Treatment of EGFR mutant advanced NSCLC › content › download › 194348 › 3503276 › file › 20… · Recruitment period Aug 09 –Feb 11 Apr 10 –Nov 11 Primary PFS analysis

Treatment of

EGFR mutant

advanced NSCLC

Raffaele Califano

Department of Medical Oncology

The Christie and Manchester University Hospital

Manchester, UK

Disclosure

Honoraria and consultancy fees: AstraZeneca, Boeringher Ingelheim, Lilly Oncology, Roche, Pfizer,

MSD, Bristol Myers Squibb, Takeda and Novartis

Grants paid to Institution for conduct of clinical trials or contracted research: Roche,

AstraZeneca, Pfizer, Clovis, Lilly Oncology, MSD, BMS, Abbvie, Takeda and Novartis

Stock Ownership: The Christie Private Care

Non-remunerated activities: Principal investigator for trials with Roche, AstraZeneca,

Pfizer, Clovis, Lilly Oncology, MSD, BMS, Abbvie, Takeda and Novartis

Leadership roles (non remunerated): ESMO

Other non remunerated membership: EORTC

Outline

Data on first-line

Overcoming T790M mutation

Conclusion

EGFR-TKIs in

pre-treated NSCLC patients

Thatcher et al, Lancet 2005; Shepherd et al, NEJM 2005,

ISEL BR.21

EGFR activating mutations

Lynch et al, NEJM 2004

EGFR activating mutations

Sharma et al, Nat Rev Cancer 2007

Gefitinib

IPASS Trial

Never or lightex-smoker with

adenocarcinomaPS 0–2

Stage IIIB or IVchemo-naive

NSCLCN=1217

R

A

N

D

O

M

I

Z

E

Gefitinib (250 mg/day)

Carboplatin/Paclitaxelup to 6 cycles

Mok et al, NEJM 2009

PFS in ITT population

5.7 vs 5.8 months

Carboplatin / paclitaxel

Gefitinib 609 212 76 24 5 0

608 118 22 3 1 0

363

412

0 4 8 12 16 20 24 Months

0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

At risk :

GefitinibCarboplatin /

paclitaxel

IPASS - Biomarker

analysis

N=1217(100%)

N=1038 biomarker

consent(85%) N=683

provided samples

(56%)

N=437 evaluable for EGFR mutation

(36%)

PFS in EGFR M+ and M-

9.5 vs 6.3 months

EGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, p<0.0001

HR (95% CI) = 0.48 (0.36, 0.64) p<0.0001

Gefitinib (n=132)Carboplatin / paclitaxel (n=129)

ITT populationCox analysis with covariates

HR (95% CI) = 2.85 (2.05, 3.98)p<0.0001

132 71 31 11 3 0129 37 7 2 1 0

108103

0 4 8 12 16 20 24

GefitinibC / P

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

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f p

rog

ress

ion

-fre

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urv

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l

At risk :91 4 2 1 0 085 14 1 0 0 0

2158

0 4 8 12 16 20 24

0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

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ress

ion

-fre

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Gefitinib (n=91)Carboplatin / paclitaxel (n=85)

Months Months

Overall Survival

609 423 239 118 38 0

608 401 212 104 32 0

514

524

0 4 8 12 16 20 28 Months

Gefitinib

Carboplatin / paclitaxel

0.0

0.2

0.4

0.6

0.8

1.0Probabilityof survival

At risk : 24

0

1

18.8 vs 17.4 months

HR 0.90; P = 0.109

Gefitinib

Carboplatin /

paclitaxel

ORR in EGFR M+ and WT

p=0.0148 p<0.0001 p=0.3037

% p

atie

nts

with

su

sta

ine

d

clin

ica

lly r

ele

va

nt

imp

rove

me

nt

Quality of life

Gefitinib in Asian Studies

EGFR M+

Study N Regimen RR (%) PFS HR

NEJ002 230 G 73.7 10.80.30

C/P 30.7 5.4

WJTOG

3405

177G 62.1 9.2

0.48

C/D 32.2 6.3

Maemondo et al, NEJM 2010; Mitsudomi et al, Lancet Oncol 2010

Erlotinib

Erlotinib in EGFR M+

Study N Regimen RR (%) PFS HR

OPTIMAL 165 E 83 13.10.16

C/G 36 4.6

EURTAC 174E 56 9.7

0.37Platinum

doublet15 5.2

Zhou et al, Lancet Oncol 2011; Rosell et al, Lancet Oncol 2012;

