Phase 3 Study of Ivonescimab (AK112) vs. Pembrolizumab as First-line Treatment for PD-L1-positive Advanced NSCLC: HARMONi-2 C. Zhou1,2, J. Chen3, L. Wu3, L. Wang1, A. Xiong1, B. Liu4, J. Yao5, H. Zhong6, J. Li7, Y. Cheng8, Y. Sun9, H. Ge10, Q. Shi11, M. Zhou12, Z. Han13, J. Wang14, Q. Bu15, Y. Zhao16, J. Chen17, J. Yang18, M. Xia18 1Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai/CN; 2East Hospital Affiliated To Tongji University, shanghai/CN; 3Hunan Cancer Hospital, Changsha/CN; 4Harbin Medical University Cancer Hospital, Harbin/CN; 5The First Affiliated Hospital of Henan University of Science and Technology, Luoyang/CN; 6Shanghai Chest Hospital, Shanghai/CN; 7The First Affiliated Hospital of Gannan Medical University, Ganzhou/CN; 8Jilin Cancer Hospital, Changchun/CN; 9Shandong Cancer Hospital and Institute, Jinan/CN; 10The Fourth Hospital of Hebei Medical University, Shijiazhuang/CN; 11Fuzhou Tuberculosis Prevention and Treatment Hospital, Fuzhou/CN; 12Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou/CN; 13The Affiliated Hospital of Xuzhou Medical University, Xuzhou/CN; 14The Fifth Medical Center of the General Hospital of Chinese People's Liberation Army, Beijing/CN; 15The First affiliated hospital of Guangxi Medical University, Nanning/CN; 16Henan Cancer Hospital, Zhengzhou/CN; 17Fujian Cancer Hospital, Fuzhou/CN; 18Akeso Biopharma, Inc., Zhongshan/CN 1Caicun Zhou | HARMONi-2 Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
Caicun Zhou | HARMONi-2 • Honoraria as a speaker: Lilly China, Sanofi, BI, Roche, MSD, Qilu, Hengrui, Innovent Biologics, C-Stone, LUYE Pharma, TopAlliance Biosciences Inc, Amoy Diagnositics. • Advisor: Innovent Biologics, Hengrui, Qilu, TopAlliance Biosciences Inc. Disclosures Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 2 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
• Anti-PD-1/L1 monotherapy or in combination with chemotherapy has been the standard of care for the first- line treatment of PD-L1 positive aNSCLC without driver gene alterations. • Monotherapy with an immune checkpoint inhibitor provides limited clinical benefit for PD-L1 positive aNSCLC1-2. • Ivonescimab (AK112) is a novel bispecific antibody against PD-1 and VEGF and has shown promising clinical efficacy and safety as front-line therapy for patients with PD-L1-positive aNSCLC in the phase 2 study (AK112-202)3. • HARMONi-2 (AK112-303, NCT05499390) is a randomized, double-blind, phase 3 study to compare the efficacy of ivonescimab with pembrolizumab as first-line treatment in patients with PD-L1-positive aNSCLC. • A sample size of approximately 388 patients and 264 PFS events would provide 90% power to detect a hazard ratio (HR) of 0.67. • An interim analysis of PFS was planned when 185 (70%) IRRC-assessed PFS events occurred. Background 1. Mok TSK, et al. Lancet. 2019;393(10183):1819-1830. 2. Yang JC, et al.J Thorac Oncol. 2024;19(6):941-953. 3.Wang L, et al. J Thorac Oncol. 2024;19(3):465-475. Abbreviations: PD-1, programmed death receptor 1; PD-L1, programmed death ligand 1; aNSCLC, advanced non-small cell lung cancer; VEGF, vascular endothelial growth factor; PFS, progression-free survival; IRRC, independent radiology review committee. Caicun Zhou | HARMONi-2 Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 3 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
