Post-marketing observational study of Japanese patients with EGFR mutation-positive (EGFRm+) NSCLC treated with daily afatinib (final report)

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1 Post-marketing observational study of Japanese patients with EGFR mutation-positive (EGFRm+) NSCLC treated with daily afatinib (final report) Nobuyuki Yamamoto, 1 Toshihiro Nukiwa, 2 Yoichi Nakanishi, 3 Akihiko Gemma, 4 Masaya Mizushima, 5 Tomoyuki Takayama, 6 Jun Kumazawa, 7 Hisaya Azuma, 5 Kazuo Tamura 8 1 Third Department of Internal Medicine, Division of Pulmonology and Medical Oncology, Wakayama Medical University, Wakayama, Japan; 2 Japan Anti-Tuberculosis Association, Tokyo, Japan; 3 Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyusyu University, Fukuoka, Japan; 4 Nippon Medical School, Tokyo, Japan; 5 Clinical Development & Medical Affairs, Medical Division, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan; 6 Statistics Analysis Department 2, PMS Division, EPS Corporation, Tokyo, Japan; 7 Post Marketing Surveillance Group, Pharmacovigilance, Nippon Boehringer Ingelheim Co., Ltd, Tokyo, Japan; 8 General Medical Research Center, School of Medicine, Fukuoka University, Fukuoka, Japan Presented at the IASLC 18th World Conference on Lung Cancer (WCLC), Yokohama, Japan, October 15 18, 2017

2 Background and study design Afatinib, an irreversible ErbB family blocker, significantly improved PFS versus chemotherapy in two pivotal trials, 1,2 and OS was significantly longer with afatinib in patients with Del19 mutation 3 The results in the Japanese subgroup were consistent with those in the overall population 4 Based on these results, afatinib was approved in Japan (in 2014) for the treatment of patients with inoperable or recurrent EGFRm+ NSCLC 5,6 However, data on afatinib use in the Japanese population in the clinical setting was limited at the time of approval Therefore, we initiated this prospective, post-marketing surveillance study in Japanese patients, to evaluate the safety and effectiveness of daily afatinib use in general practice Due to its broad label in Japan, afatinib is used across multiple treatment lines, i.e. EGFR TKI-naïve and EGFR TKI-pretreated patients

3 Background and study design (cont d) Patients Inoperable or recurrent EGFRm+ NSCLC (Japanese Package Insert) Target: 1,500 patients Observation: 12 months Afatinib 50 mg, 40 mg, 30 mg or 20mg qd* 0 1M 6M 12M

4 Background and study design (cont d) Primary Objective endpoint Secondary endpoints ClinicalTrials.gov Investigation of long-term use of afatinib in general practice Incidence of ADRs/ serious ADRs (safety) ORR (effectiveness) ADRs of special interest: diarrhea, rash/acne, nail effects and ILD (safety) NCT Patients received afatinib at the approved dose (20 50 mg/day) and were observed following treatment initiation for 52 weeks/until premature discontinuation Data were included for all patients who received afatinib during the investigational period, thus minimizing patient selection bias *Approved doses in Japan; Grouped term ADR, adverse drug reaction (defined as causally related by the investigator and/or sponsor); ILD, interstitial lung disease; M, months; ORR, objective response rate; QD, once daily

5 Patients As of February 2017, 1,602 patients enrolled at 374 sites were included in the analysis Age class,* % 67 Median age, years [range: 34 90] <65 65 <75 75 Gender, % Starting dose, % Tumor histology, % 30 mg mg mg 77.5 Adenocarcinoma 97.0 Mixed 0.6 Others 1.4 Squamous 0.9 Large cell 0.1 *Age data missing for 3 patients Tumor histology data missing for one patient

6 Patients (cont d) BMI, % ECOG PS, % Smoking history, % <25 kg/mg 2 25 kg/mg Never smoked Exsmoker Current smoker BMI data missing for 24 patients; Smoking history unknown for 12 patients; BMI, body mass index; ECOG PS, Eastern Cooperative Oncology Group performance status

