Year in Review: Therapeutic Advances in Treating …...– ASCO Chicago 2017 – ESMO Madrid 2017 – WCLC Japan 2017 Outline 3 Molecular Classification of NSCLC: 2017 Rosell and Karachaliou

Year in Review: Therapeutic Advances in Treating Advanced NSCLC

2017 Conversations in Oncology in Shanghai, China

Barbara Melosky

BI Symposium

2

• Discuss the current treatment algorithms in non-squamous NSCLC

• Provide an overview of recent advances: review updates from

– ELCC Geneva 2017

– ASCO Chicago 2017

– ESMO Madrid 2017

– WCLC Japan 2017

Outline

3

Molecular Classification of NSCLC: 2017

Rosell and Karachaliou. Lancet. 2016;387:154-155.

Mutations in Adenocarcinoma

4

Driver Mutations in Adenocarcinoma

1. Barlesi F et al. Lancet. 2016;387:1415-1426; 2. Kris MG et al. JAMA. 2014;311:1998-2006; 3. Zheng D Oncotarget. 2016;7:41691-41702.

China3

5

EGFR Mutations

6

Del19 and L858R: Most Common Mutations in

the Tyrosine Kinase Domain of EGFR in NSCLC

Sharma et al. Nat Rev Cancer. 2007;7:169.

Del19 = exon 19 deletions; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; L858R = exon 21 L858R point mutation;

NSCLC = non–small cell lung cancer.

7

IPASS: PFS1 EURTAC: PFS2

1. Mok et al. N Engl J Med. 2009;361:947; 2. Rosell et al. Lancet Oncol. 2012;13:239.

9.5 months 10.4 months

• Gefitinib: 9.5 months

• Chemotherapy: 6.3 months

– HR 0.48; 95% CI 0.36-0.64; P<0.001

• Erlotinib: 10.4 months

• Chemotherapy: 5.2 months

– HR 0.34; 95% CI 0.23, 0.49; P<0.001

8

Sub-group analyses of progression-free survival in the

intention-to-treat population2

Exon 19 Del

L858R

L858R

HR = 0.43

HR = 0.81

1. Wu et al. Lung Cancer. 2017;104:119-125; 2. Rosell et al. Lancet Oncol. 2012;13:239.

IPASS: PFS1 EURTAC: PFS2

9

IPASS1: OS EGFR Mutation + EURTAC2 Overall Survival

Overall Survival

1. Wu et al. Lung Cancer. 2017;104:119-125; 2. Rosell et al. Lancet Oncol. 2012;13:239.

10

LUX-Lung 3 and LUX-Lung 6:

Significant Improvement in PFS

1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213; 3. Data on file. Boehringer Ingelheim.

Time of Progression Free Survival (Months)

Es

tim

ate

d P

FS

Pro

ba

bilit

y

Afatinib LUX-Lung 3

Cis/Pem LUX-Lung 3

Afatinib LUX-Lung 6

Cis/Gem LUX-Lung 6

No. at risk:

LL3 Afatinib 204 169 143 115 75 49 30 10 3 0

LL3 Cis/Pem 104 62 35 17 9 6 2 2 0 0

LL6 Afatinib 216 186 152 116 82 55 33 11 4 0

LL6 Cis/Gem 62 21 7 1 0 0 0 0 0 0

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0 LUX-Lung 31 (n=308)

Afatinib vs Cis/Pem

LUX-Lung 62,3 (n=324)

Afatinib vs Cis/Gem

Median PFS 13.6 mo vs 6.9 mo 11.0 mo vs 5.6 mo

HR for PFS 0.47, P<0.0001 0.25, P<0.0001

*Exon 19 deletions or exon 21 [L858R] substitutions.

PFS = progression-free survival.

13.6 mo. in LL3

11.0 mo in LL6

Patients with common mutations*

11

LUX-Lung 6

LUX-Lung 3 and LUX-Lung 6:

OS in Del19 Subgroup

Yang et al. Lancet Oncol. 2015;16:141.

112 108 105 102 96 93 83 80 72 62 58 51 34 30 21 6 1 0

57 55 50 46 43 37 33 27 25 22 20 16 10 6 1 1 0 0

Afatinib

Cis/Pem

No. at risk:

124 122 118 115 106 99 90 80 73 69 59 39 16 8 1 0

62 58 53 49 44 35 30 28 26 21 18 11 4 3 0 0

1.0

0.8

0.6

0.4

0.2

0

Esti

mate

d O

S P

rob

ab

ilit

y

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51

Time (Months)

1.0

0.8

0.6

0.4

0.2

0

Esti

mate

d O

S P

rob

ab

ilit

y

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45

Time (Months)

Afatinib

Cis/Gem

No. at risk:

Afatinib

Cis/Pem

Afatinib

Cis/Gem

IMPRESSIVE

33.3 months 31.4 months

Prespecified Endpoint

LUX-Lung 3

Afatinib

(n=112)

Cis/Pem

(n=57)

Median,

months 33.3 21.1

HR (95% CI)

P-value

0.54 (0.36–0.79)

P=0.0015

Afatinib

(n=124)

Cis/Gem

(n=62)

Median,

months 31.4 18.4

HR (95% CI)

P-value

0.64 (0.44–0.94)

P=0.0229

12

The Impact of 1st-line TKIs on OS: Meta-Analysis of

Phase III Trials by Mutation Type – Del19

Kato et al. ISPOR 2015. PCN40.

