
==== Front
ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01451-0
10.1016/j.esmoop.2024.103682
103682
Original Research
QL1701 (a proposed trastuzumab biosimilar) versus reference trastuzumab plus docetaxel as first-line therapy for HER2-positive metastatic breast cancer: a multicenter, randomized, double-blinded, parallel-controlled, phase III equivalence trial
Zhang Q.-Y. 1†
Cai R.-G. 2†
Song G.-H. 3†
Li C.-J. 4
Zhang B.-H. 4
Kang X.-Y. 4
Li H.-P. huipingli2012@hotmail.com
3∗
Xu B.-H. xubinghe@medmail.com.cn
2∗
QL1701 investigators
1 Breast Cancer Ward 1, Harbin Medical University Cancer Hospital, Harbin
2 National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing
3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing
4 Clinical Research and Development Center, Qilu Pharmaceutical Co., Ltd., Jinan, China
∗ Correspondence to: Prof. Bing-He Xu, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Tel: +86-13501028690 xubinghe@medmail.com.cn
∗ Prof. Hui-Ping Li, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52, Fucheng Road, Haidian District, Beijing 100142, China. Tel: +86-13811012595 huipingli2012@hotmail.com
† These authors contributed equally to the manuscript and thus share the first authorship.

05 9 2024
9 2024
05 9 2024
9 9 103682© 2024 The Author(s)
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

QL1701 is a proposed biosimilar to the reference trastuzumab (Herceptin®). This trial compared the efficacy and safety of QL1701 with the reference trastuzumab in first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

Materials and methods

This randomized, double-blinded, parallel-controlled, phase III equivalence trial was conducted in 73 centers in China. Eligible patients with histologically or cytologically diagnosed HER2-positive metastatic breast cancer were randomly assigned (1 : 1) to receive either QL1701 or reference trastuzumab in combination with docetaxel (every 3 weeks) for eight cycles as the first-line treatment. Then, in patients with objective responses or stable disease, the QL1701 or reference trastuzumab with or without docetaxel was maintained for totally up to 12 months if tolerated. The primary endpoint was 24-week objective response rate (ORR) assessed by an independent review committee (IRC). The equivalence margin was 0.80-1.25 with a 90% confidence interval (CI) for the ORR ratio (QL1701 to reference trastuzumab).

Results

Between 29 April 2020 and 15 March 2022, 474 patients were randomized, and 473 received either QL1701 (n = 236) or reference trastuzumab (n = 237). The risk ratio for 24-week ORR was 1.07 (90% CI 0.94-1.21). The 90% CI fell within the pre-specified equivalence margin of 0.80-1.25. The 24-week ORR assessed by IRC was 59.7% (95% CI 53.2% to 66.1%) versus 56.1% (95% CI 49.5% to 62.5%) in QL1701 and the reference trastuzumab, respectively. As of 12 April 2023, there were no notable differences in progression-free survival (median: 8.3 versus 8.4 months) and overall survival (1-year rate: 95.1% versus 93.3%) between the two groups. Safety, pharmacokinetic (PK), and immunogenicity profiles were similar between the two groups.

Conclusion

QL1701 demonstrated equivalent efficacy and similar safety to the reference trastuzumab when combined with docetaxel in the first-line treatment of patients with HER2-positive metastatic breast cancer, with similar PK and immunogenicity profiles.

Highlights

• QL1701 demonstrated equivalent efficacy to the reference trastuzumab for HER2-positive metastatic breast cancer.

• The efficacy equivalence was validated in the per protocol set population and subgroup analysis according to stratification.

• QL1701 demonstrated a similar safety profile, PK, and immunogenicity to the reference trastuzumab.

• QL1701 provides a novel option for HER2-positive metastatic breast cancer, increasing the accessibility to trastuzumab.

