REVISIÓN ESTADIOS IV SEGUNDA LÍNEA “WILD TYPE” Sergio Vázquez Estévez Servicio Oncoloxía Médica Hospital Universitario Lucus Augusti. Lugo Baiona, 25 Abril

REVISIÓN ESTADIOS IV SEGUNDA LÍNEA “WILD TYPE”

Sergio Vázquez EstévezServicio Oncoloxía MédicaHospital Universitario Lucus Augusti. Lugo Baiona, 25 Abril 2015

MOLECULAR BASIS

Wild-type EGFR plays an important role in tumour cell survival and proliferation

PI3K-AKT pathway MAPK pathway

EGFR WT

EGFR Mut+

P P P P

Yarden, et al. Mol Cell Biol 2001

Promotes cell survival

Promotes cell proliferation

Activation of EGFR/HER1

EGFRWild Type

P P P P

EGFRMut+

Ligand-dependent activation Ligand-independent activation

ATP

Jorissen, et al. Exp Cell Res 2003; Wang, et al. Nat Struct Mol Biol 2011

Inhibition of EGFR WT and EGFR Mut+ signalling by Erlotinib

Wild-type EGFR

EGFRMut+

Erlotinib prevents ATP binding and blocks

intracellular signalling

XXJorissen, et al. Exp Cell Res 2003; Wang, et al. Nat Struct Mol Biol 2011;

Moyer, et al. Cancer Res 1997; Carey, et al. Cancer Res 2006

ATP ATP

ERLOTINIB ERLOTINIB

Inhibition of EGFR WT and EGFR Mut+ signalling by Erlotinib

Datos de PK del estudio BR.21 y del estudio de unión a proteínas plasmáticas OSI-774-TILL-01; Valores IC50 de la inhibición celular de la actividad quinasa.

Carey K, et al. Cancer Res 2006;66:8163–71

28 56 84 112 140 168

1,000

100

10

0

Time (days)

Fre

e E

rloti

nib

con

cen

trati

on

(n

g/m

L)

IC50 EGFR wild-type

IC50 EGFR

mut

CLINICAL RESULTS

BR.21

Shepherd, et al. N Engl J Med 2005

BR.21: Patient characteristics

CharacteristicTarceva(n=488)

Placebo(n=243)

Median age (years) 62 59

Female (%) 35 34

PS 0, 1 (%) 13, 52 14, 54

PS 2, 3 (%) 26, 9 23, 9

Adenocarcinoma (%) 50 49

Prior regimens 1, 2, 3 (%) Prior platinum (%)

50, 49, 193

50, 49, 192

Response to prior chemotherapy (%) CR/PR SD PD

403921

403921

Measurable disease (%) 88 87

Tarceva (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

*HR and p (log-rank test) adjusted for stratificationfactors at randomisation and HER1/EGFR status

BR.21: Overall Survival

42.5% improvement in median survival

Surv

ival dis

trib

uti

on f

unct

ion

Survival time (months)

HR=0.73, p<0.001*

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Tarceva

Placebo

Shepherd F, et al. N Engl J Med 2005;353:123-32

BR.21: Progression-free survival

HR=0.61, p<0.001*

Tarceva (n=488)

Placebo (n=243)

Median survival (weeks) 9.7 8.0

6 months PFS (%) 25 10

25%

10%

Surv

ival dis

trib

uti

on f

unct

ion

Survival time (months)

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Tarceva

Placebo

Shepherd F, et al. N Engl J Med 2005;353:123-32

*HR and p (log-rank test) adjusted for stratificationfactors at randomisation and HER1/EGFR status

BR.21: OS benefits with Tarceva vs placebo across patient subgroups in BR.21

Subgroup analyses of OS in the BR.21 study showed that the survival benefit with Tarceva versus placebo was evident in almost all patient subgroups. Active second-line treatment with Tarceva should therefore be considered for patients regardless of their clinical or patient characteristics

Shepherd, et al. N Engl J Med 2005

Kaplan-Meier Survival Curves BR21

Role KRAS and EFGR in BR21. J Clin Oncol 26:4268-4275.

SATURN: Tarceva versus placebo as 1st line maintenance in NSCLC following chemotherapy

Stratification factors: EGFR IHC (positive vs negative vs indeterminate) Stage (IIIB vs IV) ECOG PS (0 vs 1) CT regimen (cis/gem vs carbo/doc vs others) Smoking history (current vs former vs never) Region

1:1

Chemonaïve advanced

NSCLCn=1,949

Non-PDn=889

4 cycles of 1st-line

platinum-based

doublet*Placebo PD

Erlotinib150mg/day

PD

Mandatory tumour sampling

*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel; cisplatin/vinorelbine; carboplatin/gemcitabine; carboplatin/docetaxel; carboplatin/paclitaxelEGFR = epidermal growth factor receptor; IHC = immunohistochemistry

Co-primary endpoints: PFS in all patients PFS in patients with EGFR IHC+ tumours

Secondary endpoints: Overall survival (OS) in all patients and those

with EGFR IHC+ tumours; OS and PFS in EGFR IHC– tumours; biomarker analyses; safety; time to symptom progression; quality of life (QoL)

