1. Medical Oncology Department University Hospital Perugia, Italy
Advantages and disavantages of irreversible EGFR-TKI
Lucio Crinò, MD
Medical Oncology Department
University Hospital Perugia, Italy

2. Evolution of Knowledge in NSCLC From Histology to Molecular Classification
Li, et al. J Clin Oncol 2013

3. EGFR mutations in NSCLC

4. 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

5. 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: Li et al. Oncogene. 2008;27:4702;
Köhler J et al. Onkologie 2013;36:

6. Dacominitinb mechanism of action
Dacomitinib is an irreversible pan-HER 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

7. 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.

8. Potency and inhibition of cell proliferation of oral EGFR tyrosine kinase inhibitors
Peters S et al. Cancer Treatment Reviews (2014)

9. Studies of EGFR TKIs versus chemotherapy as first-line therapy in EGFR Act Mut+ NSCLC
Study
EGFR TKI
Median PFS in TKI arm (months)
Median PFS in chemotherapy arm (months)
Median OS in TKI arm (months)
Median OS in chemotherapy arm (months)
OPTIMAL
Erlotinib
13.1
4.6
22.7
28.9
First Signal
Gefitinib
8.4
6.3
27.2
25.6
IPASS
9.5
21.6
21.9
WJTOG 3405
5.3 36 39
NEJSG 002
10.8
5.4
27.7
26.6
EURTAC
10.4
5.2
19.3
19.5
LUX-3
Afatinib
11.1
6.7
28.1
28.2
LUX-6
11.0
5.6
Not reported, immature

10. LUX-Lung 3 and 6: OS in common mutations
Presented By James Yang at 2014 ASCO Annual Meeting

11. Combined OS analysis: common mutations (n=631)
Presented By James Yang at 2014 ASCO Annual Meeting

12. Combined OS analysis in common mutations: subgroups
Presented By James Yang at 2014 ASCO Annual Meeting

13. Combined OS analysis: mutation categories
Presented By James Yang at 2014 ASCO Annual Meeting

14. 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)
(n=239)
Gem/Cis
(n=113)
Drug-related AEs
100 96 99
Drug-related AE grade ≥3 49 48 36 60
Drug-related AEs leading to discontinuation
8a,b 12 6c 40
Discontinuation due to rash
2.1 (5 pts)
Discontinuation due to diarrhoea
1.3 (3 pts)
Drug-related SAE 14 5 7
Related SAE leading to death
1.7 (4 pts)d
0.4 (1 pt)e
0.9 (1 pt)e
aIncludes 3 patients (1%) who discontinued due to diarrhoea, no discontinuations for rash.
bIncludes 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.
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 ASCO Annual Meeting. Oral Presentation

15. Afatinib LL3 (n=229) / LL6 (n =239 ) Pem/Cis (n=111) / Gem/Cis (n=113)
Most Frequent Treatment-Related Adverse Events (>20% Difference Between Treatment Arms)
LUX-Lung 31, / LUX-Lung 62, %
Afatinib LL3 (n=229) / LL6 (n =239 )
Pem/Cis (n=111) / Gem/Cis (n=113)
All Grades
Grade 3
Grade 4
Rash/acnea
89.1 / 80.8
16.2 / 14.2
0.0 / 0.4
6.3 / 8.8
Diarrhoea
95.2 / 88.3
14.4 / 5.4
15.3 / 10.6
Paronychia/nail effecta
56.8 / 32.6
11.4 / 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
Decreased appetite
20.5 / 10.0
3.1 / 1.3
53.2 / 40.7
2.7 / 1.8
Vomiting
17.0 / 9.6
3.1 / 0.8
42.3 / 80.5
2.7 / 15.9
0.0 / 3.5
Fatiguea
17.5 / 10.0
1.3 / 0.4
46.8 / 36.3
12.6 / 0.9
Nausea
17.9 / 7.5
65.8 / 75.2
3.6 / 7.1
0.0 /0.9
Dry skin
29.3 / NA
0.4 / NA
1.8 / NA
Pruritus
18.8 / 10.9
0.4 / 0.4
Neutropenia
0.9 / 2.1
31.5 / 54.0
15.3 / 17.7
2.7 / 8.8
Anemia
3.1 / 5.4
27.9 / 27.4
4.5 / 7.1
1.8 / 1.8
Leukopenia
1.7 / 3.3
0.04 / 0.4
18.9 / 51.3
8.1 / 13.3
0.0 / 1.8
ALT increase
7.4 / 20.1
0.0 / 1.7
0.0 / 0.9
AST increase
5.2 / 15.1
1.8 / 10.6
aGrouped term for closely related AEs.
ALT = alanine aminotransferase; AST = aspartate aminotransferase.
1. Sequist et al. J Clin Oncol. 2013;31: Wu et al. Lancet Oncol. 2014;15:213.