Key words

QL1701
biosimilar
trastuzumab
HER2-positive
metastatic breast cancer
first-line therapy
==== Body
pmcIntroduction

Human epidermal growth factor receptor 2 (HER2) overexpression occurs in ∼15%-20% of breast cancers, conferring a particularly aggressive subtype of the disease with a poor prognosis and a high recurrence rate.1,2 The introduction of multiple anti-HER2 agents has dramatically improved the prognosis in both early and advanced HER2-positive breast cancer.3,4 Though several anti-HER2 agents are currently used in clinical practice, trastuzumab is likely to remain a mainstay, which targets HER2 and has been approved for the treatment of early and advanced HER2-positive breast cancer.5 Adding trastuzumab to docetaxel shows superiority to docetaxel by prolonging the overall survival (OS) from 22.7 to 31.2 months with an almost doubled objective response rate (ORR; 61% versus 34%) as first-line treatment in patients with HER2-positive metastatic breast cancer.6 As growing evidence of trastuzumab in improving survival in both early and metastatic breast cancer, trastuzumab-based therapy plays a pivotal role in the treatment of HER2-positive breast cancer and has been approved by the US Food and Drug Administration (FDA) and National Medical Products Administration (NMPA) of China.4,7, 8, 9, 10 However, the cumulative cost of trastuzumab surged by 78% from 2005 to 2017, which confined the accessibility for patients with HER2-positive breast cancer to trastuzumab.11 Although trastuzumab-based therapy is considered the standard of care among patients with early or advanced HER2-positive breast cancer, prescription for trastuzumab is confined for the high price and patients are not treated with the optimal regimen. Real-world observation studies reported that 26.3%-49.2% of patients with HER2-positive breast cancer in China did not receive trastuzumab as first-line therapy for metastatic disease, while the percentage was 12.2% in the United States.12,13 About 27%-54% of patients with HER2-positive metastatic breast cancer do not receive HER2-targeted treatment in first-line or later-line therapy in Western Europe or the United States.14 Developing trastuzumab biosimilars provides a significant possibility, and the introduction of trastuzumab biosimilars is estimated to generate projected drug cost savings, varying from 15% to 35% price discount, expanding the accessibility to trastuzumab.11,15, 16, 17, 18, 19 According to the guidelines of the European Medicines Agency (EMA), FDA, and World Health Organization (WHO), a proposed biosimilar must demonstrate similarity to the reference product stepwise in physicochemical and biological features, and in nonclinical, pharmacokinetic/pharmacodynamic (PK/PD), and clinical studies.20, 21, 22, 23

QL1701 is a proposed trastuzumab biosimilar developed by Qilu Pharmaceutical Co., Ltd. (Jinan, China). Preclinical pharmacology and toxicology studies showed that QL1701 was consistent with trastuzumab (Herceptin®) in safety and PK (unpublished data by Qilu Pharmaceutical Co., Ltd.). Furthermore, a phase I study in 96 healthy Chinese male volunteers confirmed the PK equivalence and comparable safety of QL1701 with trastuzumab (Prof. Qing Wen, Central Hospital Affiliated to Shandong First Medical University, unpublished data). This phase III trial was designed to further compare the efficacy, safety, and immunogenicity of QL1701 versus the reference trastuzumab in combination with docetaxel in the first-line treatment of Chinese patients with HER2-positive metastatic breast cancer.

Materials and methods

Study design and patients

This randomized, double-blinded, parallel-controlled, phase III equivalence trial (clinicaltrials.gov, NCT05629949) was conducted in 73 centers (Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103682) in China. Eligible patients were females who were 18-75 years old and diagnosed with locally recurrent or metastatic breast adenocarcinoma with a histologically confirmed HER2-positive status. HER2 positivity was defined as local or central laboratory documentation of HER2-positive overexpression by immunohistochemistry (IHC), i.e. IHC 3+, or IHC 2+ with FISH confirmation (amplification ratio ≥ 2.0).24 Patients were enrolled on the basis of locally and/or centrally identified HER2 positivity according to the results of IHC and/or FISH. Additional eligibility criteria for inclusion were an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, at least one measurable lesion per RECIST 1.1, normal left ventricular ejection fraction (LVEF; >50%), and adequate hematologic, hepatic, and renal function. Besides, eligible patients were naïve to systemic chemotherapy or targeted therapy for recurrent or metastatic disease. If endocrine therapy has been carried out, it must be stopped at least 2 weeks before enrollment. For patients with recurrent disease who had received prior relevant neoadjuvant or adjuvant therapy, anti-HER2 treatment should be discontinued 12 months before enrollment, while other non-HER2-related treatment should be discontinued at least 1 month before enrollment.

