Ensartinib updated the efficacy and quality of life data at the World Conference on Lung Cancer (WCLC) World Wide Virtual Event, January 28-31, 2021 Dr. Yi-long Wu presented the poster titled “Quality-of-life outcomes and subgroup analysis in a phase 3 randomized study of ensartinib vs. crizotinib in anaplastic lymphoma kinase (ALK)-positive NSCLC patients: EXALT3”

QUALITY-OF-LIFE OUTCOMES AND SUBGROUP ANALYSIS IN A PHASE 3 RANDOMIZED STUDY OF ENSARTINIB VS CRIZOTINIB IN ANAPLASTIC LYMPHOMA KINASE (ALK)-POSITIVE NSCLC PATIENTS: EXALT3 Wu Y,1 Wang Z,2 Wu G,3 Poddubskaya E,4 Mok T,5 Reck M,6 Chiappori A,8 Lee DH,9 Breder V,10 Orlov S,11 Cicin I,12 Cheng Y,13 Liu Y,14 Fan Y,15 Yen J,16 Zhou J,17 Liang C,17 Mao L,17 Selvaggi G,17 Horn L,18 Wakelee H19 1Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China; 2Beijing Cancer Hospital, Beijing China; 3Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; 4Sechenov University, Moscow, Russia; 5The Chinese University of Hong Kong, Hong Kong, China; 6LungClinic, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 8Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 9Asan Medical Center, Seoul, South Korea; 10Russian Cancer Research Center - Blokhin, Moscow, Russia; 11Pavlov First Saint Petersburg State Medical University, St Petersburg, Russia; 12Trakya University, Edirne, Turkey; 13Jilin Cancer Hospital, Changchun, China; 14The First Hospital of China Medical University, Shenyang, China; 15Zhejiang Cancer Hospital, Hangzhou, China; 16 Guardant Health, Redwood City, CA, USA; 17Xcovery Holdings, Inc., Palm Beach Gardens, FL, USA; 18Vanderbilt-Ingram Cancer Center, Nashville, TN, USA; 19Stanford Cancer Institute, Stanford University, Stanford, CA, USA Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China DISCLOSURES Commercial Interest Relationship(s) AstraZeneca, BI, BMS, Eli Lilly, MSD, Pfizer, Roche Speakers bureau AstraZeneca, BI, Novartis Consultant AstraZeneca, BMS, Pfizer Contracted research 0 1 2 IC50 Kinase EphA2 TRKC TRKA ALK Ensartinib TK Profile Introduction ALK, anaplastic lymphoma kinase; IC50, half maximal inhibitory concentration; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor. 1. Tsao AS, et al. J Thorac Oncol. 2016;11(5):613-638; 2. Lovly CM, et al. Cancer Res. 2011;71(14):4920-4931; 3. Horn L, et al. Clin Cancer Res. 2018;24(12):2771-2779; 4. Fang WF, et al. J Clin Oncol. 2018;36(Suppl 15):e21122; 5. Yang Y, et al. Lancet Respir Med. 2020;8(1):45-53. • Oncogenic rearrangements of the ALK gene occur in approximately 5%-7% of patients with NSCLC1 • Ensartinib is a potent, second-generation, once-daily oral ALK inhibitor, with broad preclinical activity against ALK resistance mutations2 – Ensartinib potency is more than 10 times greater than that of crizotinib in enzymatic assays2 • In phase 1/2 trials, ensartinib has shown promising antitumor activity in patients with ALK TKI–naive, crizotinib-refractory, advanced ALK-positive NSCLC, including those with brain metastases3-5 Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Primary endpoint: blinded independent review committee (BIRC)–assessed median PFS (mPFS) per RECIST v1.1 in ITT population Key secondary endpoints: OS, ORR/DOR (overall and brain), TTF in the brain, QOL (EORTC, LCSS) • Stage IIIB/IV NSCLC • ALK+ by local FDA-approved assays or central confirmation by FISH (Abbott) • ECOG PS 0-2 • No prior ALK inhibitor • ≤1 Prior chemotherapy regimen Ensartinib 225 mg QD Stratified by: • Prior chemotherapy • ECOG PS • Asia Pacific vs ROW • Brain metastases at BL Crizotinib 250 mg BID Randomized 1:1 • No crossover allowed • Trial fully accrued as of Nov 2018 eXalt3: Global Phase 3, Open-Label, Randomized, Multicenter Study1 ALK, anaplastic lymphoma kinase; BID, twice daily; BL, baseline; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; EORTC, European Organisation for Research and Treatment of Cancer; FDA, US Food and Drug Administration; FISH, fluorescence in situ hybridization; ITT, intent to treat; LCSS, Lung Cancer Symptom Scale; NSCLC, non-small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; QD, once daily; QOL, Quality of life; RECIST 1.1, Response Evaluation Criteria in Solid Tumors version 1.1; ROW, rest of world; TTF, time to treatment failure. 