Agent Study Hazard Ratio

(95% CI)

Afatinib

LUX-Lung 3 0.53 (0.36-0.79)

LUX-Lung 6 0.64 (0.44-0.94)

Total 0.59 (0.45-0.77)

Erlotinib

ENSURE 0.79 (0.48-1.30)

EURTAC 0.94 (0.57-1.54)

OPTIMAL 1.52 (0.91-2.52)

Total 1.04 (0.71-1.51)

Gefitinib

IPASS 0.86 (0.61-1.22)

NEJ002 0.83 (0.52-1.34)

WJTOG3405 1.19 (0.65-2.18)

Total 0.90 (0.70-1.17)

13

LUX-Lung 7

Park et al. ESMO Asia. December 2015.

ESMO ASIA 2015

*Central or local test. †Dose modification to 50, 30, 20 mg permitted in line with prescribing information.

Co-primary endpoints:

• PFS

(independent review)

• TTF

• OS

Secondary endpoints:

• ORR

• Time to response

• Duration of response

• Tumour shrinkage

• HRQoL

• Stage IIIB/IV

adenocarcinoma of

the lung

• EGFR mutation

(Del19 and/or L858R)

in the tumour tissue*

• No prior treatment for

advanced/metastatic

disease

• ECOG PS 0/1

Stratified by:

• Mutation type (Del19/L858R)

• Brain metastases

(present/absent)

• Treatment beyond progression allowed if deemed beneficial by investigator

• RECIST assessment performed at Weeks 4 and 8, and every 8 weeks thereafter until Week 64, and

every 12 weeks thereafter

1:1

Afatinib

40 mg QD†

Gefitinib

250 mg QD

14

Afatinib Gefitinib

Median, mo 11.0 10.9

HR (95% CI)

P-value

0.74 (0.57-0.95)

0.0178

Afatinib vs Gefitinib: Updated Outcomes – PFS

Paz-Ares L et al. Ann Oncol. 2017, epub ahead of print.

Es

tim

ate

d P

FS

pro

bab

ilit

y

0 3 6 9 12 18 15 21 24 27 30 33 36 39 42 45 48 51

1.0

0.8

0.6

0.4

0.2

0

Time (months)

160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0

159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0

No. at risk: Afatinib

Gefitinib

16%

7%

Afatinib

Gefitinib HR .74

15 *P=0.0067; †P=0.0029.

TTF = time from randomization to discontinuation for any reason.

Afatinib vs Gefitinib: Updated Outcomes – TTF

Park K et al. Lancet Oncol. 2016;17(5):577-89.

No. at risk:

Afatinib 160 148 133 113 91 68 56 48 40 25 18 9 5 0 0

Gefitinib 159 144 120 103 74 59 43 30 21 11 6 6 2 2 0

Afatinib Gefitinib


HR (95% CI)

P-value

0.73 (0.58-0.92)

0.0073

Time to treatment failure (months)

Es

tim

ate

d p

rob

ab

ilit

y o

f b

ein

g

free

of

trea

tmen

t fa

ilu

re

1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42

25%*

13%

Afatinib

Gefitinib

13.7 vs 11.5 months

16

0%

20%

40%

60%

80%

ITT Del19 L858R

OR

R

Afatinib vs Gefitinib: Objective Response and

Disease Control Rate by Independent Review


P=0.002

73%

56%

69%

42%

75%

66%

Afatinib Gefitinib

Median DoR , months

(95% CI)

10.1

(8.2, 11.1)

8.3

(7.3 – 10.2)

Disease control rate (N) 91.3% (146) 87.4% (139)

P=0.150 P=0.003

Afatinib

Gefitinib

69% vs 42% 73% vs 56%

17

Updated Overall Survival From LUX-Lung 7

Corral J et al. ELCC 2017; #93PD.

