ADCs in EGFR-Mutation Resistant NSCLC.pptx

lung cancer

1. DR.PRASHANT KUMBHAJ MD,DM (Medical Oncology), MRCP SCE (Medical Oncology), ECMO,FIMSA,MAMS,PDCR PROFESSOR (Medical Oncology) Mahatma Gandhi Hospital & Medical College Jaipur,Rajasthan,India ADCs in EGFR -Mutation Resistant NSCLC

2. Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Resistance Mechanisms 1. On-Target (EGFR-Dependent) Resistance Mechanisms ( a) Secondary Mutations in EGFR • T790M mutation (most common with first-generation TKIs like erlotinib/gefitinib): • Substitution of threonine with methionine at position 790 reduces TKI binding. • Responsible for resistance in about 50-60% of patients treated with first- and second-generation TKIs.

3. • Third-generation TKIs (e.g., osimertinib) are effective against T790M. • C797S mutation (resistance to third-generation TKI osimertinib): • Substitution at cysteine 797 prevents covalent binding of osimertinib. • Occurs in patients after osimertinib treatment. • Resistance can develop with or without the presence of the T790M mutation.

4. (b) EGFR Amplification • Increased copies of the EGFR gene may overcome the inhibitory effects of TKIs. • Results in continuous signaling despite TKI treatment

5. 2. Off-Target (EGFR-Independent) Resistance Mechanisms These involve activation of alternative pathways or mutations in other genes, allowing cancer cells to bypass the inhibited EGFR signaling:

6. (a) Activation of Alternative Signaling Pathways • MET Amplification: • Activates the PI3K-AKT and MAPK pathways independent of EGFR. • Common mechanism of resistance, especially after osimertinib. • HER2 Amplification: • Also leads to activation of downstream pathways, bypassing EGFR inhibition. • BRAF or KRAS Mutations: .

7. (b) Transformation to Other Histological Types Small cell lung cancer (SCLC) and Squamous cell transformation: • EGFR-mutant NSCLC may transform into SCLC, which is resistant to TKIs. • Associated with loss of RB1 and TP53 genes. • Epithelial-to-Mesenchymal Transition (EMT): • Cells change phenotype, becoming more invasive and resistant. • Associated with increased expression of mesenchymal markers (e.g., vimentin, N-cadherin).

8. Mechanisms of Resistance to Osimertinib in EGFR -Mutated NSCLC Later-line Osimertinib First-line Osimertinib Schoenfeld. Clin Cancer Res. 2020;26:2654. Unknown 29% EGFR C797X* 28% EGFR SV768IL 3% EGFR amp 3% ALK fusion* 5% BRAF fusion 5% KRAS mut 3% HER2 mut* 3% MET ex14 alt 3% MET amp 6% Squamous cell 8% Small cell 6% Unknown 59% EGFR G724S 3% EGFR amp 4% RET fusion 4% BRAF fusion 4% KRAS mut 4% MET amp 7% Squamous 7% Small cell 4% Pleomorphic 4% On target Off target Transformation *T790M retained.

9. HER3: Biology HER3 is a member of ERRB/HER protein kinase family 1,2 Lacks tyrosine kinase activity HER3 itself is not an oncoprotein but heterodimerizes with other RTKs to activate oncogenic signaling 2 HER3 expression can mediate resistance to targeted therapy (eg, resistance to EGFR-targeted therapies in lung cancer) 2,3 1. Dokala. Oncogene. 2016;36:2337. 2. Lyu. Acta Pharm Sin B. 2018;8:503. 3. Yonesaka. Cancers (Basel). 2021;13:1047. Ligand VEGFR EGFR-HER3 HER2-HER3 MET-HER3 ↑ transcription, ↑ protein synthesis, ↑ proliferation Apoptosis PLC PKC JAK STAT SRC RAS SOS RAF MEK MAPK ERK PI3K AKT mTOR BIM PTEN EGFR homodimer P P HGF

