Transcript Diapositiva 1

Advantages and disavantages of
irreversible EGFR-TKI
Lucio Crinò, MD
Medical Oncology Department
University Hospital Perugia, Italy
Evolution of Knowledge in NSCLC
From Histology to Molecular Classification
Li, et al. J Clin Oncol 2013
EGFR mutations in NSCLC
Second generation EGFR TKIs
• The second-generation of EGFR TKIs has the advantage of
forming covalent, irreversible bonds with the target, which should
increase their effectiveness through a prolonged inhibition of
EGFR signaling
• Furthermore, the prolonged and irreversible inhibition of the
receptor has the potential for further improvement in response to
treatment over the first-generation TKIs such as erlotinib and
gefitinib
• To date, irreversible oral TKIs that target simultaneously multiple
members of the EGFR family are currently in clinical development
for NSCLC, including afatinib, dacomitinib and neratinib.
• Preclinical studies showed that irreversible TKIs killed cells with
acquired resistance to first-generation TKIs.
Becker K et al., World J Clin Oncol. 2014
Afatinib Is the First Irreversible ErbB Family
Blocker
• Afatinib selectively, covalently binds
and irreversibly blocks ErbB family
receptors EGFR, HER2, and ErbB4
• Afatinib prevents ligand-dependent
ErbB3 phosphorylation in
preclinical studies
Solca et al. J Pharmacol Exp Ther. 2012;343:342. Li et al. Oncogene. 2008;27:4702;
Köhler J et al. Onkologie 2013;36:510-518
Dacominitinb mechanism of action
• Dacomitinib is an irreversible panHER tyrosine kinase inhibitor with
activity against EGFR, HER2 and
HER4.
• Preclinical activity against
– EGFR sensitising mutations
– EGFR T790M
– wild-type HER2
– mutant HER2
Peters S., Cancer Treatment Review, 2014
Pharmacokinetics of afatinib and dacomitinib
• Afatinib undergoes minimal metabolism by the cytochrome
P450 system but is a substrate of p-glycoprotein. P-glycoprotein
inducers (rifampicin,carbamazepine, phenytoin, phenobarbital,
St. John’s Wort ) may therefore lower systemic drug
concentrations of afatinib.
• Coadministration of a P-glycoprotein inhibitor (ritonavir,
cyclosporine, ketoconazole, erythromycin, verapamil, and
others) can increase afatinib exposure.
• As oral drugs, gastric contents and pH may also impact
bioavailability. Afatinib absorption is reduced when taken with
a high fat meal whereas erlotinib absorption is increased and
patients are directed to take both medications on an empty
stomach
USA: Boehringer Ingelheim Pharmaceuticals, Inc Ridgefield 2013.
Potency and inhibition of cell proliferation of oral
EGFR tyrosine kinase inhibitors
Peters S et al. Cancer Treatment Reviews (2014)
Studies of EGFR TKIs versus chemotherapy as
first-line therapy in EGFR Act Mut+ NSCLC
Study
Median
Median
OS in
PFS in TKI Median PFS in
TKI
Median OS in
arm
chemotherapy
arm
chemotherapy
EGFR TKI (months)
arm (months) (months) arm (months)
OPTIMAL
Erlotinib
13.1
4.6
22.7
28.9
First Signal
Gefitinib
8.4
6.3
27.2
25.6
IPASS
Gefitinib
9.5
6.3
21.6
21.9
WJTOG
3405
Gefitinib
8.4
5.3
36
39
NEJSG 002
Gefitinib
10.8
5.4
27.7
26.6
EURTAC
Erlotinib
10.4
5.2
19.3
19.5
LUX-3
Afatinib
11.1
6.7
28.1
28.2
5.6
Not
reported,
Not reported,
immature
LUX-6
Afatinib
11.0
LUX-Lung 3 and 6: OS in common mutations
Presented By James Yang at 2014 ASCO Annual Meeting
Combined OS analysis: common mutations (n=631)
Presented By James Yang at 2014 ASCO Annual Meeting
Combined OS analysis in common mutations: subgroups
Presented By James Yang at 2014 ASCO Annual Meeting
Combined OS analysis: mutation categories
Presented By James Yang at 2014 ASCO Annual Meeting
LUX-Lung 3 and LUX-Lung 6:
Summary of Adverse Events
% of Patients
LUX-Lung 31,2
LUX-Lung 63,4
Afatinib
(n=229)
Pem/Cis
(n=111)
Afatinib
(n=239)
Gem/Cis
(n=113)
Drug-related AEs
100
96
99
99
Drug-related AE grade ≥3
49
48
36
60
Drug-related AEs leading to discontinuation
8a,b
12
6c
40
0
0
2.1 (5 pts)
0
1.3 (3 pts)
0
0
0
14
14
5
7
1.7 (4 pts)d
0
0.4 (1 pt)e
0.9 (1 pt)e
Discontinuation due to rash
Discontinuation due to diarrhoea
Drug-related SAE
Related SAE leading to death
aIncludes
3 patients (1%) who discontinued due to diarrhoea, no discontinuations for rash.
