Slides
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Dr. Daniel SW Tan, P. Danchaivijitr, Y . Shinno, C. Ho, J. Zugazagoitia, T. Inoue, G-W. Lee, A.J. de Langen, A. Sezer, A. Pender, C. Dooms, F . Cappuzzo, Y . Fujiwara, Y . Runglodvatana, A.C. Gelatti, S. Novello, K. Stencel, N. Reguart, J. Alatorre-Alexander, G.G-Y . Lai, N. Girard, C. Schulz, Y . Elamin, M. Nishio, H. Yu, B. Besse, Y . He, R. Sopariwala, M. Liu, V . Wacheck, F . Benedetti, J. Heymach Zipalertinib Plus Chemotherapy for 1st Line NSCLC With EGFR Exon 20 Insertions: Results From the Phase 3 Trial (REZILIENT 3)
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Disclosures • Consultant: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, DKSH, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche, Beigene, Zymeworks, Genmab, Astellas, and Takeda • Grant/Research support: ACM Biolabs, Amgen, AstraZeneca, and Pfizer • Advisor/Stock options: PRISM.AI and T-Knife Therapeutics • Board/Directorship: HutchMed and Epoch Biosciences 2
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Background • NSCLC with EGFR exon 20 insertions (ex20ins) comprise 5–10% of EGFR mutations and represents a heterogeneous molecular subgroup with variable responses to EGFR-directed therapies1 • Amivantamab (1L in combination with platinum-based chemotherapy) and sunvozertinib have shown improved PFS vs chemotherapy in randomized trials2,3 • Zipalertinib (TAS6417, CLN-081) is a TKI with high selectivity to EGFR with ex20ins compared with wild-type EGFR 3 1L, first-line; CNS, central nervous system; EGFR, epidermal growth factor receptor; IC 50, half maximal inhibitory concentration; NSCLC, non–small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor; WT, wild-type. 1. Lau ELY, et al. Drugs. 2026;86:1075–90. 2. Zhou C, et al. N Engl J Med. 2023;389:2039–51. 3. Zhou C, et al. N Engl J Med. 2026;395:765–75. 4. Piotrowska Z, et al. J Clin Oncol. 2025;43:2387–97. Unique pyrrolopyrimidine scaffold Irreversible covalent bond with C797 High selectivity over wild type In phase I/II studies, demonstrated clinical activity (including CNS and post-amivantamab)4 Zipalertinib
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Zipalertinib (100 mg BID) + Pemetrexed/Platinum (Carboplatin or cisplatin) Pemetrexed/Platinum (Carboplatin or cisplatin) Zipalertinib REZILIENT 3: 1L Zipalertinib + Chemotherapy vs Chemotherapy 122 clinical sites globally Study overseen by IDMC REZILIENT :Researching Zipalertinib in EGFRmt Non–Small Cell Lung Cancer Tumors 1L, first line; BICR, blinded independent central review; BID, twice daily; DoR, duration of response; ECOG PS, Eastern Cooperative Oncology Group Performance Status; EGFRmt, epidermal growth factor receptor mutant; ex20ins, exon 20 insertions; HR, hazard ratio; IDMC, Independent Data Monitoring C ommittee; NSCLC, non–small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression- free survival, PRO, patient-reported outcome; R, randomization. Stratification factors: • ECOG PS • Brain metastases (Yes/No) • Region (Asia/Non-Asia) Zipalertinib + Pemetrexed/Platinum (Carboplatin or cisplatin) R Safety Lead-in (N=6) Randomized Phase 3 Study (NCT05973773) (N=280)Eligibility criteria: • 1L metastatic NSCLC • Local testing of EGFRmt ex20ins for eligibility • ECOG PS 0 or 1 • Stable brain metastases permitted • Archival tissue available Primary: • PFS by BICR Secondary • OS • PFS (investigator) • ORR • DoR • Safety • PROs Optional Cross-over Safety lead-in completed: Combination safe to proceed as assessed by IDMC Primary analysis: at 162 PFS events to detect HR 0.60, 2-sided α: 0.05, 90% power Pre-specified interim analysis: • At 122 PFS events (data cutoff date May 29, 2026) • If one-sided P<0.0098, superiority to be claimed 4
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5 Characteristics Zipalertinib + Chemotherapy (n=140) Chemotherapy (n=139) Median Age (min–max) 66.5 (30–89) 64.0 (27–82) Female, n (%) 92 (65.7) 88 (63.3) Never Smoker 83 (59.3) 85 (61.2) Region per IVRS, n (%) Asia 56 (40.0) 56 (40.3) Rest of world 84 (60.0) 83 (59.7) ECOG PS, n (%) 0/1 58 (41.4)/82 (58.5) 56 (40.3)/83 (57.6) Histology, n (%) Adenocarcinoma 136 (97.1) 135 (97.1) Other/non-squamous 4 (2.9) 4 (2.9) Baseline Brain Metastasis, n (%) 44 (31.4) 44 (31.7) REZILIENT 3: Baseline Characteristics ECOG PS, Eastern Cooperative Oncology Group Performance Status; IVRS, interactive voice response system.
