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

Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 1
 Disclosures

• 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.

Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 2
 Background
• 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.

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.
Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 3
 HARMONi-2 (AK112-303) Study Design
A randomized, double-blind, phase 3 studya

Patient Population Ivonescimab

• Stage IIIB-IV aNSCLC 20 mg/kg Q3W (N=198) Treatment until
• No prior systemic therapy
R no clinical benefit,
• No EGFR mutations or ALK 1:1 unacceptable toxicity
rearrangements
or up to 24 months
• ECOG PS 0 or 1 Pembrolizumab
N=398
• PD-L1 TPS ≥1% 200 mg Q3W (N=200)

Stratification
• Clinical stage (IIIB/C vs. IV) Endpoints
• Histology (SQ vs. non-SQ)
Primary: PFS by blind IRRC per RECIST v1.1
• PD-L1 TPS (≥50% vs. 1-49%) Secondary: OS, PFS assessed by INVs, ORR, DoR, TTR and safety
Exploratory: QoL

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 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 4
 Baseline Characteristics
Characteristics, n (%) Ivonescimab Pembrolizumab Total
(n = 198a) (n = 200a) (n = 398a)
<65 97 (49.0) 85 (42.5) 182 (45.7)
Age (years)
≥65 101 (51.0) 115 (57.5) 216 (54.3)
Male 164 (82.8) 169 (84.5) 333 (83.7)
Sex
Female 34 (17.2) 31 (15.5) 65 (16.3)
0 25 (12.6) 26 (13.0) 51 (12.8)
ECOG PS
1 173 (87.4) 174 (87.0) 347 (87.2)
Never 39 (19.7) 38 (19.0) 77 (19.3)
Smoker Current 39 (19.7) 42 (21.0) 81 (20.4)
Former 120 (60.6) 120 (60.0) 240 (60.3)
IIIB/C 15 (7.6) 16 (8.0) 31 (7.8)
Clinical stage
IV 183 (92.4) 184 (92.0) 367 (92.2)
SQ 90 (45.5) 91 (45.5) 181 (45.5)
Tumor centrally locatedb 65 (72.2) 57 (62.6) 122 (67.4)
Pathology 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)
≥50% 83 (41.9) 85 (42.5) 168 (42.2)
PD-L1 TPS
1-49% 115 (58.1) 115 (57.5) 230 (57.8)
Yes 25 (12.6) 28 (14.0) 53 (13.3)
Liver metastases
No 173 (87.4) 172 (86.0) 345 (86.7)
Yes 33 (16.7) 39 (19.5) 72 (18.1)
Brain metastases
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.
Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 5
 Primary endpoint: PFS per IRRC Ivonescimab
(n = 198)
Pembrolizumab
(n = 200)
mPFS, mos 11.14 5.82
(95% CI) (7.33, NE) (5.03, 8.21)
Stratified HR 0.51
(95% CI) (0.38, 0.69)
p-value <0.0001

9-mo: 56% (47, 64)

9-mo: 40% (32, 48)

Median Follow-up: 8.67 months

Ivonescimab demonstrated a statistically significant improvement in PFS vs. pembrolizumab with HR = 0.51,
and a 5.3 months improvement in mPFS.
Abbreviations: mPFS, median progression-free survival; IRRC, independent radiology review committee; mo, month; NE, not estimable; HR: hazard ratio; CI, confidence interval.

Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 6
 PFS Subgroup Analyses
Ivonescimab Pembrolizumab Unstratified Hazard Ratio
Events/Patients Events/Patients (95% CI)
Overall 72/198 112/200 0.51 (0.38, 0.69)
Age
<65 37/97 50/85 0.53 (0.34, 0.81)
≥65 35/101 62/115 0.52 (0.34, 0.79)
Sex
Male 58/164 94/169 0.53 (0.38, 0.74)
Female 14/34 18/31 0.49 (0.24, 0.99)
ECOG PS
0 4/25 19/26 0.18 (0.06, 0.54)
1 68/173 93/174 0.60 (0.44, 0.82)
Smoking Status
Never 13/39 22/38 0.39 (0.19, 0.77)
Current smoker 12/39 20/42 0.51 (0.24, 1.07)
Former smoker 47/120 70/120 0.57 (0.39, 0.74)
Liver metastases
Yes 12/25 18/28 0.47 (0.23, 0.98)
No 60/173 94/172 0.53 (0.39, 0.74)
Brain metastases
Yes 14/33 25/39 0.55 (0.28, 1.05)
No 58/165 87/161 0.53 (0.38, 0.74)
Distant metastatic sites
≥3 25/49 33/51 0.58 (0.34, 0.97)
<3 47/149 79/149 0.49 (0.34, 0.71)
Clinical stage
IIIB/C 5/15 5/16 1.01 (0.29, 3.51)
IV 67/183 107/184 0.49 (0.36, 0.67)
Pathology
Squamous 35/90 56/91 0.50 (0.33, 0.76)
Non-Squamous 37/108 56/109 0.55 (0.36, 0.84)
PD-L1 TPS
≥50% 25/83 45/85 0.48 (0.29, 0.79)
1-49% 47/115 67/115 0.54 (0.37, 0.78)

