eXalt3 Trial

[Slide 1] JAMA Oncology RCT: Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer POPULATION INTERVENTION FINDINGS 149 Men, 141 Women 290 Patients randomized In the intent-to-treat population, the median PFS was significantly longer with ensartinib than with crizotinib " !!!!! 100 80 Eligible adult patients had advanced, recurrent, Progression-free survival, % 60 Ensartinib 40 or metastatic non-small cell lung cancer that was positive for anaplastic lymphoma kinase 20 143 Oral ensartinib 147 Oral crizotinib Crizotinib Median age, 54 y (range, 25-90 y) 225 mg Once daily 250 mg Twice daily 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time, mo SETTINGS/LOCATIONS PRIMARY OUTCOME 120 Centers Blinded independent review committee-assessed progression-free Median PFS in 21 countries survival (PFS) according to Response Evaluation Criteria In Solid 25.8 mo with ensartinib vs 12.7 mo with crizotinib Tumours (RECIST). version 1.1 (HR, 0.51; 95% CI, 0.35-0.72; P<.001) Horn L. Wang Z. Wu G. et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial. JAMA Oncol. © AMA Published online September 2. 2021. doi:10.1001/jamaoncol.2021.3523

[Slide 1] First Things First: Navigating ALK-Positive Metastatic Non-Small Cell Lung Cancer Treatment Options Eric K. Singhi and Eric S. Nadler Efficacy outcomes and common AEs with first-line ALK TKIs recommended¹.ᵃ in patients with ALK-positive advanced NSCLC Treatment Trial Efficacy outcomes Common AEsb Rash (71%) mFU: 23.8 months Increased ALT (50%) Ensartinib² eXalt3 mPFS: 25.8 months Increased AST (38%) (2-year results) 2-year OS rate: 78% Constipation (31%) 2nd generation n=143 1-year CIR of CNS Cough (31%) progression: 4%cd Pruritus (30%) Nausea (28%) Edema (27%) Diarrhea (58%) mFU: 40.4 months Increased blood CPK (50%) Brigatinib³ ALTA-1L mPFS: 24.0 months Cough (36%) (3-year results) 4-year PFS rate: 36% Nausea (33%) 2nd generation 4-year OS rate: 66% n=137 Hypertension (32%) 4-year IC PFS rate: 46% Increased AST (26%) Back pain (26%) mFU for PFS: 37.8 months mPFS: 34.8 months Alectinib4,5,6 ALEX 4-year PFS rate: 44% Constipation (37%) 2nd generation (5-year results)' 7-year OS rate: 49%' Anemia (26%) n=152 2-year CIR of CNS progression as first site of progression: 7%h Hypercholesterolemia (72%) Hypertriglyceridemia (66%) Edema (57%) mFU for PFS: 60.2 months Peripheral neuropathy (44%) Lorlatinib⁷ CROWN mPFS: not reached Increased weight (44%) 3rd generation (5-year results) 5-year PFS rate: 60% Fatigue (30%) 5-year OS rate: NR n=149 Arthralgia (28%) 5-year IC PFS rate: 92% Cognitive effects (28%) Hypertension (26%) Anemia (25%) *NCCN recommended preferred first line ALK TKIs Any grade treatment emergent AEs that occurred in >25% of patients. Assessed per blinded independent review committee "In patients without baseline brain metastases (n=81). "High rate of censoring and a small sample size The 7-year OS rate is reported from the final OS analysis results after mFU of 53. months Assessed per investigator. "In patients without baseline brain metastases (n=88). The required number of OS events for a protocol-specified second interim analysis were not met at the CROWN 5-year analysis. OS follow-up is currently ongoing. AE, adverse event; ALK, anaplastic lymphoma kinase; ALT. alanine aminotransferase; AST, aspartate transaminase/aspartate aminotransferase; CIR, cumulative incidence rate; CNS, central nervous system; CPK creatine phosphokinase; IC, intracranial; mFU, median follow-up; mPFS, median progression free survival; NCCN, National Comprehensive Cancer Network"; NR, not reached; NSCLC, non-small cell lung cancer, OS, overall survivat PFS, progression free survival; TKL tyrosine kinase inhibitor; ALP, alkaline phosphatase 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines") for Non-Small Cell Lung Cancer 2026. D National Comprehensive Cancer Network, Inc. 2025. All rights reserved. Accessed November 6, 2025. To view the most recent complete version of the guideline, go online to NCCN org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 2. Horn et al. JAMA Oncol. 2021;7(11):1617-1625. 3. Camidge DR, et al. J Thorac Oncol. 2021;16(12):2091-2108. 4. Mok T. et al. Ann Oncol. 2020;31(8):1056-1064. 5. Burudpakdee C, et al. Lung Cancer. 2018;119:103-111. 6. Peters S, et al. Ann Oncol. 2026;37(1):92-103. 7. Solomon BJ, et al. Clin Oncol 2024;42:3400-3409.