A randomized, double-blind, phase 3 studya Stratification • Clinical stage (IIIB/C vs. IV) • Histology (SQ vs. non-SQ) • PD-L1 TPS (≥50% vs. 1-49%) HARMONi-2 (AK112-303) Study Design Patient Population • Stage IIIB-IV aNSCLC • No prior systemic therapy • No EGFR mutations or ALK rearrangements • ECOG PS 0 or 1 • PD-L1 TPS ≥1% R 1:1 Ivonescimab 20 mg/kg Q3W (N=198) Pembrolizumab 200 mg Q3W (N=200) Treatment until no clinical benefit, unacceptable toxicity or up to 24 months N=398 Endpoints Primary: PFS by blind IRRC per RECIST v1.1 Secondary: OS, PFS assessed by INVs, ORR, DoR, TTR and safety Exploratory: QoL Caicun Zhou | HARMONi-2 a Patients were randomized from November 2022 to August 2023. Data cut off: January 29, 2024. Abbreviations: aNSCLC, advanced non-small cell lung cancer; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ECOG PS, Eastern Cooperative Oncology Group performance score; PD-L1, programmed death ligand 1; TPS, tumor proportion score; R, randomization; SQ, squamous cell carcinoma; Q3W, every three weeks; PFS, progression-free survival; IRRC, independent radiology review committee; OS, overall survival; INV, investigator; ORR, overall response rate; DoR, duration of response; TTR, time to response; QoL, quality of life. Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 4 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
Baseline Characteristics Characteristics, n (%) Ivonescimab (n = 198a) Pembrolizumab (n = 200a) Total (n = 398a) Age (years) <65 97 (49.0) 85 (42.5) 182 (45.7) ≥65 101 (51.0) 115 (57.5) 216 (54.3) Sex Male 164 (82.8) 169 (84.5) 333 (83.7) Female 34 (17.2) 31 (15.5) 65 (16.3) ECOG PS 0 25 (12.6) 26 (13.0) 51 (12.8) 1 173 (87.4) 174 (87.0) 347 (87.2) Smoker Never 39 (19.7) 38 (19.0) 77 (19.3) Current 39 (19.7) 42 (21.0) 81 (20.4) Former 120 (60.6) 120 (60.0) 240 (60.3) Clinical stage IIIB/C 15 (7.6) 16 (8.0) 31 (7.8) IV 183 (92.4) 184 (92.0) 367 (92.2) Pathology SQ 90 (45.5) 91 (45.5) 181 (45.5) Tumor centrally locatedb 65 (72.2) 57 (62.6) 122 (67.4) Tumor with cavitation/necrosisb 9 (10.0) 7 (7.7) 16 (8.8) Tumor encasing large blood vesselb 6 (6.7) 1 (1.1) 7 (3.9) Non-SQ 108 (54.5) 109 (54.5) 217 (54.5) PD-L1 TPS ≥50% 83 (41.9) 85 (42.5) 168 (42.2) 1-49% 115 (58.1) 115 (57.5) 230 (57.8) Liver metastases Yes 25 (12.6) 28 (14.0) 53 (13.3) No 173 (87.4) 172 (86.0) 345 (86.7) Brain metastases Yes 33 (16.7) 39 (19.5) 72 (18.1) No 165 (83.3) 161 (80.5) 326 (81.9) a Patients who received randomization. b In 181 patients with SQ. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance score; PD-L1, programmed death ligand 1; TPS, tumor proportion score; SQ, squamous cell carcinoma. Caicun Zhou | HARMONi-2 Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 5 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
9-mo: 40% (32, 48) Median Follow-up: 8.67 months 9-mo: 56% (47, 64) Primary endpoint: PFS per IRRC Abbreviations: mPFS, median progression-free survival; IRRC, independent radiology review committee; mo, month; NE, not estimable; HR: hazard ratio; CI, confidence interval. Caicun Zhou | HARMONi-2 Ivonescimab demonstrated a statistically significant improvement in PFS vs. pembrolizumab with HR = 0.51, and a 5.3 months improvement in mPFS. Ivonescimab (n = 198) Pembrolizumab (n = 200) mPFS, mos (95% CI) 11.14 (7.33, NE) 5.82 (5.03, 8.21) Stratified HR (95% CI) 0.51 (0.38, 0.69) p-value <0.0001 Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 6 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
0.06 0.1 1 10 Ivonescimab Better Pembrolizumab Better PFS Subgroup Analyses Ivonescimab Pembrolizumab Events/Patients Events/Patients Overall 72/198 112/200 Age <65 37/97 50/85 ≥65 35/101 62/115 Sex Male 58/164 94/169 Female 14/34 18/31 ECOG PS 0 4/25 19/26 1 68/173 93/174 Smoking Status Never 13/39 22/38 Current smoker 12/39 20/42 Former smoker 47/120 70/120 Liver metastases Yes 12/25 18/28 No 60/173 94/172 Brain metastases Yes 14/33 25/39 No 58/165 87/161 Distant metastatic sites ≥3 25/49 33/51 <3 47/149 79/149 Clinical stage IIIB/C 5/15 5/16 IV 67/183 107/184 Pathology Squamous 35/90 56/91 Non-Squamous 37/108 56/109 PD-L1 TPS ≥50% 25/83 45/85 1-49% 47/115 67/115 Caicun Zhou | HARMONi-2 Abbreviations: PFS, progression-free survival; ECOG PS, Eastern Cooperative Oncology Group performance score; PD-L1, programmed death