Efficacy of EGFR TKIs in Patients With NSCLC With Uncommon

EGFR Mutations 2017 WCLC- PACIFICO Yokohama Convention Center

Terufumi Kato, MD

Kanagawa Cancer Center,Yokohama, Japan

BI Symposium

2

Faculty Disclosure

• Honoraria: AstraZeneca; Boehringer Ingelheim; Chugai Pharma; Kyowa

Hakko Kirin; Lilly; Ono Pharmaceutical; Pfizer; Roche; Taiho Pharmaceutical

• Consulting or Advisory Role: AstraZeneca; Nippon Boehringer Ingelheim;

Ono Pharmaceutical

• Research Funding: Abbvie; Astellas Pharma; AstraZeneca; Bristol-Myers

Squibb; Chugai Pharma; Daiichi Sankyo; Kyowa Hakko Kirin; Lilly; Merck

Sharp & Dohme; Nippon Boehringer Ingelheim; PAREXEL; Pfizer; Quintiles;

Shionogi Pharma; Taiho Pharmaceutical; Takeda; Yakult Honsha

3

EGFR Mutations in NSCLC

Mitsudomi et al., Cancer Science, 2007

Mitsudomi et al., Cancer Science, 2007

EGF binding EGF binding TM Tyrosine kinase Autophosphorylation

Exon 2 5 7 13 16 17 18-21 22-24 28

68

8

72

8

72

9

76

1 7

62

82

3

82

4

87

5

Exon 18 (nucleotide binding loop) Exon 19 Exon 20

Exon 21 (activation loop)

Ex19Del L858R

G719X L861Q Ex20 Ins

4

Common or Uncommon/Non-classical (N=1,632)

Shen et al. Lung Cancer. 2017;110:56.

Single, uncommon/non-classical mutations

or insertion: 8%

Exon 21 single 1%

Exon 20 single 1%

insertions 3%

Exon 19 single 0.4%

Exon 18 single 3%

Uncommon/non-classical mutation with Del19/L858R: 6%

Complex uncommon/non-classical, without Del19 and L858R: 2%

Del19

(n=354)

42% Ex21

L858R

(n=356)

42%

5

• Irreversible second- and third-generation TKIs overcome resistance induced by

uncommon secondary mutations

In Vitro Activity of First-, Second-, and Third-Generation TKIs

Against Uncommon EGFR Mutations

Chiba M et al. BMC Cancer. 2017;17:281.

Gefitinib

Erlotinib

Afatinib

Dacomitinib

Osimertinib IC50 (

nM

)

10000

0

5

10

15

20

25

30

35

40

45

50

L858R L858R/L747S L858R/D761Y L858R/T854A L858R/T790M

6

In Vitro Activity of First-, Second-, and Third-Generation

TKIs Against Uncommon EGFR Mutations • In separate assays, first- and third-generation TKIs demonstrated reduced activity against cell lines harbouring

uncommon mutations, whereas the response to afatinib was similar across cell lines

1. Saxon et al. J Thorac Oncol. 2017;12:884; 2. Banno et al. Cancer Sci. 2016;107:1134.

TKI = tyrosine kinase inhibitor; IC50 = 50% inhibitory concentration.

1 1 1

20

2.5 3.6

32

3.5

20

0

10

20

30

40

IC50 r

ati

o r

ela

tive

to

L8

58

R

L861Q and S768I2

L858R L861Q S768I L858R L861Q S768I L858R L861Q S768I

Erlotinib Afatinib Osimertinib

125

100

75

50

25

0 0 0.001 10 1 0.1 0.01

µM

Cell v

iab

ilit

y (

%)

Afatinib

Gefitinib

Osimertinib

125

100

75

50

25

0 0 0.001 10 1 0.1 0.01

µM

Cell v

iab

ilit

y (

%)

L858M/L861Q1

L858R

Afatinib

Gefitinib

Osimertinib

L858M/L861Q

7

EGFR Exon 18 Mutations in Lung Cancer:

Molecular Predictors of Augmented Sensitivity to Afatinib as

Compared with First- or Third-Generation TKIs

• Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively.

Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%

• Patients with lung cancers harbouring G719X exhibited higher response rate to afatinib (80%) than to 1G TKIs

(35%–56%)

Kobayashi Y et al. CCR 2015.

IC90s o

f E

GF

R-T

KIs

in

Tra

nsfe

cte

d

Ba/F

3 C

ells (

nm

ol/

L)

104

103

102

101

100

10–1 Gefitinib Erlotinib Afatinib Dacomitinib AZD9291

882

187 213

7

9,350

884

215 167

6

>10,000

448*

2,717

69

1.7

0.7 0.9

0.3

>100

29 16

166

6

1.6

>1,000

3,078

400*

1.1

53

62 93

Del 18

E709K

G719A

Del 19

WT

Ctrough

Del 19 40% (n=563)

Ins 20 4% (n=63)

Others 5% (n=71)

Exon 18 3% (n=45)

L858R 47% (n=660)

G719A (n=22)

G719S (n=9)

G719C (n=8)

G719R (n=1)

G719V (n=1)

E709H + G719C (n=1)

Del E709_T710 ins D (n=3)

*

*

*

8

Case Report: Afatinib in a TKI-Pretreated Patient With

EGFR L858M/L861Q (in cis) • 62-year-old Caucasian female with extensive involvement of a poorly differentiated adenocarcinoma

• Worsening disease with 4 months of erlotinib and 4 months of chemotherapy

• Radiographic response 2 months after initiation of afatinib

• Remained on afatinib, with Grade 1 diarrhoea as her only side effect, for 10 months and continues treatment

Saxon et al. J Thorac Oncol. 2017;12:884.

9

Clinical Data in TKI-Pretreated Patients: Radiographic

Responses After Suboptimal Response to Other EGFR-TKIs

Peled et al. J Thorac Oncol. 2017;12:e81.

Patient With ex19del, T790M, and G724S

C797S

T790M

G724S

ex19del

TP53

Mar-15 Sep-15 Oct-15 Dec-15 Mar-16

2.9

0.1

0.3

6.5

19.5

24.2

33

23.6

33.7

7.8

23.7

15.1

39.6

2.6

45.7

60.1

Cell-free DNA tumor response. Cell-free DNA analysis of total somatic alteration burden detected over five time points and

the EGFR variant-specific results over time reflect responses to changes in matched therapy. TP53, tumor protein p53

Apr-14

Gefitinib

Jun-15

Osimertinib

Sep-15

Osimertinib + Afatinib

Dec-15

Pemetrexed

10

Clinical Data in TKI-Pretreated Patients: Best Response in Patients

With LMD Harbouring Uncommon Mutations

• 3/11 patients with leptomeningeal carcinoma treated with afatinib harboured an uncommon Exon 18

mutation (L719X)

• Median CSF concentration in all 11 patients was 2.88 nM (afatinib’s IC50 for EGFR being 0.5 nM).

PFS and OS in patients harbouring a G719X mutation were 5.6 months (2.0-10.0) and 7.0 months

(5.6 ongoing to 13.0)

Tamiya et al. Anticancer Res. 2017;37:4177.

aTreatment continued after data cutoff; bCensored at data cutoff (patient still alive).

LMD = leptomeningeal disease; CSF = cerebrospinal fluid; PFS = progression-free survival; OS = overall survival; NE = Not evaluated; PR = partial response;

PD = progressive disease.

Plasma CSF

Best

Response PFS (Days) OS (Days)

1 146.9 NE PR 309 396

2 192.0 6.0 PD 61 212

3 767.6 0.8 PR 171a 171b

Concentration of Afatinib in Plasma and CSF, Penetration Rate, and Efficacy in

Patients With EGFR Mutation-Positive NSCLC With LMD

Concentration (nM)

11

Clinical Data in TKI-Pretreated Patients:

Time to Treatment Failure With Afatinib • 66 uncommon mutations were reported (18.4% of all known EGFR mutations in the compassionate-use programme)

– Majority of patients (67%) received afatinib as third- or fourth-line treatment, with median treatment duration of 3.6 months

• No significant difference between median TTF for patients with uncommon/non-classical mutations (3.6 months) compared

with those with Del19 (4.6 months) or L858R (5.8 months) mutations

Heigener et al. Oncologist. 2015;20:1167.

