OptiTROP-Lung-03 Trial

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[Slide 1] Background and OptiTROP-Lung03 Study Design Sac-TMT is a TROP2 ADC with a unique bifunctional linker that maximizes delivery of a belotecan-derivative topo I inhibitor payload to tumor cells. The OptiTROP-Lung03 study (NCT05631262) previously demonstrated statistically significant PFS and OS benefits with sac-TMT VS docetaxel in previously treated EGFRm NSCLC1. After median follow-up 12.2 months, HR for PFS by BIRC was 0.30 (95% CI 0.20-0.46, one-sided p<0.001) and HR for OS was 0.49 (95% CI 0.27-0.88 one-sided p=0.007). Based on results of this study, sac-TMT has been recently approved by China NMPA establishing it as the first TROP2-ADC approved for lung cancer. Here, we report the results of pre-specified final OS analysis from this study, including updated PFS and safety. Key Eligibility Primary Endpoint ECOG score 0 or 1 Sac-TMT Treatment until disease progression, ORR* assessed by BIRC Nsq-NSCLC (stage IIIB/IIIC ineligible for 5 mg/kg IV, Q2W intolerable toxicity, or any other Secondary endpoints surgery or radical radiotherapy or stage IV) R reason for discontinuation PFS EGFR-sensitizing mutations, including 19. 2:1 Del and L858R OS Progression after prior combination or ORR assessed by investigator sequential treatment with EGFR-TKIs and Docetaxel After PD verified by BIRC, patients could DOR, DCR, TTR platinum-based chemotherapy 75 mg/m2 IV, Q3W be permitted to cross over to receive sac- Safety TMT. Stratification factors: Brain metastases present vs absent) 1 Fang et al. BMJ2025 Tumor response was assessed using RECIST version 1.1. Confirmed ORR TROP2 trophoblest cell surface inligen 2. ADC. antibody drug conjugate PFS, progression from aurival 08 overall oursival EGFRm EGER mutaled no fyeasine kinane inbibitor, NSCLC non-mall all lung cancer HR hazand natio CI confidence interval BRC, blinded independent roview committe NMPA National Medical Products Administration IV, PD. programs discase ORR objective response note DOR funation of response, DCR discase control TTR, - to response, R, randomization, RECIST Response Evaluation Critona in Sold Turnors Yunpeng Yang Organisers Partners Content of this presentation IN copyright and responsibility of the author Permission B required for to use ESMO IASLC ESTRO h ETOP-IBCSG --- [Slide 2] Overall Survival After a median follow-up of 23.8 months, sac-TMT continues to demonstrate clinically meaningful and statistically significant improvements in OS compared to docetaxel. (Note: for the docetaxel group, 41% of pts received sac-TMT as subsequent anti-cancer therapy. Sac-TMT Docetaxel 100 (n 91) (n 46) OS events, n (%) 51 (56.0) 33 (71.7) 80 Median OS, months (95% CI) 20.0 (14.8, NE) 13.5 (8.0. 17.2) Sac-TMT 18-month OS rate, % (95% CI) 54.7(43.9,64.3) 34.0 (20.7, 47.7) mOS: 20.0 mo HR: 0.63 (95% Cl: 0.40, 0.98) Overall Survival (%) 60 40 Docetaxel mOS: 13.5 mo 20 Sac-TMT Docetaxel + Censored 0 0 3 6 9 12 15 18 21 24 27 Time (Months) No. at Risk Sac-TMT 91 88 83 73 63 54 49 41 16 0 Docetaxel 46 42 35 28 24 21 15 15 7 0 Yunpeng Yang Organisers Partners Content of this presentation is copyright and responsibility of the author Permission is required for to use ESMO IASLC ESTRO h ETOP-IBCSG --- [Slide 3] Overall Survival Adjusted for Crossover In the docetaxel group, 41% of pts received sac-TMT as subsequent anti-cancer therapy. After using pre-specified RPSFT model adjusted for