Afatinib

Primary endpoint: PFS (IRR)

Pemetrexed/Cisplatin q21d up to 6 cycles

(n=115)

Afatinib 40mg OD (n=230)Stage IIIB/IV Adeno

PS 0–1

Chemotherapy-naïve

EGFR mutant

(n=345)

R

LUX-LUNG 3

Sequist LV, et al, JCO 2013

2:1

Primary endpoint: PFS (IRR)

Only East Asia

Cisplatin/Gemcitabineup to 6 cycles (n=122)

Afatinib 40mg OD (n=242)Stage IIIB/IV

PS 0–1

Chemotherapy-naïve

EGFR mutant

(n=364)

R

LUX-LUNG 6

Wu Y-L, et al, Lancet Oncol 2014

2:1

LUX-Lung 3 and 6

Efficacy

LUX-LUNG 3 LUX-LUNG 6

Afatinib n=230

Cis/pem n=115

Afatinibn=242

Cis/gemn=122

ORR (%) 56.1 22.5 66.9 23

Median PFS (mos)

11.1 6.9 11.0 5.6

HR (95% CIl)0.58 (0.43–0.78)

p=0.00040.28 (0.20-0.39)

P<0.0001

Other Endpoints

Better tolerated

↑Symptom control

↑Global health status/QoL

Afatinib arm

LUX-Lung 3 and 6:

Updated OS

LUX-Lung 3 (n=345) LUX-Lung 6 (n=364)

Recruitment period Aug 09 – Feb 11 Apr 10 – Nov 11

Primary PFS analysis Feb 12 (221 events) Oct 12 (221 events)

Required maturity of

OS At least 209 events At least 237 events

OS analysis Dec 13 (213 events;

61.7%)

Jan 14 (246 events;

67.6%)

Median OS follow-up 41 months 33 months

OS result, overall

population

28.2 vs 28.2 months

HR=0.88, p=0.3850

23.1 vs 23.5 months

HR=0.93, p=0.6137

Yang, et al, Lancet Oncol 2015

Trials of EGFR-TKIs vs CT in M+

Study N Median PFS (mos) Median OS (mos)

TKI Chemo HR (95 % CI) TKI Chemo

IPASS 261 9.5 6.3 0.48 (0.36-0.64) 21.6 21.9

First Signal 42 8.0 6.3 0.54 (0.26-1.10) 27.2 25.6

NEJ002 194 10.4 5.5 0.35 (0.25-0.50) 27.7 26.6

WJTOG 172 9.2 6.3 0.48 (0.33-0.71) 36 39

OPTIMAL 154 13.7 4.6 0.16 (0.10-0.26) 22.6 28.8

EURTAC 174 10.4 5.1 0.34 (0.25–0.54) 19.3 19.5

LUX-LUNG 3 345 11.1 6.9 0.58 (0.43-0.78) 28.2 28.2

LUX-LUNG 6 364 11.1 5.6 0.28 (0.20-0.39 23.1 23.5

What’s the best

1st/2nd generation

EGFR-TKI?

Lux-Lung 7

Afatinib 40 mg OD

Gefitinib 250 mg OD

1:1

Stage IIIB/IV adenocarcinoma

EGFR mutation (Del19 and/or L858R)

No prior treatment for advanced/metastatic disease

ECOG PS 0/1N= 319

Stratified by

Mutation type (Del19/L858R)

Brain metastases (present/absent)

Primary endpoints: PFS (IRR), TTF, OSPaz-Ares et al, Ann Oncol 2017

Treatment beyond

progression allowed

Efficacy

Afatinib(n=160)

Gefitinib(n=159)

HR

(95%CI)p

PFS (months)11.0 10.9 0.74

(0.57–0.95)

0.0178

TTF (months)13.7 11.5 0.75 (0.60-

0.94)

0.0136

OS (months)27.9 24.5 0.86

(0.66–1.12)

0.2580

ORR and DOR

p=0.002

Afatinibn=112/160

Gefitinibn=89/159

Afatinib (n=112)