No. at risk:

Afatinib 160 153 139 111 94 74 59 41 23 2 0

Gefitinib 159 148 133 105 80 62 53 39 22 2 0

Afatinib Gefitinib


HR (95% CI)

P-value

0.85 (0.66, 1.09)

0.1950

0.8

1.0

0.6

0.4

0.2

0

0 6 12 18 24 54 48 42 36 30 60

61%

51%

28%

20%

Time to death (months)

Es

tim

ate

d o

ve

rall

su

rviv

al

pro

bab

ilit

y

Afatinib

Gefitinib

ELCC 2017

27.9 vs 24.5 months

18

OS By EGFR Mutation Subtype


Del19 L858R

Afatinib

Gefitinib

0 6 12 18 24 30 36 42 48

93 88 82 68 61 50 40 27 17

93 86 79 66 52 39 33 24 15

0

Es

tim

ate

d O

S p

rob

ab

ilit

y

Time (months)

Afatinib

Gefitinib

No. at risk:

1.0

0.8

0.6

0.4

0.2

54

1

1

0 6 12 18 24 30 36 42 48

67 65 57 43 33 24 19 14 6

66 62 54 39 28 23 20 15 7

0

Time (months)

1.0

0.8

0.6

0.4

0.2

54

1

1

Afatinib Gefitinib


HR (95% CI)

P-value

0.82 (0.58-1.15)

0.242

Afatinib Gefitinib


HR (95% CI)

P-value

0.89 (0.61-1.31)

0.566

ELCC 2017

19

LUX-Lung 7: Side Effects

Park et al. ESMO Asia, 2015. Abstract LBA2_PR.

Four cases of ILD

three of them ≥ grade 3 No case of ILD

20

0

5

10

15

20

25

30

< ≥ < ≥ < ≥ < ≥

60 years 65 years 70 years 75 years

Me

dia

n O

S

OS Outcome With Afatinib Depending On Age Group


Total randomized 62 98 88 72 123 37 141 19

Patients died 41 68 65 53 82 27 95 14

21

Long-term Responders (LTRs), Defined by

Receiving Afatinib ≥3 Years1

1.Schuler M et al. 2017, ECCO; #1991; 2. Wu Y-L et al. ESMO 2014. Poster 1251P; 3. Paz-Ares L et al. ESMO 2016. Abstract 2988.

LTR = long-term responder.

• Post-hoc analysis identified 24 (LL3), 23 (LL6) and 19 (LL7) patients (LTRs) who received ≥3 years of afatinib

Es

tim

ate

d P

FS

pro

bab

ilit

y

Time (months)

LL3 PFS

LL6 PFS

LL7 TTF

PFS in LL3/LL62 and TTF in LL73

1.0

0.8

0.6

0.4

0.2

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

0.0

22

Tumour Volume Change in LL3/6/7

Schuler M et al. 2017, ECCO; #1991.

CR† (n=5; 8%)

PR† (n=47; 71%)

SD† (n=9; 14%)

NN† (n=5; 8%)

Ma

xim

um

tu

mo

ur

vo

lum

e c

ha

ng

e (

%)

-100

-80

-60

-40

-20

0

20

*Patients were ordered by maximum percentage decrease in tumour volume from baseline; †Tumour volume change not available for seven patients (two patients with NN

in LL3, one patient with a CR and three patients with NN in LL6, and one patient with SD in LL7). CR = complete response; PR = partial response; SD = stable disease;

NN = non-CR, non-progressive disease.

Long term responder (n=66)*†

23

What about adding Bevacizumab?

Kato T et al. ASCO 2014. Abstract 8005.

24

Afatinib plus Bevacizumab (ABC Trial)

Hata A et al. ASCO 2017, abstract 9034.

ASCO 2017

ORR 18.2 % SD 72%

25

• Advanced NSCLC with

EGFR-activating

mutation(s)

• No prior systematic

treatment of advanced

NSCLC

• No CNS metastasis

• No prior EGFR TKI or

other TKI

• ECOG PS 0, 1

Dacomitinib

45 mg PO QD

(N=227)

Gefitinib

250 mg PO QD

(N=225)

Primary endpoint

PFS by blinded

independent review R 1:1

(N=452)

Secondary endpoints

PFS (investigator

assessed), ORR, DOR,

TTF, OS, safety, PROs Stratify

Race (Asian vs non)

EGFR M+(exon 19 vs 21)

ARCHER 1050: Dacomitinib

Mok TS et al. ASCO 2017, abstract LBA9007.

ASCO 2017

26

ORR


ORR 74.9% ORR 71.6%

27

Daco (N=227) Gef (N=225)

Number of events, n (%) 136 (59.9%) 179 (79.6%)

Median PFS (95% Cl) 14.7 (11.1,

16.6)

9.2 (9.1,

11.0)

HR (95% Cl) 0.59 (0.47–0.74)

P<0.0001

Dacomitinib

225

227

0 42 36 30 24 18 12 6

0.0

0.2

0.4

0.6

0.8

1.0

155

154

69

106

34

73

7

20

1

6

0

0

0

0

Pro

ba

bilit

y o

f P

FS

Months

++Censored.

PFS rate

30.6% vs

9.6%

Gefitinib

No. at risk

Progression-Free Survival


14.7 mo vs 9.2 mo

Dacomitinib

Gefitinib

28

Dose Modification

Presented by Tony Mok at 2017 ASCO Annual Meeting.