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REZILIENT 3: Primary Endpoint PFS by BICR 6 100 90 80 70 60 50 40 30 20 10 0 Probability of PFS 0 3 6 9 12 15 18 21 24 27 Time since randomization (months) Total Failed Censored Median 95% CI Zipalertinib + Chemotherapy: 140 50 90 14.5 months (12.9, 21.4) Chemotherapy: 139 72 67 8.5 months (7.0, 10.9) Hazard Ratio: 0.50 (95% CI 0.34, 0.73) P=0.00015 140 139 109 102 81 73 59 36 40 20 22 14 7 6 4 3 0 1 0 Number at risk Zipalertinib + chemotherapy Chemotherapy Censor C (48.2%) Censor Z+C (64.3%) BICR, blinded independent central review; C, chemotherapy; CI, confidence interval; NE, not estimable; PFS, progression- free survival; Z+C, zipalertinib + chemotherapy. ∆ 6 months
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Subgroup Zipalertinib + Chemotherapy Event n/N (%) Chemotherapy Event n/N (%) Hazard Ratio HR (95% CI) Baseline ECOG PS 0 18/58 (31.0) 24/56 (42.9) 0.56 (0.30, 1.04) 1 32/82 (39.0) 48/83 (57.8) 0.54 (0.34, 0.85) Brain Metastases Yes 21/44 (47.7) 30/44 (68.2) 0.38 (0.21, 0.67) No 29/96 (30.2) 42/95 (44.2) 0.62 (0.38, 0.99) Region Asia 26/56 (46.4) 29/56 (51.8) 0.82 (0.48, 1.40) ROW 24/84 (28.6) 43/83 (51.8) 0.40 (0.24, 0.66) Sex Male 17/48 (35.4) 29/51 (56.9) 0.39 (0.21, 0.73) Female 33/92 (35.9) 43/88 (48.9) 0.63 (0.40, 1.00) Age <65 20/63 (31.7) 42/71 (59.2) 0.38 (0.22, 0.65) ≥65 30/77 (39.0) 30/68 (44.1) 0.78 (0.47, 1.30) Smoking History Yes 21/57 (36.8) 30/54 (55.6) 0.47 (0.27, 0.82) No 29/83 (34.9) 42/85 (49.4) 0.60 (0.37, 0.96) REZILIENT 3: BICR PFS by Subgroups 7 CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio; ROW, rest of world . 0 0.5 1 1.5 Favors ChemotherapyFavors Zipalertinib + Chemotherapy
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REZILIENT 3: Tumor Response by BICR Response (RECIST v1.1) Zipalertinib + Chemotherapy (n=140) Chemotherapy (n=139) Best Overall Response, n (%) Complete response 9 (6.4) 3 (2.2) Partial response 82 (58.6) 53 (38.1) Stable disease 29 (20.7) 55 (39.6) Progressive disease 4 (2.9) 12 (8.6) Objective Response Rate, % (95% CI) 65.0 (56.49, 72.86)a 40.3 (32.06, 48.94) Disease Control Rate, % (95% CI) 89.3 (82.94, 93.88) 81.3 (73.81, 87.40) Duration of Response Zipalertinib + Chemotherapy (n=91) Chemotherapy (n=56) Duration of Response, median in months (95% CI) 14.2 (10.51, NE) 9.9 (6.80, NE) Time to Response, median in months 1.4 2.6 8 aP-value <0.0001 vs chemotherapy alone. BICR, blinded independent central review; CI, confidence interval; NE, not estimable; RECIST, response evaluation criteria in solid tumors .