[Slide 1] FDA Q Search III Menu IN THIS SECTION Resources for Information I Approved Drugs FDA approves ensartinib for ALK-positive locally advanced or metastatic non- small cell lung cancer

[Slide 1] 2020 Presidential Symposium AUGUST 8, 2020 I WORLDWIDE Conclusions Ensartinib achieved 25.8 months mPFS in the ITT population and NR (HR = 0.45) in the mITT population as assessed by the BIRC in this preplanned interim analysis Leora Horn With longer follow-up, ensartinib is trending toward further improved mPFS overall and in patients without brain metastases at baseline Ensartinib showed superior efficacy in the brain over crizotinib Ensartinib showed a favorable safety profile with low-grade rash and transaminitis as the Topic: most frequent treatment-related AEs Phase III Randomized Study Ensartinib represents a new first-line treatment option for patients with ALK+ NSCLC of Ensartinib vs Crizotinib in Anaplastic Lymphoma Kinase (ALK) Positive NSCLC Patients: eXalt3 Dr Leora Horn, Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, @HornLeora --- [Slide 2] JAMA Oncology RCT: Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer POPULATION INTERVENTION FINDINGS 149 Men, 141 Women 290 Patients randomized In the intent-to-treat population, the median PFS was significantly longer with ensartinib than with crizotinib " !!!!! 100 80 Eligible adult patients had advanced, recurrent, Progression-free survival, % 60 Ensartinib 40 or metastatic non-small cell lung cancer that was positive for anaplastic lymphoma kinase 20 143 Oral ensartinib 147 Oral crizotinib Crizotinib Median age, 54 y (range, 25-90 y) 225 mg Once daily 250 mg Twice daily 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Time, mo SETTINGS/LOCATIONS PRIMARY OUTCOME 120 Centers Blinded independent review committee-assessed progression-free Median PFS in 21 countries survival (PFS) according to Response Evaluation Criteria In Solid 25.8 mo with ensartinib vs 12.7 mo with crizotinib Tumours (RECIST). version 1.1 (HR, 0.51; 95% CI, 0.35-0.72; P<.001) Horn L. Wang Z. Wu G. et al. Ensartinib vs crizotinib for patients with anaplastic lymphoma kinase-positive non-small cell lung cancer: a randomized clinical trial. JAMA Oncol. © AMA Published online September 2. 2021. doi:10.1001/jamaoncol.2021.3523 --- [Slide 3] 07:30 a Voi) LTE LTE1 if all X did FDA approves ensar. Post : fda.gov FDA Q Search = Menu IN THIS SECTION Resources for Information Approved Drugs FDA approves ensartinib for ALK-positive locally advanced or metastatic non-small cell lung cancer f Share X Post Email On December 18, 2024, the Food and Drug Administration approved ensartinib (Ensacove, Xcovery Holdings, Inc.) for adult patients with anaplastic lymphoma kinase (ALK)-positive locally advanced or metastatic non-small cell lung cancer (NSCLC) who have not previously received an ALK-inhibitor. Full prescribing information for Ensacove will be posted on Drugs@FDA. Efficacy and Safety Efficacy was evaluated in eXALT3 --- [Slide 4] varied between ALK inhibitors. Alectinib led to the highest levels of cross- resistance to other ALKi, approximately 3x higher. Lorlatinib led to highest levels of cross-resistance to other drug classes. Treatment with lorlatinib led to resistance in 13 other drug classes. Ensartinib led to least cross-resistance to ALKi and other drug classes. While the H3122 derived cells more rapidly evolved ALKi resistance, first line treatment with ensartinib sensitized them to lorlatinib, extending overall response to ALKi. Conclusions: The