• Dacomitinib

– First dose reduction: 30 mg/day

– Second reduction: 15 mg/day

• Gefitinib

– 250 mg every two days

30% 40%

29

Molecular Mechanisms of Acquired Resistance

to First-/Second-Generation EGFR TKIs

Yu HA et al. Clin Cancer Res. 2013;19:2240-47.

30

.

AURA 3: PFS1

1. Mok TS et al. N Engl J Med. 2017;376:629-40; 2. Papadimitrakopoulou VA et al. IASLC 2016. Abstract 4452.

CNS PFS in AURA 32

Osimertinib

(n=279)

Platinum-

pemetrexed

(n=140)

Median progressive-free

survival, mo 10.1 (8.3-12.3) 4.4 (4.2-5.6)

HR for disease progression

or death (95% CI)

P-value

0.82 (0.58-1.15)

0.242

Pro

ba

bilit

y o

f

pro

gre

ss

ion

-fre

e s

urv

iva

l

Month

No. at risk 0

0

100

80

60

40

20

0 3 6 9 12 15

0

1.0

0.8

0.6

0.4

0.2

18 Intracranial Response Rate: 70%

CNS PFS 11.7 months vs 5.6 months

Osimertinib

Platinum-pemetrexed

Osimertinib 80 mg (n=75)

Chemotherapy (n=41)

Median follow-up: Chemotherapy, 4.1 months

Osimertinib, 5.5 months

10.1 months vs 4.4 months

31

FLAURA

Soria J-C, et al. N Engl J Med. Nov 18, 2017 [Epub]. DOI: 10.1056/NEJMoa1713137.

ESMO 2017

Stratification

Exon 19 del/ L858R

Asian/non-Asian

Crossover was allowed for

patients in the SoC arm,

Patients with locally advanced or

metastatic NSCLC

• PS 0 / 1

• Exon 19 deletion / L858R

• No prior systemic anti-cancer /

EGFR-TKI therapy

• Stable CNS mets allowed

Endpoints

• Primary endpoint: PFS

Randomised 1:1

Gefitinib, erlotinib not stratified

No afatinib or dacomitinib

No uncommon mutations

Brain mets not stratified

If no brain mets: followup in CNS not specified

N = 556

EGFR-TKI;

Gefitinib or Erlotinib

(n=277)

Osimertinib (n=279)

32

FLAURA Primary Endpoint: PFS

Soria J-C, et al. N Engl J Med. Nov 18, 2017 [Epub]. DOI: 10.1056/NEJMoa1713137.

1.0

0.8

0.6

0.4

0.2

0.0 0 3 6 9 12 15 18 21 24 27

Osimertinib

Erlotinib/gefitinib

Pro

ba

bilit

y o

f

pro

gre

ss

ion

-fre

e s

urv

iva

l

Time from randomisation (months)

Osimertinib Erlotinib/

gefitinib

Median PFS, months

(95% CI)

18.9

(15.2, 21.4)

10.2

(9.6, 11.1)

HR (95% CI)

P-value

0.46 (0.37-0.57)

<0.001 18.9 vs 10.2 months

ESMO 2017

Osimertinib Erlotinib/

gefitinib

Median PFS, months

(95% CI)

17.7

(15.1, 21.4)

9.7

(8.5, 11.0)

HR (95% CI)

P-value

0.45 (0.36-0.57)

<0.001

PFS Assessed by Investigator

PFS Assessed by Independent Review

33

Does Sequence Matter?

OS in Patients Treated With 3rd-gen TKIs in LUX-Lung 7


Afatinib

N=30

Gefitinib

N=26

Median, mo NE 48.3

HR (95% CI)

p-value

0.49 (0.20–1.19)

0.107

20% / 17% who discontinued afatinib/gefitinib received 3rd-generation TKIs

(osimertinib, olmutinib, rociletinib) E

sti

ma

ted

ove

rall

su

rviv

al

pro

ba

bil

ity

No. at risk:

Afatinib 30 30 30 30 30 30 29 29 29 29 28 28 26 21 17 14 8 1 0

Gefitinib 26 26 25 25 25 24 23 23 23 22 22 22 20 17 17 10 4 1 0

Time to death (months)

0.8

1.0

0.6

0.4

0.2

0

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57

ELCC 2017

4 years

4 years+

34

EGFR: Advanced NSCLC

Melosky B et al. Clinical Lung Cancer. In Press.

*Dacomitinib will soon be included in the algorithm.

EGFR mutation

testing L858R 19Del

Uncommon

mutations

Plasma cfDNA

testing

Tumour rebiopsy

(T790M only)

4th Line Immunotherapy

1st Line EGFR TKI: afatinib, dacomitinib,*

gefitinib, erlotinib EGFR TKI: afatinib

preferred

EGFR TKI: afatinib

preferred

3rd Line Immunotherapy Chemotherapy Doublet

2nd Line Chemotherapy Doublet Osimertinib

T790M-

T790M- T790M+

T790M+

Brain Mets

Osimertinib

35

ALK Mutations

36

PROFILE 1014:

First-line Crizotinib vs Pem/Cis PFS

Solomon BJ et al. N Engl J Med. 2014;371:2167-2177.

