EGFR TKI sequencing: does order matter?€¦ · Girard. Future Oncol 2018. Epub ahead of print. Wild-type EGFR Intrinsic mutant EGFR e.g. Acquired T790M EGFR Second-generation TKI
Post on 22-Oct-2020
2 Views
Preview:
Transcript
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
*
PF
S (
month
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
IC50
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
PF
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
Resp
on
se r
ate
(%
)
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
Pro
ba
bilit
y o
f P
FS
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
(n=225)
Osimertinib
(n=279)
Erlotinib or
gefitinib
(n=277)
Treatment
discontinuation
rate
6.2% 6.3% 9.7% 6.7% 10% 14%
Most common
Grade ≥3 AEs
Diarrhoea 12%
Rash/acne 9%
Liver enzyme
elevation 9%
Rash/acne 3%
Acne 14%
Diarrhoea 8%
Paronychia 7%
Liver enzyme
elevation 12%
Dyspnoea 3%
Diarrhoea 2%
Decreased
appetite 2%
Rash/acne 7%
Liver enzyme
elevation 12%
Second- or third-generation TKIs versus first-generation TKIs
15
Hirsh, et al. J Clin Oncol 2016;34(Suppl.): Abstract 9046.
Treatment-related AEs in patients who
had a dose reduction from 40 mg (n=63)
0
20
40
60
80
100
Any Diarrhoea Rash/acne Stomatitis Nail effect
Pati
en
ts (
%)
0
20
40
60
80
100
Any Diarrhoea Rash/acne Stomatitis Nail effect
Pati
en
ts (
%)
All grades Grade ≥3
Befo
re r
ed
ucti
on
(≥40 m
g)
Aft
er
red
ucti
on
(<40 m
g)
PFS in patients who received a dose reduction
within the first 6 months of treatment
45 34 28 22 15 11 10 9 7 3 1 0 0 47
113 97 78 66 45 32 23 17 12 6 3 2 1 0
Es
tim
ate
d P
FS
pro
ba
bil
ity 1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Months No. at risk:
16
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
TKIs are standard up front
Evidence #1
Not all TKIs are equal
Evidence #2
Biology drives sequence
Evidence #3
Please see slide notes for copyright acknowledgements
17
• Impact of specific EGFR mutations and clinical characteristics on outcomes after treatment with EGFR TKIs versus chemotherapy in EGFRm+ lung cancer: a meta-analysis
EGFRm+, epidermal growth factor receptor mutation positive.
Lee, et al. J Clin Oncol 2015;33:1958–65.
Trial HR 95% Cl HR 95% Cl
Exon 19 deletions Exon 21 L858R substitution
ENSURE 0.20 0.12–0.33 0.54 0.32–0.91
EURTAC 0.27 0.17–0.43 0.53 0.29–0.97
LUX-Lung 3 0.28 0.18–0.44 0.73 0.46–1.16
LUX-Lung 6 0.20 0.13–0.32 0.32 0.19–0.54
NEJ002 0.24 0.15–0.38 0.33 0.20–0.54
OPTIMAL 0.13 0.07–0.24 0.26 0.14–0.48
WJTOG 3405 0.42 0.26–0.66 0.69 0.44–1.07
AII 0.24 0.20–0.29 0.48 0.39–0.58
TKI Chemotherapy TKI Chemotherapy
First-line: PFS efficacy of TKIs is different in EGFR del19/L858R mutations
Please see slide notes for copyright acknowledgements
18
Kato, et al. Value Health 2015;18:A436 (Abstract PCN40).
