Ana Rima
Moving Beyond Clinical Trials,
Review on 1st Line Afatinib
Real World Data
Conflict of interest statement
I have received honoraria for speeches from Eli Lilly,
Roche and from Boehringer Ingelheim for
participation in an advisory board and for a speech
Introduction
Global incidence of all cancer (2018)
Incidence of Lung Cancer (2018)
5
*SEER 21 areas 2006-2012, All Races, Both Sexes by SEER Summary Stage 2000 SEER 2016.
US lung cancer diagnosis and 5-year survival by stage
at diagnose (SEER 21 AREAS)
2009–2015
20%
22% 51%
7%
Percent of cases by stage
57.4%
30.8%
5.2% 8.2%
0%
10%
20%
30%
40%
50%
60%
70%
5-year relative survival
Localized (confined to primary site) Regional (spread to regional lymph
nodes)
Distant (cancer has metastasized) Unknown (unstaged)
57,16 : 55,2, 4,3
Pembagian pasien kanker paru berdasarkan PS
dan stadium saat terdiagnosis di bangsal paru
RSDM (non VIP) 2018, (n=182)
Stadium saat terdiagnosis
RSDM 2018
I-IIIA 1%
IIIB 9%
IV 90%
I-IIIA
IIIB
IV
PENYULIT (RSDM data 2018)
51%
1%
1%
2%
6%
14%
5%
13%
3% 1%
2%
1% Efusi pleura
SVKS
Limfadenopati
Nodul tiroid
brain metastasis
bone metastasis
liver metastasis
efusi pleura + bone metastasis
efusi pleura + liver metastasis
efusi pleura + bone & brain metastasis
bone + liver metastasis
efusi pleura + limfadenopati
RSDM 2018
HYSTOLOGICAL TYPE
20%
38,5%
23,6%
2,9%
15%
SquamousCellCarcinoma
Adenocarcinoma
othersubtypes
Large CellCarcinoma
Small CellLung Cancer
Referensi: 1. Yatabe Y, et al. EGFR mutation testing practices within the Asia Pacific region: Results of a multicenter
diagnostic survey. J Thorac Oncol 2015;10: 438-45; 2. Forrest, L., McMillan, D. & Ardle, C. (2005). An evaluation of the impact of a multidisciplinary team, in a single centre, on treatment and survival in patients with inoperable non-small-cell lung cancer.
British Journal of Cancer 93:977-978. doi: 10.1038/sj.bjc.66028253; 2. Cruz, C., Tanoue, L. & Matthay, R.
(2011). Lung Cancer: Epidemiology, Etiology, and Prevention. Clin Chest Med 32(4). doi: 10.1016/j.ccm.2011.09.001
19%
70%
0%
2%
7%
2%
Squamous cell caAdeno caLarge cell caSmall cell cahigh grade endocrine caother
RSDM 2018
ADENOCA PARU
YG DIKIRIM KE KALGEN
1 JAN – 31 DES 2018
N : 188
SAMPEL KURANG
N: 10 (5%)
DIPERIKSA EGFR N: 178 (95%)
EXON 18 N:0
EXON 21 N: 22 (31%)
EXON 20 N: 0
EXON 19 N: 40 (57%)
MUTASI EGFR (+)
N: 70 (39%)
MUTASI EGFR (-) N: 108 (61%)
CAMPURAN N: 8(12%)
EXON 19 & 20
N:2 EXON 19 & 21
N:4
EXON 20 & 21
N:1
EXON 19,20,21
N:1
RSDM 2018 2017: 42,6%
Mode of Action of Afatinib
Afatinib randomized multicenter clinical trial data in
1L treatment
Afatinib Real World Evidences in 1L treatment
- Eficacy
- Side efects
Mode of Action of Afatinib
Ligand Binding and Receptor Dimerisation Lead to Activation of Proliferation and Survival Pathways
Homodimer Heterodimer
HER2 (ErbB2) lacks a ligand-binding domain, and it is the preferred dimerisation partner for the other receptors.
Adapted from Yarden and Pines. Nat Rev Cancer. 2012;12:553; Hynes and Lane. Nat Rev Cancer. 2005;5:341.
Activation of
downstream
signaling pathways
Broad Inhibition of ErbB Dimerisation Partners Is Required for Maximum Efficacy
Doebele et al. Lung Cancer. 2010;69:1-12; Hynes and Lane. Nat Rev Cancer. 2005;5:341; Li et al. Oncogene. 2008;27:4702; Spicer and Rudman. Target Oncol. 2010;5:245.