0.06 0.1 1 10
Ivonescimab Better Pembrolizumab Better
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.
Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 7
 Key PFS Subgroup Analyses
PD-L1 Low (TPS 1-49%) PD-L1 High (TPS ≥50%)
Stratified HR 0.54 Stratified HR 0.46
(95% CI) (0.37, 0.79) (95% CI) (0.28, 0.75)

PD-L1 expression

Squamous Non-Squamous
Stratified HR 0.48 Stratified HR 0.54
(95% CI) (0.31, 0.74) (95% CI) (0.36, 0.82)

NSCLC Histology

Ivonescimab showed meaningful improvement in PFS vs. pembrolizumab in patients with both low and high PD-L1,
with squamous or non-squamous advanced NSCLC.
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.
Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 8
 ORR, DCR and DoR per IRRC

Ivonescimab Pembrolizumab
(n = 198) (n = 200)
ORR, % 50.0 38.5
(95% CI) (42.8, 57.2) (31.7, 45.6)
DCR, % 89.9 70.5
(95% CI) (84.8, 93.7) (63.7, 76.7)
Median DoR, mos NR NR
(95% CI) (NE, NE) (8.28, NE)

ORR and DCR were higher with ivonescimab vs.

pembrolizumab.

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 is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 9
 Safety Summary
TRAEs The Most Common TRAEs (incidence ≥10%)
Ivonescimab Pembrolizumab
Safety Summary, n (%) (n = 197a) (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)
b
Leading to death 1 (0.5) 2 (1.0)
Ivonescimab showed a manageable safety profile,
which was consistent with previous studies.

TRAEs in SQ Subgroup
Ivonescimab Pembrolizumab
Safety Summary, n (%) (n = 90a) (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)
Ivonescimab also demonstrated a tolerable safety The differences in AEs were predominantly proteinuria, hypertension,
profile in SQ patients. and laboratory abnormalities.
who received ≥1 dose of study treatment. b The incidence of ≥grade 3 Hypertension was 0.5%.
a Patients

Abbreviations: AEs, adverse events; TRAEs, treatment-related adverse events; SQ, squamous cell carcinoma.
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Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 10
 Immune-Related and Possible VEGF-Related AEs
irAEs Possible VEGF-Related AEs
Ivonescimab Pembrolizumab
Ivonescimab Pembrolizumab Safety Summary, n (%)
Safety Summary, n (%) (n = 197a) (n = 199a)
(n = 197a) (n = 199a)
Possible VEGF-Related
94 (47.7) 42 (21.1)
irAEs (all grades) 59 (29.9) 56 (28.1) AEs (all grades)
Grade≥3 20 (10.2) 2 (1.0)
Grade≥3 14 (7.1) 16 (8.0)
Ivonescimab Pembrolizumab
Serious irAEs 11 (5.6) 22 (11.1) Safety Summary by (n = 197a) (n = 199a)
Classification, n (%)
All Grade Grade≥3 All Grade Grade≥3
Leading to discontinuation 0 5 (2.5)
Proteinuria 62 (31.5) 6 (3.1) 20 (10.1) 0
Leading to death 0 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)
Ivonescimab exhibited similar irAEs to that of Arterial thromboembolism 2 (1.0) 2 (1.0) 1 (0.5) 0
pembrolizumab. Venous thromboembolism 0 0 1 (0.5) 0

• All VEGF-related AEs were grades 1-3 in both arms.

• Grade 3 haemorrhage was observed in two patients with non-SQ
aPatients who received ≥1 dose of study treatment.
Abbreviations: VEGF, vascular endothelial growth factor; irAEs, immune-related AEs; AEs, adverse
and was not reported in SQ
patients in the ivonescimab arm.
events; SQ, squamous cell carcinoma.
Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 11
 Global Health Status – EORTC QLQ-C30
Time to deterioration of global health status – EORTC QLQ-C30a

Stratified HR 0.92
(95% CI) (0.63, 1.33)

Median time to deterioration (mos):

NR (9.63, NE)

Median time to deterioration (mos):

9.92 (8.02, NE)

Ivonescimab was associated with comparable, numerically better time to deterioration of global health status.
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.
Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 12
 Conclusions
• 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.

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%).
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.

Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 13
 Acknowledgments

• 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.

Ivonescimab is an investigational therapy not approved by any regulatory authority other than 2024 World Conference on Lung Cancer
Caicun Zhou | HARMONi-2 China’s National Medical Products Administration (NMPA) Presidential Symposium, 9/8/24, San Diego, CA 14