Olmutinib (BI 1482694; HM61713), an EGFR mutant-specific inhibitor, in + NSCLC: #378 efficacy and safety at the RP2D

Keunchil Park,1* Jong-Seok Lee,2 Ki Hyeong Lee,3 Joo-Hang Kim,4 Byoung Chul Cho,5 Young Joo Min,6 Jae Yong Cho,7 Ji-Youn Han,8 Bong-Seog Kim,9 Jin-Soo Kim,10 Dae Ho Lee,11 Jin Hyoung Kang,12 Eun Kyung Cho,13 Hoon-Gu Kim,14 Kyung Hee Lee,15 Hoon Kyo Kim,16 In-Jin Jang,17 Hyo-Yeon Kim,18 Jeewoong Son,18 Dong-Wan Kim17

1Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; 2Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea; 3Chungbuk National University Hospital, Cheongju, North Chungcheong, South Korea; 4CHA Bundang Medical Center, CHA University, Gyeonggi-Do, South Korea; 5Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea; 6Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, South Korea; 7Gangnam Severance Hospital, Seoul, South Korea; 8Center for Lung Cancer, National Cancer Center, Goyang, South Korea; 9VHS Medical Center, Seoul, South Korea; 10Seoul National University, Boramae Medical Center, Seoul, South Korea; 11Asan Medical Center, Seoul, South Korea; 12Seoul St Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea; 13Gachon University Gil Medical Center, Incheon, South Korea; 14Gyeongsang National University Hospital, Jinju, South Gyeongsang, South Korea; 15Yeungnam University Medical Center, Gyeonsan, North Gyeongsang, South Korea; 16St. Vincent's Hospital, Suwon, South Korea; 17Seoul National University Hospital, Seoul, South Korea; 18Hanmi Pharmaceutical Co., Ltd., Seoul, South Korea

