Afatinib

Il trattamento di prima linea nel
paziente con mutazione EGFR
Vanesa Gregorc
Thoracic Oncology and Melanoma area coordinator
IRCCS Ospedale San Raffaele
Milano
Who should be tested for EGFR mutations?
•
•
•
•
Non-squamous NSCLC
NSCLC NOS
Adenosquamous NSCLC
Squamous cell carcinoma if
– Low smoking exposure
– Young age
Smoking exposure and EGFR mutations
Pack-year
%EGFR+
0-15
>=16
30-51
0-10
Pham et al, JCO 2006
Lung Cancer Consortium Mutation
- 16 US cancer centers
- Test 10 driver mutations
in 1000 lung
adenocarcinomas
At half of LCMC sites, multiplexed testing for all mutations
is now routine practice in their pathology departments
(ASCO 2011)
EGFR mutations
Sequist et al, JCO 2007
Test EGFR su DNA circolante
Douillard et al, Br J Cancer 2013
Quale EGFR-TKI
in EGFR mutati? Indicazioni AIFA
Gefitinib
Indicato in qualunque linea in EGFR mutati
Erlotinib
Indicato in I linea negli EGFR mutati;
II-III linea indipendentemente da EGFR
Afatinib
Indicato in I linea negli EGFR mutati
1st line: EGFR-TKIs vs CT
Author
Study
N (EGFR
mut. +)
EGFR-TKI
Median PFS*
(months)
PFS* HR
Mok
IPASS
261
Gefitinib
9.8 vs. 6.4
0.48
Lee
First-SIGNAL
42
Gefitinib
8.4 vs. 6.7
0.54
Mitsudomi
WJTOG 3405
177
Gefitinib
9.2 vs. 6.3
0.49
Maemondo
NEJGSG002
228
Gefitinib
10.8 vs. 5.4
0.30
Zhou
OPTIMAL
154
Erlotinib
13.1 vs. 4.6
Rosell
EURTAC
175
Erlotinib
9.7 vs. 5.2
0.37
Yang
LUX-Lung 3
345
Afatinib
11.1 vs. 6.9
0.58
364
Afatinib
11.0 vs 5.6
0.28
296
Icotinib
NA
NA
Wu
Shi
*Primary endpoint
LUX-Lung 6
CONVINCE
0.16
PFS with TKIs better for del19 than L858R
Del19 HR: 0.24
L858R HR: 0.48
MTE12: Therapy for Driver Mutation Positive Advanced NSCLC – Federico Cappuzzo
p for interaction < 0.001
Lee et al. JCO 2015
PFS
Lancet Oncology, Feb 2015
LUX-Lung 3: OS in Common Mutations and Del19
in Asian and Whole Population
Common Mutations
Del19
LUX-Lung 3
LUX-Lung 3
(All)
(Asian population)
LUX-Lung 3
LUX-Lung 3
(All)
(Asian population)
Afatinib
n=203
Cis/Pem
n=104
Afatinib
n=149
Cis/Pem
n=75
31.6
28.2
31.7
29.1
PFS in overall population
Median,
months
HR (95%CI)
P value
0.78 (0.58–1.06)
P=0.1090
0.82 (0.57–1.17)
P=0.2771
0.6
0.4
0.2
Afatinib
n=82
Cis/Pem
n=41
33.3
21.1
33.3
22.9
0.54 (0.36–0.79),
P=0.0015
0.57 (0.36–0.90)
P=0.0153
0.6
0.4
Afatinib (All)
Afatinib (Asian)
Afatinib (Asian)
Cis/Pem (All)
Cis/Pem (All)
Cis/Pem (Asian)
Cis/Pem (Asian)
0
0
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51
0
3
6
9
12 15 18 21 24 27 30 33 36 39 42 45 48 51
Time (months)
Time (months)
No. of patients
Afatinib
Cis/Pem
Afatinib
Cis/Pem
Cis/Pem
n=57
HR (95%CI)
P value
0.8
0.2
Afatinib (All)
Afatinib
n=112
Median,
months
Estimated OS probability
Estimated OS probability
0.8
1.0
PFS in overall population
1.0
203 197 188 181 171 162 143 133
104 98 92 86 81 71 63 55
149 148 141 135 126 121 106 98
75 70 66 61 57 51 45 42
No. of patients
121
52
91
40
108 101 90 58
47 40 35 26
81 77 67 47
37 31 27 20
Sequist et al. CMSTO 2014. Oral presentation. Abstract 3341.