1. Selvaggi G, et al. J Thoracic Oncol 2020;15(suppl 10):E41-E42. Oral presentation at the 2020 WCLC virtual Presidential Symposium by L Horn. Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China 106 screen failed Ensartinib n=121 Crizotinib n=126 290 randomized ALK+ NSCLC patients (ITT) Ensartinib n=143 Crizotinib n=147 247 patients ALK+ by centralAbbott FISH test (mITT) 396 screened patients1 n=22 Ensartinib • 13 no residual tissue • 2 samples not informative • 7 samples tested negative n=21 Crizotinib • 12 no residual tissue • 7 samples not informative • 2 samples tested negative 43 patients total were centrally not confirmed as ALK+ ALK, anaplastic lymphoma kinase; FISH, fluorescence in situ hybridization; ITT, intent to treat; mITT, modified ITT; NSCLC, non-small cell lung cancer 1. Selvaggi G, et al. J Thoracic Oncol 2020;15(suppl 10):E41-E42. Oral presentation at the 2020 WCLC virtual Presidential Symposium by L Horn. Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Study Summary from the 2020 WCLC Presidential Symposium1 • An interim analysis was presented August 8, 2020, based on a database lock date of July 1, 2020 • In the ITT population, ensartinib achieved a median progression free survival (PFS) of 25.8 vs 12.7 months for crizotinib; HR, 0.51 (95% CI, 0.35-0.72); P=.0001 • In the modified ITT population (patients with centrally confirmed ALK+ NSCLC), median PFS with ensartinib was not reached vs 12.7 months for crizotinib; HR, 0.45 (95% CI, 0.30-0.66); P<.0001 • In the modified ITT population, median overall survival (OS) was not reached in either the ensartinib or crizotinib arm – 24-month OS for ensartinib was 77.9% vs 78.2% for crizotinib • Ensartinib showed a favorable safety profile with low-grade rash and transaminitis as the most frequent treatment- related AEs • Here we present an update of efficacy based on a December 8, 2020, data cut, exploratory biomarker analyses, and quality of life (QOL) data AE, adverse event; ALK, anaplastic lymphoma kinase; HR, hazard ratio; ITT, intent to treat; NSCLC, non-small cell lung cancer; PFS, progression-free survival. 1. Selvaggi G, et al. J Thoracic Oncol 2020;15(suppl 10):E41-E42. Oral presentation at the 2020 WCLC virtual Presidential Symposium by L Horn. Ensartinib (n=121) Crizotinib (n=126) mPFS (95% CI), mo NR (20.2-NR) 12.7 (8.9-16.6) Hazard ratio (95% CI) 0.45 (0.31-0.65) P value (stratified log-rank test) <.0001 Ensartinib (n=143) Crizotinib (n=147) mPFS (95% CI), mo 31.3 (20.2-NR) 12.7 (9.2-16.6) Hazard ratio (95% CI) 0.50 (0.36-0.71) P value (stratified log-rank test) <.0001 Median follow-up, mo Ensartinib 27.6 Crizotinib 22.8 Median follow-up, mo Ensartinib 27.6 Crizotinib 21.9 Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China 33.0% 17.0% 54.4% 48.7% 0 0 20 40 60 80 100 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Ensartinib Crizotinib No. at risk Time, months PFS, % 143 125 107 98 86 78 74 66 56 43 23 20 10 4 1 1 147 124 94 75 56 43 34 27 21 18 4 3 2 1 1 0 48 51 1 0 0 0 32.2% 16.6% 56.4% 50.5% 0 0 20 40 60 80 100 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Ensartinib Crizotinib No. at risk Time, months PFS, % 121 107 91 84 75 67 63 57 50 38 18 15 6 3 1 1 126 109 82 66 50 38 30 24 20 18 4 3 2 1 1 0 48 51 1 0 0 0 PFS per IRC, ITT Population PFS per IRC, mITT Population Updated PFS (December 8, 2020) IRC, independent reviewer committee; ITT, intent to treat; mITT, modified ITT; mPFS, median PFS; NR, not reached; PFS, progression-free survival. 