10. HER3: Role in Oncogenesis Ligand binding leads to heterodimerization of RTKs with HER3 Cytoplasmic oncogenic signaling is activated, in particular via the PI3K/AKT/mTOR pathway Also MEK/MAPK, Jak/Stat, Src kinase Signaling leads to cell proliferation and blocks apoptosis End result: promotion of cancer cell survival, proliferation, and progression Also induces expression of genes responsible for drug resistance, cancer metastasis Dokala. Oncogene. 2016;36:2337. Lyu. Acta Pharm Sin B. 2018;8:503. ↑ transcription, ↑ protein synthesis, ↑ proliferation EGFR-HER3 HER2-HER3 MET-HER3 HGF HER3 Apoptosis PI3K AKT mTOR BIM PTEN

11. HER3 Expression in NSCLC HER3 is widely expressed in normal lung tissue HER3 mutations and HER3 amplification are not commonly seen in tumors HER3 expression by IHC is seen in 83% of NSCLC cancers 87% of lymph node metastases and 92% of brain metastases High levels of expression often are associated with progression Sithanandam. Cancer Gene Ther. 2008;15:413. Scharpenseel. Sci Rep. 2019;9:7406. Kumagai. Thorac Cancer. 2018;9:466. HER3 Protein Immunohistochemistry on NSCLC Samples Primary lung tumors Brain metastases

12. Assessment of HER3 Expression HER3 expression level is typically determined using IHC (similar to HER2) Definition of expression levels is not standardized and varies somewhat between tumor types Clinical trials may quantitate using H-score rather than categorical grouping HER3 testing is not currently recommended Clinical trials of HER3-targeted agents have not used HER3 expression as inclusion criteria Jänne. ASCO 2019. Abstr 9010. Li. Oncotarget. 2017;8:67140. Ye. Scientific Reports. 2022;12:12894. Images from Chao. PLoS ONE;2015:e0142135, under terms and conditions of the Creative Commons Attribution 4.0 International license (CC BY 4.0: https://creativecommons.org/licenses/by/4.0/). Completely negative staining or faint staining in < 10% of tumor cells 1+ Faint or incomplete staining in >10% of tumor cells 2+ Weak-to-moderate staining in >10% of tumor cells 3+ Strong staining in >10% of tumor cells Low/Negative High/Positive

13. Prognostic Implications of HER3 Overexpression HER3 expression level is associated with poor prognosis and treatment resistance in NSCLC HER3 Expression and Risk of Progression and Relapse Scharpenseel. Sci Rep. 2019;9:7406. Mo to Metastasis Cumulative Survival (%) Metastatic Progression RFS (Mo) RFS Negative (n = 6) Strong (n = 4) Intermediate (n = 26) P = .006; log-rank test 100 80 60 40 20 120 100 40 60 80 20 Cumulative Survival (%) Negative (n = 6) Strong (n = 4) Intermediate (n = 26) P = .013; log-rank test 100 80 60 40 20 120 100 40 60 80 20

14. p110 p85 Proposed Role of HER3 in EGFR TKI Resistance Acquired resistance to EGFR TKI therapy is frequently seen in NSCLC and breast cancer Studies in cell culture suggest negative feedback from decreased AKT signaling leads to increased HER3 phosphorylation and reactivation of the PI3K pathway Amplification of MET may be one contributing feedback mechanism Arteaga. Nat Med. 2007;13:675. Engelman. Science. 2007;316:1039. Sergina. Nature. 2007;445:437. EGFR TKI MET P P TK P P TK Pathogenic Signaling EGFR HER3 AKT p110 p85 EGFR-Targeted Therapy TK TK X EGFR TKI p110 p85 TK TK X Escape Mechanism P P AKT TK P

