EGFR Mutation: Clinical Evidence and Resistance to TKIs Tony SK Mok, MD Professor, Department of...

EGFR Mutation: Clinical Evidence and

Resistance to TKIs

Tony SK Mok, MDProfessor, Department of Clinical Oncology

The Chinese University of Hong KongHong Kong, China

Consultant

AstraZeneca Pharmaceuticals LP, Merck Serono, Roche Laboratories Inc, Taiho Pharmaceutical Co Ltd

Speakers BureauAstraZeneca Pharmaceuticals LP, Lilly USA LLC, Roche Laboratories Inc

Disclosure Slide

Clinical Evidence

Early Clinical Experience

Prospective Studies of Unselected Patients Treated with EGFR TKIs

Study Patient # Agent RR PFS or OS

IDEAL 11 210Gefitinib250 mg500 mg

18.4%19.0%

PFS2.7 months2.8 months

IDEAL 22 221Gefitinib250 mg500 mg

12.0%9.0%

OS7.0 months6.9 months

BR-213 488 Erlotinib8.9%

PFS2.2 months

ISEL4 1,129 Gefitinib8.2%

OS5.6 months

1 J Clin Oncol 21:2237-2246, 2003; 2 JAMA 290:2149-2158, 2003;3 N Engl J Med 353:123-132, 2005; 4 Lancet 366:1527-1537, 2005

1 J Clin Oncol 21:2237-2246, 2003; 2 JAMA 290:2149-2158, 2003;3 N Engl J Med 353:123-132, 2005; 4 Lancet 366:1527-1537, 2005

Author # screenedEGFR

mutations Agent RR TTP

Inoue1 99 16 Gefitinib 75% 9.7 mos

Paz-Ares2 1,047 127 Erlotinib 82% 13.3 mos

Tamura3 118 32 Gefitinib 75% ND

Sutani4 100 38 Gefitinib 78% 9.4 mos

Morikawa5 123 46 Gefitinib 62% 9.7 mos

Sequist6 98 31 Gefitinib 55% 11.4 mos

Prospective Studies of Patients with EGFR Mutations Treated with EGFR TKIs

1 Inoue A et al. J Clin Oncol 2006;24(21):3340-6; 2 Paz-Ares L et al. J Clin Oncol 2006;24(185 Suppl): Abstract 7020; 3 Tamura K et al. Br J Cancer 2008;98:907-14; 4 Sutani A et al. Br J Cancer 2006;95:1483-9; 5 Morikawa N et al. J Clin Oncol 2006;24(185 Suppl):Abstract 7077; 6 Sequist LV et al. J Clin Oncol 2008;26(15):2442-9.

1 Inoue A et al. J Clin Oncol 2006;24(21):3340-6; 2 Paz-Ares L et al. J Clin Oncol 2006;24(185 Suppl): Abstract 7020; 3 Tamura K et al. Br J Cancer 2008;98:907-14; 4 Sutani A et al. Br J Cancer 2006;95:1483-9; 5 Morikawa N et al. J Clin Oncol 2006;24(185 Suppl):Abstract 7077; 6 Sequist LV et al. J Clin Oncol 2008;26(15):2442-9.

IPASS

Gefitinib(250 mg/day)

Carboplatin (AUC 5 or 6)/

paclitaxel (200 mg/m2)

3 weekly†

1:1 randomisation

Patients• Chemonaïve

• Age ≥18 years

• Adenocarcinoma histology

• Never or light ex-smokers*

• Life expectancy≥12 weeks

• PS 0-2

• Measurable Stage IIIB/IV disease

* Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked ≤10 pack years; † limited to a maximum of 6 cycles Carboplatin/paclitaxel was offered to gefitinib patients upon progressionPS, performance status; EGFR, epidermal growth factor receptor

EndpointsPrimary• Progression-free survival (non-inferiority)

Secondary• Objective response rate• Overall survival • Quality of life• Disease-related symptoms • Safety and tolerability

Exploratory• Biomarkers

– EGFR mutation– EGFR gene-copy number– EGFR protein expression

Mok TS et al. N Engl J Med 2009;361(10):947-57; Mok TS et al. Proc ESMO 2008;Abstract LBA2.

