PAPILLON Trial

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Treatment with RYBREVANT® (amivantamab-vmjw) Plus Chemotherapy Resulted in Statistically Significant and Clinically Meaningful Improvement in Progression-Free Survival in Patients with Newly Diagnosed EGFR Exon 20 Insertion Mutation- Positive Non-Small Cell Lung Cancer PRARMACENTICAL COMPANIES OF janssen Johnson-Johnson

[Slide 1] PAPILLON: Phase 3 Study Design Key Eligibility Criteria Amivantamab-Chemotherapy Primary endpoint: Progression-free survival Treatment-naîve a (n=153) (PFS) by BICR according to RECIST v1.1° locally advanced or Secondary endpoints: metastatic NSCLC Objective response rate (ORR)c Documented Duration of response (DoR) EGFR Exon 20 Chemotherapy Overall survival (OS)c insertion mutations (n=155) PFS after first subsequent therapy (PFS2) ECOG PS 0 or 1 Symptomatic PFS Time to subsequent therapyd Stratification Factors Dosing (in 21-day cycles) Safety ECOG PS Amivantamab: 1400 mg (1750 mg if >80 kg) for the first 4 weeks, then 1750 mg (2100 mg if >80 kg) every 3 weeks starting at week 7 (first day History of brain of cycle 3) metastases Chemotherapy on the first day of each cycle: Optional crossover to 2nd-line Prior EGFR TKI use Carboplatin: AUC5 for the first 4 cycles amivantamab monotherapy® Pemetrexed: 500 mg/m2 until disease progression PAPILLON (ClinicalTrials.gov Identifier: NCT04538664) enrollment period: December 2020 to November 2022; data cut-off: 3-May-2023. Removed as stratification factor since only 4 patients had prior EGFR TKI use (brief monotherapy with common EGFR TKIs was allowed if lack of response was documented). Patients with brain metastases were eligible if they received definitive treatment and were asymptomatic, clinically stable, and off corticosteroid treatment for >2 weeks prior to randomization. Key statistical assumption: 300 patients with 200 events needed for 90% power to detect an HR of 0.625 (estimated PFS of 8 vs 5 months). PFS, ORR, and then os were included in hierarchical testing. These secondary endpoints (time to subsequent therapy and symptomatic progression-free survival) will be presented at a future congress. *Crossover was only allowed after BICR confirmation of disease progression; amivantamab monotherapy on Q3W dosing per main study. MADRID congress ESMO AUC. area under the curve; BICR, blinded independent central review: ECOG PS, Eastern Cooperative Oncology Group performance status; EGFR, epidermal growth factor receptor; HR, hazard ratio; 2023 NSCLC, non-small cell lung cancer; Q3W, every 3 weeks; RECIST, Response Evaluation Criteria in Solid Tumors; TKI, tyrosine kinase inhibitor. Copies of this presentation obtained through OR --- [Slide 2] Primary Endpoint: Progression-free Survival by BICR Amivantamab-chemotherapy reduced risk of progression or death by 60% Median PFS 100 Median follow-up: 14.9 months (95% CI) Amivantamab-Chemotherapy 11.4 mo (9.8-13.7) Chemotherapy 6.7 mo (5.6-7.3) 80 HR, 0.395 (95% CI, 0.30-0.53); P<0.0001 60 48% LL ALL 40 31% LL T Amivantamab-Chemotherapy 20 13% 3% Chemotherapy 0 9 12 15 18 21 24 0 3 6 Months No. at risk Amivantamab- Chemotherapy 153 135 105 74 50 33 15 3 0 155 131 74 41 14 4 2 1 0 Chemotherapy Consistent PFS benefit by investigator: 12.9 vs 6.9 mo (HR, 0.38; 95% CI, 0.29-0.51; P<0.0001a) congress MADRID 2023 ESMO Nominal P-value: endpoint not part of hierarchical hypothesis testing. BICR. blinded independent central review; CI. confidence interval; HR, hazard ratio; mo, months: PFS, progression-free survival.