crossover, sac-TMT significantly improved OS over docetaxel with 55% lower risk of death. Sac-TMT Docetaxel 100 (n = 91) (n 46) OS events, n (%) 51 (56.0) 30 (65.2) 80 Median OS, months (95% CI) 20.0 (14.8, NE) 11.2 (8.0, 16.1) Sac-TMT 18-month OS rate, % (95% CI) 54.7(43.9,64.3) 9.1(0.7,31.7) 60 mOS: 20.0 mo HR: 0.45 (95% Cl: 0.28, 0.73) Overall Survival (%) 40 Docetaxel mOS: 11.2 mo 20 Sac-TMT Docetaxel Censored 0 0 3 6 9 12 15 18 21 24 27 Time (Months) No. at Risk Sac-TMT 91 88 83 73 63 54 49 41 16 0 Docetaxel 46 41 35 28 21 9 I 1 0 Data outoff December 11. 2025 Median follow-up was 23.8 months RPSF T. rank-pronerving structural failure time Yunpeng Yang Organisers Partners Content of this presentation is copyright and responsibility of the author Permission is required for re-use ESMO IASLC ESTRO h ETOP-IBCSG --- [Slide 4] Conclusions Sac-TMT continues to demonstrate clinically meaningful and statistically PFS by investigator significant improvements in PFS and OS compared to docetaxel. Sac-TMT Median 7.9 mo Sac-TMT is the first therapy to achieve long-term OS benefits in patients with Docetaxel 2.8 mo HR: 0.23, 95% CI: 0.15 0.35 advanced EGFRm NSCLC who had progressed after EGFR TKI and OS platinum-based chemotherapy. Sac-TMT Docetaxel Median 20.0 mo 13.5 mo Sac-TMT continues to have a manageable safety profile with no new safety HR: 0.63, 95% CI: 0.40 0.98 signals identified after a median follow up of ~2 years. RPSFT model adjusted OS for crossover Sac-TMT Median 20.0 mo Sac-TMT has been recently approved by China NMPA for EGFRm NSCLC Docetaxel 11.2 mo pts after EGFR TKIs based on results of OptiTROP-Lung04 study, which HR: 0.45, 95% CI: 0.28 0.73 have been published in the NEJM. 1 The results of final OS analysis from OptiTROP-Lung03 study underscore sac-TMT as a promising new treatment option for pretreated EGFR-mutant NSCLC. 1 Fang of al al., NE.IM 2025 Yunpeng Yang Organisers Partners Content of this presentation is copyright and responsibility of the author Permission B required for re use ESMO IASLC ESTRO h ETOP-IBCSG

[Slide 1] Who are the patients who do not need adjuvant chemotherapy? OCEANIC (TOGA 20/007) Resected Outcomes: Stage IIA-IIIA NSCLC Cohort 1: Osimertinib BUT not randomised study DFS at 3 years N=100 alone design and no control arm - Co-mutation ctDNA negative and status Secondary: will the results be enough to Resected IIA-IIIA co-mutation negative 80mg daily for 3 years (tumour) OS NSCLC (AJCC 8th Ed) Adverse Events change practice? (mixed small cell QoL ineligible) ctDNA Cohort 2: EGFR activating (post surgery) Tertiary: mutation (ex19del, Chemotherapy associations L858R, G719X, L861Q, followed by osimertinib between outcomes S7681), and T790M ctDNA positive and/or co-mutation positive and prognostic/ No prior treatment Chemotherapy for 4 cycles followed by osimertinib 80mg daily for 3 years predictive ECOG 0-1 biomarkers Brain MRI ACTRN12623000552684 Stephanie P.L. Saw Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. https://thoraciconcology.org.au --- [Slide 2] Acquired resistance post-TKI is even more complex Post-3G EGFR TKI Only liquid biopsy data available post-F2 and M1 Resistance Plasma analysis set FLAURA osimertinib Acquired gene Osimertinib Osimertinib Functional groups monotherapy alteration, (%) chemotherapy monotherapy (n=109) (n=68) (n=99) Mediated by single Mediated by other C797S 2(3) 10(10) 7(6) (6) EGFR mutations genetic alterations mechanisms Other uncommon 