49
20
41
17
32
10
29
10
9
5
9
5
1
1
1
1
0
0
0
0
Afatinib 112 108 105 102 96 93
Pem/Cis 57 55 50 46 43 37
Afatinib 82 81 78 75 70 68
Cis/Pem 41 40 37 33 31 26
83
33
59
22
80
27
56
20
72
25
52
18
62
22
45
17
58
20
43
15
51
16
37
11
34
10
27
7
30
6
24
5
21
1
18
1
6
1
6
1
1
0
1
0
0
0
0
0
HR for OS in del19
Kato T et al., ISPOR 2015; PCN40
HR for OS in L858R
Crossover from CT to TKI
75%
53%
52%
95%
76%
Adapted from West, ASCO 2014
HR for OS in L858R
Kato T et al., ISPOR 2015; PCN40
Outcome in caso di
mutazioni non comuni
Yang et al, WCLC 2013
Survey (n = 562, 10 countries):
first-line choice in EGFR mutated
Spicer et al, ELCC 2015
OPEN Questions:
EGFR-TKI and OBD vs MTD,
side effects, dosage, drug
interaction, drug reductions
Fatigue:
Afatinib: 10-17%
Gefitinib: 10-39%
Erlotinib: 5-57%
Anorexia:
Afatinib: 10-20%
Gefitinib: 14-44%
Erlotinib: 31%
Transaminitis:
Erlotinib: 6%
Afatinib: 11%
Gefitinib: 40-60%
Paronichia:
Erlonib: 4%
Gefitinib: 13-32%
Afatinib: 32-56%
Stomatitis:
Erlonib: 13%
Gefitinib: 9-40%
Afatinib: 50-72%
Vomiting:
Erlonib: 1%
Afatinib: 9-17%
Gefitinib: 12-19%
Diarrhoea:
Erlonib: 25-57%
Gefitinib: 34-54%
Afatinib: 88-95%
Skin Rash:
Gefitinib: 49-85%
Erlotinib: 73-79%
Afatinib: 80-89%
Modified from Landi L , Expert Opin Pharmacother 2014
Afatinib Plasma Levels in Patients Who Dose Reduced and
Those Who Remained on Afatinib 40 mg
Individual data with median
and 25th/75th percentiles
•
Dose reduction was
more likely in patients
with higher plasma
concentrations
Geometric mean
plasma concentrations
– 24.4 ng/mL after
dose reduction to 30
mg ≥4 days
previously (n=38)
– 23.7 ng/mL in
patients who
remained on 40 mg
(n=126)
140
Trough plasma concentrations (ng/mL)
•
10th/90th percentiles
Datapoints outside
percentiles
120
100
80
60
40
20
0
40 mg
(n=122)
40 mg
(n=10)
C2V1 (Day 22)
40 mg
(n=126)
30 mg
(n=38)
C3V1 (Day 43)
: patients who remained on 40 mg until C3V1 (n=126); , patients who dose reduced to 30 mg before C3V1
(n=38; only 10 of these patients had valid trough concentrations on 40 mg afatinib at C2V1 [the rest had either no
PK sampling due to dose interruption, were already on 30 mg afatinib or were excluded due to invalid sampling])
Yang et al. ASCO 2015 #8073
23
PFS in Patients Who Had or Had Not Dose
Reductions Within the First 6 Months
<40 mg in first 6 months
≥40 mg in first 6 months
<40 mg in first
6 months (n=105)
≥40 mg for first
6 months (n=124)
11.3
11.0
Median PFS (mo)
PFS in overall population
Estimated PFS probability
1.0
1.25 (0.91–1.72)
0.175
HR (95% CI)
P-value
0.8
0.6
0.4
0.2
0
0
3
6
9
12
15
18
21
24
27
15
16
6
4
2
1
0
0
Time (months)
No. at risk
<40 mg in first 6 months
≥40 mg for first 6 months
105
124
87
93
75
76
58
62
41
36
26
24
Median PFS was similar in patients who had afatinib dose reductions in the