Table 1 Summary of Ongoing Clinical Trials for EGFR Ex20Ins Targeted Therapies Drug Name Trial Number Treatment Lines Phase Treatment Primary Outcome Recruitment Status Sunvozertinib NCT05668988 Frontline III Sunvozertinib VS. platinum-based chemotherapy PFS Recruiting Furmonertinib NCT05607550 Frontline III Furmonertinib VS. platinum-based chemotherapy PFS Recruiting Zipalertinib NCT05973773 Frontline III Zipalertinib-platinum-bad Chemotherapy VS. platinum-based chemotherapy PFS Recruiting YK-029A CTR20230490 Frontline III YK-029A VS. platinum-based chemotherapy PFS Recruiting JMT101 NCT05132777 Backline II JMT101+Osimertinib ORR Recruiting PLB1004 CTR20231534 Backline II PLB1004 ORR Recruiting BEBT-109 CTR20213409 Backline II BEBT-109 ORR Recruiting AP-1898 NCT04993391 Backline I/II AP-L1898 Safety and Tolerability ORR Recruiting BDTX-189 NCT04209465 Backline 1/11 BDTX-189 Phasel:Safety and Tolerability, PR2D;Phasell:ORR Recruiting HS-10376 NCT05435274 Backline I/II HS-10376 Phasela:MTD,PR2D;Phaselb/I1:ORR Recruiting BLU-451 NCT05241873 Backline I/II BLU-451 Phasel:MTD,PR2D;Phasell:ORR Recruiting BAY 2927088 NCT05099172 Backline I BAY 2927088 Safety and Tolerability Recruiting NIP142 CTR20220597 Backline I NIP142 Phasela:DLT and MTD,Phase IB:ORR Recruiting FWD1509 MsOH NCT05068024 Backline I FWD1509 MsOH Safety and Tolerability Recruiting Abbreviations: DLT = dose limiting toxicity; MTD = maximal tolerated dose; ORR = objective response rate; PFS = progression-free survival; PR2D = recommended phase II dose.

MADRID ESMO congress 2023 - Amivantamab Plus Chemotherapy vs Chemotherapy as First-line Treatment in EGFR Exon 20 Insertion-mutated Advanced Non-small Cell Lung Cancer (NSCLC) Primary Results From PAPILLON, a Randomized Phase 3 Global Study Nicolas Girard Keunchil Park,2.* Ke-Jing Tang,3 Byoung Chul Cho,* Luis Paz-Ares, Susanna Cheng, Satoru Kitazono, Muthukkumaran Thiagarajan,* Jonathan W. Goldman, Joshua K. Sabari, 10 Rachel E. Sanborn, 11 Aaron S. Mansfield,12 Jen-Yu Hung,13 Sanjay Popat, 14 Josiane Mourão, 15 Archan Bhattacharya, 16 Trishala Agrawal,1 S. Martin Shreeve, Roland E. Knoblauch, Caicun Zhou - I - - Theres Versites, France Send / First Unive Division Dolutes Medical I - New - Cellomia, OR, MN Claic, - High UK PA, USA CA School === Milation MO MADRID MADRID ESMocongress --- PAPILLON Primary Endpoint: Progression-free Survival by BICR Amivantamab-chemotherapy reduced risk of progression or death by 60% 100 Median PFS Median follow-up: 14.9 months (95% CI) Amivantamab-Chemotherapy 11.4 mo (9.8-13.7) Patients who are progression-free (%) 80 Chemotherapy 6.7 mo (5.6-7.3) HR, 0.395 (95% CI, 0.30-0.53); P<0.0001 60 48% 40 31% u Amivantamab-Chemotherapy 20 13% 3% Chemotherapy 0 0 3 6 9 12 15 18 21 24 No. at risk Months Amivantamab- Chemotherapy 153 135 105 74 50 33 15 3 0 Chemotherapy 155 131 74 41 14 4 2 1 0 MADRID congress Consistent PFS benefit by investigator: 12.9 vs 6.9 mo (HR, 0.38; 95% CI, 0.29-0.51; P<0.0001ᵃ) 2023 ESMD *Nominal P-value; endpoint not part of hierarchical hypothesis testing. BICR, blinded independent central review, CI, confidence interval; HR, hazard ratio, mo, months; PFS, progression-free survival