Complete Blockade of the ErbB Family Enhances the Effect on Important Signaling Pathways
Targeting the whole ErbB Family enhances the effect on important
signaling pathways
Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342.
Afatinib Is the First Irreversible ErbB Family Blocker
Afatinib covalently binds and irreversibly blocks EGFR, HER2, and ErbB4
O
N
N
N
F
Cl
O
N
O
N
N
S
O
N
S
O
N
N
N
F
Cl
O
O
N
O
N
Afatinib
Afatinib covalently
bound
• ErbB3 does not have a kinase domain and cannot be directly blocked by afatinib
• Afatinib prevents ligand-dependent ErbB3 phosphorylation in preclinical studies
0 0 300 1000 300 100
– + – + + +
Afatinib (nM)
Heregulin
pErbB3
Anti-phospho-immunoblotting has shown that afatinib prevents ligand (heregulin)-stimulated ErbB3
phosphorylation
Li et al. Oncogene. 2008;27:4702; Solca et al. J Pharmacol Exp Ther. 2012;343:342.
Review of Afatinib clinical trial data
in 1L treatment
The LUX-Lung Clinical Trial Programme: First Line Studies
LUX-Lung 3 and LUX-Lung 6 Study Design
Afatinib 40 mg/db
Cisplatin + Pemetrexed 75 mg/m2 + 500 mg/m2 IV q21d, up to 6 cycles
Stage IIIB (wet)/IV lung adenocarcinoma EGFR mutation in tumour
(central lab testing; TheraScreen® EGFR29a RGQ PCR)
Cisplatin + Gemcitabine 75 mg/m2 + 1000 mg/m2 D1, D8
IV q21d, up to 6 cycles
Randomisation 2:1 Stratified by EGFR mutation
(Del19/L858R/other)
Primary end point: PFS (RECIST 1.1, independent review)c
Secondary end points: OS, PROd, ORR, DCR, DOR, tumour shrinkage, safety
1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213.
LUX-Lung 31
(n=345) LUX-Lung 6
2
(n=364; Asian pts)
LUX-Lung 3: Primary End Point PFS by Independent Review
LUX-Lung 6: Primary End Point PFS by Independent and Investigator Review
LUX-Lung 7 - Study Design
Randomisation
1:1
Afatinib 40 mg once daily Gefitinib 250 mg once daily
• Stage IIIb/IV adenocarcinoma of the lung • EGFR mutation (Del19 and/or L858R) in the tumour tissue# • No prior treatment for advanced/metastatic disease • ECOG PS 0-1
Primary endpoints: PFS (independent review)#, TTF, OS
Stratified by mutation type (Del19 vs L858R)
and presence of brain metastases (yes vs no)
Secondary endpoints: ORR, time to and duration of response, duration of disease control, tumour shrinkage, HRQoL, safety
# local or central test # Tumor assessment performed at week 4, 8, every 8 weeks until w64 and every 12 weeks thereafter
Treatment beyond progression allowed if deemed beneficial by investigator.
Park K et al. Lancet Oncol, 2016
PFS by Independent Review: Reduce risk of progression of up to 27% (HR: 0.73)
Park K et al. Lancet Oncol, 2016, Epub; * P=0.0176 †. P=0.0184
PFS and ORR with Afatinib in Common Mutations
(LUX-Lung 3/6/7) have always been consistent across
trials
LUX-Lung 3 and LUX-Lung 6: Summary of Adverse Events
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 (Cis/Gem). SAE = serious adverse event; ILD = interstitial lung disease; ARDS = acute respiratory distress syndrome.
1. Sequist et al. J Clin Oncol. 2013;31:3327; 2. Wu et al. Lancet Oncol. 2014;15:213.
% of Patients
LUX-Lung 31 LUX-Lung 6
2
Afatinib
(n=229)
Cis/Pem
(n=111)
Afatinib
(n=239)
Cis/Gem
(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
Discontinuation due to rash 0 0 2.1 (5 pts) 0
Discontinuation due to diarrhoea 1.3 (3 pts) 0 0 0
Drug-related SAE 14 14 5 7
Related SAE leading to death 1.7 (4 pts)d 0 0.4 (1 pt)e 0.9 (1 pt)e
Conclusion from Afatinib Clinical Trials
Review
Afatinib demonstrated consistent PFS which was around
11-14 months
PFS was better in common mutation group compared to
overall population
Afatinib showed consistent ORR efficacy which was 60-
70%
Safety profile was consistent across clinical trials
LUX-Lung 2: Yang et al. Lancet Oncol. 2012;13:539; Yang et al. J Clin Oncol. 2012;30(suppl). Abstract LBA7500 and oral;
LUX-Lung 3: Sequist et al. J Clin Oncol. 2013;31:3327; LUX-Lung 6: Wu et al. Lancet Oncol. 2014;15:213;
LUX-Lung 7: Park et al. Ann Oncol 2015;26: (suppl 9; abstract LBA2)
Review of Afatinib Real World Evidences
in 1L treatment
Afatinib Showed Consistent Efficacy between Real
World Data and Clinical Trial
What is Real World Data (RWD)?