In the present study, patients with a definite confirmation of brain metastases (except those who had been assessed asymptomatic or asymptomatic for at least 4 weeks after local lesion management and did not require steroid treatment) were excluded. Local treatment for brain metastases before enrollment included surgery, radiotherapy, or symptomatic supportive therapy. Additionally, patients were excluded if they had a significant medical illness that would increase the risk associated with the patient’s participation in the study, or had a history of any other cancer within the last 5 years other than cured cervical carcinoma in situ, basal cell carcinoma, or squamous cell carcinoma of the skin. The complete list of inclusion and exclusion criteria are presented in the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2024.103682.

The protocol was approved by the relevant institutional ethics committees for each center, or the independent ethics committee at each participating center. This trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and all applicable regulatory requirements. Patients provided written informed consent before enrollment.

Randomization and masking

Eligible patients were randomly assigned (1 : 1) to receive either QL1701 or the reference trastuzumab (Herceptin®) in combination with docetaxel. Randomization was conducted using a centralized block randomization system and stratified by the time from initial diagnosis to metastatic disease (≥2 years or <2 years), prior trastuzumab exposure (never or with previous trastuzumab treatment discontinued at least 12 months before enrollment), and hormone receptor status [estrogen receptor (ER) and/or progesterone receptor (PR) positive or both negative]. Each factor included two levels, and thus there were eight stratification combinations. Treatment allocation was blinded using an interactive web or voice response system and was blinded to patients, investigators, evaluators, and sponsors. Since the appearance of QL1701 and trastuzumab appeared not identical, only the study nurse or pharmacist responsible for preparing and managing the medication was unblinded.

Treatments

QL1701 (Qilu Pharmaceutical Co., Ltd., Jinan, China) or the reference trastuzumab (Roche, Basel, Switzerland) was administered at a loading dose of 8 mg/kg over a 90-min intravenous infusion on day 1 of cycle 1, followed by 6 mg/kg once every 3 weeks. Docetaxel (Qilu Pharmaceutical Co., Ltd., Jinan, China) was given at 75 mg/m2 over a 70-min intravenous infusion on day 2 of cycle 1 and then 60 min after QL1701 or the reference trastuzumab in the following cycles. QL1701 or the reference trastuzumab in combination with docetaxel was administered for at least eight cycles unless the participant experienced disease progression or unacceptable toxicity.23

After completing the eight-cycle treatment (24 weeks), patients with objective response or stable disease (on the basis of graphic and clinical assessment) continued QL1701 or the reference trastuzumab treatment alone or in combination with docetaxel as maintenance therapy until disease progression, unacceptable toxicity, death, investigator decision, withdrawal of consent, or totally up to 12 months, whichever occurred first (Supplementary Figure S1, available at https://doi.org/10.1016/j.esmoop.2024.103682). After end of the study, trastuzumab treatment might continue at the discretion of the investigator, if the patients did not experience disease progression or unacceptable toxicity. Dose reductions of QL1701 or the reference trastuzumab during the study were not permitted. Though concurrent endocrine therapy was recommended for ER-positive and HER2-positive metastatic breast cancer according to the National Comprehensive Cancer Network breast cancer guideline version 3.2024, endocrine therapy was not allowed during the study based on the previous studies.4,25,26

Endpoints and assessments

The primary endpoint was 24-week ORR [the sum of complete response (CR) and partial response (PR) at the best overall response] assessed by an independent review committee (IRC).23 The secondary endpoints included 24-week ORR assessed by investigators, time to response (TTR; the time from the start of treatment to the first documented CR or PR), duration of response (DoR; the time from first documented CR or PR to disease progression or death), disease control rate [DCR; the sum of CR, PR, and stable disease (SD) at the best overall response], progression-free survival (PFS), 1-year OS, safety, PK, and immunogenicity. PFS was defined as the time from randomization to disease progression or death from any cause, whichever occurred first. The OS was calculated as the time interval from the start of treatment until death from any cause. PK was assessed by the minimum serum concentration (Ctrough). Immunogenicity was characterized by the presence of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs). Only blood samples that were confirmed with ADA positivity were further analyzed for NAbs.