Crizotinib

(N=172)

Chemotherapy

(N=172)

Events, n (%) 100 (58) 137 (80)

Median, months 10.9 7.0

HR (95% CI) 0.45 (0.35−0.60)

<0.0001

0

Time (Months) 172 120 65 38 19 7 1 0

171 105 36 12 2 1 0 0

No. at risk

Crizotinib

Chemotherapy

100

80

60

40

20

0

5 10 15 20 25 30 35

PF

S P

rob

ab

ilit

y (

%)

Crizotinib

Chemotherapy

37

ALEX

• Advanced or metastatic

ALK+ NSCLC

• Treatment-naive

• ECOG PS 0−2

• Asymptomatic brain

metastases allowed

R

A

N

D

O

M

I

Z

E

ENDPOINTS

• Primary

‒ PFS by investigator review

• Secondary

‒ PFS by IRC

‒ Time to CNS progression

‒ ORR, DOR

‒ OS

‒ Safety and tolerability

‒ Patient-reported outcomes

Stratify:

• ECOG PS (0/1 vs 2)

• Race (Asian vs non-Asian)

• Brain metastases (present vs

absent)

Alectinib vs Crizotinib: Global ALEX Trial

Shaw et al. ASCO 2017. Abstract LBA9008.

ASCO 2017

38

PFS 25.7 months


ASCO 2017

Alectinib vs Crizotinib

NR vs 11.1 months HR .47

PFS Independent Review PFS Investigator

25.7 vs 10.4 months HR .50

39

CNS Prevention


ASCO 2017

Crizotinib

(N=151)

Alectinib

(N=152)

CNS metastases

by IRC (%)

Present 58 (38) 64 (42)

Absent 93 (62) 88 (58)

CNS metastases

treatment (%)

n 58 64

None 36 (62) 37 (58)

Whole brain

RT

16 (28) 17 (27)

Brain surgery 1 (2) 1 (2)

38% vs 42%

40

ASCEND 4: Phase 3 Randomized Global

Open-label Study

Castro Jr G. WCLC 2016. Oral Presentation PL03.07

Inclusion criteria

• Stage IIIB/IV ALK+ NSCLC

• Treatment-naive

• WHO PS 0-2

• Neurologically stable brain

metastases (symptomatic or

not)

Chemotherapy

Four cycles

Pemetrexed 500 mg/m2 + cisplatin 75 mg/m2

or

Pemetrexed 500 mg/m2 + carboplatin AUC 5–6

R

1:1

Ceritinib 750 mg/day†

• Daily oral dosing in fasted state

41

Immature but favors ceritinib

ASCEND-4 Outcomes


42


ASCEND-4 Outcomes

72.7 CNS Response

43

Efficacy and Updated Safety of Ceritinib

(450 mg or 600 mg) With Low-Fat Meal vs

750 mg Fasted in ALK+ Metastatic NSCLC Authors: Cho BC,1 Obermannova R,2 Bearz A,3 Kim DW,4 Orlov S,5 Borra G,6 Kim SW,7 Postmus P,8

Laurie S,9 Park K,10 Geater SL,11 Bettini A,12 Osborne K,13 Passos VQ,14 Chen Z,14 Dziadziuszko R15

WCLC 2017

Cho BC. WCLC 2017. Abstract 9366.

44

ASCEND-8: Phase 1, Randomized, Global, Open-label,

Parallel Design Study


Inclusion criteria

• Stage IIIB/IV ALK+ NSCLC

• Treatment-naive* (efficacy analysis)

or previously treated with ≥1 systemic

therapy (PK analysis included both)

• ALK+ status was assessed by

Ventana IHC (treatment-naive) or

FDA approved FISH (previously

treated)

• WHO PS 0-2

• Neurologically stable brain

metastases (symptomatic or not)

R

1:1:1

Ceritinib 450 mg/day with low-fat meal

Ceritinib 600 mg/day with low-fat meal

Ceritinib 750 mg/day under fasted conditions

WCLC 2017

45

ASCEND-8 Efficacy


Ceritinib 450 mg fed

(N = 41)


(N = 40)

Ceritinib 750 mg fasted

(N = 40)

Overall response rate (CR+PR), n (%)

(95% CI)

32 (78.0)

(62.4-89.4)

30 (75.0)

(58.8-87.3)

28 (70.0)

(53.5-83.4)

Disease control rate (CR+PR+SD+non-

CR/non-PD), n (%) (95% CI)

38 (92.7)

(80.1-98.5)

37 (92.5)

(79.6-98.4)

36 (90.0)

(76.3-97.2)

Median time to response, weeks

(95% CI)

6.3

(6.0-6.9)

6.3

(6.1-12.1)

6.3

(6.0-12.3)

ORR and DCR are clinically relevant and consistent among the 3 treatment arms.