15. HER3 Expression Increases With Acquired EGFR TKI Resistance Transcriptome analysis showed increase in HER3 associated with PI3K/AKT/mTOR signaling Yonesaka. Clin Cancer Res. 2022;28:390. HER3 Expression Before and After EGFR Treatment Leading to Resistance (N = 48) IHC H-Score Pre-treatment Post-treatment Pre Post Mean H-score 100.8 155.9 P = .0007 HER3 H-Score 300 200 100 * 300 200 100

16. Investigational Agents Targeting HER3 Uliano. ESMO Open. 2023;8:100790. HER3 HER2 EGFR IGF-1 Anti–HER3-Abs Patritumab Seribantumab Lumretuzumab GSK2849330 CDX-3379 Barecetamab AV-203 Elgemtumab HMBD-001 U3P1287/01 SIBP-03 Bispecific EGFR/HER3 Abs SI-B001 Duligotuzumab Bispecific HER2/HER3 Abs Zenocutuzumab MM-111 Bispecific IGF-1/HER3 Abs Isitarumab Anti–HER3-ADC Patritumab deruxtecan Bispecific EGFR/HER3 ADC BL-01D1

17. Patritumab Deruxtecan (HER3-DXd): Novel HER3-Targeted Antibody–Drug Conjugate Hashimoto. Clin Cancer Res. 2019;25:7151. Jänne. Cancer Discov. 2022;12:74. Human Anti-HER3 IgG1 mAb Conjugation Chemistry Drug linker conjugated to cysteine residues of mAb Cysteine residue Deruxtecan Cys O O O O N O O H O O H N N H NH HN H N O O O O N N NH OH F H CH 3 CH 3 Tetrapeptide-Based Cleavable Linker Topoisomerase I Inhibitor Payload (DXd) Exatecan derivative

18. HERTHENA-Lung01: Phase II Study of Patritumab Deruxtecan in EGFR -Mutated NSCLC Multicenter, randomized, open-label phase II trial Yu. Future Oncol. 2023;19:1319 . Yu. WCLC 2023. Abstr OA05.03. Yu. JCO. 2023;41:5363. Median f/u for efficacy: 18.9 mo (range: 14.9-27.5) Median tx duration for safety: 5.5 mo (range: 0.7-18.2) Patients with advanced EGFR -mutated NSCLC progressing on most recent systemic therapy; prior treatment with EGFR TKI* and platinum-based chemotherapy; inactive or previously treated asymptomatic brain mets allowed; pretreatment tissue biopsy required but not selected for by HER3 expression (N = 277) HER3-DXd 5.6 mg/kg IV Q3W fixed dose (n = 226 † ) HER3-DXd IV Q3W uptitration ‡ (n = 51 § ) *Protocol amended to require prior osimertinib. † n = 226 enrolled; n = 225 received ≥1 dose. ‡ Dosing: 3.2 mg/kg C1D1, 4.8 mg/kg C2D1, 6.4 mg/kg C3D1+. § n = 51 enrolled; n = 50 received ≥1 dose. Enrollment discontinued after risk–benefit assessment. Primary endpoint: confirmed ORR by BICR Key secondary endpoint: DoR by BICR Current Report