first 6 months and those who remained on afatinib 40 mg once daily
CI, confidence interval; HR, hazard ratio
Yang et al. ASCO 2015 #8073
24
Pharmacokinetic parameters for EGFR TKI
Parameter
Reversible EGFR - TKI
Irreversible EGFR - TKI
Gefitinib
Erlotinib
Afatinib
Dacomitinib
Usual starting dose
(mg/day)
250
150 (100)
40 (50/30/20)
45
T max (h)
3-7
4
2-5
≈6
Vol distr. (L)
1700
232
2870
2600
Protein binding (%)
≈ 90
≈ 95
≈ 95
97-98
t ½ (h)
48 -72
36
37
72
Metabolism
Extensive
Extensive
Minimal
Extensive
Renal excretion
4%
9%
< 5%
3%
Accumulation
1.5 to ≈4 fold
1.5 to ≈5.4fold
2 to 3 fold
≈ 6 fold
Gastric PH effect
Reduces abs
Reduce abs
Not known
Reduces abs
Food effect
Not relevant
AUC 34-66%
AUC 39%
Not relevant
Drug interaction
CYP
CYP
P-gp transp
Potent CYP 2D6
sub
Adapted from S. Peters et al. Cancer Treatments review 40(2014) 917-926
Afatinib è indicato nel trattamento di pazienti adulti naïve agli inibitori tirosinchinasici del
recettore del fattore di crescita dell’epidermide (EGFR-TKI) con carcinoma polmonare non a
piccole cellule (NSCLC) localmente avanzato o metastatico con mutazione(i) attivante(i) l’EGFR.
OPEN Questions:
Direct comparisons?
LUX Lung 7: phase IIb trial of
afatinib vs gefitinib
• Patients with
– Advanced lung adenocarcinoma
– Documented common EGFR mutations (del19 or L858R)
– First line (no prior treatment)
• N = 264
Randomization
Afatinib 40 mg
Gefitinib 250 mg
Primary endpoint: PFS and disease control rate at 12 months
ClinicalTrials.gov. NCT01466660.
ARCHER 1050: phase III trial of
dacomitinib vs gefitinib
• Patients with
– Advanced NSCLC
– Documented common EGFR mutations (del19 or L858R ± T790M)
– First line (no prior treatment)
• N = 440
Randomization
Dacomitinib 45 mg
Primary endpoint: PFS
ClinicalTrials.gov. NCT01774721
Gefitinib 250 mg
OPEN Questions:
EGFR-TKIS clinical strategy?
Del19/L858R: first line TKI and post
progression treatment
PFS (months)
T790M+
(60%)
9-11
Gefitinib, erlotinib
AZD9291, Rociletinib
?
10-13
Afatinib
8-9
?
Del19/L858R: first line TKI and post
progression treatment
PFS (months)
?
AZD9291, Rociletinib
?
Randomized trials of 3rd vs 1st generation
TKI in 1L are ongoing
OPEN Questions:
T790M in TKI-naïve patients
EURTAC: PFS according to T790M and treatment
T790M detected in 65.2% of patient
9.7 months
6.0 months
Costa et al. Clinical Cancer Research 2014
T790M in TKI-naïve patients
•
20 T790M TKI-naïve patients (2% of EGFR-mutant tumors)
–
–
16/20 concurrent L858R
4/20 concurrent exon 19 deletion
Yu et al. Ann Oncol 2014
PFS under TKIs inT790M+ patients
Yu et al. Ann Oncol 2014
Irreversible TKIs and T790M: small therapeutic window
T790M
Relative IC50
100x
T790M
Wt
Wt
T790M
EGFRm
EGFRm
10x
Wt
1x
EGFRm
Gefitinib
Erlotinib
Afatinib
Dacomitinib
Ideal T790M
inhibitor
Adapted from Oxnard
OPEN Questions:
EGFR-TKIS resistance
EGFR-Tkis & future?
