IR/PR ASCO 2018: YH25448, a 3 rd Generation EGFR TKI, in Patients with EGFR TKI resistant NSCLC: Phase I/II Study Results

YH25448, a 3rd Generation EGFR-TKI, in Patients with EGFR-TKI-resistant NSCLC: Phase I/II Study Results Byoung Chul Cho1, Ji-Youn Han3, Sang-We Kim4, Ki-Hyeong Lee5, Dong-Wan Kim6, Yun-Gyoo Lee7, Gyeong-Won Lee8, Jong-Seok Lee9, Eun Kyung Cho10, Joo-Hang Kim11, Sung Sook Lee12, Young Joo Min13, Jin-Soo Kim14, Sang Won Shin15, Hye Ryun Kim1, Min Hee Hong1, Jin Seok Ahn2, Heung Tae Kim3, Soongyu Choi16, Myung-Ju Ahn2 1Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea, 2Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, 3Center for Lung Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea, 4Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea, 5Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Chungcheongbuk-do, Korea, 6Seoul National University Hospital, Seoul, Korea, 7Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea, 8Gyeongsang National University Hospital, Gyeongsang National University of Medicine, Jinju, Gyeongsangnam-do, Korea, 9Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Gyeonggi-do, Korea, 10Gachon University Gil Medical Center, Incheon, Korea, 11CHA Bundang Medical Center, CHA University, Seongnam, Gyeonggi-do, Korea, 12Inje University College of Medicine, Inje University Haeundae Paik Hospital, Busan, Korea, 13Ulsan University Hospital, University of Ulsan College of Medicine, Ulsan, Korea, 14Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea, 15Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea, 16Yuhan R&D Institute, Yuhan Corporation, Yongin, Gyeonggi-do, Korea INTRODUCTION Poster #356 Poster presented at 2018 ASCO annual meeting, June 1-5, 2018, Chicago, USA; Abstract #9033 RESULTS CONCLUSIONS ▪ The majority of patients who had treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) eventually relapse with disease progression within 1 to 2 years1). The T790M mutation in exon 20 of EGFR was present up to 60 % of resistant cases2). ▪ Brain metastasis (BM) is present in one-quarter of patients at diagnosis, and about half of patients with EGFR-mutated lung cancer develop brain metastases within 3 years3). ▪ YH25448 (lazertinib) is a potent, highly mutant-selective and irreversible 3rd generation EGFR-TKI that is able to penetrate the blood-brain barrier, and targets both the T790M mutation and activating EGFR mutations (EGFRm) while sparing wild type. METHODS ▪ The aim of this study was to evaluate the safety, tolerability, pharmacokinetics and efficacy of YH25448 when given orally to Korean patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with acquired resistance to prior EGFR-TKI treatments (ClinicalTrials.gov identifier NCT03046992). ▪ An open-label, multicenter, phase I/II study was performed with YH25448 20 to 320 mg once daily in the dose escalation cohort across 7 dose levels and 40 to 240 mg once daily in the expansion cohort across 5 dose levels (Figure 1). ▪ In the dose escalation cohort, 6 patients were enrolled in each dose level using the rolling six manner. The safety review committee determined the escalation of next dose level using the safety assessment during the 28-day evaluation period. ▪ In the dose expansion cohort, up to 20 patients were enrolled. The T790M-positive of tissue biopsy was confirmed using Roche cobas® EGFR mutation test v2 at central laboratory. Figure 1. Study Design * The dose extension cohort was initiated at April 2018. RP2D; recommended phase 2 dose Baseline Demographics and Characteristics ▪ A total of 118 patients were enrolled as of 20 April 2018. ▪ Thirty-eight patients were in the dose escalation cohort and 80 patients were in the dose expansion cohort (Table 1). ▪ Median age was 62.5 years and 60% of patients were female. ▪ 83% of patients were T790M+ NSCLC. Table 1. Baseline Demographics and Characteristics * Tested in a central laboratory. # Patients may have more than one prior regimen. Percentages are calculated based on