19. HERTHENA-Lung01: Responses in EGFR -Mutated NSCLC Yu. WCLC 2023. Abstr OA05.03. Yu. JCO. 2023;41:5363. Johnson. ESMO 2023. Abstr 1319MO. Efficacy Outcome HER3-DXd 5.6 mg/kg​ All Patients (N = 225) Received 3G EGFR TKI (n = 209) Confirmed ORR, % (95% CI) 29.8 (23.9-36.2) 29.2 (23.1-35.9) Best overall response, n (%) CR PR SD PD NE 1 (0.4) 66 (29.3) 99 (44.0) 43 (19.1) 16 (7.1) 1 (0.5) 60 (28.7) 91 (43.5) 41 (19.6) 16 (7.7) DCR, % (95% CI) 73.8 (67.5-79.4) 72.7 (66.2-78.6) Median DoR, mo (95% CI) 6.4 (4.9-7.8) 6.4 (5.2-7.8) Median PFS, mo (95% CI) 5.5 (5.1-5.9) 5.5 (5.1-6.4) Median OS, mo (95% CI) 11.9 (11.2-13.1) 11.9 (10.9-13.1) CNS Outcome HER3-DXd 5.6 mg/kg​ Baseline Brain Mets (n = 95) Baseline Brain Mets Not Irradiated (n = 30)* CNS confirmed ORR, % (95% CI) 20.0 (12.5-29.5) 33.3 (17.3-52.8) CNS best overall response, n (%) CR PR SD/non-CR/non-PD PD NE 15 (15.8) 4 (4.2) 57 (60.0) 13 (13.7) 6 (6.3) 9 (30.0) † 1 (3.3) 13 (43.3) 4 (13.3) 3 (10.0) CNS DCR, % (95% CI) 80.0 (70.5-87.5) 76.7 (57.7-90.1) Median CNS DoR, mo (95% CI) 9.2 (8.1-11.1) 8.4 (5.8-9.2) *Patients with measurable target lesions = 7. Those with nontarget lesions only = 23. † Patients with nontarget lesions only = 8.

20. HERTHENA-Lung01: Antitumor Activity Across EGFR TKI Resistance Mechanisms Yu. WCLC 2023. Abstr OA05.03. Yu. JCO. 2023;41:5363. Type of EGFR TKI Resistance Mechanism EGFR Dependent Only (n = 34) EGFR Independent Only (n = 81) Both EGFR Dependent and Independent (n = 32) None Identified (n = 77) Confirmed ORR, % (95% CI) 32.4 (17.4-50.5) 27.2 (17.9-38.2) 37.5 (21.1-56.3) 27.3 (17.7-38.6) Antitumor Activity With HER3-DXd 5.6 mg/kg (N = 225) Confirmed Best Overall Response (BICR) + Ongoing treatment CR PR SD PD NE Best Change in Sum of Diameters (BICR) From Baseline (%) 100 80 60 40 20 -20 -40 -60 -80 -100 + + + + + + + + + + + + ORR, All Patients (N = 225): 29.8% ORR, Received 3G EGFR TKI (n = 209): 29.2%

21. HERTHENA-Lung01: Safety Summary Yu. WCLC 2023. Abstr OA05.03. Yu. JCO. 2023;41:5363. Most Common TEAEs Occurring in ≥15% of Patients (N = 225) Safety Outcome, n (%) HER3-DXd 5.6 mg/kg (N = 225) Any TEAE Associated with treatment d/c Associated with dose reduction Associated with dose interruption 224 (99.6) 16 (7.1) 48 (21.3) 91 (40.4) TEAE grade ≥3 146 (64.9) Treatment-related TEAE Grade ≥3 Serious TEAE Associated with death 215 (95.6) 102 (45.3) 34 (15.1) 4 (1.8) Adjudicated ILD (as treatment related) Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 Median time to onset, days (range) 12 (5.3) 1 (0.4) 8 (3.6) 2 (0.9) 1 (0.4) 53 (9-230) *Grouped preferred terms. 66 44 42 36 34 33 31 28 27 26 25 19 18 17 17 16 16 Patients (%) Grade ≥3 Grade 1/2 Nausea Thrombocytopenia* Decreased appetite Neutropenia* Constipation Anemia* Fatigue Diarrhea Vomiting Leukopenia* Alopecia Asthenia Dyspnea AST increased Hypokalemia Cough Abdominal pain* 63 3 21 23 3 39 19 16 34 19 14 6 25 26 1 26 1 16 10 25 14 5 14 4 1 16 12 5 16 16 100 20 40 60 80