20.9% 14.4% 53.5% 47.5% 0 0 20 40 60 80 100 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Ensartinib Crizotinib No. at risk Time, months PFS, % 121 107 92 84 75 69 66 61 56 48 21 20 5 3 1 1 126 111 92 79 60 47 35 28 23 18 5 4 3 1 1 0 48 51 1 0 0 0 Ensartinib (n=121) Crizotinib (n=126) mPFS (95% CI), mo 33.2 (18.3-NR) 12.9 (11.0-15.0) Hazard ratio (95% CI) 0.45 (0.32-0.64) P value (log-rank test) <.0001 Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China PFS by INV (mITT population, December 8, 2020) INV, investigator; mITT, modified intent to treat; mPFS, median PFS; NR, not reached; PFS, progression-free survival. 78% 0 0 20 40 60 80 100 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 Ensartinib Crizotinib No. at risk Time, months OS, % 121 117 114 111 104 98 93 91 91 77 42 29 10 5 1 1 126 121 120 114 112 105 100 94 85 60 28 20 11 5 2 0 48 51 1 0 0 0 Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Updated OS (mITT population, December 8, 2020) mOS, median OS; mITT, modified intent to treat; NR, not reached; OS, overall survival.. Ensartinib (n=121) Crizotinib (n=126) mOS (95% CI), mo NR (NR-NR) NR (NR-NR) Hazard ratio (95% CI) 0.90 (0.55-1.49) P value (log-rank test) .695 Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Methods: Biomarker Analyses • Tumor tissue – Tissue obtained (archival, fresh biopsy) at study entry and post-treatment upon progression, if possible • Circulating tumor DNA (ctDNA) – Approximately 20 mL of blood was collected pre-dose on cycle 1, day 1 and on day 1 of each cycle through the end of trial. Between 1 to 4 mL of plasma was processed for ctDNA analysis • ALK variant types, maximum somatic variant allele frequency and co-occurring somatic variants in EGFR, KRAS, PIK3CA, and TP53a were evaluated using next-generation sequencing – Analyses were performed at a certified, College of American Pathologists–accredited, laboratory (Guardant Health, Inc) Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China ctDNA detected Activating EGFR/KRAS/PIK3CA SNV/Indel, any TP53 variant C1D1 Max VAFa Overview of Patient Mutational Profile Based on ctDNA ALK, anaplastic lymphoma kinase; C1D1, cycle 1, day 1; ctDNA, circulating tumor DNA; EOT, end of trial; Max VAF, maximum somatic variant allele frequency; SNV, single-nucleotide variation; V, variant. a Low VAF (white) to high VAF (dark blue, ≈50%). • EML4-ALK fusions were detected in 22 patients – 13 patients had variant type 1 – 8 patients had variant type 3 – 1 EML4-ALK fusion with no associated variant type was identified • 7 patients without an ALK fusion had a driver mutation in EGFR/KRAS Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China ALK SNVs Detected in V1 and V3 Fusions at Disease Progression ALK, anaplastic lymphoma kinase; C1D1, cycle 1, day 1; EOT, end of trial; SNV, single-nucleotide variation; V, variant. • 7/15 (46.7%) patients with an ALK+ fusion detected at progression on ensartinib had an ALK resistance SNV – ALK resistance SNVs were acquired at EOT in 5/5 (100%) patients with both C1D1 and EOT timepoints – In patients with ALK V1, G1269A was detected in 2 patients, while 2 patients had E1210K mutations – G1202R was detected only in patients with ALK V3 – Concurrent mutations, E1210K and F1174V, were detected in 1 patient with ALK V3 Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China PRO: QOL Measures • The EORTC C30/LC13 QOL questionnaire is a health-related QOL instrument consisting of 13 items for use in lung cancer clinical trials; the patient assesses symptoms or problems experienced over the past week – EORTC C30/LC13 items were summarized by time point. A higher score signifies a better QOL – Time to deterioration (TTD) is defined at the time from date of randomization to a worsening of ≥10 points (on a 100-point scale) in each item score of the EORTC C30/LC13 • The LCSS is a QOL assessment designed for use in clinical trials in patients with lung cancer – Patients are asked to assess 6 symptoms and their effect on symptomatic distress, functional