Sequential treatment with afatinib and osimertinib in real-world patients with EGFR mutation-positive advanced NSCLC: the GioTag study

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1 Scan the QR code for an electronic copy of the poster and supplementary material Sequential treatment with afatinib and osimertinib in real-world patients with EGFR mutation-positive advanced NSCLC: the GioTag study Maximillian J. Hochmair, 1 Tanja Cufer, 2 Alessandro Morabito, 3 Desiree Hao, 4 Cheng-Ta Yang, 5 Ross Soo, 6 James C-H Yang, 7 Rasim Gucalp, 8 Balazs Halmos, 8 Lara Wang, 9 Amanda Golembesky, 10 Angela Märten, 10 Kenneth O Byrne 11 1 Otto Wagner Hospital, Vienna, Austria; 2 University of Ljubljana, Ljubljana, Slovenia; 3 Istituto Nazionale Tumori, "Fondazione G.Pascale"-IRCCS, Napoli, Italy; 4 University of Calgary, Calgary, Alberta, Canada; 5 Chang Gung Memorial Hospital, Taoyuan, Taiwan, 6 National University Hospital, Singapore, Singapore; 7 National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; 8 Montefiore/Albert Einstein Cancer Center, Bronx, New York, USA; 9 Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan; 10 Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 11 Princess Alexandra Hospital, Brisbane, QLD, Australia Poster 86 Background Despite initial responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFR mutation-positive (EGFRm+) NSCLC, acquired resistance inevitably develops 1 The predominant mechanism of resistance to the first- and second-generation EGFR TKIs is the T790M mutation % T790M Patients with Del19 EGFR mutations have ~75% chance of developing the T790M mutation during treatment with first- and second-generation EGFR TKIs 5 The third-generation EGFR TKI, osimertinib, is approved to treat T790M-positive disease, with prolonged disease control seen in the second-line setting 6 In contrast, resistance to first-line osimertinib is heterogeneous, with no putative resistance mechanism identified in >60% of patients, 7 nor any approved targeted treatment for patients with resistance Treatment with sequential EGFR TKIs, with osimertinib reserved for second-line use, is an option to maximise duration of chemotherapy-free treatment Objective To assess outcomes in patients with EGFRm+ (Del19, L858R) NSCLC receiving sequential afatinib and osimertinib in a real-world clinical setting Methods 27 50% Other Study design A global observational study to evaluate outcomes among patients who received first-line afatinib followed by osimertinib (NCT ) Conducted in 10 countries (Austria, Canada, Israel, Italy, Japan, Singapore, Slovenia, Spain, Taiwan and the USA) Maximum of 15 patients per site Retrospective review (December 2017 May 2018) of medical and electronic health records of consecutive patients treated in real-world practice Inclusion criteria Received first-line afatinib for Del19/L858R EGFRm+ disease, developed T790M mutation, and were subsequently treated with second-line osimertinib Started osimertinib 10 months prior to enrolment* Exclusion criteria Receipt of any other first- or second-line treatments Active brain metastases Treatment within a clinical trial *There was no specified lower limit on duration of osimertinib treatment; Use of osimertinib within a compassionate use or expanded access program was permitted Primary outcome Time on treatment (ToT) Defined as the time from the first dose of afatinib to the last dose of osimertinib, or death Patient disposition Received first-line afatinib (N=204) Treated with osimertinib (N=204) Ongoing patients (N=98) Results Discontinuations were due to: PD (n=190) AE/ADR (n=10) Other/no data (n=4) Discontinuation (n=106), due to: PD (n=98) AE/ADR (n=2) Death (n=4) Other (n=6) ADR, adverse drug reaction; AE, adverse event; PD, progressive disease Patient baseline characteristics* N=204 Female, n (%) 110 (53) Median age, years (range) 60 (30 86) Median weight, kg (range) 70 (37 116) Median BMI, kg/m 2 (range) 25 (15 45) Ethnicity, n (%) Asian 50 (24) Non-Asian 138 (67) Stage IV disease, n (%) 197 (96) EGFR mutation, n (%) Del (73) L858R 53 (26) Del19 + L858R 1 (<1) ECOG PS 0 1 / 2, n (%) 153 (75) / 31 (15) Brain metastases present, n (%) 21 (10) *At start of afatinib therapy; Other n=10, missing data n=6 Missing data n=20 BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status Time on treatment Median follow-up was 28.2 months Treatment probability All patients Time (months) Patients at risk Time on treatment by patient subgroups Subgroup Overall Ethnicity Non-Asian Asian Age <65 years 65 years EGFR mutation Del19 L858R Brain metastases Yes No ECOG PS 0/1 2 N Time on treatment (months) Median ToT, months (90% CI) Overall 27.6 ( ) Time on afatinib 11.9 ( ) Time on osimertinib 14.3 ( ) Duration of afatinib and osimertinib treatment Patients NR, not reached Time on afatinib Treatment-free interval Time on osimertinib Patient ongoing on treatment Time on treatment (months) Median ToT, months (90% CI) 27.6 ( ) 27.6 ( ) 46.7 (26.8 NR) 27.6 ( ) 27.6 ( ) 30.3 ( ) 19.1 ( ) 19.4 (16.0 NR) 28.4 ( ) 31.3 ( ) 22.2 ( ) Asian vs non-asian Treatment probability EGFR mutation (Del19 vs L858R) Patients with poor prognosis also appear to derive clinical benefit ECOG PS 2 (n=31): median ToT 22.2 months Stable brain metastases (n=21): median ToT 19.4 months Overall survival: Landmark analysis All patients and ECOG PS 0/1 Survival probability Patients at risk All patients ECOG PS 0/ Key findings and conclusions Sequential afatinib and osimertinib therapy is feasible and potentially effective in patients with EGFRm+ NSCLC who acquire T790M Median ToT 27.6 months in real-world setting ToT was particularly prolonged in Asian patients (46.7 months) and those with Del19 (30.3 months) Whilst prospective studies are needed to determine the optimum treatment sequence, the GioTag study and other recent work suggest this approach might offer sustained clinical benefit while avoiding chemotherapy 8,9 1. Hirsh V. Ther Adv Med Oncol 2018;10: Arcila ME, et al. Clin Cancer Res 2011; Hochmair M, et al. J Thorac Oncol 2017;12:S Sequist LV, et al. Sci Transl Med 2011;3:75ra26 5. Hochmair M, et al. Fut Oncol 2018;28: Non-Asian Asian All patients ECOG PS 0/1 6 Median ToT, months (90% CI) 79% Del19 (n=150) 30.3 ( ) References 2-year survival rate 6. Mok TS, et al. NEJM 2017;376: Scan the QR code for an electronic copy of the poster and supplementary content Non-Asian (n=138) Del19 and ECOG PS 0/1 (n=114) 36.4 ( ) All patients Asian (n=50) Events Median ToT, months (90% CI) Time (months) Time (months) 27.6 ( ) Patients at risk Non-Asian Asian Treatment probability Del19 Del19 and ECOG PS 0/1 L858R Patients at risk Time (months) Del L858R Del19 and ECOG PS 0/1 84% 46.7 (26.6 NR) L858R (n=53) 19.1 ( ) ECOG PS 0/1 79% 84% Maturity 50% 41% Potential Study Limitations Introduction of immortal time bias as patients who died on first-line afatinib were excluded Under-representation of patients deriving long-term benefit from afatinib These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions. 7. Ramalingam S.S, et al. Presented at ESMO 2018, Munich, Germany (abstract LBA50) 8. Tamiya M, et al. Ann Oncol 2018;29 (Suppl. 8):viii493 viii Sequist LV, et al. Ann Oncol 2017;28 (Suppl. 5):abstract 1349P Presented at the British Thoracic Oncology Group Annual Conference, Dublin, Ireland, January 2019 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, funded by Boehringer Ingelheim, was provided by Jessica Sturgess of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster.