IPASS: Biomarker Study

EGFRF protein overexpression

by IHC

EGFRF gene polysomy

by FISH

EGFRF mutation by PCR sequencing

365 samples (30%) 406 samples (33%) 437 samples (36%)

266 positive (73%) 249 positive (61%) 261 positive (60%)

Mok TS et al. N Engl J Med 2009;361(10):947-57.

Overall Population: Progression-Free Survival

Carboplatin/ paclitaxel

Gefitinib

Median PFS (months)4 months progression-free6 months progression-free12 months progression-free

5.761%48%25%

5.874%48%7%

609 212 76 24 5 0608 118 22 3 1 0

363412

0 4 8 12 16 20 24 Months0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

At risk :

609453 (74.4%)

608497 (81.7%)

NEvents

HR (95% CI) = 0.741 (0.651, 0.845) p < 0.0001

Gefitinib

Gefitinib demonstrated superiority relative to carboplatin/paclitaxel in terms of PFS

Primary Cox analysis with covariatesHR <1 implies a lower risk of progression on gefitinib

Carboplatin/paclitaxel

Mok TS et al. Proc ESMO 2008;Abstract LBA2.

Objective Response Rate in EGFR Mutation Positive and Negative Patients

Gefitinib Carboplatin/paclitaxel

EGFR M+ odds ratio (95% CI) = 2.75(1.65, 4.60), p = 0.0001

EGFR M- odds ratio (95% CI) = 0.04(0.01, 0.27), p = 0.0013

Overallresponserate (%)

(n = 132) (n = 129) (n = 91) (n = 85)

Odds ratio >1 implies greater chance of response on gefitinib

71.2%

47.3%

1.1%

23.5%

Mok TS et al. Proc ESMO 2008;Abstract LBA2.

IPASS: EGFR Mutation and Progression-Free Survival

EGFR mutation positive EGFR mutation negative

Treatment by subgroup interaction test, p < 0.0001

HR (95% CI) = 0.48 (0.36, 0.64) p < 0.001

No. events gefitinib, 97 (73.5%)No. events C/P, 111 (86.0%)

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

ITT populationCox analysis with covariates

HR (95% CI) = 2.85 (2.05, 3.98) p < 0.001

No. events gefitinib, 88 (96.7%)No. events C/P, 70 (82.4%)

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

bab

ility

of

pro

gre

ssio

n-f

ree

surv

ival

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

bab

ility

of

pro

gre

ssio

n-f

ree

surv

ival


Months Months

Mok TS et al. N Engl J Med 2009;361(10):947-57; Copyright © 2009 Massachusetts Medical Society.

IPASS: 2010 OS by EGFR Mutation Status (ITT)

EGFR Mutation +

00

Patients at risk:GefitinibC / P

132129

126123

10395

7068

2426

1115

121112

8880

5855

4648

3840

67

30

Time from randomisation (months)

Pro

bab

ilit

y o

f su

rviv

al

EGFR Mutation -

520 4 8 12 16 20 4424 28 32 36 40 48

1.0

0.8

0.6

0.4

0.2

0.0

00

51

9185

6976

5257

4044

2933

2625

11

1919

1616

1111

83

01

Time from randomisation (months)

520 4 8 12 16 20 4424 28 32 36 40 48

1.0

0.8

0.6

0.4

0.2

0.0

Pro

bab

ilit

y o

f su

rviv

al


HR (95% CI) 1.00 (0.76, 1.33); p = 0.990 No. events G 104 (79%) C/P 95 (74%) Median OS G 21.6 months C/P 21.9 months


HR (95% CI) 1.18 (0.86, 1.63); p = 0.309No. events G 82 (90%) C/P 74 (87%)Median OS G 11.2 months C/P 12.7 months

Treatment by subgroup interaction test, p = 0.480

Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinibNo formal adjustment made for multiple testing