Real World Data (RWD) is defined as data collected
from sources outside of traditional clinical trials
RWD is fundamental to capturing the benefit and risk
after a product has received regulatory approval
Generation and management of RWD can turn it into
real world evidence (RWE) to support beneficial clinical
trial results and actionable decisions for more
successful patient outcomes
Real World Experience of 1st Line Afatinib from National
Taiwan University Hospital, Hsinchu, Taiwan
mPFS 19del: 12.2 mo
vs
L858R: 10,3 mo
Real World Experience of 1st Line Afatinib from National Cancer
Center, Singapore
Kim YJ et al., WCLC 2017 (Poster# P3.01-023)
Real World Experience of 1st Line Afatinib from
Samsung Medical Center, Seoul, Korea
N=165 (Oct’14-Dec’16): 49% female, 26% brain mets, and 40 mg starting dose
PFS OS
In Indonesia GIOTRIF® as monotherapy is indicated for the treatment of patients with : • locally advanced or metastatic non-small cell lung cancer (NSCLC) with adenocarcinoma is predominantly, Epidermal
Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult; locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The recommended starting dose of afatinib is 40 mg orally once daily
Second-generation
and First-generation TKIs in Asia
(Asia data)
Real World Experience of 1st Line TKIs from
Samsung Medical Center, Seoul, Korea
2014-2016: NAfatinib=165 NGefitinib=230, NErlotinib=72
Kim Y et al., Cancer Res Treat; 2018
PFS OS Afatinib = 19.1 mo
Gefitinib = 13.7 mo
Erlotinib = 14.0 mo
Afatinib = NR
Gefitinib = 33 mo
Erlotinib = NR
In Indonesia GIOTRIF® as monotherapy is indicated for the treatment of patients with : • locally advanced or metastatic non-small cell lung cancer (NSCLC) with adenocarcinoma is predominantly, Epidermal
Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult; locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The recommended starting dose of afatinib is 40 mg orally once daily
Second-generation
and First-generation TKIs
(Non-Asia data)
PFS & OS
Real World Experience of 1st Line Afatinib from 13 Hospitals, Czech Republic
Skrickova J et al. WCLC 2017 (Poster # P2.03-023)
NGefitinib=138; NErlotiinib=47; NAfatinib=102: 65% female, 40 mg starting dose
Oct’13-Mar’17
In Indonesia GIOTRIF® as monotherapy is indicated for the treatment of patients with : • locally advanced or metastatic non-small cell lung cancer (NSCLC) with adenocarcinoma is predominantly, Epidermal
Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult; locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The recommended starting dose of afatinib is 40 mg orally once daily
Tolerability and Dose Modification
AE Profile Comparison from Prospective Trials
Study N Dose reduction rates ≥ Grade 3 AEs (%)
Diarrhea Stomatitis Skin rash Paronychia
LUX-Lung 31 230 Total 53%:
30 mg (52%); 20 mg (19%) 14.4 8.7 16.2 11.4
LUX-Lung 62 242 Total 28%:
30 mg (28.0%); 20 mg (4.2%) 5.4 5.4 14.6 0.0
LUX-Lung 73 160 Total 42%:
30 mg (39%); 20 mg (13%) 13.0 4.0 9.0 2.0
SMC-KR4 165 Total 67.9%:
30 mg (48.5%); 20 mg (19.4%) 2.4 0.6 1.8 2.4
NCC-SG5 125 NA 4.1 2.5 0.8 0.8
CGMH-TW6 79 Total 62.0%
30 mg (62.0%); 20 mg (4.0%) 6.3 2.5 5.1 8.7
KMUH-TW7 48 40 mg starting
30 mg starting
5.0
0.0
0.0
0.0
16.0
0.0
16.0
3.0
1. Sequist L et al. J Clin Oncol. 2013;31:3327; 2. Wu YL et al. Lancet Oncol. 2014;15:213; 3. Park K et al. Lancet Oncol. 2016;17(5):577-89; 4. Tan WL et al. CSCO 2017
(poster# B0129); 5. Kim YJ et al. WCLC 2017 (poster# P3.01-023); 6. Liu CY et al. Oncotarget 2017;8(57):97602-97612; 7. Yang CJ et al. BMC Pharmacol Toxicol.