number of patients in the safety analysis population who received at least one dose of IP. Dose escalation (n=38) Dose expansion (n=80) Overall (N=118) Age in years, median (range) 60 (28, 82) 63 (37, 84) 62.5 (28, 84) Male, n (%) 13 (34) 34 (43) 47 (40) Adenocarcinoma, n (%) 37 (97) 80 (100) 117 (99) T790M status*, n (%) Positive 18 (47) 80 (100) 98 (83) Negative 20 (53) 0 20 (17) AJCC stage, n (%) IIIB 2 (5) 1 (1) 3 (3) IV 36 (95) 79 (99) 115 (97) Prior lines of systemic therapy, median (range) 2 (1, 6) 1 (1, 6) 1.5 (1, 6) Number of prior EGFR-TKIs, median (range) 1 (1, 2) 1 (1, 3) 1 (1, 3) Regimen # , n (%) Gefitinib 27 (71) 54 (68) 81 (69) Erlotinib 9 (24) 21 (26) 30 (25) Afatinib 5 (13) 15 (19) 20 (17) Pharmacokinetics ▪ Median Tmax,ss of YH25448 was 2 hours. ▪ Mean terminal elimination half-life of YH25448 was 64.7 hours following single dose of 240 mg. ▪ Steady state was achieved by 7-15 days after first-dosing, and mean AUC accumulation ratio was 1 to 2 following multiple doses. ▪ AUCss of YH26334 (major metabolite) was 2 to 4% of that of YH25448. ▪ Exposures of YH25448 increased dose-dependently at steady state (Figure 2) Anti-tumor Efficacy ▪ Of the evaluable patients (n=110) with the confirmed response at the date of data cut-off (DCO), the objective response rate (ORR) was 61% (95% confidence interval [CI], 51.8 to 70.0) across all dose levels by investigator assessment (Table 2, Figure 3). - The ORR for 92 of the T790M+ patients was 66% (95% CI, 56.6 to 76.0), and for 18 of the T790M- patients was 33% (95% CI, 11.6 to 55.1). ▪ The disease control rate (DCR) was 89% across all dose levels (95% CI, 83.3 to 94.9). ▪ In patients with BM (n=11), the intracranial ORR was 55% (95% CI, 25.1 to 84.0) (Figure 3C). ▪ The longest duration of response was 9.7 months and the median duration of response has not reached yet. ▪ The median progression-free survival has not calculated yet at the date of DCO. Table 2. Summary of Anti-tumor Efficacy (Confirmed Response) T790M +/- 20mg 40mg 80mg 120mg 160mg 240mg 320mg Overall Evaluable patients a 3 27 20 25 23 9 3 110 Best overall response b , n (%) Complete response 0 0 0 0 0 0 0 0 Partial response 2 (67) 17 (63) 11 (55) 18 (72) 12 (52) 7 (78) 0 67 (61) Stable disease 1 (33) 7 (26) 6 (30) 7 (28) 8 (35) 2 (22) 0 31 (28) Progressive disease 0 2 (7) 3 (15) 0 1 (4) 0 3 (100) 9 (8) Not evaluable 0 1 (4) 0 0 2 (9) 0 0 3 (3) ORR, n (%) 2 (67) 17 (63) 11 (55) 18 (72) 12 (52) 7 (78) 0 67 (61) DCR, n (%) 3 (100) 24 (89) 17 (85) 25 (100) 20 (87) 9 (100) 0 98 (89) T790M + 20mg 40mg 80mg 120mg 160mg 240mg Overall Evaluable patients a 2 25 18 22 18 7 92 Best overall response b , n (%) Complete response 0 0 0 0 0 0 0 Partial response 2 (100) 16 (64) 11 (61) 16 (73) 10 (56) 6 (86) 61 (66) Stable disease 0 7 (28) 4 (22) 6 (27) 7 (39) 1 (14) 25 (27) Progressive disease 0 2 (8) 3 (17) 0 1 (6) 0 6 (7) Not evaluable 0 0 0 0 0 0 0 ORR, n (%) 2 (100) 16 (64) 11 (61) 16 (73) 10 (56) 6 (86) 61 (66) DCR, n (%) 2 (100) 23 (92) 15 (83) 22 (100) 17 (94) 7 (100) 86 (93) a Patients who have baseline and two post-baseline RECIST assessments, or patients who have discontinued prior to the second post-baseline RECIST assessment; b Best overall response is based on investigator’s assessment of disease status or lesion measurements using RECIST v1.1. ▪ YH25448 (lazertinib) demonstrated the promising antitumor efficacy. - The confirmed ORR was 61% across all dose levels in patients with locally advanced or metastatic NSCLC with acquired resistance to prior EGFR-TKI treatments. - In particular, the confirmed ORR in patients with T790M+ was 86% at lazertinib 240 mg dose level. - In patients with BM, the intracranial ORR was 55% across all dose levels. ▪ Lazertinib demonstrated a good safety profile and tolerability. - No DLT was observed up to lazertinib 320 mg. - A total of 89% of TEAEs were mild. - There were no dose-dependently increased TEAEs. ▪ In conclusion, lazertinib was safe, well-tolerated and exhibits promising systemic and intracranial antitumor activities at multiple dose levels in EGFRm+ NSCLC patients. ▪ The dose extension cohort as the first-line setting has been initiated from April 2018. REFERENCES ACKNOWLEDGEMENTS This study was sponsored by Yuhan Corporation. All authors would like to thank the patients and their families, as well as the staffs and investigators at all study sites. 