Moving Beyond Clinical Trials, Review on 1st Line...

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



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



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


30 mg (28.0%); 20 mg (4.2%) 5.4 5.4 14.6 0.0


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.



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



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



TERIMA KASIH

Date post:	07-Mar-2020
Category:	Documents
Upload:	others
View:	5 times
Download:	0 times

Moving Beyond Clinical Trials, Review on 1st Line...

Documents