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REZILIENT 3: Overall Survival 9 9 aBased on 53 patients with progressive disease, of whom 34 crossed over. C, chemotherapy; NE, not estimable; Z+C, zipalertinib + chemotherapy. Total Failed Censored Median 95% CI Zipalertinib + chemotherapy: 140 24 116 NE (NE, NE) Chemotherapy: 139 31 108 NE (18.4, NE) Hazard Ratio: 0.72 (95% CI, 0.42–1.23) P=0.11082 9 12 15 18 21 24 27 Time since randomization (months) 630 20 100 90 80 70 60 50 40 30 10 0 Overall survival probability (%) 140 139 Number at risk Zipalertinib + Chemotherapy Chemotherapy 127 126 98 97 79 67 56 47 38 31 19 22 8 11 3 4 0 0 • 64.2 % crossover to zipalertiniba • Median follow-up 10.9 months Censor C Censor Z+C
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REZILIENT 3: Safety Summary Zipalertinib + Chemotherapy (n=140), n (%) Chemotherapy (n=136), n (%) Treatment-Related Adverse Events 138 (98.6) 120 (88.2) Grade ≥3 treatment-related adverse events 113 (80.7) 55 (40.4) Serious Adverse Events 71 (50.7) 45 (33.1) Treatment-related serious adverse events 53 (37.9) 17 (12.5) Zipalertinib Pemetrexed Carbo/ cisplatin Pemetrexed Carbo/ cisplatin AE Leading to Treatment Interruption 116 (82.9) 104 (74.3) 70 (50) 60 (44.1) 40 (29.4) AE Leading to Dose Reductions 61 (43.6) 68 (48.6) 46 (32.9) 29 (21.3) 21 (15.4) AE Leading to Drug Discontinuationa 24 (17.1) 44 (31.4) 22 (15.7) 16 (11.8) 7 (5.1) Adverse Events With Outcome of Deathb 13 (9.3) 4 (2.9) TRAE with outcome of death 3 (2.1) 0 Sepsis/septic shock 3 (2.1) 0 Chemotherapy Administration Platinum choice: Carboplatin/cisplatin 138/4c 123/14c Pemetrexed number of cycles (median , range) 7 (1-35) 8 (1-36) 10 aRefers to the regimen where a component was the primary reason for treatment discontinuation. bDeath events were: Z+C: sepsis (3), pneumonia (1), respiratory tract infection (1), septic shock (1), acute respiratory failure (1), dyspnea (1), hemoptysis (1), respiratory failure (1), death (1), sudden death (1), diabetic ketoacidosis (1). C: sepsis (1), pneumonia (1), acute respiratory failure (1), cerebrovascular acc ident (1). cReflects some patients received both agents. AE, adverse event; C, chemotherapy; Carbo, carboplatin; TRAE, treatment -related adverse event; Z+C, zipalertinib + chemotherapy.
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REZILIENT 3: Summary of Adverse Events Adverse Event in ≥25%a, % Zipalertinib + Chemotherapy (n=140) Chemotherapy (n=136) Any Grade Grade ≥3 Any Grade Grade ≥3 Anemiaa 80.7 48.6 50.0 12.5 Neutropeniab 50.7 33.6 40.4 22.1 Thrombocytopeniac 56.4 30.0 19.9 8.1 Rash 45.7 10.7 6.6 0 Nausea 44.3 3.6 41.9 0.7 Constipation 32.1 0 30.9 0 Paronychia 31.4 1.4 0 0 Stomatitis 28.6 5.0 7.4 0.7 Diarrhea 27.1 1.4 8.8 0 Pneumonitisd 5.7 2.1 2.2 1.5 11 aIncludes anemia and/or reduced red blood cells. bIncludes neutropenia and/or decreased neutrophils. cIncludes thrombocytopenia and/or platelets decreased. dIncludes those with ≥25% and/or EGFR-associated toxicity. Pneumonits included as an EGFR-associated AE of interest though reported <25%.
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REZILIENT 3: Cytopenias Observed With Combination 12 Platinum aAdverse events represent grouped terms (either blood term or lab term decreased). All-Treated Population for Zipalertinib + Chemotherapy arm 100 70 60 50 40 30 20 10 0 Percentage of patients First 4 Cycles (n=140) After 4 Cycles (n=113) First 4 Cycles Grade 4 Grade 3 Grade 2 Grade 1 After 4 Cycles Grade 4 Grade 3 Grade 2 Grade 1
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Conclusions • REZILIENT-3 met its primary endpoint, with Zipalertinib and chemotherapy demonstrating statistically significant improvement in PFS compared to chemotherapy alone • 6-month improvement in median PFS (14.5 months vs 8.5 months, HR of 0.5, P=0.00015) • Increased ORR (65% vs 40.3%, P<0.0001) with improved duration of response (14.2 m vs 9.9 m) • Although the combination resulted in more Grade 3 adverse events, these were largely related to cytopenias and associated sequelae • Particularly observed in first 4 cycles during combination with platinum doublet; • Patient selection, dose modifications and supportive care measures • Zipalertinib in combination with platinum-based chemotherapy is a new highly efficacious option for frontline treatment of metastatic EGFR ex20ins-mut NSCLC • Study ongoing to further characterize the AE profile and OS benefit • REZILENT 4 (NCT 07128199) Phase 3 study for adjuvant zipalertinib in early stage resected NSCLC with uncommon EGFRmt 13 AE, adverse event; EGFR, epidermal growth factor receptor; EGFR mt, epidermal growth factor receptor mutant; HR, hazard ratio; m, months; NSCLC, non– small cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression- free survival.
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14 Acknowledgments • Trial participants, their families, and caregivers • Investigators, team members and site staff (represents 122 sites across 24 countries in Asia, North America, South America, and Europe) • Steering committee