7 Patients (cont d) EGFR mutation status, n (%) EGFR mutation Positive 1578 (98.5) Del19 Positive 1020 (63.7) L858R Positive 421 (26.3) T790M Positive 65 (4.1) Mutation status missing/unknown in some patients (EGFR mutation, 1.2%; Del19, 11.2%; L858R, 24.5%; T790M, 32.7%)

8 Safety Most common ADRs* of any grade ( 5% of patients) Safety set (n=1,602) All Grade 3 Any ADR,* n (%) 1,525 (95.2) 581 (36.3) Infections and infestations Paronychia 540 (33.7) 59 (3.7) Diarrhea 1,257 (78.5) 242 (15.1) Gastrointestinal disorders Stomatitis 495 (30.9) 62 (3.9) Nausea 122 (7.6) 16 (1.0) Vomiting 90 (5.6) 16 (1.0) Rash 652 (40.7) 56 (3.5) Skin/subcutaneous tissue disorders Dermatitis acneiform 185 (11.5) 22 (1.4) Acne 129 (8.1) 15 (0.9) Dry skin 83 (5.2) 3 (0.2) Metabolism and nutrition disorders Decreased appetite 220 (13.7) 76 (4.7) *Includes neoplasms (n=242; 15.1%) as well as AEs; According to Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0

9 Safety (cont d) ADRs of special interest The most frequently reported ADRs (all grade/grade 3 4) were diarrhea (78%/15%), rash/acne* (59%/6%), stomatitis* (31%/4%), nail effects* (38%/4%) Real ILD occurred in 60 (4%) of patients overall, and ILD* (all grade/ grade 3 4/grade 5) occurred in 4%/2%/1% of patients Patients, n (%) Median time to onset, days [range] Diarrhea 1,257 (78.5) 5 [1 316] Rash/acne* 938 (58.6) 11 [1 406] Stomatitis* 512 (32.0) 9 [1 327] Nail effects* 602 (37.6) 38 [1 526] ILD 60 (3.7) 35.5 [3 329] *Grouped term; Median time to onset is based on the grouped term (patients with ILD/ILD-like events; n=70)

10 Safety (cont d) Dose reductions/discontinuations due to ADRs of special interest 762 (48%) patients had 1 afatinib dose reduction; 341 (21%) patients discontinued due to AEs only Diarrhea Rash/acne* Stomatitis* Nail effects* ILD* Dose reduction, % Permanent discontinuation, % Diarrhea Rash/acne* Stomatitis* Nail effects* ILD* Four patients (<1%) experienced creatinine elevation following grade 3 diarrhea ADR frequency was associated with starting dose, but was not unfavorably influenced by age, ECOG PS, number of prior chemotherapies, or previous EGFR TKIs *Grouped term

11 Safety (cont d) ADRs in safety set, by subgroup Grade 3 ADRs by subgroup n ADRs Odds ratio (95% CI) Grade 3 ADRs Odds ratio (95% CI) Age, years <75 1, (95.7) 482 (37.3) (93.2) 0.62 (0.37, 1.04) 98 (31.9) <25 1, (95.2) 494 (37.3) BMI, kg/m (95.3) 1.02 (0.54, 1.93) 78 (30.7) ECOG PS Number of prior chemotherapies Prior EGFR TKIs Starting dose, mg (96.7) 208 (32.4) 0.79 (0.60, 1.03) 0.74 (0.56, 0.99) (94.7) 0.61 (0.35, 1.04) 281 (38.0) 1.28 (1.03, 1.60) (91.6) 0.37 (0.18, 0.77) 59 (41.3) 1.47 (1.01, 2.13) (95.2) 0.68 (0.20, 2.33) 25 (39.7) 1.37 (0.81, 2.33) (86.7) 0.22 (0.05, 1.04) 8 (53.3) 2.38 (0.85, 6.66) (97.5) 219 (45.1) (95.4) 0.53 (0.23, 1.22) 87 (36.1) 0.69 (0.50, 0.95) (93.1) 0.34 (0.16, 0.71) 75 (27.4) 0.46 (0.33, 0.63) (94.2) 0.41 (0.21, 0.80) 200 (33.3) 0.61 (0.48, 0.78) No (97.1) 278 (42.5) Yes (93.9) 0.46 (0.27, 0.78) 303 (32.0) (86.1) 29 (25.2) 0.64 (0.52, 0.78) (93.1) 2.18 (1.06, 4.48) 78 (31.7) 1.38 (0.84, 2.27) 40 1, (96.5) 4.40 (2.39, 8.07) 474 (38.2) 1.83 (1.18, 2.83)