22. HERTHENA-Lung01 CNS Analysis: Cumulative Incidence of CNS Progression, Non-CNS Progression, and Death Patients With a History of Brain Mets (n = 115) Patients Without a History of Brain Mets (n = 110) CNS Progression, % (95% CI)  6 mo 20.4 (13.2-28.8) 12 mo 23.8 (15.9-32.7) Non-CNS Progression, % (95% CI)   6 mo 34.4 (25.2-43.8) 12 mo 51.5 (40.8-61.3) CNS Progression, % (95% CI)  6 mo 2.0 (0.4-6.3) 12 mo 3.1 (0.8-8.0) Non-CNS Progression, % (95% CI)  6 mo 38.3 (28.8-47.7) 12 mo 58.4 (47.7-67.7) CNS Non-CNS Death 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Cumulative Incidence Mo 21 3 6 9 12 15 18 Patients at Risk, n 115 69 31 16 9 15 1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Cumulative Incidence Mo 21 3 6 9 12 15 18 Patients at Risk, n 110 75 47 25 19 15 6 1 24 Yu. JCO. 2023;41:5363. Johnson. ESMO 2023. Abstr 1319MO.

23. HERTHENA-Lung02: Phase III Study of Patritumab Deruxtecan in EGFR -Mut NSCLC Multicenter, randomized, open-label phase III study Mok. ESMO 2022. Abstr 1095. NCT05338970. Patients with locally advanced or metastatic nonsquamous NSCLC with EGFR- activating mutation (ex19del or L858R); 1-2 prior lines of EGFR TKI treatment including progression after third-generation EGFR TKI; stable brain metastases allowed; tumor biopsy required, but selection not based on HER3 expression (planned N = 560) HER3-DXd 5.6 mg/kg IV Q3W (n = 280) Platinum-Based CT Four 21-day cycles: cisplatin 75 mg/m 2 or carboplatin AUC5 and pemetrexed 500 mg/m 2 Q3W* (n = 280) Primary endpoint: PFS by BICR (RECIST v1.1) Secondary endpoints: PFS by investigator, ORR, DoR, DCR, TTR, safety Disease progression, death, or unacceptable toxicity *Pemetrexed may be continued as maintenance. Stratified by prior third-generation EGFR TKI (osimertinib vs other; 1L vs 2L); region (Asia vs RoW), brain metastases (yes vs no) Data from the HERTHENA-Lung02 trial is anticipated to be released at an upcoming medical meeting.

24. Ongoing Phase I Combination Study of Patritumab Deruxtecan With Osimertinib Multicenter, open-label phase I study Primary endpoint: ORR by BICR (RECIST v1.1) Secondary endpoints: ORR by investigator, DoR, DCR, TTR, PFS, OS, safety NCT04676477. Primary endpoint: Safety Secondary endpoints: ORR, DoR, DCR, TTR, PFS, OS Dose Escalation Dose Expansion Patients with locally advanced or metastatic NSCLC with EGFR- activating mutation (ex19del or L858R); prior osimertinib; no prior CT (total target N = 252) Patients with locally advanced or metastatic NSCLC with EGFR- activating mutation (ex19del or L858R); prior osimertinib; no prior CT HER3-DXd 3.2, 4.8, 5.6 mg/kg IV Q3W + Osimertinib 80 mg PO QD (n = 3-6 per dose cohort) HER3-DXd + Osimertinib RCD* (n = 60) HER3-DXd 5.6 mg/kg IV Q3W (n = 60) *A third treatment arm may be added if 2 RCDs are determined. If osimertinib RCD = 80 mg, a cohort of first-line patients will be added (n = 30)