IPASS: 2010 Comparison of Post-Discontinuation Treatments

C/P

Gefitinib20 patientsongoing*

* % exclude the 20 patients in the gefitinib arm with ongoing randomised treatment (3 M+, 1 M-, 16 M unknown); † Patients may have also received other chemotherapy and/or EGFR TKI during the study; Radiotherapy, surgery, medical procedures and other treatments excluded; ‡ Categories are not mutually exclusive

78%

Mutation +(N = 261)

Mutation -(N = 176)

Mutation unknown (N = 780)

Received no further systemic treatment

Received further treatment

Received platinum-based chemotherapy at some time†

Received an EGFR TKI at some time†

Received other chemotherapy

22%

68%(55% C/P)

26%

15%

78%

23%

73%(57% C/P)

14%14%

77%

36%

54%(46% C/P)

19%10%

64%

29%

64%(47% G, 23% E,

7% other)‡

8%

71%

29%

51%(39% G, 8% E,

6% other)‡

21%

71%

43%

47%(40% G, 11% E,

5% other)‡

8%

57%

Treatment sequence in patients with EGFR mutation

GefitinibGefitinib ChemoChemo 2nd/3rd-line therapy2nd/3rd-line therapy DeathDeath

2nd/3rd-line therapy2nd/3rd-line therapy DeathDeathChemoChemo GefitinibGefitinib

2nd/3rd-line therapy2nd/3rd-line therapy DeathDeathChemoChemo x

Over 20 to 24 months

12 months

Crossover Explains the Similar Survival

Author Study N (EGFR mut +) RR Median PFS Median OS

Mok et al IPASS 26671.2% vs

47.3%9.8 vs 6.4 months

21.6 vs 21.9 months

Lee et alFirst-

SIGNAL42

84.6% vs 37.5%

8.4 vs 6.7 months

30.6 vs 26.5 months

Mitsudomi et alWJTOG

340586

62.1% vs 32.2%

9.2 vs 6.3 months

Pending

Maemondo et alNEJGSG0

02114

73.7% vs 30.7%

10.8 vs 5.4 months

30.5 vs 23.6 months

Zhou et al OPTIMAL 15483% vs

36%13.1 vs 4.6

monthsNA

Rosell et al EURTAC 13558% vs

15%

9.7 vs 5.2 months

NA

Mok et al. NEJM 2009; Lee et al. WCLC 2009; Mitsudomi et al. Lancet Oncology 2010; Maemondo. NEJM 2010Mok et al. NEJM 2009; Lee et al. WCLC 2009; Mitsudomi et al. Lancet Oncology 2010; Maemondo. NEJM 2010

Summary of First-Line EGFR TKI in Patients with EGFR Mutation

EGFR TKI Resistance

1. Previously received treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib)

2. Either of the following:A. A tumor that harbors an EGFR mutation known to be associated with drug

sensitivity (ie, G719X, exon 19 deletion, L858R, L861Q)B. Objective clinical benefit from treatment with an EGFR TKI as

defined by either:i. Documented partial or complete response (RECIST or WHO), or ii. Significant and durable (≥6 months) clinical benefit (stable disease as

defined by RECIST or WHO) after initiation of gefitinib or erlotinib3. Systemic progression of disease (RECIST or WHO) while on continuous

treatment with gefitinib or erlotinib within the last 30 days4. No intervening systemic therapy between cessation of gefitinib or erlotinib and

initiation of new therapy

1. Previously received treatment with a single-agent EGFR TKI (eg, gefitinib or erlotinib)

2. Either of the following:A. A tumor that harbors an EGFR mutation known to be associated with drug

sensitivity (ie, G719X, exon 19 deletion, L858R, L861Q)B. Objective clinical benefit from treatment with an EGFR TKI as

defined by either:i. Documented partial or complete response (RECIST or WHO), or ii. Significant and durable (≥6 months) clinical benefit (stable disease as

defined by RECIST or WHO) after initiation of gefitinib or erlotinib3. Systemic progression of disease (RECIST or WHO) while on continuous

treatment with gefitinib or erlotinib within the last 30 days4. No intervening systemic therapy between cessation of gefitinib or erlotinib and

initiation of new therapy

Clinical Definition: Jackman Criteria for EGFR TKI Resistance

Jackman et al. JCO 2010; Mok JCO 2010

Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors. Abbreviations: EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor; RECIST, Response Evaluation Criteria in Solid Tumors.

