EGFR TKI sequencing:
does order matter?
Nicolas Girard
Thorax Institut Curie-Montsouris, Paris, France
In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung cancer (Stage IIIb/IV) with activating mutations of EGFR
(exon 19 deletions or exon 21 L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the treatment of patients with
locally advanced or metastatic squamous cell cancer of the lung whose carcinoma progressed during or after platinum-based chemotherapy and for
whom immunotherapy is not suitable.
2
Disclosures
• Consultancy, symposia and research for Boehringer Ingelheim
• Consultancy, symposia, research and hospitality for Roche
• Consultancy, research and symposia for AstraZeneca
3
Indications:
In Switzerland, afatinib is approved as monotherapy for patients with non-small cell lung
cancer (Stage IIIb/IV) with activating mutations of EGFR (exon 19 deletions or exon 21
L858R substitutions), not previously treated with EGFR TKIs. It is also indicated for the
treatment of patients with locally advanced or metastatic squamous cell cancer of the
lung whose carcinoma progressed during or after platinum-based chemotherapy and for
whom immunotherapy is not suitable.
Posology:
The recommended dose is 40 mg once daily, orally. Maximum daily dose in squamous
cell carcinoma of the lung is 50 mg, orally. Not recommended in patients with an eGFR
4
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; TKI, tyrosine kinase inhibitor.
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
TKIs are standard up front
Evidence #1
Please see slide notes for copyright acknowledgements
5
First- and second-generation EGFR TKIs are standard in the
first-line treatment of NSCLC harbouring common EGFR
mutations
*PFS not reported for common mutations only. EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; .
Gefitinib. Summary of Product Characteristics, 2010; Maemondo M, et al. N Engl J Med 2010;362:2380–8; Mitsudomi T, et al. Lancet Oncol 2010;11:121–8; Mok TS, et al. N Engl J Med 2009;361:947–57;
Rosell, et al. Lancet Oncol 2012;13:239–46; Sequist, et al. J Clin Oncol 2013;31:3327–34; Wu, et al. Lancet Oncol 2014;15:213–22; Wu, et al. Ann Oncol 2015;26:1883–9; Zhou, et al. Lancet Oncol 2011;12:735–
42.
*
*
9.7
11
13.1
9.2
10.8
9.5
13.6
11
5.2 5.5
4.6
6.3
5.4
6.3
6.9
5.6
0
2
4
6
8
10
12
14
16
*
Better PFS versus platinum-based chemotherapy
Gefitinib* Erlotinib Afatinib Platinum-based chemotherapy
*
P
F
S
(
m
o
n
th
s
)
6
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
Not all TKIs are equal
Evidence #2
TKIs are standard up front
Evidence #1
Please see slide notes for copyright acknowledgements
7
HER2, human epidermal growth factor 2.
Girard. Future Oncol 2018. Epub ahead of print.
Wild-type EGFR
Intrinsic mutant
EGFR Acquired T790M EGFR
Second-generation TKI
Third-generation TKI
K K K K K K
K Kinase domain
Activity range
Activity
Reversible binding to wild-type and mutant EGFR
Inactive on T790M mutant
Irreversible covalent binding to EGFR, ErbB2 and ErbB4 to inhibit all ErbB
family signalling
Broader activity to overcome EGFR TKI-resistant mutations
Specificity for EGFR T790M mutant; EGFR
wild-type sparing
Irreversible covalent binding to mutant EGFR
EGFR inhibition
ErbB family blockade
EGFR mutant-specific
inhibitor
First-generation TKI Activity range Erlotinib
Gefitinib
Afatinib
Dacomitinib
Osimertinib
K
ErbB heterodimers,
e.g. HER2: ErbB3
Range
First-, second- and third-generation EGFR TKIs are
not equal: activity against EGFR mutations
Please see slide notes for copyright acknowledgements
8
IC50, half-maximal inhibitory concentration.
Cross, et al. Cancer Discov 2014;4:1046–61; Hirano, et al. Oncotarget 2015;6:38789–803; Li, et al. Oncogene 2008;27:4702–11.
EGFR mutant: L858R, exon 19 del Wild-type EGFR T790M
First-, second- and third-generation EGFR TKIs are
not equal: activity against EGFR mutations
Afatinib
EGFRm
Wild-type
T790M
Osimertinib
EGFRm
Wild-type
T790M
100×
10×
1×
Gefitinib
EGFRm
Wild-type
T790M
IC
5
0
9
BCRP, breast cancer resistance protein; CYP, cytochrome P450 enzyme; UGT, UDP-glycosyltransferase.