2017;18(1):82.
In Indonesia GIOTRIF® as monotherapy is indicated for the treatment of patients with : • locally advanced or metastatic non-small cell lung cancer (NSCLC) with adenocarcinoma is predominantly, Epidermal
Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult; locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The recommended starting dose of afatinib is 40 mg orally once daily
1. Yang J et al. J Clin Oncol. 33, 2015 (suppl; abstr 8073); 2. Schuler M et al. ELCC 2016. #138PD; 3. Hirsh
V. J Clin Oncol. 2016;34(suppl; abstr 9046).
Dose Reduction of Afatinib Reduced Drug-Related AEs without Compromising Efficacy in LUX-Lung Trials
Treatment-related AEs in patients who had a dose
reduction from 40 mg (n=63) in LUX-Lung 7
What happened after Afatinib failure?
Publications on T790M+ Rate post 1st-Line Afatinib: 50-70% has the possibility of sequential to T790M+ specific blocker in
second line (third Gen TKI)
# Country Center N T790M +
Reference n %
1 AT Otto Wagner Hospital, Vienna 27 18 66.7 Hochmair M et al. WCLC 2017
(P2.03-025)
2 KR Samsung Medical Center, Seoul 20 9 45 Kim YJ et al. WCLC 2017
(poster# P3.01-023)
3 TW National Taiwan University Hospital,
Hsinchu Branch 28 9 32.1
Liang SK et al. Oncotarget 2017;
2017;8(52):90430-90443
4 JP Research Institute for Diseases of the
Chest, Fukuoka 37 16 43.2
Tanaka K et al. Oncotarget
2017;8(40):68123-30
5 USA Massachusetts General Hospital,
Boston 11 4 36
Campo M et al. J Thorac Oncol
2016;11(11):2022-26
6 TW National Taiwan University Hospital,
Taipei Branch 14 7 50
Wu SG et al. Oncotarget
2016;7(11):12404-13
7 Multiple AURA Ph II Extension 31 21 68 Yang JC et al. J Clin Oncol
2017;35(12):1288-96
Total 168 84 50.0
In Indonesia GIOTRIF® as monotherapy is indicated for the treatment of patients with : • locally advanced or metastatic non-small cell lung cancer (NSCLC) with adenocarcinoma is predominantly, Epidermal
Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult; locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The recommended starting dose of afatinib is 40 mg orally once daily
T790M+ Rate post 1st-Line TKI
RSDM 2018
(n = 58)
EGFR mutation
(Pre TKI)
EGFR mutation
(progress)
n %
Exon 19 No mutation 28
Exon 19
Exon 19
Exon 19
Exon 21
Exon 21
Exon 21
Exon 19
Exon 19 , 20
Exon 20 , 21
No mutation
Exon 20
Exon 20 , 21
2
15
1
8
2
2
Exon 19, 20 Exon 20 2
Exon 19, 20, 21
No mutation
2
T790M rate:
34,4%
Median Overall Survival was 41.3 mths and 2-year OS rate was 80%.
CI = confidence interval.
Hochmair MJ et al. Future Oncol. 2019 (Epub ahead of print)
Conclusion
Afatinib RWD support the data from 1st line LUX-Lung trials, indicating that Afatinib is a
potent ErbB family blocker for the 1st line treatment of EGFR M+ NSCLC
Afatinib RWD has consistently shown clinical efficacy at par or even better than its clinical
trial results
Afatinib has further demonstrated its strong efficacy with well manageable AE profiles in
real world setting
– Efficacious for both Del19 and L858R mutations
– Dose reduction could help in managing AE frequency and severity without
compromising efficacy
– AEs are manageable and ≥G3 AEs are less than those in 1st line LUX-Lung trials
– Afatinib is more efficacious than 1st Gen TKIs with the similar resistance profile
(possibility to continue treatment post-first line progression with 3rd gen TKI)
More real world data of Afatinib are needed to support beneficial clinical trial results and
actionable decisions for more successful patient outcomes
In Indonesia GIOTRIF® as monotherapy is indicated for the treatment of patients with : • locally advanced or metastatic non-small cell lung cancer (NSCLC) with adenocarcinoma is predominantly, Epidermal
Growth Factor Receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, TKI-naive adult; locally advanced or metastatic NSCLC of squamous histology progressing on or after platinum-based chemotherapy. The recommended starting dose of afatinib is 40 mg orally once daily
TERIMA KASIH