EGFR TKI EGFR TKI

EGFR TKIResistanceby RECIST

StopEGFR TKI?

RECIST Criteria

1cm 1.3cm 5cm

Riely et al. Clin Can Res 13:5150, 2007Riely et al. Clin Can Res 13:5150, 2007

Cessation of EGFR TKI upon Progression

Changes in tumor on CT and FDG-PET

After stopping gefitinib or erlotinib

After restarting gefitinib or erlotinib

3 wks after adding everolimus

Median change in tumor diameter

Mean change in tumor diameter

Range in change in tumor diameter

+9%

+9%

-13% to +29%

-1%

1%

-14% to +23%

-8%

-9%

-34% to +15%

Median change in tumor volume

Mean change in tumor volume

Range in change in tumor volume

+50%

+61%

-4% to +260%

-1%

-4%

-27% to +15%

-11%

-10%

-40% to +26%

Median change in SUVmax

Mean change in SUVmax

Range in change in SUVmax

+18%

+23%

-17% to +87%

-4%

-11%

-45% to +62%

-18%

-11%

-39% to +82%

45 Females Treated with Gefitinib for Exon 19 Mutation Positive Disease Since 2005

Aug 2008 Oct 2008 Apr 2009

Aug 2009 Dec 2009 May 2010

What Happens at EGFR TKI Resistance in Patients with EGFR Mutation?

Primary resistance(<10%)

Primary resistance(<10%) Early Early LateLate

Primary resistance(<10%)

Primary resistance(<10%) Early Early LateLate

Mechanism unknownMechanism unknownT790M: 50%

c-MET overexpression: 20%Others: 30%

T790M: 50% c-MET overexpression: 20%

Others: 30%

What accounts for the difference in time

to resistance?

What accounts for the difference in time

to resistance?

What Happens at EGFR TKI Resistance in Patients with EGFR Mutation?

Kobayashi S et al. N Engl J Med 2005;352;(8):786-92. Copyright © 2005 Massachusetts Medical Society.

What Do We Know about T790M?

• Acquired point mutation resulting in threonine-to-methioine amino acid change at positive 790

Study Technique # cases/# EGFRm

Inukai, CR 2006Sequencing

Enriched PCR1/98 (1%)4/98 (4%)

Sequist, JCO 2008 Sequencing 2/34 (6%)

IPASS, NEJM 2009 SARMS 7/261 (3%)

Maheswaran, NEJM 2009 SARMS 10/36 (28%)

Rossell ASCO 2010Taqman + PNA probe

45/129 (35%)

Hata, JTO, 2010 PNA-LNA clamp 3/318 (1%)

Incidence of De-Novo T790M

Rosell R et al. Proc ASCO 2010;Abstract 7514.

Difference in PFS Is Partly Attributed to the Pre-existing T790M Mutation• SLCG: 129 erlotinib treated patients with activated

EGFR mutation subjected to Taqman sequencing for exon 20 T790M

• 35% found to have pre-treatment co-existence of T790M mutation

• PFS in T790M +ive: HR 4.35; 1.85-10.17 (p = 0.001)

Study N Median 95% CI p-value

T790M positive 45 12 7.6–16.4 0.05(*)

T790M negative 84 18 14.1–21.9

Oxnard et al. CCR publication online Dec 2010

Implication of “Acquired T790M”

Post-progression survival• Median T790M positive (n = 58), 19 months• Median T790M negative (n = 35), 12 months• p-value = 0.036

Overall survival• Median T790M positive (n = 58), 39 months• Median T790M negative (n = 35), 26 months• p-value = 0.007

Continue TKIContinue TKI

Current Treatment Options

Continue TKI and add chemotherapyContinue TKI and add chemotherapy

Continue TKI and add cetuximabContinue TKI and add cetuximab

Stop TKI and use chemotherapyStop TKI and use chemotherapy

Irreversible TKI (trial)Irreversible TKI (trial)