activities, and global quality of life on 9 visual analog scales – Results were summarized by time point. A lower score signifies a better QOL – TTD is defined as the time from date of randomization to a worsening of ≥15 points (on a 100-point scale) in each item score • Patients completed both QOL instruments at baseline, Day 1 (pre-dose), C2D1, C3D1, then approximately every 8 weeks (2 cycles), and at the End of Trial Treatment visit EORTC, European Organisation for Research and Treatment of Cancer; LCSS, Lung Cancer Symptom Scale; PRO, patient-reported outcome; QOL, quality of life. 0 2 4 6 8 10 12 14 16 18 20 22 24 0 5 10 15 20 Months EORTC Global Score Change from Baseline, LS mean ± SE Ensartinib Crizotinib 0 2 4 6 8 10 12 14 16 18 20 22 24 -15 -10 -5 0 Months LCSS Global Score Change from Baseline, LS mean ± SE Ensartinib Crizotinib Change from Baseline in LCSS Better Worse BetterWorse Change from Baseline in EORTC Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China QOL (ITT population) • Patients treated with ensartinib had better QOL scores on both the EORTC and LCSS • Benefit appeared to be maintained over time EORTC, European Organisation for Research and Treatment of Cancer; LCSS, Lung Cancer Symptom Scale; LS, least squares; QOL, quality of life. Time to Deterioration TTD is defined as the time from date of randomization to a worsening of at least 10 points (on a 100-point scale) in each item score of the EORTC C30/LC13 and of at least 15 points (on a 100-point scale) in each item score of the LCSS Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China QOL (ITT population) EORTC-C30/LC13 LCSS Ensartinib n=143 Crizotinib n=147 Ensartinib n=143 Crizotinib n=147 Median TTD, months 22.2 15.9 NR NR 95% CI 12.6-33.2 11.2-NR NR-NR 36.9-NR HRa 0.86 0.73 95% CI 0.60-1.24 0.43-1.25 P-value 0.419 0.253 a HR estimate with covariates in Cox model. EORTC, European Organisation for Research and Treatment of Cancer; HR, hazard ratio; LCSS, Lung Cancer Symptom Scale; TTD, time to deterioration. Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Conclusions • This is an update of the eXalt3 phase III trial of ensartinib vs crizotinib based on an additional 5 months follow-up since the readout of the preplanned interim analysis on July 1, 2020 • As of December 8, 2020, median PFS by IRC of ensartinib reached 31.3 months in the ITT population and median PFS by INV of ensartinib reached 33.2 months in the mITT population with a 27.6-month median follow-up • The favorable trend of OS is confirmed with a 2-year OS rate of 78% although analysis remains immature • Exploratory biomarkers analysis showed a distinct resistance profile for ensartinib, with emerging E1210K and G1269A mutations and less frequent G1202R mutations (seen only in V3 cases) as detected using NGS on ctDNA at progression • Patient-reported outcome measures showed improved QOL and a longer time to QOL deterioration in ensartinib- vs crizotinib-treated patients • Finally, updated efficacy data confirm that ensartinib represents a new therapeutic option in the first-line setting for patients with ALK+ NSCLC ALK, anaplastic lymphoma kinase; ctDNA, circulating tumor DNA; INV, investigator; IRC, independent review committee; ITT, intent to treat; mITT, modified ITT; mPFS, median PFS; NGS, next-generation sequencing; non-small cell lung cancer; OS, overall survival; PFS, progression-free survival; QOL, quality of life; V, variant. eXalt3 Study Y Wu, Guangdong Provincial People’s Hospital & Guangdong Academy of Medical Sciences, Guangzhou, China Acknowledgements • The authors thank – The patients, their families, and their caregivers – The eXalt3 investigators and their team members at each study site • All authors contributed to and approved the presentation; writing and editorial assistance was provided by Alex Loeb, PhD, Chrysalis Medical Communications

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