25. Izalontamab Brengitecan: EGFRxHER3 Bispecific ADC Zhang. ESMO 2023. Abstr 1316MO. Ma. Lancet Oncol. 2024;25:901. Phase Ia/Ib dose escalation and dose expansion study Patients ≥18 yr and ≤75 yr of age (phase Ia) or ≥18 yr of age (phase Ib) with locally advanced or metastatic NSCLC or other solid tumors, ECOG PS 0-1, measurable disease per RECIST V1.1, failure of standard therapy or without feasible treatment options (Q3W safety cohort: N = 369; NSCLC cohort: N = 113) Primary endpoint: DLT, MTD, RP2D Secondary endpoints: PK, ADA, ORR, DCR, DoR BL-B01D1 QW dosing 0.27, 1.5, 3.0 mg/kg IV ɑEGFR Human EGFR affinity: high Cat B cleavable linker Ed-04 (TOPI inhibitor) wt Fc IgG1 ɑHER3 Human HER3 affinity: low BL-B01D1 D1D8 Q3W dosing 2.5, 3.0, 3.5 mg/kg IV BL-B01D1 D1 Q3W dosing 4.5, 5.0, 6.0 mg/kg IV Dose Escalation Dose Expansion NSCLC Nasopharyngeal carcinoma SCLC Head and neck squamous cell carcinoma

26. Izalontamab Brengitecan: Response Rates in NSCLC All patients in the current analysis received Q3W dose regimens Zhang. ESMO 2023. Abstr 1316MO. Ma. Lancet Oncol. 2024;25:901. All NSCLC (n = 102) Treated/No CNS Mets (n = 75) Untreated CNS Mets (n = 27) Median prior tx lines (range) 3 (1-8) 3 (1-8) 3 (1-7) Prior TKI/ICI, % 92 93 89 Prior PBC, % 89 91 85 ORR, % 51.0 52.0 48.1 cORR, % 39.2 41.3 33.3 DCR, % 87.3 86.7 88.9 mDoR, mo 8.5 12.3 4.2 mPFS, mo 5.6 6.8 4.1 EGFR -Mutated NSCLC EGFR Wild-Type NSCLC All (n = 40) Treated/No CNS Mets (n = 13) All (n = 62) 2L Post PBC (n = 26) Prior CT lines, % 1 2+ 25 50 25 8 46 46 42 56 100 ORR, % 67.5 69.2 40.3 50.0 cORR, % 52.5 61.5 30.6 38.5 DCR, % 87.5 92.3 87.1 80.8 mDoR, mo 8.5 12.3 NR NR mPFS, mo 5.6 15.0 5.4 6.7

27. Izalontamab Brengitecan: Tumor Response in NSCLC Zhang. ESMO 2023. Abstr 1316MO. Ma. Lancet Oncol. 2024;25:901. cPR PR SD PD cPR PR SD PD EGFR -Mutated NSCLC (N = 40) All NSCLC (N = 102) BOR Change From Baseline 60 40 20 -20 -40 -60 -80 -100 BOR Change From Baseline 60 40 20 -20 -40 -60 -80 -100 ORR, EGFR -Mutated NSCLC: 67.5% ORR, All NSCLC: 51.0%

28. Izalontamab Brengitecan: Safety in All Tumor Types Zhang. ESMO 2023. Abstr 1316MO. Ma. Lancet Oncol. 2024;25:901. Overall Safety Summary All Q3W (N = 369) Median follow-up (months) 3.9 TEAE, n (%) Grade ≥3 Grade ≥4 Serious Associated with death Associated with dc Associated with delay Associated with reduction 363 (98) 249 (67) 125 (34) 142 (38) 17 (5) 12 (3) 102 (28) 50 (14) TRAE, n (%) Grade ≥3 Grade ≥4 Serious Associated with death* 351 (95) 226 (61) 115 (31) 108 (29) 8 (2) TRAE ≥15%, % All Q3W (N = 369) 2.5 mg/kg D1D8 Q3W (N = 278) 4.5 mg/kg D1 Q3W (N = 40) Any ≥ G3 Any ≥ G3 Any ≥ G3 Leukopenia 65 32 61 27 73 33 Anemia 64 24 64 22 73 25 Neutropenia 59 36 53 29 70 45 Thrombocytopenia 55 28 53 27 58 23 Nausea 36 <1 33 1 40 Asthenia 31 <1 28 1 33 Decreased appetite 29 <1 26 <1 38 Alopecia 25 21 43 Stomatitis 25 1 22 1 28 3 Vomiting 22 1 20 1 33 3 Diarrhea 17 <1 15 <1 30 Skin disorders 17 <1 14 <1 25 3 Hypokalemia 15 2 16 1 5 3 Hypoalbuminemia 13 15 5 1 grade 2 ILD was observed *Septic shock (n = 3); pneumonia (n = 2); respiratory failure, myelosuppression, gastrointestinal infection (n = 1 each).