2 Sequential treatment with afatinib and osimertinib in real-world patients with EGFR mutation-positive advanced NSCLC: the GioTag study Maximillian J. Hochmair, 1 Tanja Cufer, 2 Alessandro Morabito, 3 Desiree Hao, 4 Cheng-Ta Yang, 5 Ross Soo, 6 James C-H Yang, 7 Rasim Gucalp, 8 Balazs Halmos, 8 Lara Wang, 9 Amanda Golembesky, 10 Angela Märten, 10 Kenneth O Byrne 11 1 Otto Wagner Hospital, Vienna, Austria; 2 University of Ljubljana, Ljubljana, Slovenia; 3 Istituto Nazionale Tumori, "Fondazione G.Pascale"-IRCCS, Napoli, Italy; 4 University of Calgary, Calgary, Alberta, Canada; 5 Chang Gung Memorial Hospital, Taoyuan, Taiwan; 6 National University Hospital, Singapore, Singapore; 7 National Taiwan University Hospital and National Taiwan University Cancer Center, Taipei, Taiwan; 8 Montefiore/Albert Einstein Cancer Center, Bronx, New York, USA; 9 Boehringer Ingelheim Taiwan Limited, Taipei, Taiwan; 10 Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 11 Princess Alexandra Hospital, Brisbane, QLD, Australia Presented at the British Thoracic Oncology Group Annual Conference, Dublin, Ireland, January 2019