PAPILLON Primary Endpoint: Progression-free Survival by BICR Amivantamab-chemotherapy reduced risk of progression or death by 60% 100 Median follow-up: 14.9 months Median PFS (95% CI) Amivantamab-Chemotherapy 11.4 mo (9.8-13.7) Patients who are progression-free (%) 80 Chemotherapy 6.7 mo (5.6-7.3) HR, 0.395 (95% CI, 0.30-0.53); P<0.0001 60 48% 40 31% Amivantamab-Chemotherapy 20 13% 3% Chemotherapy 0 0 3 6 9 12 15 18 21 24 No. at risk Months Amivantamab- Chemotherapy 153 135 105 74 50 33 15 3 0 Chemotherapy 155 131 74 41 14 4 2 1 0 congress Consistent PFS benefit by investigator: 12.9 vs 6.9 mo (HR, 0.38; 95% CI, 0.29-0.51; P<0.0001ᵃ) MADRID 2023 ESMO Nominal P-value; endpoint not part of hierarchical hypothesis testing. BICR, blinded independent central review, CI, confidence interval; HR, hazard ratio; mo, months; PFS, progression-free survival Capies of no - OR at for --- PAPILLON Best Response and ORR by BICR Amivantamab-Chemotherapy Chemotherapya 40 40 20 20 Best change from baseline in 0 SoD of target lesions (%) 0 -20 -40 CR Best change from baseline in SoD of target lesions (%) -20 -40 CR -60 -60 PR PR SD SD -80 -80 PD PD NE/Unknown NE/Unknown -100 -100 BICR-assessed responseb Amivantamab-Chemotherapy (n=153) Chemotherapy (n=155) Mean percent change of SoD -53%c -34% ORR 73% (95% CI, 65-80) 47% (95% CI, 39-56) Odds ratio 3.0 (95% CI, 1.8-4.8); P<0.0001 Best response, n (%) Complete response 6 (4) 1 (1) Partial response 105 (69) 71 (47) Stable disease 29 (19) 62 (41) Progressive disease 4 (3) 16 (11) NE/Unknown 8 (5) 2 (1) Median time to response 6.7 wk (range, 5.1-72.5) 11.4 wk (range, 5.1-60.2) Consistent results with investigator assessment: ORR of 66% vs 43% (OR, 2.6; P<0.0001) *Patients without postbaseline tumor assessment were not included in this plot. No. of patients with measurable disease at baseline by BICR was 152 in both arms; response data presented among all responders. Nominal P<0.001; endpoint not part of hierarchical testing. congress ADRID 23 ESMO BICR, blinded independent central review, CI, confidence interval; CR, complete response; mo, month; NE, not evaluable; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease; SoD, sum of diameters; wk, weeks. Capies OR --- PAPILLON Interim Overall Survivala Amivantamab-chemotherapy shows trend in reducing risk of death by over 30% 100 80 74% 72% Patients who survived (%) Amivantamab-Chemotherapy 60 68% 54% 40 Median os Median follow-up: 14.9 months (95% CI) Amivantamab-Chemotherapy NE (NE-NE) 20 Chemotherapy 24.4 mo (22.1-NE) Chemotherapy HR, 0.675 (95% CI, 0.42-1.09); P=0.106 0 71 of 107 (66%) 0 3 6 9 12 15 18 21 24 27 patients whose No. at risk Months disease progressed Amivantamab- crossed over to Chemotherapy 153 144 133 115 88 60 38 15 5 0 amivantamabᵇ Chemotherapy 155 153 144 110 85 57 37 24 6 0 *There were 70 deaths in the study at the time of the prespecified interim OS analysis, which represents 23% of all randomized patients and 33% of the -210 projected deaths for the final OS analysis. A total of 71 patients (65 patients as part of the crossover arm plus an additional 6 patients off-protocol) received second-line amivantamab monotherapy out of 107 chemotherapy-randomized patients congress MADRID 2023 ESMO with disease progression. CI, confidence interval; HR, hazard ratio; mo, months; NE, not estimable; OS, overall survival Cash If 50 everys OR - are for personal --- PAPILLON