29. Phase I Study of SHR-A2009, a HER3-Targeted ADC, in Advanced Solid Tumors First-in-human, multinational phase I trial of SHR-A2009, novel ADC comprising a fully human anti-HER3 IgG1 mAb with cleavable peptide linker and DNA topoisomerase I inhibitor payload Patients with patients with advanced, unresectable, or metastatic solid tumors whose disease is relapsed/refractory after standard therapy; ECOG PS 0/1 1.5 mg/kg 3.0 mg/kg 4.5 mg/kg 6.0 mg/kg 7.5 mg/kg Primary endpoints: safety, tolerability, RP2D Secondary endpoints: preliminary efficacy, PK, immunogenicity Dose Escalation: SHR-A2009 Q3W (n = 22) Dose Expansion (n = 20) Zhou. ESMO 2023. Abstr 658MO. 9.0 mg/kg 10.5 mg/kg 12.0 mg/kg 13.5 mg/kg SMC decision 6.0 mg/kg Q3W 9.0 mg/kg Q3W i3 + 3 Dose Escalation Indication Expansion 3-4 selected dose cohorts 8-10 patients per cohort MTD/MAD RP2D 20-30 patients per cohort EGFR- mutant NSCLC NSCLC, no EGFR mutation Other solid tumors

30. SHR-A2009: Tumor Response in Advanced Solid Tumors Zhou. ESMO 2023. Abstr 658MO. All Solid Tumors All Doses (n = 36) ORR, n (%) 9 (25.0) DCR, n (%) 26 (72.2) Median DoR, mo (range) 7.0 (2.8-8.5) 6-mo PFS, % (95% CI) 46.4 (27.0-63.8) Patients With NSCLC All Doses (n = 30) ORR, n (%) 9 (30.0) DCR, n (%) 23 (76.7) Median DoR, mo (range) 7.0 (2.8-8.5) 6-mo PFS, % (95% CI) 49.8 (28.8-67.8) 60 40 20 -20 -40 -60 Best Change in Sum of Diameter From Baseline (%) 4.5 mg/kg 3.0 mg/kg 1.5 mg/kg 9.0 mg/kg 7.5 mg/kg 6.0 mg/kg Tumor type EGFR activating mutation Prior 3rd-generation EGFR-TKI LC CRC GBC LC LC CRC CRC LC LC OC LC LC LC LC LC LC LC LC LC LC LC EC LC LC LC LC LC LC LC LC LC LC Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del Ex19Del L858R L858R L858R L858R L858R L858R L858R L858R G719X Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y LC

31. SHR-A2009: HER3-Targeted ADC in NSCLC Cohort First-in-human, multinational phase I dose escalation/expansion trial in patients with advanced/metastatic solid tumors (N = 42) NSCLC cohort: 34/36 EGFR -mutated, 34/34 prior EGFR TKI, 29/34 prior third-gen EGFR TKI Zhou. ESMO 2023. Abstr 658MO. NCT05114759. NSCLC Cohort 1.5 mg/kg (n = 3) 3.0 mg/kg (n = 3) 4.5 mg/kg (n = 3) 6.0 mg/kg (n = 8) 7.5 mg/kg (n = 3) 9.0 mg/kg (n = 10) All Doses (N = 30) ORR, n (%) 1 (33.3) 1 (33.3) 3 (37.5) 1 (33.3) 3 (30.0) 9 (30.0) DCR, n (%) 2 (66.7) 2 (66.7) 3 (100) 5 (62.5) 2 (66.7) 9 (90.0) 23 (76.7) mDoR, mo (range) NE NE 7.0 (7.0-7.0) 5.7 (2.8-8.5) NE NE 7.0 (2.8-8.5)