1. Camidge DR, et al. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nature reviews Clinical oncology 2014; 11: 473-81. 2. Cortot AB and Jänne PA. Molecular mechanisms of resistance in epidermal growth factor receptor-mutant lung adenocarcinomas. Eur Respir Rev. 2014; 23(133): 356-66. 3. Rangachari D, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung cancer (Amsterdam, Netherlands) 2015; 88: 108-11. Table 4. TEAEs Occurring ≥ 10 % of All Patients Patients with TEAEs, n (%) 20mg (n=3) 40mg (n=27) 80mg (n=20) 120mg (n=25) 160mg (n=23) 240mg (n=15) 320mg (n=5) Overall (N=118) Pruritus 0 4 (15) 4 (20) 4 (16) 8 (35) 7 (47) 1 (20) 28 (24) Rash 0 5 (19) 1 (5) 6 (24) 6 (26) 3 (20) 2 (40) 23 (19) Decreased appetite 1 (33) 4 (15) 3 (15) 3 (12) 5 (22) 2 (13) 2 (40) 20 (17) Constipation 1 (33) 3 (11) 6 (30) 4 (16) 3 (13) 1 (7) 1 (20) 19 (16) Diarrhea 0 3 (11) 0 2 (8) 4 (17) 4 (27) 1 (20) 14 (12) Percentages are based on the total number of patients in the safety analysis population within relevant dose level. Patients with two or more adverse events with the same AE term is counted only once for that AE term. Table 3. Safety Overview of Overall TEAEs Patients with TEAEs, n (%) 20mg (n=3) 40mg (n=27) 80mg (n=20) 120mg (n=25) 160mg (n=23) 240mg (n=15) 320mg (n=5) Overall (N=118) TEAEs 3 (100) 24 (89) 17 (85) 23 (92) 20 (87) 15 (100) 5 (100) 107 (91) Drug related TEAEs 2 (67) 16 (59) 11 (55) 18 (72) 14 (61) 13 (87) 4 (80) 78 (66) Serious TEAEs 1 (33) 4 (15) 3 (15) 4 (16) 3 (13) 0 2 (40) 17 (14) Drug related serious TEAEs 0 2 (7) 1 (5) 1 (4) 0 0 0 4 (3) TEAEs with grade ≥ 3 0 3 (11) 1 (5) 2 (8) 4 (17) 1 (7) 2 (40) 13 (11) Drug related TEAEs with grade ≥ 3 0 1 (4) 0 1 (4) 0 0 0 2 (2) TEAEs leading to Death 0 0 0 0 0 0 0 0 Dose reduction 0 0 0 2 (8) 0 2 (13) 1 (20) 5 (4) Dose interruption 1 (33) 3 (11) 2 (10) 3 (12) 1 (4) 0 1 (20) 11 (9) Discontinuation 0 2 (7) 1 (5) 0 0 0 0 3 (3) Percentages are based on the total number of patients in the safety analysis population. Drug related TEAEs are events with relationship certain, probable/likely, possible, unlikely, unassessable/unclassifiable, or missing. Safety and Tolerability ▪ No dose-limiting toxicities (DLT) were observed up to YH25448 320 mg in the dose escalation cohort. ▪ A total of 89% of treatment-emergent adverse events (TEAEs) were mild (CTCAE grade ≤ 2) at all dose levels (Table 3). ▪ The most common TEAEs were pruritus (24%), rash (19%), decreased appetite (17%), constipation (16%) and diarrhea (12%) (Table 4). There was no interstitial lung disease. ▪ The TEAEs leading to dose-reduction, interruption and discontinuation were observed in 4%, 9% and 3% of patients, respectively. ▪ Any TEAEs of CTCAE grade ≥ 3 was observed in 11% of patients. The most frequently TEAEs of CTCAE grade ≥ 3 were pulmonary embolism (3%), hyponatremia (2%), nausea (2%) and pneumonia (2%). ▪ There were no dose-dependently increased TEAEs. Figure 2. Plasma Concentrations of YH25448 at Steady State Data represents the arithmetic mean+standard deviation Red dashed line represents the IC50 value (70 ng/mL) of EGFR phosphorylation in H1975 cell line Figure 3. Best Percentage Change in Target-Lesion Size (A) Overall patients (n=110) (B) T790M+ patients (n=92) These waterfall plots include the unconfirmed response data; x: discontinuation or disease progression; y: Imputed values for patients who discontinued and had no evaluable target lesion assessments (C) Intracranial lesion in patients with BM (n=11) For more information, please contact us at: [email protected] , +82-31-899-4203, or visit www.yuhan.co.kr T790M- T790M-

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