Gefitinib (n=89)

Median DoR (mos)

10 .1 8.3

95% CI (8.2–11.1) (7.3–10.2)

73% 56%

Adverse Events

Events, %

Afatinib(n=160)

Gefitinib(n=159)

Any AE 98.8 100.0

Drug-related AEs 97.5 96.2

AEs leading to dose reduction* 41.9 1.9*

Drug-related AEs leading to

discontinuation6.3 6.3

Serious AEs 44.4 37.1

Drug-related serious AEs 10.6 4.4†

Drug-related fatal AE - 0.6‡

*No dose reductions foreseen for gefitinib according to prescribing information†Including four patients with drug-related ILD (no drug-related ILD on afatinib)‡One patient died of hepatic failure

ARCHER 1050

Advanced NSCLC• Adenocarcinoma

• EGFR exon 19/21 mut+

• First-line treatment

• PS 0-1

• No brain metastases

N=440

RANDOMIZE

Dacomitinib45mg qd

Gefitinib 250mg qd

Primary endpoint: PFSPrimary endpoint: PFS

Wu et al, lancet oncology 2017

ARCHER 1050: PFS (IRR)

SAEs and dose modification

OutcomeDacomitinib

(n = 227)Gefitinib (n = 224)

Serious AE, n (%)AnyTreatment related

Causing discontinuation Causing death

62 (27.3)21 (9.3)22 (9.7)2 (0.9)

50 (22.3)10 (4.5)15 (6.7)1 (0.4)

Median duration of dose reduction, mos (range)

11.3 (0.1-33.6) 5.2 (0.3-17.8)

Reduced dose given, n (%) 30 mg/day15 mg/day

87 (38.3)63 (27.8)

NA

Pts requiring dose reduction, n (%) 150 (66.1) 18 (8.0)

Mechanism of resistance to

1st/2nd generation EGFR-TKIs

Camidge DR et al. Nat Rev Clin Oncol. 2014

Tackling T790M

resistance mutation

Osirmetinib

Inhibition of T790M

Inhibition of EGFRm

Low activity on wt EGFR Lower incidence of rash and diarrhoea

Overcome resistance

Continue targeting sensitizing mutations

Potential to…

wt EGFR T790MEGFRm

TAGRISSO

Cross DAE, et al. Cancer Discovery 2014

Osirmetinib

Clinical development

AURA2 (n=210)

Osimertinib 80 mg QD

T790M

positive

T790M

negative

Central T790M mutation testing* of biopsy

sample collected following confirmed disease

progression

Patients with confirmed EGFRm locally

advanced or metastatic NSCLC who have

progressed following prior therapy with an

approved EGFR-TKI

Escalation

Expansion

Ph

ase

I

AURA Phase II Extension (n=201)


AURA Phase II Extension (n=201)


Cohort 1

20 mg

Negative

Cohort 2

40 mg

Cohort 5

240 mg

Rolling six design

Cytology

Tablet

Negative

Cohort 3

80 mg n=63

Negative

Cohort 4

160 mg

Positive Positive PositivePositivePositive Positive

Biopsy† Biopsy

First-line First-line

AURA Ph I/II AURA2 Ph II

Not eligible

for enrollment

Patients with T790M-positive aNSCLC whose disease has progressed

following either one prior therapy with an EGFR-TKI or following treatment

with both EGFR-TKI and other anticancer therapy

Pooled Phase II

Janne PA et al, NEJM 2015; Goss et al, Lancet Oncol 2016

AURA Ph I (80 mg)N=63

AURA pooled Ph II (80 mg) N=411

Median PFS*, months (95% CI) 9.7 (8.3, 13.6) 11.0 (9.6, 12.4)

Remaining alive and progression-free,† % (95% CI)

12 months

18 months

24 months

41 (29, 53)

29 (18, 41)

17 (8, 30)

48 (42, 53)

NC

NC

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

Pro

babi

lity

of P

FS

441 332 271 205 161 38 0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.01.0

0.0

Pro

babi

lity

of P

FS

1

Number of patients at risk:

Osimertinib 80 mg

Month0 3 6 9 12 15 18

63 55 48 36 25 20

21 24 27

15 9 5

Number of patients at risk:

Osimertinib 80 mg

0 3 6 9 12 15 18 21 24 27

Month

AURA Ph I AURA pooled Ph II

Progression-Free Survival

Yang JCH, et al. ELCC 2016

Adverse Events

AE category, all causality, n (%) AURA Ph I (80 mg)N=63*

AURA pooled Ph II (80 mg)

N=411†

Any AE 62 (98) 406 (99)

Any AE ≥Grade 3 29 (46) 149 (36)

Any AE leading to death 1 (2) 14 (3)

Any AE leading to dose interruption 16 (25) 87 (21)

Any AE leading to dose reduction 1 (2) 16 (4)

Any AE leading to discontinuation 3 (5) 26 (6)

Any serious AE 18 (29) 107 (26)

AE category, causally-related‡

Any AE 57 (91) 364 (89)

Any AE ≥Grade 3 11 (18) 56 (14)

Any AE leading to discontinuation 0 16 (4)

Any serious AE 3 (5) 23 (6)

Yang JCH, et al. ELCC 2016

AURA3 study

Key eligibility criteria

• Locally advanced or

metastatic NSCLC

• Evidence of disease

progression following first-line

EGFR-TKI therapy

• Documented EGFRm and

central confirmation of tumour

EGFR T790M mutation after first-

line EGFR-TKI treatment

• PS 0 or 1

• No more than one prior line of

treatment for advanced

NSCLC

• Stable asymptomatic CNS

metastases allowed

R

2:1

Osimertinib 80 mg OD

(n=279)

Platinum-pemetrexed

+/-

maintenance

pemetrexed

(n=140)

Optional crossover: Protocol

amendment allowed patients on

chemotherapy to begin post-

BICR confirmed progression

open-label osimertinib treatment

Endpoints Primary:

•PFS by investigator assessment

(RECISTv1.1)

Secondary and exploratory:

•OS

•ORR

•DoR

•DCR

•Tumour shrinkage

•BICR-assessed PFS

•PROs

•Safety and tolerability

Mok TS et al, NEJM 2016

Progression-free Survival

(investigator)Pro

ba

bili

ty o

fPro

gre

ssio

n-f

ree

Su

rviv

al 1.0

0.8

0.6

0.4

0.2

0

0 3 6 9 12 15 18

Months

Osimertinib (n=279)

Platinum-pemetrexed

(n=140)

HR for disease progression or death,0.30 (95% Cl, 0.23–0.41) P<0.001

Median PFS (95% Cl)

10.1 (8.3–12.3)

4.4 (4.2–5.6)

Response Rate

Osimertinib (n=279)

Platinum-pemetrexed

(n=140)

ORR, % (95% CI) 71% (65, 76) 31% (24, 40)

Odds ratio* (95% CI) 5.39 (3.47, 8.48); P<0.001

Complete response, n (%)

Partial response, n (%)

Progression, n (%)

RECIST progression, n (%)

Death

Not evaluable, n (%)

4 (1)

193 (69)

18 (6)

15 (5)

3 (1)

1 (<1)

2 (1)

42 (30)

26 (19)

22 (16)

4 (3)

10 (7)

DCR, % (95% CI) 93 (90, 96) 74 (66, 81)

Odds ratio (95% CI) 4.76 (2.64, 8.84); P<0.001

Median time to response, weeks (95% CI) 6.1 (NC, NC) 6.4 (6.3, 7.0)

Median DoR, months (95% CI) 9.7 (8.3, 11.6) 4.1 (3.0, 5.6)

Safety AE category*, n (%) Osimertinib

(n=279)Platinum-pemetrexed

(n=136)

Any AE 273 (98) 135 (99)

Any AE Grade ≥3 63 (23) 64 (47)




AE category, possibly causally related†, n (%)

Any AE 231 (83) 121 (89)

Any AE Grade ≥3 16 (6) 46 (34)

Any AE leading to death 1 (<1) 1 (1)



Adverse EventsN (%) 15% cut-off

Osimertinib (n=279) Platinum-pemetrexed(n=136)

Any grade Grade ≥3 Any grade Grade ≥3Any AE 273 (98) 63 (23) 135 (99) 64 (47)

