Sequential treatment with afatinib followed by 3rd generation EGFR TKI: subgroup analysis of the

GIDEON trial – a prospective non-interventional study in EGFR-mutated NSCLC patients in Germany

Wolfgang Brückl1, Martin Reck2, Barbara Hermes3, Eckart Laack4, Justyna

Rawluk5, Rudolf M. Huber6, Christopher Hoffmann7, Andrea Schüler7

1Department of Respiratory Medicine, Allergology and Sleep Medicine, Paracelsus Medical

University, General Hospital Nuernberg, Nuernberg, Germany; 2LungenClinic Grosshansdorf,

Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 3Department of Internal Medicine II, University of Tübingen, Germany; 4Hemato-Oncology

Hamburg, Hamburg, Germany; 5Faculty of Medicine, University of Freiburg, Germany;

Department of Hematology and Oncology, Medical Centre - University of Freiburg, Freiburg,

Germany; 6Respiratory Medicine and Thoracic Oncology, Internal Medicine V, Ludwig-

Maximilians-University of Munich and Thoracic Oncology Centre Munich, Munich, Germany; 7Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

Presented at the 2019 European Society of Medical Oncology (ESMO) congress, Barcelona, Spain, 27 September–01 October 2019

Introduction: EGFR TKIs in NSCLC

• Three generations of EGFR TKIs are now widely available for the treatment of

EGFRm+ NSCLC: erlotinib and gefitinib (1st-generation), afatinib and dacomitinib

(2nd-generation), and osimertinib (3rd-generation)1

• Head-to-head trials showed 2nd- and 3rd-generation EGFR TKIs are more

effective than 1st-generation TKIs2–4

EGFRm+, EGFR mutation-positive; TKI, tyrosine kinase inhibitor

Introduction: rationale for sequencing afatinib and osimertinib

• Resistance to first-line EGFR TKI treatment inevitably develops5, thus consideration

of the optimal treatment sequence is required (Figure 1)

• The predominant mechanism of resistance to 1st- and 2nd-generation EGFR TKIs is

development of the EGFR T790M mutation (50–70% of patients5–7); osimertinib is

highly effective in this patient population8

• Conversely, resistance to osimertinib is highly heterogeneous9,10, and there is

currently no standard targeted treatment for patients progressing on osimertinib

Introduction: rationale for sequencing afatinib and osimertinib (cont’d)

• While osimertinib has shown impressive efficacy in first-line2, there is increasing

evidence that sequential treatment with afatinib, followed by osimertinib, may

optimise clinical outcomes1,11–13 (Figure 1)

– In GioTag (a retrospective global observational study), median TTF on afatinib

followed by osimertinib was 28.1 months (90% CI: 26.8–30.3); 2-year OS rate

was 80%, median OS was 41.3 months overall and 45.7 months in patients with

Del19+ tumours

– In a retrospective analysis of post-afatinib treatments among patients in

LUX-Lung 3, 6 and 7, median treatment duration with subsequent osimertinib

was 20.2 months (95% CI: 12.8–31.5 months)12

– A recent retrospective analysis indicated improved outcomes with second-line

osimertinib in patients treated with first-line afatinib vs. erlotinib/gefitinib13

CI, confidence interval; Del19+, Del19 mutation-positive; OS, overall survival; TTF, time to treatment failure

Figure 1. Afatinib and osimertinib sequencing in NSCLC

Chemo, chemotherapy; IO, immuno-oncology therapy; PFS, progression-free survival

Osimertinib: PFS 18.9 months1

Osimertinib: PFS 10.1 months8Afatinib: PFS 11.0–13.6 months2,14,15 Chemo/IO

Chemo/IO

Osimertinib resistance mechanisms:

• Histological transformation (19%)9

• MET amplification (15%)10

Resistance mechanisms may vary

depending on treatment line or duration10

T790M

EGFRm

C797S

Unknown

Met amplification

The GIDEON study

• GIDEON was a prospective,

non-interventional real-world study of

patients with advanced NSCLC

treated with afatinib16

• Recruitment into the GIDEON NIS

was initiated following launch of

afatinib in Germany in February 2014

– First patient in: April 2014

– Last patient in: December 2016

• 160 patients were enrolled at 49

centres across Germany (Figure 2); of

these, 151 patients received the

study drug

NIS, non-interventional study

Figure 2. Patient recruitment centres

The GIDEON study (cont’d)

CR, complete response; DCR, disease control rate; ORR, objective response rate; PR, partial response; SD, stable disease

Primary

endpoint

Key secondary

endpoints

• PFS rate at 12 months

• PFS

• OS

• ORR (CR+PR)

• DCR (CR+PR+SD)

Inclusion

criteria

• Confirmed EGFR mutation

• EGFR TKI-naïve

• PFS rate at 12 months: 54.6%

• Median PFS: 12.9 months

• Median OS: 33.6 months

Key results16

Objectives

• The aim of this subgroup analysis of the GIDEON study was to assess the first efficacy results (ORR, DCR, 12- and 24-month OS rate) of patients treated with first-line afatinib followed by osimertinib in any later line

Patients receiving afatinib followed by osimertinib

• 29 patients* in GIDEON were treated with first-line afatinib followed by osimertinib

in any later line

– At baseline, 21 (72%), 7 (24%) and 1 (3%) of these patients were positive for

Del19, L858R and Ex18–21 point mutations, respectively

– Patients who received afatinib and osimertinib therapy represent 22%, 20.5%

and 5% of patients in the Del19, L858R and Ex18–21 subgroups in the overall

GIDEON population, respectively

*1 additional patient received afatinib and osimertinib but was excluded from all analyses due to breach of study criteria

