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
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
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.
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
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
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
Garassino MC et al. Lancet Oncol. Published online July 22, 2013. http://dx.doi.org/10.1016/S1470-2045(13)70310-3
TOXICITIES
Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066
Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066
CLINICAL RESULTS IN PHASE III CLINICAL TRIALS (OVERALL PATIENT POPULATION)
Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066
CLINICAL RESULTS IN EGFRwt POPULATION
Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066
BASELINE CHARACTERISTICS OF PHASE III TRIALS
Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066
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.
Vazquez S et al. Anticancer Drugs 2013. DOI:10.1097/CAD.0000000000000066
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