Diarrhoea 113 (41) 3 (1) 15 (11) 2 (1)

Rash† 94 (34) 2 (1) 8 (6) 0

Dry skin† 65 (23) 0 6 (4) 0

Paronychia† 61 (22) 0 2 (1) 0

Decreased appetite 50 (18) 3 (1) 49 (36) 4 (3)

Cough 46 (16) 0 19 (14) 0

Nausea 45 (16) 2 (1) 67 (49) 5 (4)

Fatigue 44 (16) 3 (1) 38 (28) 1 (1)

Stomatitis 41 (15) 0 21 (15) 2 (1)

Constipation 39 (14) 0 47 (35) 0

Vomiting 31 (11) 1 (<1) 27 (20) 3 (2)

Thrombocytopaenia† 28 (10) 1 (<1) 27 (20) 10 (7)

Neutropaenia† 22 (8) 4 (1) 31 (23) 16 (12)

Leukopenia† 22 (8) 0 20 (15) 5 (4)

Anaemia† 21 (8) 2 (1) 41 (30) 16 (12)

Asthenia 20 (7) 3 (1) 20 (15) 6 (4)

Select adverse eventsInterstitial lung disease† 10 (4) 1 (<1) 1 (1) 1 (1)

QT prolongation 10 (4) 1 (<1) 1 (1) 0

Stratification

by mutation status

(Exon 19

deletion /

L858R)

and race(Asian /

non-Asian) Crossover was allowed for

patients in the SoC arm,

who could receive open-

label osimertinib upon

central confirmation of

progression and T790M

positivity

Patients with locally advanced or metastatic

NSCLC

Key inclusion criteria •≥18 years*

•Performance status 0 / 1

•Exon 19 deletion / L858R (enrolment by local# or central‡ EGFR testing)

•No prior systemic anti-cancer / EGFR-TKI therapy

•Stable CNS metastases allowed

Primary endpoint: PFS (investigator)

Secondary endpoints: objective response rate, duration of response, disease control rate, depth of response, overall survival, patient reported outcomes, safety

Randomised 1:1

RECIST 1.1 assessment every

6 weeks until objective

progressive disease

EGFR-TKI SoC§;

Gefitinib (250 mg p.o.

qd) or Erlotinib (150 mg

p.o. qd)

(n=277)

Osimertinib(80 mg p.o. qd)

(n=279)

FLAURA

Soria JC et al, NEJM 2017

Progression-free Survival

Median PFS, months (95% CI)

18.9 (15.2, 21.4)

10.2 (9.6, 11.1)

1.0

Pro

ba

bili

ty o

f p

rog

ress

ion

-fre

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urv

iva

l

0.2

0.4

0.6

0.8

0.0

0 3 6 9 12 15 18 21 24 27

Time from randomisation (months)

279277

262239

233197

210152

178107

13978

7137

2610

42

00

No. at riskOsimertinib

SoC

Osimertinib

SoC

HR 0.46(95% CI 0.37, 0.57)

p<0.0001

Safety

AE, any cause, n (%) Osimertinib (n=279) SoC (n=277)

Any AE 273 (98) 271 (98)

Any AE Grade ≥3 94 (34) 124 (45)



Any AE leading to

discontinuation

37 (13) 49 (18)

AE, possibly causally related, n (%)

Any AE 253 (91) 255 (92)

Any AE Grade ≥3 49 (18) 78 (28)

Any AE leading to death 0 1 (<1)


Safety

AEs

n (%)

Osimertinib (n=279) SoC (n=277)

Any

gradeGrade 1 Grade 2 Grade 3 Grade 4

Any

gradeGrade 1 Grade 2 Grade 3 Grade 4

Diarrhoea161

(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

acneiform71 (25) 61 (22) 10 (4) 0 0

134

(48)71 (26) 50 (18) 13 (5) 0

Decreased

appetite56 (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)

Safety

Take Home Message

EGFR-TKIs are standard of care in EGFR M+

Look for T790M resistance mutation

Osirmetinib: a new option for 1st line treatment

Documents

Treatment of EGFR mutant advanced NSCLC › content › download › 194348 › 3503276 › file › 20… · Recruitment period Aug 09 –Feb 11 Apr 10 –Nov 11 Primary PFS analysis