Safety Profile Amivantamab-Chemotherapy Chemotherapy Most common AEs of any cause (n=151) (n=155) EGFR- and MET-related AEs by preferred term (>20%), n (%) All grades Grade ≥3 All grades Grade ≥3 Associated with EGFR inhibition were increased with Paronychia 85 (56) 10 (7) 0 0 amivantamab-chemotherapy, Rash 81 (54) 17 (11) 12 (8) 0 primarily grade 1-2 Dermatitis acneiform 47 (31) 6 (4) 5 (3) 0 Stomatitis 38 (25) 2 (1) 9 (6) 0 Chemotherapy-associated Diarrhea 31 (21) 5 (3) 20 (13) 2 (1) hematologic and GI toxicities Associated with MET inhibition Hypoalbuminemia 62 (41) 6 (4) 15 (10) 0 were comparable except for Peripheral edema 45 (30) 2 (1) 16 (10) 0 neutropenia Other Neutropenia 89 (59) 50 (33) 70 (45) 35 (23) Neutropenia was transient; Anemia 76 (50) 16 (11) 85 (55) 19 (12) majority of events were not Infusion-related reaction 63 (42) 2 (1) 2 (1) 0 serious, with low rates of Constipation 60 (40) 0 47 (30) 1 (1) discontinuations Leukopenia 57 (38) 17 (11) 50 (32) 5 (3) Nausea 55 (36) 1 (1) 65 (42) 0 Pneumonitis was reported in Thrombocytopenia 55 (36) 15 (10) 46 (30) 16 (10) Decreased appetite 54 (36) 4 (3) 43 (28) 2 (1) 4 (3%) patients in the Alanine aminotransferase increased 50 (33) 6 (4) 56 (36) 2 (1) amivantamab-chemotherapy arm Aspartate aminotransferase increased 47 (31) 1 (1) 51 (33) 1 (1) COVID-19 36 (24) 3 (2) 21 (14) 1 (1) Hypokalemia 32 (21) 13 (9) 13 (8) 2 (1) Vomiting 32 (21) 5 (3) 29 (19) 1 (1) congress MADRID 2023 ESMO AE, adverse event; EGFR, epidermal growth factor receptor, GI, gastrointestinal. 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[Slide 1] Recap of ESMO 2023; Girard N, et al. 1,2 Primary Endpoint: Progression-free Survival by BICR PAPILLON Amivantamab-chemotherapy is now approved in the US for first-line treatment of EGFR Ex20ins advanced NSCLC³ 100 Median PFS Median follow-up: 14.9 mo (95% CI) Amivantamab-Chemotherapy 11.4 mo (9.8-13.7) 80 Chemotherapy 6.7 mo (5.6-7.3) HR, 0.395 (95% CI, 0.30-0.53); P<0.0001 60 48% ILL 40 ALL 31% Amivantamab-Chemotherapy 20 13% 3% Chemotherapy 0 0 3 6 9 12 15 18 21 24 Months No. at risk Ami-Chemo 153 135 105 74 50 33 15 3 0 Chemo 155 131 74 41 14 4 2 1 0 Consistent PFS benefit by investigator: 12.9 vs 6.9 mo (HR, 0.38; 95% CI, 0.29-0.51; P<0.0001) Ami-Chemo Amivantamab-Chemotherapy; BICR blinded independent central review; Chemo, Chemotherapy; CI, confidence interval; EGFR, epidermal growth factor receptor; Ex20ins, Exon 20 insertions; HR, hazard ratio; mo, months; NSCLC, non-small cell lung cancer; PFS, progression-free survival; US, United States. 1. Zhou C, et al. Engl J Med. 2023;389(22):2039-2051. 2. GirardN et al. Presented at: European Society for Medical Oncology (ESMO) 20-24 October 2023; Madrid, Spain 3.U.S. Food & Drug Administration FDA. Published online elcc March 1. 2024. Accessed March 7. 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-amivantamab-vmjw-egfr-exon-20-nsertion-mutated-non-small-cell-lung-cancer-indications. European Lung Cancer Congress 2024 The OR code