3 Background Despite initial responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patients with EGFR mutation-positive (EGFRm+) NSCLC, acquired resistance inevitably develops 1 The predominant mechanism of resistance to the first- and second-generation EGFR TKIs is the T790M mutation 2 5 Patients with Del19 EGFR mutations have ~75% chance of developing the T790M mutation during treatment with first- and second-generation EGFR TKIs 5 The third-generation EGFR TKI, osimertinib, is approved to treat T790M-positive disease, with prolonged disease control seen in the second-line setting 6

4 Background (cont d) In contrast, resistance to first-line osimertinib is heterogeneous, with no putative resistance mechanism identified in >60% of patients, 7 nor any approved targeted treatment for patients with resistance Treatment with sequential EGFR TKIs, with osimertinib reserved for second-line use, is an option to maximise duration of chemotherapy-free treatment Objective To assess outcomes in patients with EGFRm+ (Del19, L858R) NSCLC receiving sequential afatinib and osimertinib in a real-world clinical setting

5 Methods Study design A global observational study to evaluate outcomes among patients who received first-line afatinib followed by osimertinib (NCT ) Conducted in 10 countries (Austria, Canada, Israel, Italy, Japan, Singapore, Slovenia, Spain, Taiwan and the USA) Maximum of 15 patients per site Retrospective review (December 2017 May 2018) of medical and electronic health records of consecutive patients treated in real-world practice

6 Methods (cont d) Primary Outcome Time on treatment (ToT) Defined as the time from the first dose of afatinib to the last dose of osimertinib, or death *There was no specified lower limit on duration of osimertinib treatment; Use of osimertinib within a compassionate use or expanded access program was permitted

7 Results Patient disposition ADR, adverse drug reaction; AE, adverse event; PD, progressive disease

8 Results (cont d) Patient baseline characteristics* *At start of afatinib therapy; Other n=10, missing data n=6; Missing data n=20 BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status N=204 Female, n (%) 110 (53) Median age, years (range) 60 (30 86) Median weight, kg (range) 70 (37 116) Median BMI, kg/m 2 (range) 25 (15 45) Ethnicity, n (%) Asian 50 (24) Non-Asian 138 (67) Stage IV disease, n (%) 197 (96) EGFR mutation, n (%) Del (73) L858R 53 (26) Del19 + L858R 1 (<1) ECOG PS 0 1 / 2, n (%) 153 (75) / 31 (15) Brain metastases present, n (%) 21 (10)

9 Results (cont d) Time on treatment Median follow-up was 28.2 months All patients

10 Results (cont d) Duration of afatinib and osimertinib treatment

11 Results (cont d) Time on treatment by patient subgroups NR, not reached

12 Results (cont d) Asian vs non-asian

13 Results (cont d) EGFR mutation (Del19 vs L858R) Patients with poor prognosis also appear to derive clinical benefit ECOG PS 2 (n=31): median ToT 22.2 months Stable brain metastases (n=21): median ToT 19.4 months

14 Results (cont d) Overall survival: Landmark analysis All patients and ECOG PS 0/1

15 Potential Study Limitations Introduction of immortal time bias as patients who died on first-line afatinib were excluded Under-representation of patients deriving long-term benefit from afatinib Key findings and conclusions Sequential afatinib and osimertinib therapy is feasible and potentially effective in patients with EGFRm+ NSCLC who acquire T790M Median ToT 27.6 months in real-world setting ToT was particularly prolonged in Asian patients (46.7 months) and those with Del19 (30.3 months) Whilst prospective studies are needed to determine the optimum treatment sequence, the GioTag study and other recent work suggest this approach might offer sustained clinical benefit while avoiding chemotherapy 8,9

16 References 1. Hirsh V. Ther Adv Med Oncol 2018;10: Arcila ME, et al. Clin Cancer Res 2011;17: Hochmair M, et al. J Thorac Oncol 2017;12:S Sequist LV, et al. Sci Transl Med 2011;3:75ra26 5. Hochmair M, et al. Fut Oncol 2018;28: Mok TS, et al. NEJM 2017;376: Ramalingam SS, et al. Presented at ESMO 2018, Munich, Germany (abstract LBA50) 8. Tamiya M, et al. Ann Oncol 2018;29 (Suppl. 8):viii493 viii Sequist LV, et al. Ann Oncol 2017;28 (Suppl. 5):abstract 1349P Acknowledgments 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, funded by Boehringer Ingelheim, was provided by Jessica Sturgess of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster. These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions