Vera Hirsh, MD, FRCPC McGill University Health Centre Montreal, QC, CANADA

Clinical data on EGFR-TKIs and Overcoming Resistance in

Metastatic NSCLC

2nd Quebec Conference on Therapeutic Resistance in Cancer

Vera Hirsh, MD, FRCPC

McGill University Health Centre

Montreal, QC, CANADA

EGFR expression in human tumours

NSCLC 40-80%

Prostate 40-80%

Gastric 33-74%

Head and neck 90-100%

Breast 14-91%

Colorectal 25-77%

Pancreatic 30-50%

Ovarian 35-70%

Invasion

Metastasis

Late-stage disease

Poor outcome

Tumours showinghigh EGFR expression

High expressiongenerally associatedwith

ATP

Ras-Raf-MAPKProliferation

Pi3K-AKTSurvival

Ligand

Extracellular domain

Trans-membrane domain

Tyrosine kinase domain

Tyrosine phosphorylation

EGFR internalisationDegradation/recycling

EGFR signals for longerat the cell membrane

Wild Type EGFR Mutant EGFR

EGFR mutation causes conformational change and EGFR mutation causes conformational change and

increased activationincreased activation

Arteaga 2006, Gadzar et al 2004, Hendricks et al 2006, Sordella et al 2004

181921 20

N-lobe

Transmembraneregion

Extracellulardomain

ATP binding cleft

C-lobe

A-loop Chelix P-loop

TK domain

Regulatory domain

Distribution of mutation types (% of mutations)

Literature review Asian studies Non-Asian studies

Most prevalent mutation types Literature (n=1523) Literature (n=583)

Exon 19 deletion 51% 58%

Exon 21 point mutation L858R

42% 32%

Exon 20 2% 6%

Exon 18 G719A/C 3% 2%

Exon 21 L861Q 1% 1%

The distribution of activating mutations among EGFR mutation The distribution of activating mutations among EGFR mutation positive patients is similar in Asian and non-Asian studiespositive patients is similar in Asian and non-Asian studies

Some patients had more than one mutation type

BR.21 Study Design

RANDOM I ZE

Erlotinib* 150 mg daily

Placebo “150 mg”

daily

*2:1 Randomization

Stratified by:CentrePS, 0/1 vs 2/3Response to prior Rx (CR/PR:SD:PD)Prior regimens, (1 vs 2)Prior platinum, (Yes vs no)

21%

31%

*HR and P-value adjusted for stratification factors at randomization plus HER1/EGFR status.

BR.21: Overall Survival

42.5% improvement in median survival

Survival time (months)

Erlotinib

Placebo

HR=0.70 (95% CI, 0.58-0.85); P < 0.001*

Erlotinib (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Shepherd et al. N Engl J Med. 2005;353:123-132.

IPASS: first-line study design

Gefitinib(250 mg/day)

Carboplatin (AUC 5 or 6)/

paclitaxel (200 mg/m2)

3 weekly†

1:1 randomisation

*Never smokers, <100 cigarettes in lifetime; light ex-smokers, stopped 15 years ago and smoked 10 pack years†Maximum of 6 cycles Carboplatin / paclitaxel was offered to gefitinib patients upon progression; AUC, area under curve

Patients• Chemo-naïve• Age ≥18 years • Adenocarcinoma histology

• Never or light ex-smokers*

• Life expectancy≥12 weeks

• PS 0-2• Measurable stage IIIB/ IV disease

Primary• PFS (non-inferiority)

Secondary• ORR• OS • QoL• Disease-related symptoms • Safety and tolerability

Exploratory• Biomarkers

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

Endpoints

Mok et al 2009

IPASS: ORR

Odds ratio (95% CI) = 1.59 (1.25, 2.01) p=0.0001

Patients (%)

(n=609) (n=608)

Odds ratio >1 implies a greater chance of response on gefitinibOdds ratio and p-value from logistic regression with covariates Mok et al 2009

IPASS: pre-planned analysis of ORR by EGFR mutation status

Gefitinib Carboplatin / paclitaxel

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

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

ORR (%)