3 patients (1%) with ILD-like events (1 grade 1, 1 grade 3; 1 grade 5).
cIncluding 1 patient with ILD.
dPreferred terms: dyspnoea, sepsis, ARDS, death (unknown cause).
eSudden death (afatinib) and cardiac failure (Gem/Cis).
SAE = serious adverse event; ILD = interstitial lung disease;
ARDS = acute respiratory distress syndrome.
bIncludes
1. Sequist et al. J Clin Oncol. 2013;31:3327; 2.Yang ASCO 2013 ; 3. Wu et al. Lancet Oncol. 2014;15:213.
4. Wu YL. et al. 2013 ASCO Annual Meeting. Oral Presentation
Most Frequent Treatment-Related Adverse Events
(>20% Difference Between Treatment Arms)
LUX-Lung 31, / LUX-Lung 62, %
Afatinib LL3 (n=229) / LL6 (n =239 )
aGrouped
Pem/Cis (n=111) / Gem/Cis (n=113)
All Grades
Grade 3
Grade 4
All Grades
Grade 3
Grade 4
Rash/acnea
89.1 / 80.8
16.2 / 14.2
0.0 / 0.4
6.3 / 8.8
0
0
Diarrhoea
95.2 / 88.3
14.4 / 5.4
0
15.3 / 10.6
0
0
Paronychia/nail effecta
56.8 / 32.6
11.4 / 0.0
0
0/0
0
0
Stomatitis/mucositisa
72.1 / 51.9
8.37 / 5.4
0.4 / 0.0
15.3 / 5.3
0.9 / 0.0
0
Decreased appetite
20.5 / 10.0
3.1 / 1.3
0
53.2 / 40.7
2.7 / 1.8
0
Vomiting
17.0 / 9.6
3.1 / 0.8
0
42.3 / 80.5
2.7 / 15.9
0.0 / 3.5
Fatiguea
17.5 / 10.0
1.3 / 0.4
0
46.8 / 36.3
12.6 / 0.9
0
Nausea
17.9 / 7.5
0.9 / 0.0
0
65.8 / 75.2
3.6 / 7.1
0.0 /0.9
Dry skin
29.3 / NA
0.4 / NA
0
1.8 / NA
0
0
Pruritus
18.8 / 10.9
0.4 / 0.4
0
0.9 / 0.0
0
0
Neutropenia
0.9 / 2.1
0.4 / 0.4
0
31.5 / 54.0
15.3 / 17.7
2.7 / 8.8
Anemia
3.1 / 5.4
0.4 / 0.4
0
27.9 / 27.4
4.5 / 7.1
1.8 / 1.8
Leukopenia
1.7 / 3.3
0.04 / 0.4
0
18.9 / 51.3
8.1 / 13.3
0.0 / 1.8
ALT increase
7.4 / 20.1
0.0 / 1.7
0
2.7 / 15.9
0.0 / 1.8
0.0 / 0.9
AST increase
5.2 / 15.1
0.0 / 0.4
0
1.8 / 10.6
0.0 / 1.8
0
term for closely related AEs.
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
1. Sequist et al. J Clin Oncol. 2013;31:3327 2. Wu et al. Lancet Oncol. 2014;15:213.
15
Is response rate improved with irreversible EGFR-TKIs?
Comparison of best reported phase II results for EGFR TKIs in patients with EGFR-Mutant
lung cancers (Exon 19 and Exon 21)
Entered, n
CR+PR
Rate, %
Median
PFS, months
Median
OS, months
46
74
17
NR
Afatinib1
129a
66
15b
32–39
Erlotinib2
33
70
14
31
Gefitinib3
27
59
Agent
Dacomitinib
Weighted pooled analysis median PFS in patients with EGFR-mutant lung
cancers4
Erlotinib (95% CI)
365c
13.2 (12.0–14.7)
Gefitinib (95% CI)
1069d
9.8 (9.2–10.4)
a51
treated first-line; bmedian PFS: 12 months on blind review;
c12 studies; d39 studies
1Yang
JC, et al. Lancet Oncol 2012;3: 539–48.
PA, et al. J Clin Oncol 2012;epub 30April.