Cappuzzo, et al. Lancet Oncol 2010

PFS

pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0

0 8 16 24 32 40 48 56 64 72 80 88 96

Time (weeks)

Log-rank p<0.0001HR=0.68 (0.56–0.83)

Erlotinib (n=252)

Placebo (n=235)

11.1 12.4

Log-rank p=0.0059HR=0.74 (0.60–0.92)

Erlotinib (n=184)

Placebo (n=210)

11.3 12.1

1.0

0.8

0.6

0.4

0.2

0

0 8 16 24 32 40 48 56 64 72 80 88 96

Time (weeks)

SATURN: PFS according to response to first-line chemotherapy (ITT population)

SD CR/PR

Measured from time of randomisation into the maintenance phaseCoudert, et al. Ann Oncol 2012

SATURN: OS benefits with Tarceva vs placebo across SD patient subgroups

The OS benefits seen across clinical and patient characteristics with Tarceva versus placebo in BR.21 were also seen across subgroups in patients who had SD after first-line chemotherapy in the SATURN study

OS in SATURN according to clinical subgroups of patients with SD following first-line chemotherapy

Coudert, et al. Ann Oncol 2012

SATURN: OS in EGFR wild-type group with SD on first-line chemotherapy

OS

pro

bab

ilit

y

1.0

0.8

0.6

0.4

0.2

0Time (months)

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

8.7 12.4

Erlotinib (n=114)

Placebo (n=103)

HR=0.65 (0.48–0.87)Log-rank p=0.0041

Measured from time of randomisation into the maintenance phase Coudert, et al. Ann Oncol 2012

+3,7months

Meta-analysis Erlotinib vs placebo inEGFR WT NSCLC

PFS/TTF*

Osarogiagbon, et al. ASCO 2013; Zhang, et al. Lancet Oncol 2012

OS

BR.21

SATURN

BR.21 + SATURNmeta-analysis

BR.21

SATURN

BR.21 + SATURNmeta-analysis

0.2 0.4 0.6 0.8 1.0 1.5 2.0 0.2 0.4 0.6 0.8 1.0 1.5 2.0

HR

Favours EGFR TKI Favours placebo

HR

Favours EGFR TKI Favours placebo

Efficacy BR.21 and TRUST

Real practice confirms efficacy of BR.21:

1. Shepherd, et al. N Engl J Med 2005; 2. Heigener, et al. Lung Cancer 2011; 3. Reck, et al. J Thorac Oncol 2010

TITAN was an international, phase III study of second-line Tarceva versus chemotherapy (docetaxel or pemetrexed) in patients with advanced NSCLC. There were no significant differences in PFS or OS between the two treatment arms

TITAN: 2L Tarceva vs chemotherapy in patients with advanced NSCLC

TITAN: PFS and OS in patients with EGFR WT disease

Favours Erlotinib Favours chemotherapy*HR

OS

PFS

0.1 0.25 1.0 10.00.5 2.0 4.0

nHR (95% CI)

149

1491.25 (0.88–1.78)

0.85 (0.59–1.22)

Patients with EGFR WT disease

*Pemetrexed or docetaxel at the investigators’ discretion

Ciuleanu, et al. Lancet Oncol 2012

TITAN: OS in EGFR WT populationO

S e

sti

mate

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

Erlotinib (n=75)

Chemotherapy (n=74)HR=0.85 (0.59–1.22)

4.4 6.6

1.0

0.8

0.6

0.4

0.2

0

Time (months)

Ciuleanu, et al. Lancet Oncol 2012

The phase III HORG study assessed second-/third-line Tarceva versus pemetrexed in patients with advanced NSCLC. There were no significant differences in TTP or OS between the two treatment arms

HORG: 2/3L Erlotinib vs Pemetrexed in patients with advanced NSCLC

HORG: TTP and OS in patients with EGFR WT disease

Favours Tarceva Favours pemetrexed

HR

OS

TTP

0.1 0.25 1.0 10.00.5 2.0 4.0

nHR (95% CI)

55

550.92 (0.61–1.38)

1.19 (0.77–1.84)

Patients with EGFR WT disease

Karampeazis, et al. Cancer 2013

PFS Erlotinib vs Chemotherapy in EGFR WT disease

1.9

2.7

2.12.3

Zugazagoitia, et al.1

Chemotherapy:pemetrexed

Med

ian

PFS

(m

on

ths)

1. Zugazagoitia, et al. Oncology 2013; 2. Fiala, et al. Neoplasma 2013

p=0.683

p=0.879

n=150n=129

Fiala, et al.2

Chemotherapy: pemetrexed, docetaxel or

other

n=19n=21

ErlotinibChemotherapy

Meta-analysis of Erlotinib in NSCLC EGFR wild-type

OVERALL SURVIVAL Erlotinib EGFRwt HR: 0,78 (0,65-0,93) p= 0,006

Jazieh et al. Annals of Thorac Med, vol 8, issue 4, oct-dec 2013

Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3






TAILOR: 2L docetaxel vs Tarceva in Italian patients with EGFR WT disease

The phase III TAILOR study was conducted by community oncologists in Italy, which compared second-line Tarceva with docetaxel in patients with EGFR WT NSCLC.