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

ITT populationOR>1 implies greater chance of response on gefitinibOR and p-value from logistic regression with covariate

71.2

47.3

1.1

23.5

Mok et al 2009

IPASS: PFS

Primary Cox analysis with covariates; ITT populationHR <1 implies a lower risk of progression on gefitinibITT, intent-to-treat

0 4 8 12 16 20 24 Months0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

609453 (74.4%)

608497 (81.7%)

NEvents

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

GefitinibCarboplatin /

paclitaxel

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

5.761%48%25%

5.874%48%7%

Mok et al 2009

IPASS: pre-planned analysis of PFSby EGFR mutation status

0 4 8 12 16 20 24

Time from randomisation (months)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f P

FS

N

Median (m)

Gefitinib

132

9.5

Carboplatin / paclitaxel

129

6.3

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

Primary Cox analysis with covariates; intent-to-treat (ITT) populationHazard ratio (HR) <1 implies a lower risk of progression on gefitinib Mok et al 2009

EGFR M+

0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y o

f P

FS


N

Median (m)

Gefitinib

91

1.5


85

5.5

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

EGFR M-

IPASS: EGFR mutation is a strong predictor for differential PFS benefit between gefitinib and doublet chemotherapy

EGFR M+HR=0.48, 95% CI 0.36, 0.64

p<0.0001

EGFR M-

HR=2.85, 95% CI 2.05, 3.98

p<0.0001

0 4 8 12 16 20 24


0.0

0.2

0.4

0.6

0.8

1.0Probabilityof PFS

Gefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)Carboplatin / paclitaxel EGFR M- (n=85)

M+, mutation positive; M-, mutation negative

Treatment by

subgroup interaction

test, p<0.0001

PFS by EGFR mutation type: IPASS

Post hoc Cox analysis with covariates; ITT population

Exon 19 deletion L858R

0 4 8 12 16 20 24 0 4 8 12 16 20 240.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

of

PF

S0.0

0.2

0.4

0.6

0.8

1.0

Pro

ba

bil

ity

of

PF

S

Time from randomisation (months)Time from randomisation (months)

N

Gefitinib

66


74

HR (95% CI) = 0.337 (0.255, 0.560) p<0.0001

N

Gefitinib

64


47

HR (95% CI) = 0.553 (0.352, 0.868) p=0.0101

Mok et al 2009

IPASS: QoL and symptom improvement rates for overall population

p=0.0148 p<0.0001 p=0.3037% patients with sustained clinically relevant improvementa

Evaluable for QoL population ; logistic regression model with covariatesa≥6-point improvement (FACT-L and TOI); ≥2-point improvement (LCS), maintained ≥21 days

Gefitinib (n=590) Carboplatin/paclitaxel (n=561)

Mok et al 2009

IPASS: post hoc QoL and symptom improvement rates for EGFR M+ patients

Evaluable for QoL population; logistic regression model with covariatesa6-point improvement (FACT-L and TOI); 2-point improvement (LCS),maintained ≥21 days

70.2 70.275.6

44.538.3

53.9

0

10

20

30

40

50

60

70

80

Total FACT-L TOI LCS

p<0.0001 p<0.0001 p=0.0003

% patients with sustained clinically relevant improvementa

Gefitinib (n=131) Carboplatin / paclitaxel (n=128)

Mok et al N Engl J Med 2009

IPASS: 2010 updated OS analysis (ITT)

0 8 16 28 36 44 52

0.0

0.2

0.4

0.6

0.8

1.0Probabilityof survival

Patients at risk:

4 12 20 24 32 40 48

C / PGefitinib 609

608468443

331301

192151

9765

139

00

514525

400364

270232

227183

148119

4428

31

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

Gefitinib (n=609)

Carboplatin / paclitaxel (n=608)

HR (95% CI)

0.90 (0.79, 1.02); p=0.109

No. events

G 484 (80%)

C / P 470 (77%)