Figure 3. Potential for patients with PD on afatinib to receive subsequent osimertinib treatment (n=150*)

• Only 47 patients progressed on afatinib when osimertinib was

approved and reimbursed in Germany; 29/47 (62%) patients

received afatinib followed by osimertinib in a later line

• Osimertinib was initially available in Germany but was retracted

from Nov 2016–Nov 2017 following a negative reimbursement

decision. Additional patients may have received osimertinib during

this time via an international pharmacy or through a compassionate

use programme (Figure 3)

• As osimertinib is now reimbursed in Germany, it is expected that

the proportion of patients who receive osimertinib following PD on

afatinib would have increased since this study

0

10

20

30

40

50

60

70

80

90

100

% P

ati

en

ts (

n=

15

0*)

Yes Osimertinib reimbursed in Germany

Partially Osimertinib EMA-approved but not reimbursed in Germany

Hardly Patient progressed on afatinib before osimertinib approval

No Patients still on afatinib treatment after study was closed

N=47

N=39

N=50

N=14

*1 additional patient received afatinib and osimertinib but was excluded from all analyses due to breach of study criteria

EMA, European Medicines Agency; PD, progressive disease

Results: best response to first-line afatinib

Figure 4. Best response to first-line afatinib (n=25*)

Best response n (%)

CR 1 (4)

PR 20 (80)

SD 4 (16)

PD 0 (0)

• Best response to afatinib in evaluable

patients was similar to the overall

GIDEON population14

• No patient had PD

PR

CR

SD

DCR: 100%

(n=25)

ORR: 84%

(n=21)

Results: overall survival

• OS rates are shown in Table 1

– All patients were alive 12 months after afatinib treatment initiation

– The 24-month OS rate from afatinib treatment initiation was 89.3%

• Median OS data were immature at the time of writing

N

12-month 24-month

No. of

events

OS rate,

%

No. of

events

OS rate,

% (95% CI)

Overall population 29 0 100 3 89.3 (70.4–96.4)

Del19 21 0 100 2 90.0 (65.6–97.4)

L858R 7 0 100 1 85.7 (33.4–97.9)

Ex18–21 point mutation 1 0 100 0 100

Table 1. Overall survival rates from the time of afatinib initiation

Results: treatment regimens of individual patients

• Overall treatment regimens for individual patients are shown in Figure 5

– Treatment regimens for some patients contained periods without TKI treatment,

with TKI treatment beyond progression, or with additional subsequent

treatments

Figure 5. Overall time on treatment (n=28*)

*1 additional patient was not evaluable; †Patients may have received therapies other than TKIs

Duration of afatinib treatment

Duration of osimertinib treatment

Osimertinib treatment ongoing

Additional subsequent therapy

No treatment with TKI†

Disease progression

Patient alive at data cut-off

Del19

L858R

Ex18–21 point mutation

Key findings and conclusions

• In line with published data8, the number of patients in the GIDEON study who

received osimertinib in any later line was higher in the Del19+ subgroup than in

the other EGFR mutation subgroups

• Best response to first-line afatinib was similar to that achieved in the overall

GIDEON population; the DCR and ORR were 100% and 84%, respectively

• The 24-month OS rate was 89.3%; median OS was not reached

• This analysis is limited by the small patient numbers, which is due to the restricted

availability of osimertinib during the conduct of the study (Mar 2014–Dec 2017)

• In conclusion, these results support previous evidence that sequential treatment

with afatinib followed by osimertinib may provide optimal clinical outcomes in

patients with EGFRm+ NSCLC

References

1. Hochmair MG, et al. Future Oncol 2019;15:2905–14

2. Soria JC, et al. N Engl J Med 2018;378:113–25

3. Park K, et al. Lancet Oncol 2016;17:577–89

4. Wu YL, et al. Lancet Oncol 2017;18:1454–66

5. Yu HA, et al. Clin Cancer Res 2013;19:2240–7

6. Sequist LV, et al. Sci Transl Med 2011;3:75ra26

7. Hochmair MJ, et al. Target Oncol 2019;14:75‒838. Mok T, et al, N Engl J Med. 2017;376:629–40

9. Schoenfeld AJ, et al. J Clin Oncol 2019;37:9028

10. Ramalingam SS, et al. Ann Oncol 2018;29 (suppl):LBA50

11. Hochmair MG, et al. Future Oncol 2018;14:2861–74

12. Park K, et al. Lung Cancer 2019;132:126–31

13. Tamiya M, et al. Anticancer Research 2019; 39:3923–9

14. Sequist LV, et al. J Clin Oncol 2013;31:3327‒3415. Wu YL, et al. Lancet Oncol 2014;15:213‒2216. Brueckl WM, et al. ESMO 2018;#1449P

Acknowledgements

• This study was funded by Boehringer Ingelheim. The authors were fully responsible

for all content and editorial decisions, were involved at all stages of poster

development and have approved the final version

• Medical writing assistance, supported financially by Boehringer Ingelheim, was

provided by Lucinda Sinclair, of GeoMed, an Ashfield company, part of UDG

Healthcare plc, during the development of this poster

• WB reports: consulting and/or lecture fees (Abbvie, AstraZeneca, BMS, Boehringer

Ingelheim, Celgene, Chugai, Lilly, MSD, Pfizer, Roche and Stratifyer); co-author

disclosure statements can be found in the published abstract

• *Corresponding author email address: Wolfgang.Brueckl@klinikum-nuernberg.de