Agent Study HR
(95% CI)
Del19 HR
(95% CI)
Afatinib
LUX-Lung 3 0.53 (0.36–0.79) 1.30 (0.80–2.11)
LUX-Lung 6 0.64 (0.44–0.94) 1.22 (0.81–1.83)
Total 0.59 (0.45–0.77) 1.25 (0.91–1.71)
Erlotinib
ENSURE 0.79 (0.48–1.30) 1.05 (0.60–1.84)
EURTAC 0.94 (0.57–1.54) 1.00 (0.56–1.79)
OPTIMAL 1.52 (0.91–2.52) 0.92 (0.55–1.54)
Total 1.04 (0.71–1.51) 0.98 (0.72–1.35)
Gefitinib
IPASS 0.86 (0.61–1.22) 1.40 (0.91–2.15)
NEJ002 0.83 (0.52–1.34) 0.82 (0.49–1.38)
WJTOG3405 1.19 (0.65–2.18) 1.11 (0.60–2.05)
Total 0.90 (0.70–1.17) 1.11 (0.81–1.54)
First-line: OS Efficacy of TKIs Is Different in EGFR del19/L858R Mutations
L858R
0.01 100 0.1 1 10
0.01 100 0.1 1 10
0.01 100 0.1 1 10 0.01 100 0.1 1 10
100 0.1 1 10 0.01
100 0.1 1 10 0.01
Favours chemotherapy
Favours chemotherapy
Favours chemotherapy Favours chemotherapy
Favours chemotherapy
Favours chemotherapy Favours afatinib Favours afatinib
Favours erlotinib Favours erlotinib
Favours gefitinib Favours gefitinib
19
Yang, et al. Lancet Oncol 2015;16:830–8.
T790M
(n=14)
Exon
20 ins
(n=23)
Mut/
dup
exon
18-21
(n=38)
G719X
(n=18)
L861Q
(n=16)
S768I
(n=8)
Response
rate (%) 14.3 8.7 71.1 77.8 56.3 100.0
PFS (months) 2.9 2.7 10.7 13.8 8.2 14.7
OS (months) 14.9 9.2 19.4 26.9 17.1 NE
Note: A patient may be presented in more than one category.
Group 3 (n=20): Exon 20 insertions
Group 2 (n=14): T790M mutations
Group 1 (n=33): Exon 18-21: G719, L861Q
Ma
xim
um
ch
an
ge
fro
m b
as
eli
ne
(%
)
120
100
80
60
40
20
0
–20
–40
–60
–80
–100 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70
0
5
10
15
20
25
30
35
40
PF
S (m
on
ths
)
Patient index sorted by maximum percent decrease in descending order
First-line: afatinib is effective for uncommon EGFR mutations • Clinical activity of afatinib in patients with advanced NSCLC harbouring uncommon
EGFR mutations: a combined post hoc analysis of LUX-Lung 2, 3, and 6
Please see slide notes for copyright acknowledgements
20
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
TKIs are standard up front
Evidence #1
Not all TKIs are equal
Evidence #2
Biology drives sequence
Evidence #3
Please see slide notes for copyright acknowledgements
21
MET, MET proto-oncogene.
Yu, et al. Clin Cancer Res 2013;19:2240–7.
Molecular mechanisms of acquired resistance to first-/second-generation EGFR TKIs
• 155 EGFR-mutant NSCLC patients, acquired resistance after TKI
• Molecular analyses on re-biopsy specimen
MET amplification 3%
Small cell + MET 1% Small cell 1%
Small cell + T790M 2%
MET + T790M 3%
HER2 T790M 4%
T790M
60%
HER2 8%
Unknown 18%
Please see slide notes for copyright acknowledgements
22
12.74%
29.04%
5.10%
53.21%
Initial diagnosis J170 Relapse
Chemotherapy
ETV6, WNK1-WAC,
MYO18B
Molecular mechanisms of acquired resistance to first-/second-generation EGFR TKIs
Funding
Activating
Mutation Resistance
Passenger
Pathogenic AML Normal
Type cellulaire Mutations
Recurrence
HSC, haematopoietic stem cell.
Ding, et al. Nature 2015;481:506–10.
Please see slide notes for copyright acknowledgements
23
PD, progressive disease.
Mok, et al. N Engl J Med 2017;376:629–40.
Osimertinib standard of care for T790M+ acquired resistance to first-/second-generation EGFR TKIs
Patients in the population
HR for PD or death, 0.30 (95% CI: 0.23–0.41)
p
24
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
TKIs are standard up front
Evidence #1
Not all TKIs are equal
Evidence #2
Biology drives sequence
Evidence #3
Biological monitoring is key
Evidence #4
Please see slide notes for copyright acknowledgements
25
Chouaid, et al. Lung Cancer 2014;86:170–3; Kawamura T, et al. Cancer Sci 2016;107:1001–5.
Identification of T790M at acquired resistance, is tissue re-biopsy feasible?
Re-biopsy could not be done in 18% of cases, mainly because of anticoagulation that the
patient’s physician considered to be a contraindication. One patient refused re-biopsy.
Among the 82 patients who underwent re-biopsy, the sample could be analysed
histologically in 94% of cases. Cytologic samples represented only.
