>50%

Slide55

Agenda

Introduction

–

The New Taxonomy of Metastatic Non-Small Cell Lung

Cancer

(

NSCLC)

 

Module 1 –

Emerging Research Data with and Potential Clinical Role

of

Immune Checkpoint Inhibitors in the Management of Locally

Advanced

NSCLC 

Module

2 –

Integration of Anti-PD-1/PD-L1 Antibodies into Current

Treatment

Algorithms for Patients with Metastatic NSCLC

Module

3

–

Ongoing

Evaluation of Existing and Emerging Immunotherapeutic Approaches, Including Combination Strategies

  

Module

4 –

Identification

and Management of Immune-Mediated and

Other

Toxicities Associated with Checkpoint Inhibitors; Relative

Contraindications

for Patients with Existing Autoimmune Disease

Slide56

Combination Approaches to Enhance Immunotherapy Responsiveness

Kim, Chen

. Ann

Oncol

2016

Hegde

et al.

Clin

Cancer Res 2016

Can we

convert

noninflamed

tumours

to become

inflamed?

IMMUNE DESERT

CD8+ T cells absent

from

tumour

and periphery

Increase number of

antigen-specific T cells or

increase antigen presentation

IMMUNE EXCLUDED

CD8+ T cells accumulated but not efficiently infiltrated

Bring T cells

in contact with cancer cells

INFLAMED

CD8+ T cells infiltrated,

but

nonfunctional

Accelerate or remove brakes

on T cell response

Mechanisms of immunotherapy resistance

Courtesy of

Johanna C

Bendell

, MD

Slide57

Nivo

3 q2wk +

ipi

1 q12wk

(n = 38)

Nivo

3 q2wk +

ipi

1 q6wk

(n = 39)

Nivo

3 q2wk

(n = 52)

ORR

<1% PD-L1

≥1% PD-L1

≥50% PD-L1

30%

57%

100%

0%

57%

86%

14%

28%

50%

Median PFS

<1% PD-L1

≥1% PD-L1

≥50% PD-L1

4.7

mo

8.1

mo

13.6

mo

2.4

mo

10.6

mo

NR

6.6

mo

3.5

mo

8.4

mo

1-year

OS rate

<1% PD-L1

≥1% PD-L1

≥50% PD-L1

NC

90%

NC

NC

83%

100%

79%

69%

83%

CheckMate

012: Efficacy of First-Line

Nivolumab

with Ipilimumab for Advanced NSCLC by Tumor PD-L1 Expression

Hellmann MD et al.

Proc

ASCO

2016;Abstract 3001.

NR = not reached; NC = not calculated when >25% of patients are censored

Slide58

MYSTIC

Phase III Trial Design

www.clinicaltrials.gov

;

NCT02453282

. Accessed August 28, 2017.

Durvalumab

Histology-based platinum-doublet chemotherapy

Estimated accrual (n = 1,118)

Treatment-naïve, Stage IV NSCLC

No activating EGFR mutation or ALK rearrangement

Durvalumab

+

tremelimumab

Primary Endpoints:

PFS and OS of

durvalumab

+

tremelimumab

, OS

of

durvalumab

monotherapy

1:1:1

R

Slide59

Phase III MYSTIC Trial Does Not Meet Its Primary Endpoint of

PFS

Press Release

—

July 27, 2017

The combination of

durvalumab

and

tremelimumab

did not meet the primary endpoint of improving PFS compared to standard of care (

SoC

) in patients whose tumors express PD-L1 on 25% or more of their cancer cells (as determined by the VENTANA PD-L1 [SP263] assay).

As a secondary endpoint, although not formally tested,

durvalumab

monotherapy would not have met a

prespecified

threshold of PFS benefit over

SoC

in this disease setting.

The trial will continue to assess two additional primary endpoints of overall survival (OS) for

durvalumab

monotherapy and OS for the

durvalumab

plus

tremelimumab

combination. Final OS data from both primary endpoints are expected during the first half of 2018.

https://

www.astrazeneca.com

/media-

centre

/press-releases/2017/astrazeneca-reports-initial-results-from-the-ongoing-mystic-trial-in-stage-iv-lung-cancer-27072017.html

Slide60

Phase III

CheckMate 227 Trial

January 19, 2017: Company stated that it would NOT ask for accelerated approval of this combination based on

data

available at the time.