TTF = time to treatment failure.

Distribution of the 60 Rare

EGFR Mutations (N=60)

Exon 18

substitution, 1, 2%

Exon 19

insertion/deletion, 2, 3%

Exon 19 substitution, 4,

7%

Exon 20 insertion, 3, 5%

T790M, 1, 2%

Exon 21 substitution, 4,

7%

Complex mutations

incl. T790M, 29

48%

G719X, 7,

11%

Complex

mutations, 9

15%

100

75

50

25

0 0 6 12 18 24 30

Months

Tre

atm

en

t p

rob

ab

ilit

y (

%)

Del19

L858R

Uncommon

12

First-line Clinical Data: Retrospective Analysis of PFS in

57 Patients Treated With Afatinib or First-Generation TKIs • In all mutation groups analysed, the afatinib group

exhibited longer median PFS compared with first-

generation TKIs

– Entire uncommon mutations cohort, except exon

20 insertionsa: 11.0 mo vs 3.6 mo

– G719X, S768I, or L861Q: 18.3 mo vs 2.6 mo

– Uncommon mutations with Del19 or L858R:

11.0 mo vs 8.2 mo

Del19+ 18G721D; Del19+ 19L732P; Del19+ 20L792P; Del19+

20S768I + 20V774M; Del19+ 21L858R + 21K860I; 21L858R +

18E709X; 21L858R + 20S768I; 21L858R + 20V786E; 21L858R

+ 20T790M; 21L858R + 20 insertion; 21L858R + 21L833Vl

21L858R + 21K860I; 21L858R + 18G719X +20 insertion

– Uncommon mutation alone or in combination with other

uncommon mutations: 18.3 mo vs 2.8 mo

18I715V; 18K716E; 18V717G; 18G719X; 19L747P;19

insertion; 20A763_Y764 insFQEA; 20S768I; 20G779F;

21L861Q; 18G719X+21L861Q; 18E709X + 18G719X;

18G719X +20S768I; 20T790 M+ 21L861Q; 21M825L

+21R831C; 18V703L + 18L707W +18G719X; 18E709X +

18T710S + 18G719X; 19V742F + 19A743 V+ 20H773R

Shen et al. Lung Cancer. 2017;110:56.

CI = confidence interval. aexon 20 insertions (except A763_Y764 insFQEA).

No. at risk

1st TKI 30 12 8 4 2 0 0 0

2nd TKI 21 13 8 5 2 2 1 0

No. at risk

1st TKI 21 6 4 2 1 0 0 0

2nd TKI 13 8 3 3 1 1 0 0

Entire Uncommon Mutations Cohort,

Except Exon 20 Insertions

Uncommon Mutations With

Del19 or L858R

Uncommon Mutation Alone or in Combination

With Other Uncommon Mutations

G719X, S768I, or L861Q 100

90

80

70

60

50

40

30

20

10

0

PF

S (

%)

Months

0 5 10 15 20 25 30 35

Log rank P=0.03

100

90

80

70

60

50

40

30

20

10

0

PF

S (

%)

Months

0 5 10 15 20 25 30 35

No. at risk

1st TKI 14 4 3 2 1 0 0 0

2nd TKI 10 6 2 2 1 1 0 0

100

90

80

70

60

50

40

30

20

10

0 P

FS

(%

)

Months

0 5 10 15 20 25 30 35

No. at risk

1st TKI 9 6 4 2 1 0 0 0

2nd TKI 8 5 5 2 1 1 1 0

100

90

80

70

60

50

40

30

20

10

0

PF

S (

%)

Months

0 5 10 15 20 25 30 35

No. Median (mo) 95% CI

1st TKI 30 3.6 0.1-7.1

2nd TKI 21 11.0 0-22.8

Log rank P=0.24 Log rank P=0.07

No. Median (mo) 95% CI

1st TKI 9 8.2 2.1-14.3

2nd TKI 8 11.0 0-26.1

No. Median (mo) 95% CI

1st TKI 14 2.6 2.1-3.1

2nd TKI 10 18.3 0-39.2

No. Median (mo) 95% CI

1st TKI 21 2.8 2.1-3.4

2nd TKI 13 18.3 3.2-33.4

Log rank P=0.12

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First-line Clinical Data: Prospective Efficacy Assessments

in the LUX-Lung Programme • Of 600 patients given afatinib in LUX-Lung 2/3/6, 75 (12%) patients had uncommon EGFR mutations1