Median OS

G 18.8 months

C / P 17.4 months

Yang CH et al. ESMO 2010

IPASS: 2010 summary of subsequent systemic therapy (ITT)

Gefitinib (n=609)* C / P (n=608)

No further systemic treatment 31% 38%

Chemotherapy 65% 41%

Platinum based** 60% 9%

C / P** 49% 1%

EGFR TKI** 20% 52%

Gefitinib# 5% 41%

Erlotinib# 12% 14%

Other# 5% 6%

*% exclude 20 patients in the gefitinib arm with ongoing randomised treatment**Patients may have also received other chemotherapy and / or EGFR TKI during the study. Excludes single platinum based chemotherapy #Categories are not mutually exclusiveRadiotherapy, surgery, medical procedures and other treatments excluded


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


Pro

bab

ilit

y o

f su

rviv

al

EGFR mutation -

520 4 8 12 16 20 44 4824 28 32 36 40

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


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

Gefitinib (n=132)


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

Gefitinib (n=91)


HR (95% CI)

1.18 (0.86, 1.63); p=0.309

No. events

G 82 (90%)

C / P 74 (87%)

Median OS

G 11.2 months

C / P 12.7 months

Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed


IPASS: 2010 overall survival: EGFR mutation non-evaluable (ITT)

0 4 8 24 32 40 52

0.0

0.2

0.4

0.6

0.8

1.0Probabilityof survival

Patients at risk:

12 16 20 28 36 44 48

386394C / P

Gefitinib 319326

295274

150109

9968

2812

00

257225

214188

174139

13087

6536

61

00


Primary Cox analysis with covariates; a hazard ratio <1 implies a lower risk of death on gefitinib*No formal adjustment for multiple testing was made, therefore statistical significance at the traditional 5% level cannot be claimed

Gefitinib (n=386)


HR (95% CI)

0.82 (0.70, 0.96); p=0.015*

No. events

G 298 (77%)

C / P 301 (76%)

Median OS

G 18.9 months

C / P 17.2 months


4 8 16 2412 20

10821

10358

7143714

11120

0000

31271

3010

IPASS: PFS and OS by known EGFR mutation status


Pro

bab

ilit

y o

f p

rog

ress

ion

-fre

e su

rviv

al

Patients at risk:Gefitinib M+Gefitinib M-C / P M+C / P M-

1.0

0.8

0.6

0.4

0.2

0.00

13291

12985

PFS (2008)

Gefitinib EGFR M+

Gefitinib EGFR M-

C / P EGFR M+

C / P EGFR M-

13291

12985

1.0

0.8

0.6

0.4

0.2

0.00 4 8 12 16 20 5244

Time from randomisation (months)P

rob

abil

ity

of

surv

ival

OS (2010)

24 28 32 36 40 48

12669

12376

12152

11257

103409544

88298033

70266825

0000

6171

58195519

46164816

38114011

248263

115151

3001

Mutation +

Mutation -

Patients at risk excludes censored patients and those who have experienced an event Yang CH et al. ESMO 2010

IPASS conclusions: updated survival analysis

• Mature OS (secondary endpoint) was similar for gefitinib and carboplatin / paclitaxel with no statistically significant difference between treatments in the overall population

• A consistent OS outcome was observed across clinical subgroups with no significant difference in OS

• There was no significant difference in OS across the EGFR biomarker subgroups

• The true effect of the initial randomised treatment on OS is likely to have been confounded by the subsequent therapy, in particular the switching of patients to the alternative study therapy


IPASS conclusions: overall summary

• IPASS has demonstrated that positive EGFR mutation status is predictive of benefit from treatment with gefitinib over chemotherapy in terms of PFS, ORR and HRQoL

• PFS is an endpoint unlikely to be confounded by subsequent treatments, therefore is a more appropriate endpoint for evaluation of treatment effect in first-line treatment of NSCLC than OS

• IPASS has demonstrated the importance of biomarker testing in NSCLC, making a significant step towards personalised medicine

• IPASS has changed clinical practice and treatment guidelines for patients with advanced NSCLC who harbour an EGFR mutation