Re-biopsy methods (n=82)
Surgery
Adrenalectomy 1
Lung surgery 3
Node surgery 1
Biopsy
Bronchial + E-BUS 43
Pulmonary under CT 19
Liver 2
Bone 6
Skin 2
Cytology
Nodes 3
Pleura 2
Ineligible for trial:
poor PS: n=10;
comorbidity: n=7;
elderly: n=2
Ineligible for re-biopsy:
inaccessible tumour sites:
n=19 (18 brain
metastases and
one lung lesion
26
FDA, US Food and Drug Administration; FFPE, formalin-fixed, paraffin-embedded.
Oxnard, et al. J Clin Oncol 2016;34:3375–82.
Proposed algorithm for use of plasma genotyping for EGFR T790M
Acquired resistance
to EGFR TKI
All patients undergo
biopsy,
FDA-approved
FFPE assay for T790M
T790M+
T790M–
Third-generation
EGFR TKI
Chemotherapy
Acquired resistance
to EGFR TKI
FDA-approved plasma
assay for T790M and
sensitising mutations
T790M+
T790M–
Skip biopsy, start third-generation
EGFR TKI
Biopsy, FDA-approved
FFPE assay for
T790M
T790M+
T790M–
Third-generation
EGFR TKI
Chemotherapy
A
B
Please see slide notes for copyright acknowledgements
27
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
TKIs are standard up front
Evidence #1
Not all TKIs are equal
Evidence #2
Biology drives sequence
Evidence #3
Biological monitoring is key
Evidence #4
Sequence makes survival
Evidence #5
Please see slide notes for copyright acknowledgements
28
What is OS in EGFR-mutant NSCLC?
Addition of the PFS of
all treatment lines
At each patient level:
NEED for the swimmer plot of individual patients
NOT the sum of median PFS in trials
Number of lines TKIs, chemotherapy, other
x
29
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
First-/second-
generation TKI
Chemotherapy First-/second-generation TKI
Girard. Future Oncol 2018. Epub ahead of print.
Please see slide notes for copyright acknowledgements
30
Yang, et al. Ann Oncol 2015;16:141–51.
OS in EGFR-mutant NSCLC: LUX-LUNG 3 trial
Common mutations
Afatinib
(n=203)
Cis/Pem
(n=104)
Median,
months 31.6 28.2
HR (95% CI) 0.78 (0.58–1.06)
Common mutations (Del19/L858R)
(n=307)
Es
tim
ate
d O
S (
pro
ba
bilit
y)
OS (months)
0
0
1
1
9
5
32
10
49
20
58
26
90
35
101
40
108
47
121
52
133
55
143
63
162
71
171
81
181
86
188
92
197
98
203
104
No. at risk:
Afatinib
Cis/Pem
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51
Afatinib
Cisplatin/pemetrexed
Please see slide notes for copyright acknowledgements
31
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
T790M+
Osimertinib Chemotherapy? TKI?
First-/second-
generation TKI Except if molecular target
Girard. Future Oncol 2018. Epub ahead of print.
Please see slide notes for copyright acknowledgements
32
PD-1, programmed death-1; PD-L1, programmed death ligand-1.
Mok, et al. N Engl J Med 2017;376:629–40.
Ongoing osimertinib treatment at time of data cut-off (n=166)
Discontinue treatment (n=113)
• Objective PD (n=77)
• AE (n=18)
• Subject decision (n=9)
• Other (n=8)
• Severe protocol non-compliance (n=1)
AURA3: treatment beyond osimertinib
Anticancer treatment post-discontinuation of osimertinib (n=67)
• Platinum-containing chemotherapy regimen (n=48) • Non-platinum-containing chemotherapy regimen (n=18) • Radiotherapy (n=17)
• EGFR TKI (n=9)
• EGFR TKI + non-PD-1/PD-L1 (n=6)
• PD-1/PD-L1 (n=4)
33
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
Osimertinib T790M+
T790M–
Other MET/HER2 inhibitor
Chemotherapy?
Except if molecular target
TKI?
First-/second-generation TKI
First-/second-
generation TKI
Chemotherapy
Girard. Future Oncol 2018. Epub ahead of print.
Please see slide notes for copyright acknowledgements
34
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
OS DATA
FROM AURA-3
NOT YET AVAILABLE
FACT #1:
Osimertinib T790M+
T790M–
Other MET/HER2 inhibitor
Chemotherapy?