EGFR mutations are early events
No of mutations
100
Private
50
Shared
TP53
EGFR
A001
L858R
EGFR
A006
Ex 19 del
PTEN
MAP3K19
TP53
EGFR
ARID1B
TP53
EGFR
A014
L858R
A017
L858R
TP53
EGFR
A021
L858R
Trunk
EGFR
A022
Ex 20 ins
EGFR
EGFR
A027
Ex 19 del
A028
L858R
Tan, WLCC 2015
Infiammation+/-IMMS
angiogenesis
ETOP 2-11 BELIEF | 18th ECCO – 40th ESMO
European Cancer Congress, September
2015
Future perspectives
Need for a deepened understanding of mechanisms of
primary resistance to TKIs in EGFR mutated patients
• Mutation-based mechanisms:
• De novo T790M
• PIK3CA mutations (2%)
• PTEN loss (5%)
• Microenvironment mediated cancer progression:
• Angiogenesis: VEGFR, FGFR (nintedanib, ramucirumab)
• Paracrine signalling: HGF (ficlatuzumab)
• Immune escape: PD-1/PDL-1 (immunotherapy)
Erlotinib +/ramucirumab
Ongoing studies
RELAY (NCT02411448)
Erlotinib in Combination with Ramucirumab or Placebo in Previously
Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC
PROSE study: VeriStrat proteomic algorithm as a
prognostic and predictive test
VeriStrat proteomic classifier is prognostic for OS and PFS
• OS: HR Poor vs Good 2.50 [95% CI 1.88–3.31]; p<0.0001
• PFS: HR Poor vs Good 1.75 [95% CI 1.34–2.29]; p<0.0001
• Good classification group had no significant OS difference between treatment arms:
HR Erl vs CT 1.06 [95% CI 0.77–1.46], p=0.714.
• Poor classification group had significantly shorter OS on erlotinib than on chemotherapy:
HR Erl vs CT 1.72 [95% CI 1.08–2.74], p=0.022.
43
Gregorc et al. Lancet Oncol.2014 Jun;15(7):713-21
Phase II study of Ficlatuzumab+Gefitinib vs Gefitinib+placebo
VeriStrat retrospective analysis
Good
Poor
Mok et al. Ann Oncol. 2012;23(Suppl 9):ix391:Abstract 1198P
Mok et al. Ann Oncol, 25 (Suppl. 4) (2014), pp. 58–84 (Abstract 205P)
44
Erlotinib +/Ficlatuzumab
Ongoing studies
RELAY (NCT02411448)
Erlotinib in Combination with Ramucirumab or Placebo in Previously
Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC
FOCAL (NCT02318368)
Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib
in Subjects with Previously Untreated Metastatic,
EGFR-mutated NSCLC and BDX004 Positive Label
AZD9291 +/MEDI4736
Ongoing studies
RELAY (NCT02411448)
Erlotinib in Combination with Ramucirumab or Placebo in Previously
Untreated Patients with EGFR Mutation-Positive Metastatic NSCLC
FOCAL (NCT02318368)
Phase II Study of Ficlatuzumab Plus Erlotinib Versus Placebo Plus Erlotinib
in Subjects with Previously Untreated Metastatic,
EGFR-mutated NSCLC and BDX004 Positive Label
CAURAL (NCT02454933)
Phase III Study of AZD9291 in Combination with MEDI4736 (anti PD-L1
mAb)versus AZD9291 Monotherapy in patients with Locally Advanced or
Metastatic EGFR T790M positive NSCLC who have received Prior EGFR TKIs
-Drug interaction
-Patient compliance
Del 19
EGFRmutant
NSCLC
L858R
Uncommon
EGFRm
(ECOG PS, age,
education..)
-Liver function
Afatinib
Gefitinib/Erlotinib
Gefitinib/Erlotinib/Afatinib
Or CT followed by EGFR-TKis
Afatinib/Erlotinib/Gefitinib
www.lucenetwork.it
Database Center Net
Database NSCLC Navigator
Database Clinical Trial ongoing
Forum di discussione
Link a siti utili
[email protected]