I I MADRID 2023 ESMD congress congress SMO --- PAPILLON MADRID congress 2023 ESMO Amivantamab Plus Chemotherapy vs Chemotherapy as First-line Treatment in EGFR Exon 20 Insertion-mutated Advanced Non-small Cell Lung Cancer (NSCLC) Primary Results From PAPILLON, a Randomized Phase 3 Global Study ⑉ ⑉ Nicolas Girard,1 Keunchil Park,2.* Ke-Jing Tang,³ Byoung Chul Cho,4 Luis Paz-Ares,⁵ Susanna Cheng,6 Satoru Kitazono,⁷ Muthukkumaran Thiagarajan,⁸ Jonathan W. Goldman,9 Joshua K. Sabari,¹ 10 Rachel E. Sanborn,11 Aaron S. Mansfield,12 Jen-Yu Hung,¹³ Sanjay Popat,14 Josiane Mourão, 15 Archan Bhattacharya,16 Trishala Agrawal,17 S. Martin Shreeve,¹⁸ Roland E. Knoblauch,17 Caicun Zhou19 Institut Curie, Institut du Thorax Curie-Montsouris Paris, France and Paris Saclay University UVSQ Versailles France Samsung Medical Center Sungkyunkwan University School of Medicine Seoul Republic of Korea The First Affiliated Hospital of Sun Yat-sen University Guangzhou China "Division of Medical Oncology Yonsei Cancer Center. Yonsei University College of Medicine Seoul Republic of Korea Hospital Universitario 12 de Octubre Madrid Spain, *Sunnybrook Odette Cancer Centre. Toronto. ON. Canada Cancer Institute Hospital Japanese Foundation for Cancer Research Tokyo. Japan General Hospital Kuala Lumpur, Kuala Lumpur, Malaysia David Geffen School of Medicine University of California Los Angeles, Los Angeles, California USA *NYU Langone Health New York NY. USA "Earle A Chiles Research Institute Providence Cancer Institute Portland OR USA Mayo Clinic Rochester MN, USA; Department of Internal Medicine Kaohsking Medical University Hospital Kaohsiung Medical University Kaohslung Talwan "Royal Marsden Hospital NHS Foundation Trust London UK and The Institute of Cancer Research London UK; "Barretos Cancer Hospital Barretos Brazil "Janssen R&D. High Wycombe UK: Janssen R&D Spring House, PA USA: "Janssen R&D San Diego, CA USA; "Shanghai Pulmonary Hospital Tong ⑉ University School of Medicine, Shanghai, China "Current Affiliation MD Anderson Cancer Center Houston, TX, USA Copies or the resentation cotained through OR code or personal - and may not be restruced without the --- PAPILLON EGFR Exon 20 Insertion Mutations (Ex20ins) Advanced NSCLC Outcomes in newly diagnosed EGFR Ex20ins advanced NSCLC are historically poor¹-³ Reported median OS has ranged from 16 to 24 months, with a 5-year OS rate of 8%¹ Ex20ins are largely insensitive to common EGFR TKIs due to steric hindrance at the TKI-binding site⁴,⁵ Checkpoint inhibitors have failed to show benefit in this setting⁶⁷⁷ Platinum-based chemotherapy is the standard of care, but has limited efficacy Amivantamab received first approval for EGFR Ex20ins advanced NSCLC after progression on platinum-based chemotherapy 80 Best Response on Amivantamab in Post-platinum EGFR Ex20ins NSCLC8 n=81ᵃ; ORR=40%; DoR=11.1 months 60 Helical region (762-766) Near loop region (767-772) Far loop region (773-775) Not detected by ctDNA 40 Best change from baseline in SoD of target lesions (%) 20 0 -20 -40 -60 -80 -100 *One patient discontinued before any disease assessment and is not shown on the waterfall plot. ctDNA circulating-tumor DNA DoR, duration of response; EGFR epidermal growth factor receptor, NSCLC, non-small cell lung cancer, ORR, objective response rate (by blinded independent central review); OS, overall survival; SoD, sum of diameters; TKI, tyrosine kinase inhibitor MADRID congress 1. Bazhenova L, et al. Lung Cancer 2021;162:154-161 2. Ou S-H, et al. JTO Clin Res. 2023;4(10): 100558 3. Chouaid C, et al. Target Oncol 2021;16(6):801-811. 