Clinical trialsClinical trials

PDby RECIST

PDby RECIST

EGFR TKI till PDby doctor’s discretion*

EGFR TKI till PDby doctor’s discretion*

* Doctor’s discretion: Symptomatic progression, multiple progression, threat to major organ…etc* Doctor’s discretion: Symptomatic progression, multiple progression, threat to major organ…etc

Primary endpoint: OSPrimary endpoint: OS

Treatment-Beyond-Progression Study Design

Advanced stageNSCLC with

EGFR mutation

Advanced stageNSCLC with

EGFR mutation

Platinum-baseddoublet

chemotherapy

Platinum-baseddoublet

chemotherapy

EGFR TKIEGFR TKI

Phase II studyBIBW +

cetuximab

Phase II studyBIBW +

cetuximab









LUX Lung 1PF299804

LUX Lung 1PF299804







BIBW 2992 Maintains Inhibitory Activity in Cell Line with Resistant Mutation (T790M)

Kinases BIBW 2992 Lapatinib Gefitinib

EGFR wt 0.5 3 3

EGFR L858R 0.4 8 0.8

EGFR L858R/T790M 10 >4,000 1,013

Anchorage independent growth

In vitro kinase assay

EC50 [nM] Wild-type

H1666L858RH3255

L858R + T790MNCI1975 Target

Binding mode

Gefitinib 157 5 >4,000 EGFR Reversible

Erlotinib 110 40 >4,000 EGFR Reversible

BIBW 2992 60 0.7 99 EGFR/HER2 Irreversible

CP 714,724 >4,000 561 >4,000 HER2 Reversible

Lapatinib 534 63 >4,000 EGFR/HER2 Reversible

Li D et al. Oncogene 2008;27;4702-11. Li D et al. Oncogene 2008;27;4702-11.

Randomization2:1

Oral BIBW 2992 50 mg once daily plus best supportive care

Oral placebo once daily plus best supportive care

Patients with:• Adenocarcinoma of the lung • Stage IIIB/IV • Progressed after one or two lines of chemotherapy (incl one platinum-based regimen)

and ≥12 weeks of treatment with erlotinib or gefitinib• ECOG 0–2

N = 585

Primary endpoint: Overall survival (OS)

Secondary: PFS, RECIST response, QoL, safety

Countries: North America, Europe, AsiaStatus: Recruitment complete, DBL for primary analysis 6 July 2010Countries: North America, Europe, AsiaStatus: Recruitment complete, DBL for primary analysis 6 July 2010

LUX-Lung 1 – Trial Design

Statistically significant across almost all subgroups

Miller VA et al. Proc ESMO 2010;Abstract LBA1.Miller VA et al. Proc ESMO 2010;Abstract LBA1.

PFS by Independent Review

• Placebo, PFS events = 133, median = 1.1 months• Afatinib, PFS events = 275, median = 3.3 months• Hazard ratio = 0.38• p-value < 0.001

Miller VA et al. Proc ESMO 2010;Abstract LBA1.Miller VA et al. Proc ESMO 2010;Abstract LBA1.

Overall Survival

• Placebo, deaths = 114 (58.5%), median = 11.96 months (est 4.7 months)

• Afatinib, deaths = 244 (62.6%), median = 10.78 months• Hazard ratio (afatinib vs placebo) = 1.077• p-value (one-sided) = 0.7428

Summary

• EGFR mutation: Biology– Lung cancer with EGFR mutation is driven by oncogenic addiction to

EGFR signaling– High affinity to EGFR TKI inhibit tumor growth

• EGFR TKI: Clinical evidence– IPASS confirmed the role of EGFR TKI as first-line therapy in patients

with EGFR mutation– Higher tumor response rate, longer PFS and better QOL– Similar survival is explained by crossover– Five other randomized studies confirmed the findings

• EGFR TKI: Resistance– T790M and c-MET inhibition are two known mechanisms of EGFR TKI

resistance– Active investigation ongoing

EGFR Mutation: Clinical Evidence and Resistance to TKIs Tony SK Mok, MD Professor, Department of...

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