Socinski

M et al.

Proc ESMO

2016;Abstract LBA7_PR.

http

://investor.bms.com/investors/news-and-events/press-releases/press-release-details/2017/

Bristol-Myers-Squibb-Provides-Regulatory-Update-in-First-Line-Lung-Cancer/

default.aspx

1:1:1

R

PD-L1+

(≥1%)

PD-L1-

(<1%)

Disease progression

or

unacceptable toxicity

Key eligibility criteria

Stage IV or recurrent NSCLC

No prior systemic therapy for advanced disease

No EGFR/ALK mutations sensitive to available targeted inhibitor therapy

CNS metastases permitted if adequately treated ≥2 weeks prior to randomization

Stratification factor at randomization

:

Histology (squamous vs

nonsquamous

)

Nivolumab

3 mg/kg q2wk

+

ipilimumab

1 mg/kg

q6wk

Nivolumab

monotherapy

240 mg

q2wk

Chemotherapy

Nivolumab

3 mg/kg q2wk +

ipilimumab

1 mg/kg

q6wk

Nivolumab

360 mg q3wk +

chemotherapy

Chemotherapy

Slide61

Are there any situations in which you would use the combination of an anti-PD-1/PD-L1 antibody and an anti-CTLA-4 antibody outside of a trial setting for metastatic…

No

No

No

No

No

No

No

No

Yes, second or third line

Yes,

nivolumab/ipilimumab

Yes, pretreated

pt

w/

good PS

Yes,

pt

w/ good PS

after

1st-line chemo

Yes, in a fit patient

Yes, second line

Non-small cell lung cancer

Small cell lung cancer

Slide62

I haven’t and would not

I haven’t and would not

I haven’t and would not

I have as part of clinical trials and have seen significant toxicity

I haven’t and would

not

I haven’t and would not

I haven’t and would

not

Have you or would you administer targeted therapy (

eg

, an EGFR TKI or ALK inhibitor) in combination with a PD-1/PD-L1 antibody to a patient with metastatic NSCLC?

Slide63

Perhaps the IDO inhibitors

IDO

inhibitor,

LAG3

and OX40

IDO

inhibitor,

MGA271 (

MAb

targeting B7-H3

)

IDO plus

PD-1

VEGF inhibitors, A2AR inhibitors

Not sure

Not sure; several in progress, including IDO and vaccines

What other strategies combining anti-PD-1/anti-PD-L1 antibodies with other agents do you believe are particularly promising?  

Slide64

Agenda

Introduction

–

The New Taxonomy of Metastatic Non-Small Cell Lung

Cancer

(

NSCLC)

 

Module 1 –

Emerging Research Data with and Potential Clinical Role

of

Immune Checkpoint Inhibitors in the Management of Locally

Advanced

NSCLC 

Module

2 –

Integration of Anti-PD-1/PD-L1 Antibodies into Current

Treatment

Algorithms for Patients with Metastatic NSCLC

Module

3

–

Ongoing Evaluation of Existing and Emerging

Immunotherapeutic

Approaches, Including Combination Strategies  

Module

4

–

Identification

and Management of Immune-Mediated and Other Toxicities Associated with Checkpoint Inhibitors; Relative Contraindications for Patients with Existing Autoimmune

Disease

Slide65

About 10%

Too many to count

3-4

2

-

3

Several

Dozens

25+

How many patients have you had in your practice in whom anti-PD-1/anti-PD-L1 therapy was stopped because of toxicity, protocol requirements, et cetera, who experienced sustained responses (

ie

, more than 6 months) after treatment was discontinued?

Slide66

Very few

0

4

2-3

<10%

0

0

How many patients have you had in your practice who

experienced “

hyperprogression

”

upon receipt of an anti-PD-1/anti-PD-L1 antibody?

Slide67

Immune-Related Adverse Events (IRAEs) Associated with Immune Checkpoint Inhibitors

Courtesy of Julie R

Brahmer

, MD.