12 Safety (cont d) ADRs/Grade 3 ADRs by age and starting dose n ADRs Odds ratio (95% CI) Grade 3 ADRs Odds ratio (95% CI) <75 years 75 years Starting dose, mg Starting dose, mg (83.9) 14 (25.0) (94.2) 3.11 (1.17, 8.28) 52 (33.5) 1.51 (0.76, 3.02) 40 1, (96.5) 5.26 (2.40, 11.50) 416 (38.5) 1.88 (1.01, 3.48) (88.14) 15 (25.4) (91.21) 1.40 (0.48, 4.08) 26 (28.6) 1.17 (0.56, 2.46) (96.18) 3.39 (1.09, 10.54) 57 (36.3) 1.67 (0.86, 3.27) 529 (33%) patients experienced serious ADRs; the most frequent serious ADRs not due to progressive disease were diarrhea (7%) and ILD (4%) Includes neoplasms as well as AEs; Age data missing for one patient; BMI data missing for 24 patients; CI, confidence interval

13 Efficacy ORR by subgroup All patients 1, (40.1) n Patients with objective response,* n (%) Odds ratio (95% CI) Prior EGFR TKIs No (67.7) Yes (21.0) 0.13 (0.10, 0.16) Number of prior chemotherapies (includes prior EGFR TKIs in many patients) (73.5) (35.7) 0.20 (0.14, 0.28) (24.1) 0.11 (0.08, 0.16) (22.1) 0.10 (0.08, 0.14) Starting dose, mg (all patients) Previously untreated patients (36.5) (31.3) 0.79 (0.50, 1.26) 40 1, (42.1) 1.27 (0.85, 1.88) <75 years 75 years Starting dose, mg Starting dose, mg (77.8) (69.2) 0.64 (0.11, 3.81) (74.3) 0.83 (0.17, 4.05) (66.7) (76.2) 1.60 (0.39, 6.51) (71.4) 1.25 (0.39, 3.99) *Includes patients with complete response and partial response; Includes patients with previous EGFR TKI treatment

14 Key findings and conclusions This was a prospective, post-marketing surveillance study in Japanese patients, of afatinib use in general practice 1525 (95.2%) patients experienced ADRs and 529 (33%) experienced serious ADRs, including progressive disease The types and frequencies of ADRs were consistent with the known safety profile of afatinib 1 3 ADRs were predictable and generally manageable The frequency of ADRs was not notably affected by age, ECOG PS or number of previous therapies ORR with afatinib was higher in EGFR TKI-naïve patients than those who had previously been treated with EGFR TKIs (67.7% vs 21.0%) In clinical practice, patients should be closely monitored, and ADRs, particularly diarrhea and ILD, should be treated early to prevent progressing to serious ADRs

15 References 1. Sequist LV, et al. J Clin Oncol 2013;31: Wu YL, et al. Lancet Oncol 2014; Yang JC, et al. Lancet Oncol 2015;16: Kato T, et al. Cancer Sci 2015;106: PMDA. List of Approved Products. FY PDMA. Review Report: Gilotrif Acknowledgments We thank all patients and their families, and investigators and staff at all clinical sites for their valuable participation in this study. 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 Fiona Scott of GeoMed, an Ashfield company, part of UDG Healthcare plc, during the development of this poster. *Corresponding author address: nbyamamo@wakayama-med.ac.jp These materials are for personal use only and may not be reproduced without written permission of the authors and the appropriate copyright permissions