Tumor assessments were carried out at the screening period and the end of cycles 2, 4, 6, and 8 per both IRC and investigators, and then every 6 weeks only by principal investigators by computed tomography (CT) scan or magnetic resonance imaging (MRI) per RECIST 1.1, until disease progression, death, loss to follow-up, withdrawal of consent, or the initiation of a new antitumor treatment, whichever occurred first. The assessing method was kept consistent throughout the entire study.

The safety was monitored by investigators throughout the treatment period and for up to 21 days after the last dose, and continued follow-up thereafter, according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The safety of QL1701 and the reference trastuzumab was evaluated by recording the incidence, severity, and causality of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), treatment-related adverse events (TRAEs), and treatment-related serious adverse events (TRSAEs). TEAEs were defined as events that started or worsened between the first dose and 21 days after the last dose of study drugs. TRAEs were defined as events for which a causal relationship with treatment could not be excluded. SAEs were defined as death, life-threatening events, hospitalization, and/or significant disability.

Serum samples for PK and immunogenicity analysis were collected within 70 min before QL1701 or trastuzumab infusion at cycles 1, 3, 5, 7, and 9 (if applicable), and at the end-of-treatment visit or last follow-up visit. Samples were collected pre-dose at each scheduled cycle (day 1 in each cycle) and were analyzed using enzyme-linked immunosorbent assay. The mean serum concentration-time profile was described with a generalized linear model.

Statistical analysis

Based on the previous study, this trial assumed that 64% of patients would achieve 24-week ORR in both the QL1701 and trastuzumab groups.6,7,27,28 In compliance with the NMPA guidelines for clinical trials of biosimilars for trastuzumab injection in China in 2020, clinical equivalence was confirmed if the 90% confidence interval (CI) of the ratio of ORRs was within a pre-specified equivalence margin of 0.80-1.25.23 By comparing the primary efficacy endpoint in the two groups, the ratio of 24-week ORRs was assessed for statistical significance. This study had an 80% power to declare the efficacy equivalence of QL1701 and reference trastuzumab at a two-sided alpha level of 10%. Considering a 15% dropout rate, a sample size of 468 was required.

Efficacy analyses were carried out in the full analysis set (FAS) and per protocol set (PPS). The FAS included all randomized patients who received at least one dose of study drugs. The PPS included all patients in the FAS who had completed the primary endpoint evaluation without major protocol deviations. To ensure the robustness of the primary endpoint, a supplemental analysis based on patients with HER2-positive status as evaluated by the central laboratory was conducted. Safety was assessed in the safety set (SS), including all patients who received at least one dose of study drugs. The PK population was defined as all patients in the FAS who provided at least one post-dose sample for PK analysis. The immunogenicity population included all patients in the FAS who had at least one post-dose immunogenicity evaluation.

All statistical analyses were carried out using the SAS Software (version 9.4 or later, SAS Institute Inc., Cary, NC). Categorical data were presented by numbers and percentages, and continuous data were expressed as mean with standard deviation or median with range. The ORR and DCR were summarized descriptively along with the exact 95% CI. The risk ratio (RR) for ORR and DCR was calculated along with 90% CI based on the asymptotic normal approximation. A stratified Cochran–Mantel–Haenszel test was used to compare between groups. The TTR, DoR, PFS, and OS were estimated by the Kaplan–Meier method and compared using the stratified log-rank test. The hazard ratio (HR) and 90% CI for TTR, DoR, PFS, and OS were calculated from a stratified Cox proportional hazards regression model.

Results

Patient characteristics

Between 29 April 2020 and 15 March 2022, a total of 665 patients were screened, 474 patients were randomized, and 473 (QL1701 group, n = 236; trastuzumab group, n = 237) were included in the FAS population (Figure 1). Baseline characteristics were well balanced between the two groups in the FAS population (Table 1). This study was conducted in China, and >90% of patients were Han Chinese. The median ages were 53 years (range 22-75 years) and 55 years (range 29-73 years). According to central documentation, about 95% of patients in each group were HER2 IHC 3+ (58.1% versus 65.0%) or IHC 2+ and FISH positive (36.9% versus 31.2%). ER and/or PR positivity was found in 50.8% and 52.3% of patients in the QL1701 group and the trastuzumab group, respectively.Figure 1 Trial profile. FAS, full analysis set; PK, pharmacokinetic; PPS, per protocol set; SS, safety analysis set; maintenance therapy, QL1701 or reference trastuzumab treatment alone or in combination with docetaxel.