HRQoL, health-related quality of life; NSCLC, non-small-cell lung cancer; ORR, objective response rate


Kobayashi et al 2009; Lee et al 2009

†Eastern Cooperative Oncology Group*Maximum 9 cycles

Recently reported Phase III studies of gefitinib as first-line treatment for NSCLC in selected

populations

Patients• Chemo-naïve

• EGFR mutation-positive

• PS 0–1

Gefitinib250 mg/day

Carboplatin AUC 6 & paclitaxel 200 mg/m2

3-weekly

Endpoints

Primary• PFS (superiority)

Secondary• OS, ORR, QoL,

disease-related symptomssafety and tolerability

NEJ002 (Japan)

Gefitinib250 mg/day

Gemcitabine (1250 mg/m2) &

cisplatin (80 mg/m2) 3-weekly*

Endpoints

Primary• OS

Secondary• PFS, ORR, QoL,

disease-related symptomssafety and tolerability

First-SIGNAL (Korea)

Patients• Chemo-naïve

• Adenocarcinoma

• Never smokers

• ECOG† PS 0–2

84.6

37.5

0

20

40

60

80

100

PFS and ORR with first-line gefitinib versus doublet chemotherapy in EGFR mutation-positive Asian patients across three Phase III studies

71.2

47.3

0

20

40

60

80

100

p<0.0001

74.5

29.0

0

20

40

60

80

100

p<0.001p=0.002IPASS NEJ002First-SIGNAL

0 4 8 12 16 20 24

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

months

0 100 200 300 400 500

HR (95% CI) = 0.36 (0.25, 0.51) p<0.001

days

Mok et al 2009; Lee et al 2009; Kobayashi et al 2009

Gefitinib (n=98)C / P (n=100)

OR

R %

OR

R %

OR

R %

Gefitinib (n=132)C / P (n=129)

Gefitinib (n=26)G / C (n=16)

HR (95% CI) = 0.613 (0.308, 1.221) p=0.084

0 5 10 15 20 25 30

months

Pro

ba

bil

ity

of

PF

S

Pro

ba

bil

ity

of

PF

S

Pro

ba

bil

ity

of

PF

S

0.0

0.2

0.4

0.6

0.8

1.0

0.0

0.2

0.4

0.6

0.8

1.0

0.0

0.2

0.4

0.6

0.8

1.0

1st-line treatment for mutation positive patients with NSCLC

IIIB/IV NSCLCchemotherapy-naïve

EGFR mutation

Erlotinib

Platinum +taxane or gemcitabine

EURTAC – Spanish Lung Cancer GroupPhase III1:

New-generation erbB inhibitors

Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A242 Solca F et al. Proceedings, AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics. 2005;118:A244

Reversible Irreversible

Gefitinib BIBW 2992

Erlotinib Neratinib (HKI-272)

AV-412

XL647

Lapatinib PF-00299804

EGFR [nM] 0.5

HER2 [nM] 14

c-Met [nM] >10000

VEGFR [nM] >10000

BIBW 2992 – potency and selectivity (IC50):

Resistance mutationsMutations known to cause resistance to 1st-generation EGFRi include:•Exon 20 in-frame insertions•Exon 20 point-mutations (e.g. T790M)

Sharma et al. Nat Rev Cancer. 2007;7:169–181

BIBW 2992 – active against resistance mutation

NCI-H1975 cells express L858R/T790M double-mutant EGFR

Li et al. Oncogene. 2008;27:4702–4711

LUX-Lung 1: Trial design

Randomization 2:1(Double Blind)

Oral afatinib 50 mg once daily plus BSC

Oral placebo once daily plus BSC

Primary endpoint: Overall survival (OS)

Secondary: PFS, RECIST response, QoL (LC13 & C30), safety

• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter• Exploratory biomarkers:

Archival tissue testing for EGFR mutations (optional; central lab)Serum EGFR mutational analysis (all patients)

• Radiographic assessments at 4, 8, 12 wks and every 8 wks thereafter• Exploratory biomarkers:

Archival tissue testing for EGFR mutations (optional; central lab)Serum EGFR mutational analysis (all patients)

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

Demographics/prior treatment

31

Afatinib (n=390) Placebo (n=195)

Median age, (range) 58 (30–85) yrs 59 (32–82) yrs

Female (%) 59 60

ECOG PS 0/1/2 (%) 24/69/8 27/65/8

Caucasian/East Asian/other (%) 31/58/11 37/56/7

Never smoker/Light ex-smoker/Other (%) 63/7/30 62/7/31

Stage IIIB/IV (%) 4/96 3/97

Prior chemo: 1 line/> 1 line (%) 59/41 61/39

Prior EGFR TKI: E/G/E+G (%) 55/39/6 55/41/4

Median duration of prior E/G 10.2 mos 9.7 mos

≥ 48 wks duration on prior E/G (%) 45 47

< 8 wks between prior E/G and randomization (%)

57 63

CR/PR on prior E/G (%) 46 44

Disease control rate and objective responses

Independent Review

Afatinib (%) Placebo (%)

PR, (regardless of confirmation)

PR, (confirmed)

13*

7*

0.5

0.5

SD ≥ 8 wks 51 18

DCR (PR+SD) ≥ 8 wks 58** 19

Median duration of confirmed response: 24 weeks

* P < 0.01 compared to placebo** P < 0.0001 compard to placebo

Median duration of confirmed response: 24 weeks

* P < 0.01 compared to placebo** P < 0.0001 compard to placebo

PFS by independent review

Primary analysis: Overall survival

Summary of anticancer therapy after treatment discontinuation

Anticancer therapy Afatinib (%) Placebo (%)

Any 68 79

Chemotherapy 61 70

Pemetrexed 36 47

Docetaxel 21 26

Vinorelbine 15 19

Other 26 26

EGFR TKI 12 24

Anti-angiogenesis 4 6

Radiotherapy 9 14

Patient reported outcomes

*All scores were estimated from the EORTC QLQ-LC13 except for “Short of Breath” and “Pain” which used EORTC QLQ-C30; improved means that EORTC symptom scores were ≥10 points lower than baseline at any time during the study

**EORTC cough, dyspnea and pain endpoints as pre-specified in the trial protocol

LUX-Lung 2: Study design

Patients with: Adenocarcinoma of the lung Stage IIIB/IV EGFR mutation Chemo-naïve or progressive disease following first-line chemotherapy ECOG 0–2

N=120

Oral BIBW 2992 once-daily until disease progression or undue toxicity

Response assessment at 4, 8, 12 weeks; every 8 weeks thereafter

Primary endpoint: objective response rateSecondary endpoints: PFS, clinical benefit;

time to OR; duration of OR; OS; safety

ResultsHigh degree of efficiency observed:

- For all patients:

Confirmed ORR: 60%

DCR: 86%

Median PFS: 14 months

Median OS: 24 months

-For patients with del19/L858R

Confirmed ORR: 64%

DCR: 88%

Median PFS: 15 months

-Similar efficacy results in the first and second-line settings and across all subgroups-Similar magnitude of efficacy in patients with L858R as with del19 mutations

LUX-Lung 3: Phase III first-line trial in lung cancer patients with EGFR mutations

Patients (n=330) with: Stage IIIB/IV adenocarcinoma of the lung Presence of EGFR mutation in the tumour tissue ChemonaiveECOG 0 or 1

Randomization

Oral BIBW 2992 40 mg once-daily

Cisplatin/pemetrexed

2:1

Primary endpoint: PFS

Conclusion

• EGFR-TKIs for EGFR-mutated tumours are becoming standard Rx in first-line metastatic NSCLC

• BIBW 2992 activity in NSCLC, especially in EGFR-mutated tumours

- Active against receptors that are resistant to first generation inhibitors (e.g.EGFRL858R/T790M)

THANK YOU!

MC GILL UNIVERSITY

Documents

Vera Hirsh, MD, FRCPC McGill University Health Centre Montreal, QC, CANADA