WCLC 2017

46

Overview of GI Toxicities


No. of patients (%)


(N = 89)


(N = 86)

Ceritinib 750 mg fasted

(N = 90)

Preferred term Grade 1 Grade 2 Grade 3/4 Grade 1 Grade 2 Grade 3/4 Grade 1 Grade 2 Grade 3/4

Diarrhea, n (%) 41 (46.1) 8 (9.0) 1 (1.1) 38 (44.2) 13 (15.1) 2 (2.3) 43 (47.8) 18 (20.0) 7 (7.8)

Nausea, n (%) 30 (33.7) 10 (11.2) 0 30 (34.9) 13 (15.1) 5 (5.8) 28 (31.1) 12 (13.3) 5 (5.6)

Vomiting, n (%) 27 (30.3) 4 (4.5) 0 35 (40.7) 10 (11.6) 1 (1.2) 37 (41.1) 9 (10.0) 4 (4.4)

WCLC 2017

47

ALTA: Randomized Dose Evaluation of

Brigatinib

Kim DW. ASCO 2016. Abstract 9007.

48

ALTA: Tumor Response and PFS

Kim DW. ASCO 2016. Abstract 9007.

49

Lorlatinib – Covers ALK Resistance Mutations

Presented by Ignatius Ou at ASCO 2017.

Breakthrough Therapy designation from the

FDA for use in patients with ALK-positive

metastatic NSCLC previously treated with at

least one ALK TKI

ASCO 2017

50

Lorlatinib Can Cross the Blood–Brain Barrier

Presented by Sai-Hong Ignatiusou at 2017 ASCO Annual Meeting.

ASCO 2017

51

ALK+ Patients Previously Treated With ≥1 ALK TKI

Presented by Sai-Hong Ignatiusou at 2017 ASCO Annual Meeting.

ASCO 2017

3 previous treatments

52

Treatment Algorithm for Advanced NSCLC

Non-Squamous: ALK Rearrangement

Lorlatinib

53

BRAF Mutations

54

Pre-treated patients1 Treatment-naive patients2

Never Smokers 28%

BRAF Mutations

1. Planchard 2016. Lancet Oncol. 2016;17:984-93; 2. Planchard 2017. Lancet Oncol. 2017; Published Online September 11, 2017; 3. Barlesi F et al. Lancet. 2016;387:1415-

1426.

55

Synergism to block both BRAF and MEK

Abrogation of Feedback Loop of Raf by Erk

Friday et al. Cancer Res. 2008; Zhao Y & Adjei AA. Nature.

56

Dabrafenib and Trametinib Second Line:

BRAF V600E ASCO 2017

Planchard 2016. Lancet Oncol. 2016;17:984-93.

ORR 67%

PFS 10.2 months

OS 18.2 months

N=57

57

ORR 64%

N=36

PFS 10.9 months

OS 24.6 months

ESMO 2017

Dabrafenib and Trametinib First Line: BRAF V600E

1. Planchard 2017. Lancet Oncol. 2017; Published Online September 11, 2017.

58

MET Mutations

59

Emibetuzumab (Anti-MET mAB)

Scagliotti G et al. ASCO 2017, abstract 9019.

PFS in Patients with

the Highest MET

Expression (≥90%

cells MET 3+)

60

12 13 15

12 13 14 15

MET X14 Skipped

Exon 14

(regulatory domain)

Mechanism of MET Exon 14 Skipping

61

Drug Phase Clinicaltrials.gov

Crizotinib Ib NCT00585195

Mersetinib I NCT02920996

Savolitinib I NCT02897479

Cabozantinib II NCT01639508

Capmantinib II NCT02750215

Tepotinib II NCT02864992

c-Met Inhibitors in Development

Clinicaltrials.gov

62

ASCO 2017

Impact of MET Inhibitors on Survival Among Patients With

MET Exon 14 Mutant Non-Small Cell Lung Cancer

Awad M et al. ASCO 2017 Abstract 8511.

63

ASCO 2017

Outcomes in Patients with MET Exon 14 Mutations

Awad M et al. ASCO 2017 Abstract 8511.

64

ASCO 2017

PD-L1 Expression and Response to Immunotherapy in Patients With

MET Exon 14 Altered Non-Small Cell Lung Cancer

Sebari J et al. ASCO 2017 Abstract 8512.

65

ASCO 2017

Sebari J et al. ASCO 2017 Abstract 8512.

66

PD-1/L1 mAB

67

Practice Changing

Pacific Trial

https://en.wikipedia.org/wiki/File:Pacific_Ocean_-_en.png

68

Targeting PD-1 Pathway

Wolchock J et al. J Clin Oncol. 2013;31(Issue 15_suppl); abstr 9012. ^

T cell Tumour cell PD-L1 PD-1

Tumour microenvironment

- - -

PD-L1

Durvalumab

69

15% alive 5 years

70

PACIFIC: Stage lll

Paz-Ares et al. ESMO 2017, abstract LBA_PR.