4. Vyse S, et al. Signal Transduct Target Ther. 2019;4:5 5. Robichaux JP, et al. Nat Med. 2018,24(5):638-646. 6. Hou J. et al. Biomark Res. 2022;10(1):21. 7. Girard N, et al. Clin Lung Cancer. 2022,23(h):571-577. 8. Park K, et al. J Clin Oncol. 2023 2021;39(30):3391-3402 Copies peserition through code : for on without the --- PAPILLON Rationale for Combining Amivantamab and Chemotherapy Amivantamab is an EGFR and MET Trogocytosis and Antibody-dependent Cellular Cytotoxicity² bispecific antibody with immune Amivantamab-labeled cell-directing activity1-3 NSCLC tumor cell Macrophage Combining amivantamab's ability to Macrophage engage immune cells with Y chemotherapy-mediated cell death Tumor Cell could lead to deeper and more durable responses Natural Killer Cell Phase 1 data (n=20) demonstrated Video available in Mol Cancer Ther 2020. safety, tolerability, and antitumor activity of amivantamab- Chemotherapy-mediated Cell Death5,6 chemotherapy⁴ Carboplatin Pemetrexed COM Among 5 patients with treatment- CO2H naïve, EGFR Ex20ins NSCLC, Tumor Cell Tumor Cell Death 4 achieved a best response of PR EGFR, epidermal growth factor receptor, Ex20ins, Exon 20 insertion mutations; NSCLC, non-small cell lung cancer, PR, partial response. MADRID congress 2023 ESMO 1. Moores S, et al. Cancer Res. 2016,76(13):3942-3953.2. Vijayaraghavan S, et al. Mol Cancer Ther 2020;19(10):2044-2056. 3. Yun J. et al. Cancer Discov. 2020;10(8):1194-1209. 4. Nagasaka M. et al. Poster presented at WCLC; September 8-14, 2021; Virtual 5 Schaer et al. Clin Cancer Res 2019,25(23):7175-7188 6. Schoch S. et al. Int J Mol Sci 2020;21(18) 6928 Capies the obtained through OR CODE are to and may not be reproduced amount entim permission of the authors

17th " Annual ATLANTA LUNG CANCER SYMPOSIUM™ --- Subtypes of EGFR mutations a EGFR-mutant patients b Atypical EGFR mutations Classical (67.1%) Classical + T790M Exon 19 Atypical (30.8%) + atypical (2.2%) 9.4% Complex Ex20ins atypical 9.1% 9.1% Exon 20ins 20.9% Ex19del 32.7% Exon 18 Other atypical 23.7% 12.6% Exon 20pt Classical + T790M 19.2% L858R + atypical 2.2% 23.0% Exon 21 T790M 0.3% Extracellular 18.1% 6.7% Classical + T790M Trans- Other 2.0% 11.1% membrane 0.4% Total = 11,619 Total = 7,199 17th Robichaux, J.P., Le, X., Vijayan, R.S.K. et al. Structure-based classification predicts drug response in EGFR-mutant NSCLC. Nature 597, 732- 737 (2021) PIM Postgraduate Institute for Medicine Bio Ascend ATLANTA LUNG CANCER SYMPOSIUM --- Papillon: Phase 3 Amivantamab + chemotherapy frontline C Overall Survival Median Overall Survival (95% CI) mo Amivantamab-Chemotherapy Not estimable 100 Chemotherapy 24.4 (22.1-not estimable) 90 80 Amivantamab-chemotherapy Percentage of Patients 70 60 50 40 30 20 Hazard ratio for death, 0.67 (95% CI, 0.42-1.09) Chemotherapy 10 P=0.11 0 0 3 6 9 12 15 18 21 24 27 Months since Randomization No. at Risk Amivantamab-chemotherapy 153 144 133 115 88 60 38 15 5 0 Chemotherapy 155 153 144 110 85 57 37 24 6 0 17th ATLANTA Zhou J. et al. NEJM. 2023. PIM Postgraduate Institute LUNG CANCER SYMPOSIUM for Medicine Bio Ascend --- Sunvozertinib: irreversible EGFR exon20 insertion (exon20ins) inhibitor amivantamab Baseline BM NNNN NNN NN NN NNNNN 80 60 PD 40 NENENDE 20 Best Tumor Size Change (%) 0 -20 -40 -60 -80 - Sunvozertinib 300 mg (N=97) - PEPR -100 WU-KONG6 (NCT05712902 and CTR20211009) confirmed ORR was 60.8% (59/97) phase II, EGFR exon20ins, progressed on/after platinum-based chemotherapy. Analysis of 97 patients 17th PIM Postgraduate Institute ATLANTA Wang M, et al. J Clin Oncol. 2023;41916_suppl):9002. for Medicine Bio Ascend LUNG CANCER SYMPOSIUM