1(1) 4(4) 5(5) MET amplification 8(12) 11(11) 17(16) RTK amplifications ERRB2 amplification 3(4) 1(1) 2(2) BRAF V600E 1(1) 5(5) 3(3) KRAS mutation 2(3) 8(8) 3(3) On-target resistance Off-target resistance MAPK PI3K mutations Neuroendocrine EMT Squamous Tumour PIK3CA mutation 5(7) 6(6) 6(6) transformation transformation heterogeneity ER882 mutation ND 1(1) NO C797S Cis-mutation: brigatinib MET MET TKI EGFR TKI CCND1 E1 amplification 6(9) 5(5) (6) cetuximab Amivantamab Cell cycle gene amplifications CDK4 76 amplification 3(4) 5(5) 7 (6) Trans mutation st Platinum- YAP generation 3rd HER2 T-DXd IL-6 blockade etoposide WNT signalling APOBEC RET 1(1) 3(3) ND BRAF 2(3) 3(3) ND generation TKI Pyrotinib Cls inhibitors Epigenetic Fusions ALK ND 3(3) 1(1) 4th generation TKI Zongertinib writers (for Other* 3(4) 6(6) - BAY 2927088 Notch AKT example, DTPs RB1 loss (with TP53 alteration)* 2(3) Exon20ins 4(4) Sunvozertinib Hedgehog Notch lysine-specific Dormant No known acquired resistance alteration detected 46(68) 54(55) Zipalertinib Acquired EGFR TKI IGFR1 ASCLI histone cells YK-029A oncogenic Selpercatinib or demethylase 1) CSCs Furmonertinib fusions praisetinib OR Similar resistance Amivantamab Alectinib or Amivantamab + Lazertinib (n=36) Osimertinib becotarug crizotinib OR mechanisms between Trametinib OR EGFR/MET dependent XOO 18 2nd generation TKI Erdafitinib EGFR/MET independent FLAURA2 and Osimertinib EGFR* MET 68% unknown To be determined Novel CDK4/6 TP53/RB1 ation targets AXL under GFR1 Potential targets Therapeutic options HER2 . PI3K investigation RAS/RAF Less MET amp, seconda Other RTK Cell cycle EGFR, TP53/RB1 loss a Complex Resistance less complex resistance Cell cycle Cell growth Cell survival 27.8% had alterations Ami/Laz vs Osimertin ephanie P.L. Saw in >2 resistance pathways ent of this presentation is copyright and responsibility of the author. Permission is required for re-use. 1. Zhou et al, NRCO 2024; 2. Yang et al, WCLC 2024; 3. Besse et al, E --- [Slide 3] 2L landscape post-osimertinib: only combination strategies Acquired oncogenic driver Consider adding matched targeted therapy to osimertinib (e.g. ALK, C797X) Small cell transformation Platinum-based chemotherapy + ICI or osimertinib? ORR IC ORR mPFS mos ≥G3 AE Only option with Ph3 data MET amplified Savolitinib + Osimertinib 58% ? 8.2m 22.9m 57% Biomarker- Teliso-V + Osimertinib² 50% ? 7.4m ? 50% directed MET overexpression Tepotinib + Osimertinib³ 50% 29.2% 5.6m 17.8m 34% Amivantamab + Lazertinib⁴ 28% 27% 4.5m 14.8m 74% HER2 overexpression Trastuzumab Deruxtecan5 68.4% ? 8.2m 19.6m 41.7% EGFRm NSCLC Switch therapy Trial ORR mPFS PFS HR mos >G3 AE progressing on 1L osimertinib OptiTROP-Lung046 60.6% 8.3m 0.49 NR 58.0% (Sac-TMT) Preferred option by NCCN MARIPOSA-2 64% 6.3m 0.48 17.7m 72% Local ablative and ESMO guidelines (Amivantamab + carboplatin + pemetrexed) therapy for oligoprogression + ATTLAS® 69.5% 8.5m 0.62 20.6m 35.1% continue osimertinib Biomarker- (Atezolizumab + paclitaxel + carboplatin + agnostic bevacizumab) (Only Ph3 data against ORIENT-319,10 44% 7.2m 0.51 21.1m 56% PBC shown) (Sintilimab + Pemetrexed + Cisplatin + IBI305) HARMONI11 45% 6.8m 0.52 16.8m 50.0% (Ivonescimab + pemetrexed + carboplatin) *Patients with IHC90+ and/or FISH 10+ status 1L first Ink ADC, antibody-drug conjugate; AE, adverse event; ALK anaplastic ymphoms lanase, EGFR(m) epidemal growth factor receptor (enutated) FISH10+, Bucressence in seu hybridisation (MET copy number #10): HER2. human epidemal growth factor receptor 2: IC, intracrenial, IC ORR, intercranial ORR: Stephanie P.L. Saw ICI, immune checkpoint inhibitor; BHCDO+, 3+ immunehistochemistry overexpression 200% tumour cells; MET epithelist transition factor, mOS, median overall survival mPFS, median progression-blee survive): NSCLC, non-smal cell lung cancer CRR, overall response rate; VEGF. vasouse endothelist growth factor 1. Lu et al. Presented at ASCO 2025 (Abstract LBA8505); 2. Horinouchi H. at Ann Oncol 2024;34:51670; 3. Wu Y-L et at Lancet Oncol 2024,25 989- 1002. Besse 9, TO 2025 5. Planchard D. et et. - Oral presentation at WCLC 2024 (Abistract OA 05): 0. Pang of al, NEJM 2025, 7. Passaro A, at at. Ann One 77-90: a Park 5, et at. Clin Oncel 2023; 1241-51 9. Lu 5, et al Lancel Oncel 2022:23 107-79; 10. Lu S. et at Lancet Respir Med 2023; 11 624 11. Goldman et at Oral presentation at WCLC 2025. Content of this presentation is copyright and responsibility of the author. Permission is required for re-use --- [Slide 4] Do we need to continue EGFR TKI in 2L? Chemotherapy ADCs COMPEL: Global, randomised, phase III double-blind study c-MET OE EGFRm NSCLC post-TKI ORR of Teliso-V monotherapy 11.4% vs Teliso-V + Osimertinib 50.0% Patients with locally advanced / Osimertinib 00 mg (QD) metastatic EGFRm NSCLC with or without without CNS metastases cisplation 75 mgm or AUC5 Osimertinib 60 mg (Q0) Demetrexed 500 mg/m² permetrexed 500 mg/m (Q3W) PO (Q3W for 4 cycles) (non-CNS or Module 10 of ORCHARD: Dato-DXd Key Inclusion criteria: 1.1 N=98 CNS)* Aged 18 years or another Placebo (QD) discontinuation Osimertinib 60 mg PO QD Non-CNS progression on 1L osi cisplatin 75 mg/ml carboplatin AUCS Placebo (QD) certence Stratification by: permetrexed 500 mg/m2 Ext9del/ L858R permetrexed 500 mg/ml (Q3W) Analysis tumour Dato-DXd mg/kg IV Q3W CNS metastisses, (Q3W for cycles) WHO PS yes no biopsy from patients with Module 10: (n=35) Disease Follow-up EGFRm NSCLC biomarker progression for 05 progressing on 1L non-matched" Osimertinib 80 mg PO QD Primary endpoint: PFS (investigator-assessed) osimertinib monotherapy Dato-DXd mgkg IV Q3W Secondary endpoints: CNS PFS (according to CNS metastases status at baseline), non-CNS PFS, and OS (n=34) Other modules Primary analysis: Progression-free survival (PFS)* CNS PFS* in patients without baseline CNS metastases -- - 87% - - I MH 181 14.00 MAIN Primary endpoint: ORR based on RECIST v1.1 by investigator assessment I **** an Key secondary endpoints: PFST, DoR1, OS, AEs, SAEs - - 141 10 Comparing 4mg/kg VS 6mg/kg TROPION (monotherapy): AM ORR similar: 43% VS 36% ORR 43% . - 61 - is mPFS: 9.5m vs 11. 7m) mPFS 5.8m : I : : : mDoR: 6.3m VS 20.5m mDoR 7.0m Osi CTs - associated with improved PFS versus PSO CTx CWS FFS was longer with CTx versus PBO patients whot baseline CNS metasters ≥G3 AE: 34% vs 56% >G3 AE 23% Continuing osimertinib in combination with PBC improves PFS and CNS PFS over PBC alone (but trial terminated early) BUT patients in TROPION had received prior chemo! Unfair comparison with ORCHARD. Toxicities seem higher with combination albeit small numbers, await randomised data (TL-15) Stephanie P.L. Saw Content of this presentation is copyright and responsibility of the author. Permission is required for re-use. 1. Pasello, WCLC 2025 2. Camidge et al, JCO 2024 3. Hourinochi et al, Ann of Oncol 2025 4. Le and Saw, ELCC 2

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