PFS OS

Tarceva (n=109)Docetaxel (n=110)

Tarceva (n=109)Docetaxel (n=110)

0S p

robab

ility

1.0

0.8

0.6

0.4

0.2

0

Time (months)

5.4 8.2

0 2 4 6 8 10 12 14 16 18 20 1 2 3 4 5 6 7 8

2.4 2.9

PFS

pro

babili

ty

1.0

0.8

0.6

0.4

0.2

0

Time (months)

HR=0.72 (0.55–0.94)*Log-rank p=0.01

HR=0.78 (0.51–1.05)*

Log-rank p=0.10

*Unadjusted HR shown; adjusted PFS HR 0.71 (0.53–0.95), p=0.02; OS HR 0.73 (0.53–1.00), p=0.049HRs shown above are for docetaxel vs Tarceva. For comparison purposes, 1/HR values are; 1.39 (PFS) and 1.28 (OS)

0




TOXICITIES

Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066


CLINICAL RESULTS IN PHASE III CLINICAL TRIALS (OVERALL PATIENT POPULATION)


CLINICAL RESULTS IN EGFRwt POPULATION


BASELINE CHARACTERISTICS OF PHASE III TRIALS


Clinical Lung Cancer, Vol. 7, No. 6, 389-394, 2006

ANOTHER TREATMENT SELECTION FACTORS IN EGFRwt POPULATION

• Erlotinib is taken orally.• The ORR and progression-free interval related

to first-line treatment.• Toxicities related to first-line treatment.• Patient’s comorbid conditions.


Erlotinib as second-line therapy for patients with advanced non-squamous EGFR-wild type lung cancer

Characteristics of patients and tumors at baseline

Total(n=47)

Sex male, n (%) 39 (83.0)Age, median age (range) 62.0 (38.0–83.0)Smoking habits, n (%) Smokers 16 (37.2) Ex-smokers 18 (41.9) Non-smokers 9 (20.9)ECOG PS, n (%) 0 4 (8.5) 1 36 (76.6) 2 7 (14.9)Tumor histology, n (%) Adenocarcinoma 38 (80.9) Large-cell lung carcinoma 2 (4.3) Others 7 (14.9)Staging of lung cancer, n (%) Primary tumor T1b 2 (4.3) T2 / T2a 11 (23.4) / 1 (2.1) T3 4 (8.5) T4 21 (44.7) Tx 8 (17.0) Regional lymph nodes N0 9 (19.1) N2 18 (38.3) N3 17 (36.2) Nx 3 (6.4) Distant metastasis M0 1 (2.1) M1/ M1a 43 (91.5) / 3 (6.4)Main metastasis locations, n (%) Bone 18 (38.3) Lungs 15 (31.9) Kidney 13 (27.7) Pleura 13 (27.7)

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of

Sur

viva

l

3 6 9 12

Time (months)0

Median PFS=3.2 (2.7–4.2)

Progression-Free SurvivalProgression-Free Survival

Median PFS=2.33 (95% CI, 1.84–2.83)

Patients at risk:

Number of events:

47

0

18

29

3

44

1

46

-

-

0.0

0.2

0.4

0.6

0.8

1.0

Pro

babi

lity

of

Sur

viva

l

6

Time (months)0

Median PFS=3.2 (2.7–4.2)

Progression-Free SurvivalProgression-Free Survival

Median PFS=2.6 (0.4–10.9)

Patients at risk:

Number of events:

47

0

21

26

12 18 24 30 36 42 48

8

36

4

40

2

42

1

42

Survival function Censored

-

-

-

-

Overall Survival

Median OS=4.00 (95% CI, 1.18–6.82)

Erlotinib as second-line therapy for patients with advanced squamous EGFR-wild type lung cancer (GGCP 55/012)

Design

CONCLUSIONS

• SIMILAR EFFICACY OF THE THREE AGENTS (DOCETAXEL, PEMETREXED, ERLOTINIB) IN THE SECOND-LINE TREATMENT OF ADVANCED EGFRwt NSCLC.

• SELECTION OF TREATMENT WILL HAVE TO BE ACCORDING TO:– HISTOLOGICAL TYPE– PATIENT PREFERENCE– PATIENT’S COMORBID CONDITIONS– PREVIOUS OR RESIDUAL TOXICITIES– RISK OF NEUTROPENIA– RESPONSE AND DURATION OF FIRST-LINE CHEMOTHERAPY– HISTORY OF SMOKING

Documents

REVISIÓN ESTADIOS IV SEGUNDA LÍNEA “WILD TYPE” Sergio Vázquez Estévez Servicio Oncoloxía Médica Hospital Universitario Lucus Augusti. Lugo Baiona, 25 Abril