Except if molecular target
TKI?
First-/second-generation TKI Chemotherapy
First-/second-
generation TKI
Girard. Future Oncol 2018. Epub ahead of print.
Please see slide notes for copyright acknowledgements
35
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
CHALLENGE IS TO ENSURE ACCESS
FOR A MAJORITY OF PATIENTS
TO FURTHER LINES OF TREATMENT
FACT #2:
Osimertinib T790M+
T790M–
Other MET/HER2 inhibitor
Chemotherapy?
Except if molecular target
TKI?
First-/second-generation TKI Chemotherapy
First-/second-
generation TKI
Girard. Future Oncol 2018. Epub ahead of print.
Please see slide notes for copyright acknowledgements
36
Sequist, et al. Ann Oncol 2017;28(Suppl. 5): v460-v496 10.1093/annonc/mdx380
OS in patients treated with osimertinib subsequently in LUX-Lung 3, 6 and 7
No. at risk:
Afatinib 37 37 37 37 37 37 36 35 28 20 12 3 0
Es
tim
ate
d O
S p
rob
ab
ilit
y
Time to death (months)
0.8
1.0
0.6
0.4
0.2
0
0 72 6 12 18 24 30 36 42 48 54 60 66
Median follow-up = 4.7 years
37
Analysis of treatment sequence: first-/second-generation TKIs followed by third-generation TKIs
Median PFS in LUX-Lung 7
Median PFS in AURA-3 (T790M+)
OS in patients treated with
osimertinib subsequently in
LUX-Lung 3, 6, and 7
10.1 months with osimertinib
11.0 months with afatinib
10.9 months with gefitinib
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18
Months
Osimertinib
Platinum-pemetrexed
1.0
0.8
0.6
0.4
0.2
0
0
Time of PFS (mo)
Esti
mate
d P
FS
pro
ba
bil
ity
3 6 9 12 15 18 21 24 27 30 33 36 39 42
Afatinib Gefitinib
Esti
mate
d P
FS
pro
ba
bil
ity
Sequist, et al. Ann Oncol 2017;28(Suppl. 5): v460-v496 10.1093/annonc/mdx380; Mok TS, et al. N Engl J Med 2017;376:629–40; Park K, et al. Lancet Oncol. 2016;17:577.
Please see slide notes for copyright acknowledgements
38
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
Osimertinib
Osimertinib T790M+
T790M–
Other MET/HER2 inhibitor
Chemotherapy
Except if molecular target
First-/second-generation TKI Chemotherapy
First-/second-
generation TKI
Girard. Future Oncol 2018. Epub ahead of print.
Please see slide notes for copyright acknowledgements
39
FLAURA: treatment beyond osimertinib Regimen Osimertinib (n=279) Erlotinib or gefitinib (n=277)
First post-treatment anticancer therapy (including crossover osimertinib), n (%)
Discontinued randomised trial treatment 138 (49) 213 (77)
First post-treatment anticancer therapy 82 (29) 129 (47)
No post-treatment anticancer therapy 56 (20) 84 (30)
Ongoing randomised trial treatment 141 (51) 64 (23)
First post-treatment anticancer therapy, n (%)
EGFR-TKI 29 (21) 97 (46)
PD-1/PD-L1 3 (2) 2 (1)
Non-platinum chemotherapy 50 (36) 27 (13)
Platinum-based chemotherapy 48 (35) 26 (12)
Other targeted therapy 2 (1) 3 (1)
Anti-VEGF 7 (5) 4 (2)
Second post-treatment anticancer therapy, n (%)
Second post-treatment anticancer therapy 24 (9) 39 (14)
Only one post-treatment anticancer therapy 58 (21) 90 (32)
Second post-treatment anticancer therapy, n (%)
EGFR TKI 10 (7) 14 (7)
PD-1/PD-L1 2 (1) 1 (
40
FLAURA: treatment beyond osimertinib Regimen Osimertinib (n=279) Erlotinib or gefitinib (n=277)
First post-treatment anticancer therapy (including crossover osimertinib), n (%)
Discontinued randomised trial treatment 138 (49) 213 (77)
First post-treatment anticancer therapy 82 (29) 129 (47)
No post-treatment anticancer therapy 56 (20) 84 (30)
Ongoing randomised trial treatment 141 (51) 64 (23)
First post-treatment anticancer therapy, n (%)
EGFR-TKI 29 (21) 97 (46)
PD-1/PD-L1 3 (2) 2 (1)
Non-platinum chemotherapy 50 (36) 27 (13)
Platinum-based chemotherapy 48 (35) 26 (12)
Other targeted therapy 2 (1) 3 (1)
Anti-VEGF 7 (5) 4 (2)
Second post-treatment anticancer therapy, n (%)
Second post-treatment anticancer therapy 24 (9) 39 (14)
Only one post-treatment anticancer therapy 58 (21) 90 (32)
Second post-treatment anticancer therapy, n (%)
EGFR TKI 10 (7) 14 (7)
PD-1/PD-L1 2 (1) 1 (
41
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
Chemotherapy
Except if molecular target
Osimertinib T790M+
T790M–
Other MET/HER2 inhibitor
Chemotherapy
Except if molecular target
First-/second-generation TKI Chemotherapy
First-/second-
generation TKI
Girard. Future Oncol 2018. Epub ahead of print.