Cross, et al. Cancer Discov 2014;4:1046–61; Li, et al. Oncogene 2008;27:4702–11; Peters, et al. Cancer Treat Rev 2014;40:917–26;
TAGRISSO. Prescribing Information, March 2017.
First-, second- and third-generation EGFR TKIs are
not equal: metabolism
Enzymes involved in the metabolism of oral EGFR TKIs
May inhibit May induce
Drug
Metabolised by CYP enzymes
3A4 3A5 2D6 1A1 1A2 1B1 2C8 2C9
Gefitinib +++ ++ +++ ++ + –
CYP2C19 (w)
CYP2D6 (w)
UGT1A9, BRCP
Erlotinib +++ +++ + + ++ + + +
CYP3A4 (m)
CYP2C8 (m)
CYP1A1 (s)
UGT1A1 (s)
CYP1A1
CYP1A2
Afatinib – – – – – – – – – –
Dacomitinib ++ ++ + CYP2D6 (s)
Osimertinib +++ +++ – – – – – – BCRP
CYP3A4
CYP1A2
CYP2C
10
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
Not all TKIs are equal
Evidence #2
TKIs are standard up front
Evidence #1
Please see slide notes for copyright acknowledgements
11
CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat.
Corral, et al. Ann Onc 2017;28(Suppl. 2):ii28.
First- and second-generation EGFR TKIs are not
equal: antitumour activity
• Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive
NSCLC (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial
Afatinib
(n=160)
Gefitinib
(n=159)
Median, months 11.0 10.9
HR (95% CI)
p value
0.74 (0.57–0.95)
0.0178
P
F
S
(
%
)
100
80
60
40
20
0
Months
0 3 6 9 12 15 18 21 24 27 30 33 26 39 42 45 48 51
160 142 113 94 67 47 34 26 20 13 10 8 4 3 0 0 0 0
159 132 105 82 51 21 15 10 7 5 5 3 3 3 0 0 0 0
Afatinib
Gefitinib
27%
16%
16% 8%
70% 75%
69%
56%
66%
42%
0.00
0.20
0.40
0.60
0.80
ITT Del19 L858R
R
e
s
p
o
n
s
e
r
a
te
(
%
)
Gefitinib Afatinib
p=0.002 p=0.150 p=0.003
12
First- and second-generation EGFR TKIs are not
equal: antitumour activity
ARCHER 1050: Dacomitinib vs Gefitinib (excluding CNS metastases)
Daco (n=227) Gef (n=225)
Number of events,
n (%)
136 (59.9%) 179 (79.6%)
Median PFS
(95% Cl)
14.7
(11.1–16.6)
9.2
(9.1–11.0)
HR (95% Cl)
0.59 (0.47–0.74)
p
13
First- and third-generation EGFR TKIs are not
equal: antitumour activity
Date cut-off 12 Jun 2017. Tick marks indicate censored data.
Soria, et al. N Engl J Med 2018;378:113–25.
PFS in FLAURA
No. at risk
Osimertinib 279 259 229 200 170 132 66 22 3 0
Erlotinib or Gefitinib 277 235 192 138 101 69 28 5 1 0
P
ro
b
a
b
il
it
y
o
f
P
F
S
Months
0 3 6 9 12 15 18 21 24 27
0
0.2
0.4
0.6
0.8
1.0 Osimertinib
(n=279)
Erlotinib or gefitinib
(n=277)
Median PFS (95% Cl) 17.7 (15.1–21.4) 9.7 (8.5–11.0)
HR (95% Cl)
0.45 (0.36–0.57)
p
14
AE, adverse event.
1. Park, et al. Lancet Oncol 2016;17:577–89; 2. Paz-Ares, et al. Ann Oncol 2017;28:270–7; 3. Wu, et al. Lancet Oncol 2017;18:1454–66; 4. Soria, et al. N Engl J Med
2018;378:113–25.
First-, second- and third-generation EGFR TKIs
do not have equal safety
LUX-Lung 71,2 ARCHER 10503 FLAURA4
Afatinib
(n=160)
Gefitinib
(n=159)
Dacomitinib
(n=227)
Gefitinib