• The LUX-Lung programme provides the largest series of prospective efficacy data in uncommon

mutations1-4

1. Yang et al. Lancet Oncol. 2015;16:830; 2. Passaro et al. J Thorac Dis. 2013;5:383; 3. Katakami et al. J Clin Oncol. 2013;31:3335; 4. Wu et al. Lancet Oncol. 2014;15:213;

5. Yang et al. Lancet Oncol. 2012;13:539; 6. Sequist et el. J Clin Oncol. 2013;31:3327.

aEGFR mutations detected by TheraScreen EGFR29 test. Common: 19 deletions in exon 19 and L858R in exon 21; Uncommon: 3 insertions in exon 20, L861Q, T790M, G719S, G719A and G719C, and S768I.

LUX-Lung 2

Phase 2 (N=129)5

Afatinib

First- and second-line (after chemotherapy)

Direct sequ. (central)

Del19=52 L858R=54

N=23 N=23

LUX-Lung 3

Phase 3 (N=345)6

Afatinib vs Cis/Pem

First-line

EGFR29a (central)

Del19=170 L858R=138

N=37 N=26

LUX-Lung 6

Phase 3 (N=364)4

Afatinib vs Cis/Gem

First-line

EGFR29a (central)

Del19=186 L858R=138

N=40 N=26

Common mutations

Uncommon mutations;

treated with afatinib4

Mutation test

Line of treatment

Treatment

14

LUX-Lung 2, 3, and 6: Tumour Shrinkage by Independent

Review (n=67a)

• 3 patients in group 1 achieved complete response

– 1 each with G719X, K739_1744dup6, and L858R+Q709G/V

Yang et al. Lancet Oncol. 2015;16:830.

a8 patients were not included because of insufficient data. bT790M alone.

-100

-80

-60

-40

-20

0

20

40

60

80

100

120

b

b

b

Ma

xim

um

ch

an

ge

fro

m

bas

eli

ne (

%)

Group 2 (n=14): de novo T790M mutations T790M alone, T790M+Del19, T790M+L858R, T790M+G719X, T790M+L858R+G719X

Group 1 (n=33): point mutations or duplications in exons 18-21 L861Q, G719X, G719X+S768I, G719X+L861Q, E709G or V+L858R, S768I+L858R,

S768I, L861P, P848L, R776H+L858R, L861Q+Del19, K739_1744dup6

Group 3 (n=20): exon 20 insertions

15

LUX-Lung 2, 3, and 6: Response Rate, PFS, and OS by

Independent Review

Yang et al. Lancet Oncol. 2015;16:830.

T790M

(n=14)

Exon 20 ins

(n=23)

Mut/Dup

Exon 18-21

(n=38)

G719X

(n=18)

L861Q

(n=16)

S768I

(n=8)

Response rate

(%) 14.3 8.7 71.1 77.8 56.3 100.0

PFS (mo) 2.9 2.7 10.7 13.8 8.2 14.7

OS (mo) 14.9 9.2 19.4 26.9 17.1 NE

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Summary

• Afatinib has shown preclinical and clinical activity in TKI-naive and TKI-pretreated

patients with NSCLC harbouring uncommon EGFR mutations

• Activity of afatinib against uncommon EGFR mutations in patients with LMD was also

reported

• Afatinib was especially active in NSCLC tumours harbouring point mutations or

duplications in exons 18-21 (eg, G719X, S768I, L861Q K739_1744dup6, and

L858R+Q709G/V)

• Anecdotal data from erlotinib/gefitinib trials show variable and mainly limited

responses to these EGFR TKIs in patients with NSCLC harbouring uncommon

mutations

• These data could help inform clinical decisions for patients with NSCLC harbouring

uncommon EGFR mutations

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