Osimertinib
Please see slide notes for copyright acknowledgements
42
Treatment sequences in EGFR-mutant NSCLC after first-line EGFR TKI
Chemotherapy
Except if molecular target
Osimertinib T790M+
T790M–
Other MET/HER2 inhibitor
Chemotherapy
Except if molecular target
First-/second-generation TKI Chemotherapy
First-/second-
generation TKI
Girard. Future Oncol 2018. Epub ahead of print.
Osimertinib
NEED MATURE OS AND TREATMENT SEQUENCES FROM FLAURA
Please see slide notes for copyright acknowledgements
43
How to optimise sequence?
• CNS disease and progression
• Loss of patients from one line to another
• Treatment beyond progression
Optimisation
of treatments
• Anti-angiogenics
• Anti-EGFR antibodies
Understanding
of biology
• Resistance mechanisms to sequencing versus osimertinib
• Impact of de novo T790M
Clinical
factors
44
Ramalingam, et al. J Clin Oncol 2018;36:841–9.
Molecular characterization after osimertinib first-line failure (all T790M negative)
Baseline EGFR mutation
Post-dose plasma EGFR
mutation
(allelic fraction %)
Post-dose
plasma
resistance aberration(s)
identified
(allelic fraction %, copies)
Other post-
dose plasma mutations
identified
(allelic fraction %)
Total time
receiving
osimertinib (months)
Ex19del* None detected JAK2 V617F
(1.5%)
None detected 29.9+
Ex19del Ex19del (5.2%) EGFR C797S
(3.0%)
P53 R273H
(6.6%), CTNNB1 G34V
(6.5%)
27.8+
L858R L858R (16.7%) PIK3CA E545K (1.6%)
P53 H179R (13.3%), PTEN
Q171* (8.1%),
NOTCH G2299G (4.6%)
26.3
Ex19del Ex19del
(34.6%)
MET CNV (3.0
copies)
RB1 R255*
(64.1%), P53 pHis179fs
(62.9%)
26.3
Ex19del None detected KRAS G12D (8.6%)
CTNNB1 S37F (3.6%)
24.9
L858R and
T790M
L858R (4%) +
T790M (5%)
EGFR C797S
(1%)
NF2 T352M
(1.5%)
14.5
Ex19del Ex19del (7.5%) KRAS CNV (3.7
copies), EGFR CNV (3.0
copies)
P53 H175H
(15.9%), RB1 pLys427fs
(9.9%)
14.3
G719S and
S768I
G719S (6.9%) +
S768I (5.7%)
MEK1
(MAP2K1)
G128V (3.2%)
SMAD4 G358E
(4.6%),
PDGFRA S961C (1.1%)
5.6
L858R None detected HER2 ex20 ins
(12.3%), HER2 E1247K (4.2%)
P53 R213*
(6.3%), IDH2 R140Q (2.5%)
1.2
C797S 23%
Met ampl 11%
Her2 mut 11%
Mek 11%
JAK2 11%
PIK3CA 11%
Kras and EGFR ampl 11%
Kras 11%
45
Girard. Future Oncol 2018. Epub ahead of print.
Choosing the sequence in EGFR-mutant NSCLC
Sequence makes survival
Evidence #5
TKIs are standard up front
Evidence #1
Not all TKIs are equal
Evidence #2
Biology drives sequence
Evidence #3
Biological monitoring is key
Evidence #4
Please see slide notes for copyright acknowledgements
top related