32. SHR-A2009: AE Profile No dose-limiting toxicities occurred up to 10.5 mg/kg Q3W dose level Zhou. ESMO 2023. Abstr 658MO. Event, n (%) All Patients (n = 42) Median duration of treatment, mo (range) 2.8 (0.3-12.4) Any AE 42 (100) Grade ≥3 AE 21 (50.0) Any TRAE 39 (92.9) Grade ≥3 TRAE 13 (31.0) TRAE leading to dose reduction 3 (7.1) TRAE leading to dose hold 8 (19.0) TRAE leading to discontinuation 3 (7.1) TRAE leading to death 1 (2.4) Serious TRAE 4 (9.5) ILD 2 (4.8) TRAEs in ≥5% of Patients Anemia Neutrophil count decreased Nausea WBC count decreased Vomiting Decreased appetite Alopecia Fatigue GGT increased Hypoalbuminemia Dizziness AST increased ALT increased Abdominal discomfort Hyponatremia Diarrhea Blood ALP increased Urinary tract infection Proteinuria Mouth ulceration Lymphocyte count decreased Hypocalcemia Cough Bilirubin conjugated increased Grade 1/2 Grade ≥3 20 40 60 Incidence Rate (%) 50.0 47.6 47.6 40.5 40.5 38.1 35.7 26.2 23.8 11.9 11.9 11.9 11.9 11.9 9.5 9.5 9.5 7.1 7.1 7.1 7.1 7.1 7.1 7.1

33. EGRET: First-in-Human Trial of AZD9592 (EGFR and cMET Targeted ADC) in Solid Tumors Open-label, multicenter, dose escalation and dose expansion phase I study NCT05647122. Aggarwal. ASCO 2023. Abstr TPS3156. Adults with locally advanced or metastatic NSCLC or other solid tumors, asymptomatic brain mets allowed, ECOG PS 0-1 (estimated N = 162) Primary endpoints: AEs, SAEs, DLT, BL labs + ECG + vital sign changes, ORR Secondary endpoints: ORR, DoR, DCR, PFS, OS, PK, ADA Module 1 AZD9592 DL 1, 2, 3, 4, 5, n Dose Escalation Dose Expansion Locally advanced or metastatic EGFR m NSCLC DL a (n = 42) Metastatic EGFR wt NSCLC (n = 38) Locally advanced or metastatic EGFR m NSCLC DL b (n = 42) Recurrent or metastatic HNSCC (n = 37) Module 2 AZD9592 + osimertinib DL 1, 2, 3, 4, 5, n Module 3 AZD9592 + 5-FU + leucovorin + bevacizumab DL 1, 2, 3, 4, 5, n CRC Locally advanced or metastatic EGFR m NSCLC DL a (n = 42) Locally advanced or metastatic EGFR m NSCLC DL b (n = 42)

34. Key Takeaways HER3 is expressed in many solid tumors included lung cancer and is an active target of investigation in several cancer types The ability of HER3 to heterodimerize with multiple partners may allow it to contribute to resistance to multiple targeted therapies, notably including EGFR TKI treatment in NSCLC Patritumab deruxtecan (HER3-DXd) is an HER3-directed ADC that has efficacy in patients with EGFR -mutant lung cancers after progression on EGFR TKI and platinum-based chemotherapy Benefit from HER3-DXd is not associated with the degree of HER3 expression; there is no HER3-related biomarker for benefit with HER3-DXd