Table 1 Baseline characteristics of patients according to allocated group in the FAS population

	QL1701 group (n = 236)	Trastuzumab group (n = 237)	
Age			
 Mean (SD), year	54.1 (9.5)	54.3 (9.4)	
 Median (range), year	53 (22-75)	55 (29-73)	
 <65 years, n (%)	201 (85.2)	202 (85.2)	
 ≥65 years, n (%)	35 (14.8)	35 (14.8)	
Race, n (%)			
 Han Chinese	214 (90.7)	222 (93.7)	
ECOG performance status, n (%)			
 0	111 (47.0)	119 (50.2)	
 1	125 (53.0)	118 (49.8)	
HER2 status by central laboratory assessment, n (%)			
 IHC 3+	137 (58.1)	154 (65.0)	
 IHC 2+ and FISH positive	87 (36.9)	74 (31.2)	
 IHC 1+/0 and FISH positivea	5 (2.1)	3 (1.3)	
 HER2 negativeb	4 (1.7)	5 (2.1)	
 Unknownc	3 (1.3)	1 (0.4)	
Hormone receptor status, n (%)			
 ER and/or PR positive	120 (50.8)	124 (52.3)	
 ER and PR negative	116 (49.2)	113 (47.7)	
LVEF, %			
 Mean (SD)	64.4 (4.4)	64.6 (4.6)	
 Median (range)	64.0 (52.0-77.0)	64.0 (52.0-78.0)	
Metastatic or recurrent site, n (%)			
 Lymph node	154 (65.3)	146 (61.6)	
 Lung	126 (53.4)	123 (51.9)	
 Bone	97 (41.1)	106 (44.7)	
 Liver	96 (40.7)	106 (44.7)	
 Chest wall	40 (16.9)	34 (14.3)	
 Pleural effusion	25 (10.6)	25 (10.5)	
 Pleural	12 (5.1)	15 (6.3)	
 Brain	7 (3.0)	13 (5.5)	
 Kidney	2 (0.8)	0 (0.0)	
 Other	24 (10.2)	29 (12.2)	
Patients with prior neoadjuvant or adjuvant therapy, n (%)	148 (62.7)	142 (59.9)	
Patients with prior trastuzumab exposure, n (%)	20 (8.5)	21 (8.9)	
Time from initial diagnosis to treatment, months			
 Mean (SD)	25.3 (30.8)	27.5 (35.0)	
 Median (range)	11.2 (0.1-144.3)	7.4 (0.03-185.6)	
Time from initial diagnosis to metastatic disease, n (%)			
 <2 years	129 (54.7)	129 (54.4)	
 ≥2 years	107 (45.3)	108 (45.6)	
BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; ER, estrogen receptor; FAS, full analysis set; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; LVEF, left ventricular ejection fraction; PR, progesterone receptor; SD, standard deviation.

a The eight patients with local identification of HER2 positivity were considered as HER2 positive taking into account to the results of FISH positivity by central assessment and the variation between histological material. The pathologic materials of the eight patients were centrally tested by IHC and FISH simultaneously.

b The nine patients with centrally assessed HER2 negativity were directly enrolled based on the HER2 status of IHC 3+ assessed by the local laboratory.

c Results of HER2 status assessed by the central laboratory were not available in four patients for two insufficient samples and two samples not sent for central testing of IHC and FISH (three cases in the QL1701 group, one case in the reference trastuzumab group).

Most patients were diagnosed with lymph node (65.3% versus 61.6%) and lung metastasis (53.4% versus 51.9%). Approximately 60.0% of patients had progressed from prior neoadjuvant or adjuvant therapy, and no >10.0% of patients had a prior exposure of trastuzumab. About 45.0% of patients progressed into metastatic disease from the initial diagnosis of breast cancer with a time interval of >2 years. All stratification factors were equally distributed between the two treatment groups.

The PPS population comprised 466 patients (QL1701 group, n = 234; trastuzumab group, n = 232). Two patients in the QL1701 group and five patients in the trastuzumab group were excluded from the PPS population due to lack of post-dose primary efficacy evaluation data (1 versus 3) and major protocol deviations (1 versus 2). The major protocol deviations included incorrect treatment with other antitumor drugs (one patient in the QL1701 group), ineligibility for receiving endocrine therapy within 2 weeks before enrollment (one patient in the trastuzumab group), and meeting exclusion criteria with another malignant disease within 5 years (one patient in the trastuzumab group).