ligand 1; TPS, tumor proportion score; SQ, squamous cell carcinoma; CI, confidence interval; aNSCLC, advanced non-small cell lung cancer. Unstratified Hazard Ratio (95% CI) 0.51 (0.38, 0.69) 0.53 (0.34, 0.81) 0.52 (0.34, 0.79) 0.53 (0.38, 0.74) 0.49 (0.24, 0.99) 0.18 (0.06, 0.54) 0.60 (0.44, 0.82) 0.39 (0.19, 0.77) 0.51 (0.24, 1.07) 0.57 (0.39, 0.74) 0.47 (0.23, 0.98) 0.53 (0.39, 0.74) 0.55 (0.28, 1.05) 0.53 (0.38, 0.74) 0.58 (0.34, 0.97) 0.49 (0.34, 0.71) 1.01 (0.29, 3.51) 0.49 (0.36, 0.67) 0.50 (0.33, 0.76) 0.55 (0.36, 0.84) 0.48 (0.29, 0.79) 0.54 (0.37, 0.78) Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 7 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
Key PFS Subgroup Analyses Caicun Zhou | HARMONi-2 Abbreviations: PFS, progression-free survival; PD-L1, programmed death ligand 1; TPS, tumor proportion score; HR: hazard ratio; CI, confidence interval; NSCLC, non-small cell lung cancer. PD-L1 Low (TPS 1-49%) Ivonescimab showed meaningful improvement in PFS vs. pembrolizumab in patients with both low and high PD-L1, with squamous or non-squamous advanced NSCLC. Stratified HR (95% CI) 0.54 (0.37, 0.79) Stratified HR (95% CI) 0.48 (0.31, 0.74) Stratified HR (95% CI) 0.54 (0.36, 0.82) Non-SquamousSquamous NSCLC Histology PD-L1 expression Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 8 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA PD-L1 High (TPS ≥50%) Stratified HR (95% CI) 0.46 (0.28, 0.75)
Caicun Zhou | HARMONi-2 Data cut off: January 29, 2024. Abbreviations: ORR, overall response rate; DCR, disease control rate; DoR, duration of response; IRRC, independent radiology review committee; CI, confidence interval; mo, month; NR, not reached; NE, not estimable. Ivonescimab (n = 198) Pembrolizumab (n = 200) ORR, % (95% CI) 50.0 (42.8, 57.2) 38.5 (31.7, 45.6) DCR, % (95% CI) 89.9 (84.8, 93.7) 70.5 (63.7, 76.7) Median DoR, mos (95% CI) NR (NE, NE) NR (8.28, NE) ORR and DCR were higher with ivonescimab vs. pembrolizumab. ORR, DCR and DoR per IRRC Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 9 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
b a Patients who received ≥1 dose of study treatment. b The incidence of ≥grade 3 Hypertension was 0.5%. Abbreviations: AEs, adverse events; TRAEs, treatment-related adverse events; SQ, squamous cell carcinoma. TRAEs Safety Summary Caicun Zhou | HARMONi-2 Ivonescimab showed a manageable safety profile, which was consistent with previous studies. Safety Summary, n (%) Ivonescimab (n = 90a) Pembrolizumab (n = 91a) TRAEs (all grades) 77 (85.6) 73 (80.2) Grade≥3 20 (22.2) 17 (18.7) Serious TRAEs 17 (18.9) 17 (18.7) Leading to discontinuation 2 (2.2) 3 (3.3) Leading to death 0 1 (1.1) TRAEs in SQ Subgroup Ivonescimab also demonstrated a tolerable safety profile in SQ patients. Safety Summary, n (%) Ivonescimab (n = 197a) Pembrolizumab (n = 199a) TRAEs (all grades) 177 (89.8) 163 (81.9) Grade≥3 58 (29.4) 31 (15.6) Serious TRAEs 41 (20.8) 32 (16.1) Leading to discontinuation 3 (1.5) 6 (3.0) Leading to death 1 (0.5) 2 (1.0) The differences in AEs were predominantly proteinuria, hypertension, and laboratory abnormalities. The Most Common TRAEs (incidence ≥10%) Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 10 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