Resources for Information | Approved Drugs FDA approves amivantamab- vmjw for EGFR exon 20 insertion-mutated non-small cell lung cancer indications f Share X Post Email On March 1, 2024, the Food and Drug Administration approved amivantamab- vmjw (Rybrevant, Janssen Biotech, Inc.) with carboplatin and pemetrexed for the first-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA- approved test. --- METHODS The NEW ENGLAND JOURNAL of MEDICINE RESEARCH SUMMARY Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions Zhou C et al. DOI: 10.1056/NEJMoa2306441 CLINICAL PROBLEM In patients with non-small-cell lung cancer (NSCLC) with exon 20 insertions in the gene encoding epidermal growth factor receptor (EGFR), amivantamab — an EGFR mesenchymal-epithelial transition factor (MET) bispecific antibody with immune cell-directing activity — is ap- proved for use after progression occurs during or after Amivantamab EGFR receipt of first-line platinum-based chemotherapy. A pivotal phase 1 trial also showed safety and antitumor activity of amivantamab plus carboplatin-pemetrexed chemotherapy Chemotherapy (amivantamab-chemotherapy). More data on this combi- Exon 20 insertions c-MET nation therapy are needed. CLINICAL TRIAL Progression-free Survival Design: A phase 3, international, randomized trial 100 HR for disease progression or death, 0.40 (95% CI,0.30-0.53): P<0.001 assessed the efficacy and safety of amivantamab- 90 chemotherapy as compared with chemotherapy alone 80 as first-line therapy in patients with advanced NSCLC with EGFR exon 20 insertions. Percentage of Patients 70 60 Amivantamab + chemotherapy 50 11.4 mo (95% CI, 9.8-13.7) Intervention: 308 adults were assigned to receive intrave- 40 Chemotherapy nous amivantamab (1400 mg weekly for the first 4 weeks; 6.7 mo 30 (95% CI, 5.6-7.3) 1750 mg every 3 weeks starting at week 7 until progres- 20 sion occurred) plus carboplatin-pemetrexed chemotherapy 10 or chemotherapy alone, in 21-day cycles. Patients assigned 0 to chemotherapy alone could receive amivantamab mono- 0 3 6 9 12 15 18 21 24 Months since Randomization therapy after disease progression was documented. The primary outcome was progression-free survival. Most Common Adverse Events in Each Group 100 RESULTS Amivantamab . Chemotherapy Chemotherapy Efficacy: Progression-free survival was significantly 80 longer in the amivantamab-chemotherapy group than in the chemotherapy group. Safety: No new safety signal emerged for any agent. Percentage of Patients 59 60 56 54 55 45 42 40 Discontinuation of amivantamab because of adverse reactions was reported in 7% of patients. 