Occasional (5-20%)

irAEs

Grade

3/4

Uncommon

Hypophysitis

Thyroiditis

Adrenal insufficiency

Colitis

Dermatitis

Pneumonitis

Hepatitis

Pancreatitis

Motor

and sensory

neuropathies

Arthritis

Less

common:

hematologic; cardiovascular; ocular; renal

Slide68

Time of Onset and Resolution of

irAEs

Each

irAE

has different kinetics of onset

Rash first, followed by colitis,

hypophysitis

and finally hepatitis

Toxicity grade

Time (weeks)

0 2 4 6 8 10 12 14

Rash, pruritus

Liver toxicity

Diarrhea, colitis

Hypophysitis

Weber JS et al.

J Clin

Oncol

2012;30(21):

2691-7

.

Slide69

PD-1 inhibitors

(n

= 3,284

)

PD-L1 inhibitors

(n

= 2,615)

p

-value

Overall AEs

Grade 3-5 AEs

Fatigue, any grade

Diarrhea, any grade

Rash, any grade

72%

22%

19%

9%

9%

65%

21%

21%

12%

7%

0.3

0.5

0.4

0.4

0.8

Overall IRAEs

Grade

3-5

IRAEs

<1% PD-L1

≥1% PD-L1

≥50% PD-L1

16%

3.1%

6.7%

4%

1.7%

11%

6%

4.2%

2%

1%

0.04

0.6

0.07

0.01

0.4

Toxicity Profile of PD-1 versus PD-L1 Inhibitors in NSCLC: Systematic Review of 23 Studies

Pillai RN et al.

Proc IASLC

2016;Abstract OA03.06.

Slide70

Anti-PD-1 Therapy in Patients with Advanced

Melanoma and Preexisting Autoimmune Disorders (AD)

119

patients

from 13 academic tertiary referral centers

received

anti-PD-1 

antibodies

In patients with preexisting AD (N = 52), the response rate was 33%

20 (38%) patients had a flare of AD requiring immunosuppression, including

7/13 with rheumatoid arthritis

3/3 with polymyalgia

rheumatica

2/2 with

Sjogren’s

syndrome

2/2 with immune

thrombocytopaenic

purpura

3/8 with psoriasis

No patients with gastrointestinal (N = 6) or neurological disorders (N = 5) flared

Only 2 (4%) patients 

permanently

discontinued treatment due to flare, but 15 (29%) developed other

irAEs

and 4 (8%)

permanently discontinued

treatment Menzies AM et al.

Ann Oncol

2017;28(2):368-76

.

Slide71

Menzies AM et al.

Ann

Oncol

2017;28(2):368-76.

Characteristics of Immune Toxicity of Anti-PD-1 Antibodies in Patients with Preexisting Autoimmune Disorders

Immune toxicity characteristic

(N = 52)

Number (%)

Flare of AD on

anti-PD-1 antibody

Yes

No

20 (38%)

32 (62%)

Median time to flare

38 days

Grade of flare

Grade 1-2

Grade 3

Grade 4

17 (33%)

3 (6%)

0 (0%)

Anti-PD-1 antibodies induced relatively frequent immune toxicities that were often mild and easily managed without the need for treatment discontinuation.

Slide72

Outside of a protocol setting, would you generally offer an anti-PD-1/anti-PD-L1 antibody to a patient with metastatic NSCLC and a PD-L1 TPS of 60% without a targetable tumor mutation in the following situations?

Crohn’s, controlled on infliximab

No

No

Yes,

2

nd

line

Yes, 2

nd

line

Yes, 2

nd

line

Yes, 2

nd

line

Yes, 1

st

line

MS w/ no active

tx

, min.

symp

.

Yes,

3

rd

line or beyond

Yes,

1

st

line

Yes, 2

nd

line

Yes, 2

nd

line

Yes, 2

nd

line

Yes, 2

nd

line

Yes, 1

st

line

Psoriasis, local

tx

only

Yes,

1

st

line

Yes, 1st line

Yes, 1st lineYes, 2nd line

Yes, 1st lineYes, 1st line

Yes, 1st lineKidney transplant

No

No

Yes, 3rd line or beyond

No

Yes, 2nd line

Yes, 3rd line or beyond

Yes, 1st lineLiver

transplant

NoNo

No

NoNo

Yes, 3rd line or beyond

Yes, 1st line