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[Slide 1] Ensartinib (N=143) Crizotinib (N=146) Event Grade 1-2 Grade 3 Grade 4 Grade 5 Grade 1-2 Grade 3 Grade 4 Grade 5 n (%) Any AE 69 (48.3) 64 (44.8) 7 (4.9) 1 (0.7) 83 (56.8) 52 (35.6) 6 (4.1) 4 (2.7) Rash (all)a 85 (59.4) 16 (11.2) 0 0 15 (10.3) 0 0 0 Alanine aminotransferase increased 66 (46.2) 6 (4.2) 0 0 58 (39.7) 11 (7.5) 0 0 Aspartate aminotransferase increased 53 (37.1) 1 (0.7) 0 0 53 (36.3) 4 (2.7) 0 0 Constipation 45 (31.5) 0 0 0 38 (26.0) 0 0 0 Cough 43 (30.1) 1 (0.7) 0 0 20 (13.7) 0 0 0 Pruritus (all)b 40 (28.0) 3 (2.1) 0 0 7 (4.8) 0 0 0 Nausea 38 (26.6) 2 (1.4) 0 0 41 (28.1) 3 (2.1) 0 0 Edema (all)c 36 (25.2) 3 (2.1) 0 0 38 (26.0) 3 (2.1) 0 0 Anemia 31 (21.7) 1 (0.7) 0 0 17 (11.6) 2 (1.4) 0 0 Blood alkaline phosphatase increased 29 (20.3) 1 (0.7) 0 0 24 (16.4) 1 (0.7) 0 0 Pyrexia 28 (19.6) 1 (0.7) 0 0 13 (8.9) 1 (0.7) 0 0 Blood creatinine increased 27 (18.9) 0 0 0 21 (14.4) 0 0 0 Vomiting 22 (15.4) 1 (0.7) 0 0 46 (31.5) 0 0 0 Decreased appetite 22 (15.4) 0 0 0 15 (10.3) 2 (1.4) 0 0 Gamma-glutamyltransferase increased 21 (14.7) 2 (1.4) 0 0 13 (8.9) 1 (0.7) 0 0 Back pain 20 (14.0) 0 0 0 10 (6.8) 0 0 0 Pain in extremity 18 (12.6) 0 0 0 12 (8.2) 0 0 0 Arthralgia 18 (12.6) 0 0 0 7 (4.8) 0 0 0 Hypoalbuminemia 17 (11.9) 0 0 0 20 (13.7) 1 (0.7) 0 0 Upper respiratory tract infection 17 (11.9) 1 (0.7) 0 0 15 (10.3) 0 0 0 Dizziness 17 (11.9) 0 0 0 14 (9.6) 1 (0.7) 0 0 Alopecia 16 (11.2) 0 0 0 7 (4.8) 0 0 0 Dysgeusia 15 (10.5) 0 0 0 16 (11.0) 0 0 0 Fatigue 15 (10.5) 1 (0.7) 0 0 10 (6.8) 2 (1.4) 0 0 Dry skin 14 (9.8) 1 (0.7) 0 0 1 (0.7) 0 0 0 Hyperuricemia 13 (9.1) 1 (0.7) 1 (0.7) 0 6 (4.1) 0 0 0