20 0 LIMITATIONS AND REMAINING QUESTIONS Neutropenia Paronychia Rash Anemia Neutropenia Nausea Blinding of treatment assignments was not possible because of differences in drug administration, pre- medication requirements, and safety profiles. CONCLUSIONS The number of deaths in the trial was too few to provide In patients with previously untreated, advanced NSCLC robust conclusions regarding overall survival; an analysis with EGFR exon 20 insertions, progression-free survival is planned at approximately 4 years of follow-up. was significantly longer with combination amivantamab- chemotherapy than with chemotherapy alone. Links: Full Article NEJM Quick Take --- October 2, 2023 OSAKA, Japan and CAMBRIDGE, Massachusetts, October 2, 2023 - Takeda (TSE:4502/NYSE:TAK) today announced that, following discussions with the U.S. Food and Drug Administration (FDA), it will be working with the FDA towards a voluntary withdrawal of EXKIVITY® (mobocertinib) in the U.S. for adult patients with epidermal growth factor receptor (EGFR) Exon20 insertion mutation-positive (insertion+) locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on or after platinum- based chemotherapy. Takeda intends to similarly initiate voluntary withdrawal globally where EXKIVITY is approved and is working with regulators in other countries where it is currently available on next steps. --- EXCLAIM-2 (NCT04129502) Phase 3 Trial Schema Mobocertinib 160 mg daily -Treatment naive -Locally advanced or metastatic -Nonsquamous NSCLC R -EGFR ex20ins 1:1 10 endpoint: PFS by IRC N=318 2° endpoints: ORR, OS, PFS by IA, DoR, TTR, DCR, PRO, safety Subgroup analysis 1. Brain mets (yes vs no) 2. Race (Asian vs non- Asian) Platinum/Pemetrexed X 4 Crossover to mobocertinib Pemetrexed maintenance allowed 168 clinical sites The EXCLAIM-2 (NCT04129502) phase 3 trial schema. Abbreviations: EGFR ex20ins, EGFR exon 20 insertion; DCR, disease control rate; DoR, duration of response; IA, investigator assessment; IRC, independent review committee; ORR; objective response rate; OS, overall survival; mets, metastases; NSCLC, non-small cell lung cancer; PFS, progression-free survival; PRO, patient- reported outcome; TTR, time to response; VS, versus.

elcc European Lung Cares --- Exon20ins evolving landscape beyond Amivantamab Tuxobertinib (BDTX-189) EGFR/HER2 Exon20ins irreversible ATP-competitive inhibitor. BAY-2476568 STX-721 Selective & reversible EGFR exon20 ins inhibitor irreversible highly selective EGFR and ERBB2 ex20ins TKIS N lobe Exon 20 insertion YK-029A ORIC-114 3rd generation EGFR TKI EGFR/HER2 Exon20ins TKI Ph3 TKI VS chemo C lobe Sunvorzetinib Zipalertinib Pan-EGFR mutation TKI irreversible & selective EGFR exon20ins TKI Ph3 Sunvuzertinib VS chemo Ph3 Zipalertinib plus Chemo VS Chemo Furmonertinib 3rd gen EGFR/HER2 Exon20ins TKI Phase 3 ongoing Ph3 Furmonertinib VS chemo Antonio Passaro #ELCC24

[Slide 1] Key developments in common EGFRmt and ex20ins mt NSCLC A tale of stark contrasts 1L EGFR-TKIs trials FDA approval 1L 1G EGFR-TKIs in for EGFRm NSCLC commence FDA approval 1l Osimertinib, trials afatinib dacomitinib FDA approval Publication of erlotinib pretreated RELAY study NSCLC Description of FDA approval 21 FDA approval Publication of EGFR T790M Publication of osimertinib EGFR adjuvant Publication of in AR IPASS study EURTAC study 1790M+ NSCLC osimertinib FLAURA2 2004 2006 2008 2010 2012 2014 2016 2018 2020 2022 2024 Discovery of EGFR Early phase trials Publication of mutations, ind of amivantamab, PAPILLON, ex20ins Characterisation of mobocertinib 1st report selected EGFR EXCLAIM-2 ins20 mt FDA approval amivantamab, mobocertinib post PBC 10