• Patients with stage III, locally

advanced, unresectable

NSCLC who have not

progressed following

definitive platinum-based

cCRT (≥2 cycles)

• PS score 0, 1

• PD-L1 not necessary

Durvalumab

10 mg/kg q2w for

up to 12 months

N=476

Placebo

10 mg/kg q2w for

up to 12 months

N=237

2:1,

stratified by age, sex,

and smoking history R

1–42 days

post-cCRT Planned sample size: N=702 patients

Co-primary endpoints: PFS and OS

ESMO 2017

71

PACIFIC: Antitumor Activity


Durvalumab

(N=443)*

Placebo

(N=213)*

Treatment effect

(HR [95% CI])¶

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)

Non-evaluable 10 (2.3) 1 (0.5)

Duration of response, months

Median (95% Cl) NR 13.8 (6.0–NR) 0.43 (0.22–0.84) 28.4 16.0 0

5

10

15

20

25

30

35

Durvalumab(N=443)*

Placebo(N=213)*

% P

ati

en

ts (

95

% C

I)

Objective Response

P<0.001

(24.28–32.89)

(11.31–21.59)

Treatment effect (RR [95% CI])¶:

1.78 (1.27–2.51)

28.4%

16%

ESMO 2017

72

PACIFIC: PFS


PF

S p

rob

ab

ilit

y

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 9 12 15 18 21 24 27

Time from randomization (months)

Placebo

Durvalumab

476 377 301 264 159 86 44 21 4

237 163 106 87 52 28 15 4 3

1

0

No. at risk

Durvalumab

Placebo

HR 0.52 P<0.0001

16.8 vs 5.6 months

11 month difference!

50%

25%

ESMO 2017

Durvalumab

(N=476)

Placebo

(N=237)

Median PFS (95% CI), months 16.8 (13.0–18.1) 5.6 (4.6–7.8)

73

PACIFIC: Time to Distant Metastasis or Death


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 15 18 21 24 27 30

Placebo

Durvalumab

476 407 336 288 173 91 46 22 4 1 0

237 184 129 106 63 32 16 5 4 0 0

HR 0.52 P<0.0001

23.2 vs 14.6

9 month difference

ESMO 2017

No. at risk

Durvalumab

Placebo

Pro

ba

bilit

y o

f d

ea

th o

r

dis

tan

t m

eta

sta

sis

Time from randomization (months)

Durvalumab Placebo

Median time (95% CI), months 23.2 (23.2–NR) 14.6 (10.6–18.6)

74

Pneumonitis or Radiation Pneumonitis


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)

ESMO 2017

75 Surgery vs Durvalumab

25%

ESMO 2017

Practice Changing

Albain, Kathy S et al. The Lancet. 2009,9687; Paz-Ares et al. ESMO 2017, abstract LBA_PR.

50%

76

OAK: Treatment Beyond Progression

Wolchock J et al. J Clin Oncol. 2013;31(Issue 15_suppl); abstr 9012. ^


- - -

PD-L1

ASCO 2017

Atezolizumab

77

HR, 0.73

a

(95% CI, 0.62, 0.87)

P=0.0003

Atezolizumab

Docetaxel

Median 9.6 mo

Median 13.8 mo (95% CI, 8.6, 11.2)

(95% CI, 11.8, 15.7)

Months

168/332 = 50% Treated Beyond Progression

ESMO 2016

OAK: Overall Survival, ITT (N=850)

425 382 363 342 326 305 279 260 248 234 54

No. at risk

Atezolizumab

Placebo

407 223 218 205 198 188 175 163 157 141 115 74 41 28 15 4 1

425 385 336 311 286 263 236 219 195 179 37 390 168 151 140 132 123 116 104 98 90 70 51 28 16 6 3

78

ASCO 2017

Presented by David Gandara at 2017 ASCO Annual Meeting.

79

Non-randomized Comparisons Introduce Biases for OS Analysis

Presented by Solange Peters at 2017 ASCO Annual Meeting.

.

Selection Bias and not randomized

Discussant Dr. Solange Peters

ASCO 2017

80

KEYNOTE-024: Updated Analysis

Pembrolizumab Versus Platinum-based Chemotherapy

for Advanced NSCLC With PD-L1 TPS ≥50%

Julie R. Brahmer,1 Delvys Rodríguez-Abreu,2 Andrew G. Robinson,3 Rina Hui,4

Tibor Csőszi,5 Andrea Fülöp,6 Maya Gottfried,7 Nir Peled,8 Ali Tafreshi,9 Sinead Cuffe,10

Mary O’Brien,11 Suman Rao,12 Katsuyuki Hotta,13 Antonio Riccio,14 Jing Yang,14

M. Catherine Pietanza,14 Martin Reck15

WCLC 2017

81

Targeting PD-1 Pathway

Wolchock J et al. J Clin Oncol. 2013;31(Issue 15_suppl); abstr 9012.