INTRODUCTION RESULTS Table 2. Tumor response (independent assessment) • Across all patients (N=76), median treatment duration was 7.3 months Table 3. Drug-related AEs in >20% of patients (range 0.3–16.7) (Figure 4) Treated patients (N=76) Response, n (%) Evaluable for response (n=70) • A T790M mutation within exon 20 of the EGFR gene is the most common (~50% of Patients and treatment – As of February 29, 2016, 14 (18%) patients are continuing treatment, with a cases) mechanism of acquired resistance to first- and second-generation EGFR duration of over 16 months AE, n (%) All grades Grade ≥3 1–3 • Between August 2014 and April 2015 76 Korean patients with T790M+ NSCLC tyrosine kinase inhibitors (TKIs) OR (confirmed and unconfirmed) 43 (61) Diarrhea 45 (59) 0 commenced treatment with olmutinib 800 mg QD • Olmutinib (BI 1482694; HM61713) is an oral, third-generation TKI with EGFR Figure 4. Individual treatment duration (treated patients; N=76*) Pruritus 32 (42) 1 (1) mutant-specific activity against Del19, L858R, and T790M, that spares – Patient demographics and baseline characteristics are summarized in Table 1 4 wild-type EGFR Table 1. Baseline characteristics Disease control 63 (90) Rash 31 (41) 4 (5) • The safety, tolerability, pharmacokinetics, and preliminary activity of olmutinib Confirmed OR 38 (54) Nausea 30 (39) 0 were evaluated in a Phase I/II trial in Korean patients with EGFR TKI Characteristic Patients (N=76) SD / unconfirmed PR 20 (29) / 5 (7) pre-treated NSCLC5,6 Palmar-plantar erythrodysesthesia syndrome 23 (30) 3 (4) • In Phase I, the recommended Phase II dose (RP2D) was 800 mg once daily (QD), Gender, n (%) and 76 patients with T790M+ NSCLC were enrolled at this dose in a Phase II part Female 44 (58) PD 3 (4) Best response by independent review* Decreased appetite 23 (30) 0 PR (n=43) – The preliminary safety and efficacy results at 800 mg QD (as of June 2015) were SD (n=20) Dry skin 21 (28) 1 (1) 6 Median age, years (range) 60 (32–85) presented previously NE 4 (6) NE (n=10) PD (n=3) Skin exfoliation 20 (26) 1 (1) – Here we present updated efficacy and safety findings as of February 29, 2016 NE, not evaluable; PD, progressive disease; SD, stable disease ECOG PS, n (%) Onset of response 0 / 1 / 2 5 (7) / 56 (74) / 15 (20) Confirmed PR (n=38) METHODS Figure 2. Duration of response (independent assessment) Unconfirmed PR (n=5) CONCLUSIONS Identified patient ongoing (n=14) Study design Smoking history, n (%) Never / former / current 53 (70) / 21 (28) / 2 (3) 1.0 • At the RP2D of 800 mg QD, olmutinib showed meaningful clinical activity with a • Phase I/II, open-label, multicenter study (NCT01588145) 0.9 OR rate 0 10 20 30 40 50 60 70 80 favorable safety profile in Korean patients with T790M+ NSCLC progressing on • Phase II part enrolled patients with centrally confirmed T790M+ NSCLC (Figure 1) 0.8 95% CI initial EGFR TKI therapy Previous lines of systemic treatment*, n (%) Censored Treatment duration (weeks) 0.7 • Tumors were assessed every 6 weeks by investigator and independent review 1 / 2 / ≥3 19 (25) / 27 (36) / 30 (39) *6 patients were not evaluable for independent response assessment and were included in those • Confirmed ORs by independent review were observed in 38 (54%) patients, with a according to RECIST v1.1 0.6 classified as best response, NE median duration of response of 8.3 months (5.7–9.7) 0.5 • Treatment continued until disease progression, unacceptable toxicity, or other Previous EGFR TKI†, n (%) • The most common drug-related AEs were typically mild-to-moderate in intensity and 0.4 stopping criteria 58 (76) • Evidence of the anti-tumor activity of olmutinib on CNS metastases was observed in included gastrointestinal and dermatologic disorders 0.3 Probability of OR Probability a 62-year-old male patient enrolled in April 2015. The patient achieved complete 21 (28) • An ongoing global Phase II trial, ELUXA 1 (NCT02485652), is further assessing the Figure 1. Study design and expansion cohort 0.2 response (CR) in the brain by August 2015 (Cycle 6), which was sustained until efficacy and safety of olmutinib in patients with T790M+ NSCLC7 11 (14) 0.1 October 2015 (Cycle 9), when the patient came off treatment due to an adverse 5 Dose escalation (N=66) Poziotinib 2 (3) 0 event (AE) of neuropathy (Figure 5) 0 5 Time (months) 10 15 T790M+ or -negative REFERENCES EGFRm+ NSCLC Median interval from last EGFR TKI, days 61 Figure 5. CR in the brain lesion in a patient at 800 mg QD Progression on ≥2 prior Expansion/Phase II 1. Arcila ME, et al. Clin Cancer Res 2011;17:1169–80 (N=76; ongoing) T790M mutation, n (%) Figure 3. Individual tumor change (independent assessment) Baseline, March 2015 Cycle 5, July 2015 Cycle 6, August 2015 therapies, including EGFR TKI 1200 mg 2. Nguyen KS, et al. Clin Cancer Res 2009;10:281–9 Positive (local test) 76 (100) 800 mg T790M positive Evaluable patients (n=70) 3. Wu SG, et al. Oncotarget 2016;7:12404–13 650 mg Progression on ≥1 prior EGFR TKI Positive (central test) 73 (96) 20 4. Lee K-O, et al. Cancer Res 2014;74:LB-100 No symptomatic or uncontrolled 500 mg 5. Park K, et al. J Clin Oncol 2015;33(Suppl.15) (abstract 8084) CNS metastases † 0 400 mg *Including EGFR TKIs; Patients may have received more than one EGFR TKI 6. Park K, et al. APLCC 2016;poster #PA27 ECOG PS, Eastern Cooperative Oncology Group performance status 300 mg 7. Park K, et al. J Thorac Oncol 2016;11(Suppl 4):S139 (abstract 190TiP) –30 250 mg * * * * * * * Efficacy –50 * * * * * * 200 mg * * * * * * ACKNOWLEDGMENTS • 70 patients were evaluable for response by independent review. Table 2 summarizes volume change (%) PR (n=43) * * 150 mg * * * * * * * Confirmed PR (n=38) * * the best response as of February 29, 2016 * * * * 100 mg SD (n=20) * This study was funded by Co., Ltd. The authors were fully 75 mg • Figures 2 and 3 show duration of response and individual tumor change Tumor NE (n=4) Safety responsible for all content and editorial decisions, were involved at all stages of poster –100 * • 43 (61%) patients experienced tumor shrinkage qualifying for OR PD (n=3) * * • The most common drug-related AEs (all/grade ≥3) were diarrhea (59%/0%), pruritus development, and approved the final version CNS, central nervous system; EGFRm+, EGFR mutation-positive (42%/1%), rash (41%/5%), and nausea (39%/0%) (Table 3) – In the majority of patients (36/43 [84%]), onset of tumor response occurred by the Medical writing assistance, supported financially by Boehringer Endpoints and assessments in Phase II Week 6 (Cycle 2) scan (Figure 4) • 4 (5%) patients discontinued due to drug-related AEs (upper abdominal pain and Ingelheim, was provided by Fiona Scott, PhD, of GeoMed, an • Median PFS among all treated patients (n=76) by independent review was 6.9 vomiting [n=1], interstitial lung disease [n=1], peripheral neuropathy [n=1], and skin • The primary endpoint was objective response (OR) by independent assessment; • 38 (54%) patients had confirmed partial response (PR), with a median duration of Ashfield company, part of UDG Healthcare plc, during the QR months (95% confidence interval [CI]: 5.36, 9.49) exfoliation [n=1]) secondary endpoints included duration of response, progression-free survival response of 8.3 months (range 5.7–9.7) preparation of this poster (PFS), and safety – Median PFS was 8.8 months (95% CI: 3.98, 11.07) in patients with one prior • 11 (14%) patients had serious drug-related AEs Copies of this poster obtained through Quick Response (QR) Code are for code – 13 of 38 confirmed responders continue on treatment at data cut-off systemic treatment (n=19) and 6.8 months (95% CI: 4.21, 8.35) in patients with personal use only and may not be reproduced without permission from • Patients were required to undergo a baseline and at least one post-baseline tumor • There were no AEs of QT prolongation or hyperglycemia and no drug-related deaths assessment to be evaluable for independent response assessment • 63 (90%) patients experienced disease control (PR + SD) two or more prior regimens (n=57) ASCO® and the author of this poster

American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, USA, June 3–7, 2016 *Corresponding author email address: [email protected]