Caicun Zhou | HARMONi-2 Immune-Related and Possible VEGF-Related AEs • All VEGF-related AEs were grades 1-3 in both arms. • Grade 3 haemorrhage was observed in two patients with non-SQ and was not reported in SQ patients in the ivonescimab arm. irAEs Safety Summary, n (%) Ivonescimab (n = 197a) Pembrolizumab (n = 199a) Possible VEGF-Related AEs (all grades) 94 (47.7) 42 (21.1) Grade≥3 20 (10.2) 2 (1.0) Possible VEGF-Related AEs Safety Summary, n (%) Ivonescimab (n = 197a) Pembrolizumab (n = 199a) irAEs (all grades) 59 (29.9) 56 (28.1) Grade≥3 14 (7.1) 16 (8.0) Serious irAEs 11 (5.6) 22 (11.1) Leading to discontinuation 0 5 (2.5) Leading to death 0 0 Safety Summary by Classification, n (%) Ivonescimab (n = 197a) Pembrolizumab (n = 199a) All Grade Grade≥3 All Grade Grade≥3 Proteinuria 62 (31.5) 6 (3.1) 20 (10.1) 0 Hypertension 31 (15.7) 10 (5.1) 5 (2.5) 1 (0.5) Haemorrhage 29 (14.7) 2 (1.0) 22 (11.1) 1 (0.5) Arterial thromboembolism 2 (1.0) 2 (1.0) 1 (0.5) 0 Venous thromboembolism 0 0 1 (0.5) 0 a Patients who received ≥1 dose of study treatment. Abbreviations: VEGF, vascular endothelial growth factor; irAEs, immune-related AEs; AEs, adverse events; SQ, squamous cell carcinoma. Ivonescimab exhibited similar irAEs to that of pembrolizumab. Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA) 11 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
a Deterioration of global health status/quality of life (QoL) refers to a decrease of 10 points or greater from the baseline in standardized score. Time to deterioration is defined as the time from the date of randomization to the date of first occurrence of deterioration. b Patients who completed EORTC QLQ-C30. Abbreviations: mo, month; NR, not reached; NE, not estimated; HR: hazard ratio; CI, confidence interval. Global Health Status – EORTC QLQ-C30 Median time to deterioration (mos): 9.92 (8.02, NE) Median time to deterioration (mos): NR (9.63, NE) b b Ivonescimab was associated with comparable, numerically better time to deterioration of global health status. Stratified HR (95% CI) 0.92 (0.63, 1.33) Time to deterioration of global health status – EORTC QLQ-C30a Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA)Caicun Zhou | HARMONi-2 12 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA
Conclusions Caicun Zhou | HARMONi-2 • First-line ivonescimab significantly improve IRRC-assessed PFS in patients with aNSCLC and PD-L1 TPS ≥1%, compared with pembrolizumab (median PFS (mos), 11.14 vs. 5.82; HR, 0.51; p<0.0001). • PFS benefit with ivonescimab were consistent across major clinical subgroups: ◼ TPS ≥50%, HR = 0.46 (0.28, 0.75); TPS 1-49%, HR = 0.54 (0.37, 0.79) ◼ SQ, HR = 0.48 (0.31, 0.74); non-SQ, HR = 0.54 (0.36, 0.82) • Higher ORR (50.0% vs. 38.5%) and DCR (89.9% vs. 70.5%) were observed with ivonescimab vs. pembrolizumab. • OS was not matured at this time; the OS analysis is event-driven and will be reported in the future. • The safety profile of ivonescimab was consistent with prior studies and well tolerated, including in patients with SQ-NSCLC. • HRQoL with ivonescimab was comparable to pembrolizumab. Ivonescimab is an investigational therapy in this setting worldwide; ivonescimab is approved in 2L EGFRm NSCLC in China. Abbreviations: IRRC, independent radiology review committee; PFS, progression-free survival; aNSCLC, advanced non-small cell lung cancer; PD-L1, programmed death ligand 1; TPS, tumor proportion score; mo, month; HR: hazard ratio; CI, confidence interval; SQ, squamous cell carcinoma; ORR, overall response rate; DCR, disease control rate; OS, overall survival. This is the first randomized phase 3 study to demonstrate a clinically significant improvement in efficacy with a novel drug compared to pembrolizumab in aNSCLC. Ivonescimab is a novel 1st line treatment for patients with aNSCLC and positive PD-L1(TPS ≥1%). 13 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA)
Acknowledgments Caicun Zhou | HARMONi-2 • We sincerely thank all the participants and their families. • Thank you to all of the investigators and study site personnel from 55 sites. • Thanks to all personnel of Akeso Biopharma, Inc. who supported the study. 14 2024 World Conference on Lung Cancer Presidential Symposium, 9/8/24, San Diego, CA Ivonescimab is an investigational therapy not approved by any regulatory authority other than China’s National Medical Products Administration (NMPA)