Tumour Microenvironment


- - -

PD-L1

Pembrolizumab

82

PD-L1 Expression and Pembrolizumab

25% 30% 45%

83

Both Non Squamous and Squamous

ESMO 2016

KEYNOTE-024 Study Design (NCT02142738)

84

45%

28%

KEYNOTE-024: Tumor Response and PFS

Reck M et al. ESMO 2016. Abstract 437O

ESMO 2016

85

HR 0.60

50% Crossover

KEYNOTE-024: Overall Survival

Reck M et al. ESMO 2016. Abstract 437O

ESMO 2016

86

Overall Survival: Updated Analysis

Brahmer JR et al. WCLC 2017. Abstract OA 17.06

0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

T im e , m o n th s

OS

, %

P e m b r o 1 5 4 1 3 6 1 2 1 1 1 2 1 0 6 9 6 8 9 8 3 5 2 2 2 5 0

C h e m o 1 5 1 1 2 3 1 0 7 8 8 8 0 7 0 6 1 5 5 3 1 1 6 5 0

N o . a t r is k

Median (95% CI)

30.0 mo (18.3 mo–NR)

14.2 mo (9.8 mo–19.0 mo)

70.3%

54.8% 51.5%

34.5%

Events, n HR (95% CI)

Pembrolizumaba 73 0.63

(0.47–0.86)

P=0.002b Chemotherapy 96

30 months vs 14.2 months

HR 0.63

62% Crossover

WCLC 2017

87

First Line Second Line

20% 45%

WCLC 2017

KEYNOTE-024: Tumor Responses

Brahmer JR et al. WCLC 2017. Abstract OA 17.06

88

KEYNOTE-021 COHORT G: Updated Analysis

Pemetrexed/Carboplatin +/- Pembrolizumab for

Advanced NSCLC Non Squamous

WCLC 2017

89

60 pts

60 pts

ESMO 2016

Phase ll

90

Approved by the FDA!

April 2017 First line

Pem/Carbo + Pembrolizumab

ESMO 20171 WCLC 20172

56.7%

31.7%

WCLC 2017

KEYNOTE-021: Tumor Responses

1. Borghaei H et al. ESMO 2017. Abstract LBA49; 2. Borghaei H et al. WCLC 2017. Abstract OA 17.01

91

HR .54

HR .54

WCLC 2017

ESMO 20171 WCLC 20171 KEYNOTE-021: PFS

1. Borghaei H et al. ESMO 2017. Abstract LBA49; 2. Borghaei H et al. WCLC 2017. Abstract OA 17.01

92

HR .69

HR .59

HR .90

WCLC 2017

KEYNOTE-021: OS

aP value is descriptive (one sided P < 0.025). B24 additional deaths since primary analysis (pembro + PC, n=7; PC alone, n=17)

1. Langer CJ et al. Lancet Oncol. 2016;17(11):1497-1508. 2. Papadimitrakopoulou VA et al. 2017. J Clin Oncol. 35(suppl): abstract 9094.

93

WCLC 2017

94

WCLC 2017

PFS 1.7 months OS 3.4 months

Efficacy of Nivolumab: PS ≥2 Patients

95

Advanced NSCLC: Wild Type

1. Ettinger DS, et al. J Natl Compr Canc Netw 2017;15:504-535; 2. NCCN Guidelines Version 1.2018 Non-Small Cell Lung Cancer. Version 1.2018, 11/17/17.

PD-L1 Testing

1st Line

Maintenance

2nd Line

3rd Line

PD-L1

≥ 50%

PD-L1

< 50%

Pembrolizumab

Q3 w

Pembrolizumab

Q3 w

Nivolumab

Q2 w

Atezolizumab

Q3 w

Platinum

doublet

Pemetrexed/

Platinum doublet

Pemetrexed

(Non-squamous)

Based on results

of initial testing PD-L1

≥ 1%

PD-L1

> 0%

Afatinib (squamous), Erlotinib (non squamous), Docetaxel +/- Ramicirumab

96

• EGFR:

– Dacomitinib, Osimertinib, T790 testing

• ALK:

– Alectinib first line, Ceritinib, Brigatinib, Lorlatinib

• BRAF:

– Dabrafenib and Trametinib

• cMET Exon 14 Skip:

– Crizotinib

• Immunotherapy:

– PACIFIC, KN 024, KN 21G

– PD-L1, TMB and Microenvironment

Year in Review 2017

SC-CRP-00851

For more information about other BI events and collaborations, please visit www.inOncology.com

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Documents

Year in Review: Therapeutic Advances in Treating …...– ASCO Chicago 2017 – ESMO Madrid 2017 – WCLC Japan 2017 Outline 3 Molecular Classification of NSCLC: 2017 Rosell and Karachaliou