16. Is response rate improved with irreversible EGFR-TKIs
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)
Agent
Entered, n
CR+PR Rate, %
Median
PFS, months
OS, months
Dacomitinib 46 74 17 NR
Afatinib1
129a 66
15b
32–39
Erlotinib2 33 70 14 31
Gefitinib3 27 59
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.
2Janne 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.
NR, not reached; OS, overall survival

17. Progression-free survival (probability)
Is PFS improved with irreversible EGFR-TKIs? Indirect comparison in patients with classical EGFR mutations in first-line
Erlotinib: EURTAC
Gefitinib:IPASS
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
HR 0.48, p<0.0001
HR 0.37, p<0.0001
Erlotinib: median 9.7 months
Afatinib:phase III
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Median 16.8 months
Progression-free survival (probability)
Dacomitinib:phase II
HR 0.47, p<0.0001
Afatinib: median 13.6 months

18. Indirect comparison of reversible vs. irreversible EGFR-TKIs
Gefitinib
NEJSG 002
n=114
IPASS
n=607
First-SIGNAL
n=159
WJTOG3405
n=87
Rash
71.0 (5.3)
66.2 (3.1)
72.3 (1.3)
74 (2)
Diarrhoea
34.2 (0.9)
46.6 (3.8) NR
47(1)
Fatigue
10.5 (2.6)
28.3 (0.6)
34 (2)
Anorexia
21.9 (1.5)
44.7 (0)
Stomatitis
9.6 (0)
17.0 (0.2)
19 (0)
Paronychia
13.5 (0.3)
28 (1)
Vomiting
6.1 (0.9)
12.9 (0.2)
Erlotinib
OPTIMAL
n=83
CALGB30406
n=81
73.5 (2.4)
NR (7.4)
25.3 (1.2)
NR (4.9)
4.8 (0)
NR (1.2) NR
13.3 (1.2)
3.6 (0)
Afatinib
LUX-3
n=229
37 (16.2)
33 (14.4)
3 (1.3)
7 (3.1)
20 (8.7)
26 (11.4)

19. LUX-Lung 7 – Trial Design
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 by central lab
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 afatinib 40 mg once daily
Oral gefitinib 250 mg once daily
Primary endpoint: progression-free survival (PFS)
NCT

20. 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)

21. Presented By Daniel Costa at 2014 ASCO Annual Meeting
EGFR TKIs and EGFR mutated NSCLC:<br />major mechanisms of resistance to EGFR TKIs (2)
Presented By Daniel Costa at 2014 ASCO Annual Meeting

22. Modest efficacy of irreversible EGFR-TKIs Against
“de novo” and “acquired” T790M
LUX LUNG 1: RR=7%
LUX LUNG 4: RR=8%
LUX-LUNG trials
T790M
Response rate (%)
14.3
PFS (months)
2.9
OS (months)
14.9
Neratinib
RR=0% in T790M+

23. 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