Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial

doi:10.19401/j.cnki.1007-3639.2024.02.004

China Oncology ›› 2024, Vol. 34 ›› Issue (2): 161-175.doi: 10.19401/j.cnki.1007-3639.2024.02.004

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Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial

LUO Yang¹(), SUN Tao², SHAO Zhimin³, CUI Jiuwei⁴, PAN Yueyin⁵, ZHANG Qingyuan⁶, CHENG Ying⁷, LI huiping⁸, YANG Yan⁹, YE Changsheng¹⁰, YU Guohua¹¹, WANG Jingfen¹², LIU Yunjiang¹³, LIU Xinlan¹⁴, ZHOU Yuhong¹⁵, BAI Yuju¹⁶, GU Yuanting¹⁷, WANG Xiaojia¹⁸, XU Binghe¹(), SONG Lihua¹⁹

1. Department of Medical Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medicine Sciences and Peking Union Medical College, Beijing 100021, China
2. Department of Breast Medicine, Liaoning Provincial Cancer Hospital, Shenyang 110042, Liaoning Province, China
3. Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
4. Department of Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin Province, China
5. Department of Oncology, Affiliated Provincial Hospital of Anhui Medical University, Hefei 230001, Anhui Province, China
6. Department of Oncology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
7. Department of Thoracic Medical Oncology, Jilin Provincial Cancer Hospital, Changchun 130021, Jilin Province, China
8. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
9. Department of Medical Oncology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233004, Anhui Province, China
10. Breast Center, Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, Guangdong Province, China
11. Department of Oncology, Weifang People’s Hospital, Weifang 261041, Shandong Province, China
12. Gynecology Department of Linyi Cancer Hospital, Linyi 276001, Shandong Province, China
13. Breast Center, Fourth Hospital of Hebei Medical University, Shijiazhuang 050010, Hebei Province, China
14. Department of Medical Oncology, General Hospital of Ningxia Medical University, Yinchuan 750003, Ningxia Hui Autonomous Region, China
15. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
16. Department of Oncology, the Second Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
17. Department of Breast Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
18. Department of Breast Medical Oncology, the Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, Zhejiang Province, China
19. Anhui Province Key Laboratory of Gene Engineering Pharmaceutical, National and Local Joint Engineering Research Center for Precision Tumor Treatment Technology and Products, Hefei 230088, Anhui Province, China

Received:2024-01-05 Revised:2024-02-18 Online:2024-02-29 Published:2024-03-14
Contact: XU Binghe

Abstract

Abstract:

Background and purpose: For patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, trastuzumab treatment can prolong the overall survival and significantly improve the prognosis of patients. However, the reference original research trastuzumab (Herceptin^®) is more expensive. Biosimilars have comparable efficacy and safety profiles while increasing patient access to treatment. This clinical trial aimed to evaluate the efficacy, pharmacokinetics, safety and immunogenicity of the trastuzumab biosimilar AK-HER2 compared to trastuzumab (Herceptin^®) in patients with HER2-positive metastatic breast cancer. Methods: This multi-center, randomised, double-blind phase Ⅲ clinical trial was conducted in 43 subcenters in China. This study complied with the research protocol, the ethical principles stated in the Declaration of Helsinki and the quality management standards for drug clinical trials. It was approved by the hospital's medical ethics committee. The clinical trial registration agency is the State Food and Drug Administration (clinical trial approval number: 2015L04224; clinical trial registration number: CTR20170516). Written informed consent was obtained from subjects before enrollment. Enrolled patients were randomly assigned to the AK-HER2 group and the control group, respectively receiving AK-HER2 or trastuzumab (initial loading dose 8 mg/kg, maintenance dose 6 mg/kg, every 3 weeks as a treatment cycle, total treatment time is 16 cycles) in combination with docetaxel (75 mg/m², treatment duration is at least 9 cycles). The primary endpoint of this clinical trial was the objective response rate (ORR9) between the AK-HER2 group and the control group in the 9th cycle. Secondary efficacy endpoints included ORR16, disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS) and 1-year survival rate. In this study, 100 subjects (AK-HER2 group to control group=1:1) were randomly selected for blood sample collection after the 6th cycle of medication, The collection time points were 45 minutes after infusion (the end of administration), 4, 8, 24, 72, 120, 168, 336, and 504 hours after the end of administration. After collection, blood samples were analyzed by PK parameter set (PKPS). Other evaluation parameters included safety and immunogenicity assessment. Results: A total of 550 patients with HER2-positive metastatic breast cancer were enrolled in this clinical trial between Sep. 2017 and Mar. 2021. In the AK-HER2 group (n=237), 129 subjects in the experimental group achieved complete response (CR) or partial response (PR), and the ORR9 was 54.4%. There were 134 subjects in the control group (n=241) who achieved CR or PR, and the ORR9 was 55.6%. The ORR9 ratio between the AK-HER2 group and the control group was 97.9% [90% confidence interval (CI): 85.4%-112.2%, P=0.784], which was not statistically significant. In all secondary efficacy endpoints, no statistically significant differences were observed between the two groups. We conducted a mean ratio analysis of pharmacokinetics (PK) parameters between the AK-HER2 group and the control group, and the results suggested that the pharmacokinetic characteristics of the two drugs are similar. The incidence of treatment emergent adverse event (TEAE) leading to drug reduction or suspension during trastuzumab treatment was 3.6% (10 cases) in the AK-HER2 group and 8.1% (22 cases) in the control group. There was statistically significant difference between the two groups (P=0.027). The incidence rate was significantly lower in the AK-HER2 group than in the control group, and there was no statistically significant difference among the other groups. The differences in the positive rates of anti-drug antibodies (ADA) and neutralizing antibodies (NAB) between groups were of no statistical significance (P=0.385 and P=0.752). Conclusion: In patients with HER2-positive metastatic breast cancer, AK-HER2 was comparable to the trastuzumab (Herceptin^®) in terms of drug efficacy, pharmacokinetics, safety and immunogenicity.

Key words: Breast cancer, Trastuzumab, AK-HER2, Efficacy, Pharmacokinetics, Safety

CLC Number:

R737.9

LUO Yang, SUN Tao, SHAO Zhimin, CUI Jiuwei, PAN Yueyin, ZHANG Qingyuan, CHENG Ying, LI huiping, YANG Yan, YE Changsheng, YU Guohua, WANG Jingfen, LIU Yunjiang, LIU Xinlan, ZHOU Yuhong, BAI Yuju, GU Yuanting, WANG Xiaojia, XU Binghe, SONG Lihua. Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial[J]. China Oncology, 2024, 34(2): 161-175.

Figures/Tables 9

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References 31

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Item	AK-HER2 (n = 275)	Trastuzumab (n = 272)	Item	AK-HER2 (n = 275)	Trastuzumab (n = 272)
Age/year			ECOG status
Median	53.0	52.0	0	130 (47.3)	117 (43.2)
18-65	246 (89.5)	251 (92.3)	1	145 (52.7)	154 (56.8)
>65	29 (10.5)	21 (7.7)	Target lesions
Height/cm			Yes	267 (97.1)	265 (97.4)
Median	158.00	158.00	No	8 (2.9)	7 (2.6)
Weight/kg			Target lesion diameter/mm
Median	60.00	60.00	Median	57.90	61.00
Nation			History of systemic chemotherapy/targeted drug treatment for tumors
Han	257 (93.5)	257 (94.5)	Yes	185 (67.3)	172 (63.2)
Others	18 (6.5)	15 (5.5)	No	90 (32.7)	100 (36.8)
Osseous metastasis			History of endocrine therapy for tumors
Yes	123 (45.1)	118 (43.4)	No	179 (65.1)	189 (69.5)
No	150 (54.9)	154 (56.6)	Yes	96 (34.9)	83 (30.5)
ER/PgR			History of other malignant tumors
ER⁺/PgR⁺	94 (35.7)	80 (29.9)	No	273 (99.3)	271 (99.6)
ER^-/PgR^-	108 (41.1)	126 (47.0)	Yes	2 (0.7)	1 (0.4)
ER^-/PgR⁺	11 (4.2)	14 (5.2)	History of tumor radiotherapy
ER⁺/PgR^-	49 (18.6)	47 (17.5)	Yes	79 (28.8)	79 (29.0)
Unknown^*	1 (0.4)	1 (0.4)	No	195 (71.2)	193 (71.0)
HER2 positive
Yes	255 (97.0)	257 (97.7)
No	8 (3.0)	6 (2.3)

	AK-HER2 (n = 275)	Trastuzumab (n= 272)	Ratio (%)	P value
Primary endpoint (PPS)
CR	10 (4.2)	7 (2.9)
PR	119 (50.2)	127 (52.7)
SD	95 (40.1)	90 (37.3)
PD	11 (4.6)	14 (5.8)
NE	2 (0.8)	3 (1.2)
ORR9 ^*	129 (54.4)	134 (55.6)	97.9	0.784
90%CI/%	48.9-59.9	50.1-61.0	85.4-112.2
Secondary endpoint (FAS)
ORR16	142 (51.6)	142 (52.2)		0.894
DCR	248 (90.2)	241 (88.6)		0.549
CBR	159 (57.8)	164 (60.3)		0.556
PFS
Censored	161 (58.5)	175 (64.3)
Number of events	114 (41.5)	97 (35.7)
Kaplan-Meier t/months
25% (95% CI)	6.1 (4.2-6.3)	6.2 (5.4-7.7)
50% (95% CI)	10.3 (8.6-11.2)	11.7 (10.3-NE)
75% (95% CI)	NE (NE-NE)	NE (NE-NE)
PFS stratified analysis^α
Statistics	1.980			0.159
HR (95% CI)	1.21 (0.92-1.59)
PFS stratified analysis^β
Statistics	1.405			0.236
HR (95% CI)	1.18 (0.90-1.54)
OS
Censored/%	273 (99.3)	269 (98.9)
Number of events/%	2 (0.7)	3 (1.1)
Kaplan-Meier (months)
25% (95% CI)	NE (NE-NE)	NE (NE-NE)
50% (95% CI)	NE (NE-NE)	NE (NE-NE)
75% (95% CI)	NE (NE-NE)	NE (NE-NE)
OS stratified analysis^α
Statistics	0.208			0.648
HR (95% CI)	0.66 (0.11-3.98)
OS stratified analysis^β
Statistics	0.214			0.643
HR (95% CI)	0.66 (0.11-3.93)
Month 12	99.3 (97.1-99.8)	98.9 (96.6-99.6)

Parameter	Group	N	GMLS mean	95% CI	AK-HER2/trastuzumab
Parameter	Group	N	GMLS mean	95% CI	Ratio/%	90% CI
C_max,ss (μg/mL)	AK-HER2	54	141.43	134.59-148.61	95.76	90.25-101.59
	Trastuzumab	52	147.70	140.43-155.34
AUC_0-τ(h*μg/mL)	AK-HER2	49	20 911.74	19 699.20-221 98.91	97.87	91.13-105.12
	Trastuzumab	47	21 366.27	20 102.08-22 709.96
T_1/2z (h)	AK-HER2	49	164.58	153.78-176.15	98.75	91.05-107.11
	Trastuzumab	47	166.66	155.50-178.63
CLss (mL/h)	AK-HER2	49	17.20	16.15-18.32	102.21	94.80-110.20
	Trastuzumab	47	16.83	15.78-17.95
V_z (L)	AK-HER2	49	4.08	3.82-4.36	100.94	93.27-109.23
	Trastuzumab	47	4.05	3.78-4.33

Item	AK-HER2 (n=267)	Trastuzumab (n=256)	Statistics	Pvalue	Method
ADA
N (N Miss)	267 (8)	256 (16)
Pre-existing ADA)	17 (6.4)	13 (5.1)	0.402	0.526	Chi-square test
Post-baseline ADA^*	20 (7.5)	10 (3.9)	3.105	0.078	Chi-square test
Negative	239 (89.5)	236 (92.2)	1.121	0.290	Chi-square test
Treatment-induced ADA^**	11 (4.1)	7 (2.7)	0.755	0.385	Chi-square test
NAB
N (NMiss)	267 (8)	256 (16)
Post-baseline NAB^*	14 (5.2)	6 (2.3)	2.988	0.084	Chi-square test
Treatment-induced NAB^**	6 (2.2)	4 (1.6)	NA	0.752	Fisher

Safety data	AK-HER2 (n = 275)	Trastuzumab (n = 272)	Safety data	AK-HER2 (n = 275)	Trastuzumab (n = 272)
Number of TEAE	4 738	5 049	AESI related to study drug	79 (28.7)	78 (28.7)
Any TEAE	265 (96.4)	270 (99.3)	Grade 1	58 (21.1)	58 (21.3)
Grade 1	259 (94.2)	259 (95.2)	Grade 2	32 (11.6)	32 (11.8)
Grade 2	232 (84.4)	233 (85.7)	Grade 3	6 (2.2)	3 (1.1)
Grade 3	164 (59.6)	173 (63.6)	Grade 4	3 (1.1)	0 (0.0)
Grade 4	100 (36.4)	90 (33.1)	Grade 5	0 (0.0)	0 (0.0)
Grade 5	3 (1.1)	5 (1.8)	Treatment-related AEs occurring in≥10% of patients
TEAE related to study drug	173 (62.9)	176 (64.7)	Decreased white blood cell count	200 (72.7)	200 (73.5)
TEAE leading to drug withdrawal	6 (2.2)	3 (1.1)	Decreased neutrophil count	198 (72.0)	199 (73.2)
SAE	43 (15.6)	37 (13.6)	Increased alanine aminotransferase	69 (25.1)	70 (25.7)
Grade 1	5 (1.8)	7 (2.6)	Increased aspartate aminotransferase	66 (24.0)	72 (26.5)
Grade 2	17 (6.2)	18 (6.6)	Weight gain	56 (20.4)	49 (18.0)
Grade 3	12 (4.4)	15 (5.5)	Decreased platelet count	26 (9.5)	36 (13.2)
Grade 4	15 (5.5)	13 (4.8)	Anemia	114 (41.5)	125 (46.0)
Grade 5	2 (0.7)	4 (1.5)	Alopecia	66 (24.0)	62 (22.8)
SAE related to study drug	16 (5.8)	12 (4.4)	Pyrexia	32 (11.6)	45 (16.5)
Deaths	1 (0.4)	3 (1.1)	Asthenia	25 (9.1)	33 (12.1)
Deaths related to study drug	0 (0.0)	1 (0.4)	Hyperglycemia	43 (15.6)	42 (15.4)
AESI	160 (58.2)	161 (59.2)	Diarrhea	30 (10.9)	39 (14.3)
			Upper respiratory infection	36 (13.1)	22 (8.1)

Efficacy, metabolic characteristics, safety and immunogenicity of AK-HER2 compared with reference trastuzumab in patients with metastatic HER2-positive breast cancer: a multicenter, randomized, double-blind phase Ⅲ equivalence trial

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	Actual value		Change value (post-pre)
	AK-HER2	Trastuzumab	AK-HER2	Trastuzumab
Baseline
N (NMiss)^*	275 (0)	271 (1)
Mean±SD	64.738±4.872	64.140±5.035
Median	64.000	64.000
C4D1
N (NMiss)	229 (46)	222 (50)	229 (46)	222 (50)
Mean±SD	63.855±4.376	64.149±4.642	-0.578±4.974	-0.161±5.332
Median	64.000	64.000	0	0
C7D1
N (NMiss)	178 (97)	174 (98)	178 (97)	174 (98)
Mean±SD	63.718±4.085	63.856±4.564	-0.701±5.069	-0.446±5.300
Median	63.000	64.000	-1.000	-1.000
C10D1
N (NMiss)	149 (126)	147 (125)	149 (126)	147 (125)
Mean±SD	63.124±3.942	63.766±4.270	-1.294±4.989	-0.582±4.930
Median	63.000	63.000	-1.000	-0.800
C13D1
N (NMiss)	117 (158)	118 (154)	117 (158)	118 (154)
Mean±SD	63.286±4.099	63.869±4.875	-0.557±4.884	-0.415±5.985
Median	63.000	63.100	0	0
C16D1
N (NMiss)	89 (186)	93 (179)	89 (186)	93 (179)
Mean±SD	63.431±3.951	63.080±4.683	-0.159±5.276	-0.991±5.747
Median	64.000	62.000	1.000	-1.000
EOT
N (NMiss)	245 (30)	237 (35)	245 (30)	237 (35)
Mean±SD	63.503±4.560	62.876±4.564	-1.199±5.107	-1.308±5.735
Median	63.000	62.700	-1.000	-1.000