3Sequist LV, et al. J Clin Oncol 2008;26: 2442–9
4Paz-Ares L, et al. J Cell Mol Med 2010;14:51–69.
2Janne
NR, not reached; OS, overall survival
Is PFS improved with irreversible EGFR-TKIs?
Indirect comparison in patients with classical EGFR mutations in first-line
Erlotinib: EURTAC
Gefitinib:IPASS
HR 0.37, p<0.0001
HR 0.48, p<0.0001
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Gefitinib: median 9.5 months
Erlotinib: median 9.7 months
0
0
4
8
12
16
20
24
Progression-free survival (probability)
Dacomitinib:phase II
Afatinib:phase III
1.0
0.9
HR 0.47, p<0.0001
0.8
0.7
Median 16.8 months
0.6
0.5
0.4
0.3
0.2
0.1
0
0
5
10
15
20
25
30
Afatinib: median 13.6 months
Indirect comparison of reversible vs. irreversible
EGFR-TKIs
Erlotinib
Gefitinib
Afatinib
NEJSG 002
n=114
IPASS
n=607
First-SIGNAL
n=159
WJTOG3405
n=87
OPTIMAL
n=83
CALGB30406
n=81
Rash
71.0 (5.3)
66.2 (3.1)
72.3 (1.3)
74 (2)
73.5 (2.4)
NR (7.4)
37 (16.2)
Diarrhoea
34.2 (0.9)
46.6 (3.8)
NR
47(1)
25.3 (1.2)
NR (4.9)
33 (14.4)
Fatigue
10.5 (2.6)
NR
28.3 (0.6)
34 (2)
4.8 (0)
NR (1.2)
3 (1.3)
Anorexia
NR
21.9 (1.5)
44.7 (0)
NR
NR
NR
7 (3.1)
Stomatitis
9.6 (0)
17.0 (0.2)
NR
19 (0)
13.3 (1.2)
NR
20 (8.7)
Paronychia
NR
13.5 (0.3)
NR
28 (1)
3.6 (0)
NR
26 (11.4)
6.1 (0.9)
12.9 (0.2)
NR
NR
NR
NR
7 (3.1)
Vomiting
LUX-3
n=229
LUX-Lung 7 – Trial Design
LUX-Lung 7
A multicentre, randomized, open-label phase IIb of afatinib vs. gefitinib as first-line treatment for
patients with advanced and metastatic non-small cell lung cancer (NSCLC) harbouring EGFR
activating mutations
Patients with:
• Adenocarcinoma of the lung
• Presence of activating EGFR mutations in the tumor tissue either by local lab or
• Stage IIIB/IV
• No prior treatment with chemotherapy for advanced/metastatic disease
• No prior treatment with EGFR-inhibitors
• ECOG 0 or 1
by central lab
Randomize
1:1
Oral afatinib 40 mg once daily
Oral gefitinib 250 mg once daily
Primary endpoint: progression-free survival (PFS)
NCT01466660
Archer 1050 – Trial Design
Archer 1050
A multicentre, randomized, open-label phase III, clinicas study comparing dacominitinib vs.
gefitinib as first-line treatment for patients with advanced and metastatic non-small cell lung
cancer (NSCLC) harbouring EGFR activating mutations
Patients with:
• Adenocarcinoma of the lung
• Presence of activating EGFR mutations in the tumor tissue either by local lab or by central lab.
EGFR mutation status
•Stage IIIB/IV
• No prior treatment with chemotherapy for advanced/metastatic disease
• No prior treatment with EGFR-inhibitors
• ECOG 0 or 1
Randomize
1:1
Oral daconitinib 45 mg once daily
Oral gefitinib 250 mg once daily
Primary endpoint: progression-free survival (PFS)
EGFR TKIs and EGFR mutated NSCLC:<br />major mechanisms of resistance to EGFR TKIs (2)
Presented By Daniel Costa at 2014 ASCO Annual Meeting
Modest efficacy of irreversible EGFR-TKIs Against
“de novo” and “acquired” T790M
LUX LUNG 1: RR=7%
LUX-LUNG 2-3-6 trials
LUX LUNG 4: RR=8%
T790M
Response rate (%)
14.3
PFS (months)
2.9
OS (months)
14.9
Neratinib
RR=0% in T790M+
Conclusions
• No relevant differences in clinical activity
between first and second generation TKIs
• Better preclinical data of irreversible TKIs do not
translate in clinical practice
• Similar results in uncommon EGFR mutations
• More favorable Gefitinib Erlotinib toxicity profile
• Improved efficacy of Afatinib in exon 19 deletion?
• Face to Face comparative trials ongoing