Patient disposition and treatment

In the FAS population, 236 and 237 patients received at least one dose of QL1701 and the reference trastuzumab, respectively, as one patient in the QL1701 group withdrew the informed consent before QL1701 treatment. With 78 and 87 cases of treatment discontinuation, 158 (66.9%) out of 236 patients in the QL1701 group and 150 (63.3%) out of 237 patients in the reference trastuzumab group completed eight cycles of treatment, respectively (Figure 1). Reasons for discontinuation included disease progression (60 versus 61), AEs (4 versus 4), withdrawal of consent (2 versus 6), loss to follow-up (2 versus 1), investigator decision (1 versus 2), death (1 versus 1), and other (8 versus 12). After that, 141 and 123 patients received QL1701 or reference trastuzumab alone or in combination with docetaxel as maintenance therapy, respectively. With 78 and 58 cases of treatment discontinuation, 63 (44.7%) of 141 patients in the QL1701 group and 65 (52.8%) of 123 patients in the trastuzumab group completed the maintenance therapy, respectively (Figure 1). Reasons for 136 patients who did not complete the maintenance therapy included disease progression (62 versus 46), investigator decision (2 versus 1), loss to follow-up (1 versus 1), AEs (1 versus 0), withdrawal of consent (0 versus 1), death (0 versus 1), and other (12 versus 8).

As of data cut-off (12 April 2023), the median duration of study follow-up was 17.4 months (range 0.4-33.7 months) in the QL1701 group and 17.6 months (range 0.7-33.7 months) in the reference trastuzumab group, respectively. The median number of treatment cycles was 11.5 (range 1.0-19.0) for QL1701 and 9.0 (range 1.0-19.0) for the reference trastuzumab, respectively. Both the QL1701 group and the trastuzumab group exhibited a median exposure duration to docetaxel of 8.0 cycles (range 1.0-19.0 cycles).

Summary of following antitumor therapy in the FAS population is shown in the Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103682. After discontinuation of QL1701 or reference trastuzumab with or without docetaxel, a proportion of 79.7% and 76.4% of patients had received at least one treatment in QL1701 and trastuzumab groups, respectively. More than 70% of all patients received subsequent antitumor therapies, and most patients received pyrotinib (43.8%) and trastuzumab (34.7%) as anti-HER2 treatment options in overall patients. Besides, about 60% of all patients received chemotherapy, with capecitabine (43.3% in the overall patients) ranking the most frequent chemotherapy agent.

Primary efficacy endpoint

In the FAS population, the 24-week ORRs assessed by IRC were 59.7% (95% CI 53.2% to 66.1%) in the QL1701 group and 56.1% (95% CI 49.5% to 62.5%) in the trastuzumab group (P = 0.433). The RR of 24-week ORR (QL1701 to the reference trastuzumab) was 1.07 (90% CI 0.94-1.21), which was within the pre-specified equivalence margin of 0.80-1.25. There were 5 (2.1%) versus 7 (3.0%) CR, and 136 (57.6%) versus 126 (53.2%) PR at the best overall response at week 24 in the QL1701 and trastuzumab groups, respectively (Table 2). The primary efficacy analysis for 24-week ORR was also replicated in the PPS population, with an RR of 1.04 (90% CI 0.92-1.19) (Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103682). Subgroup analyses for 24-week ORR based on the time from initial diagnosis to metastatic disease, before trastuzumab exposure, hormone receptor status, age, and ECOG performance status showed similar results (Supplementary Figures S2 and S3, available at https://doi.org/10.1016/j.esmoop.2024.103682). Additionally, the results of the primary efficacy analysis in the FAS population were supported by a supplemental analysis based on central re-assessment of HER2-positive status (Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.103682). The coincidence rates for HER2-positive status by local and central laboratory assessment were high, with 97.6% in the QL1701 group and 97.7% in the trastuzumab group.Table 2 Primary and secondary efficacy endpoints in the FAS population

	QL1701 group (n = 236)	Trastuzumab group (n = 237)	RR/HR (90% CI)	
Primary endpoint per IRC				
 24-week ORR			1.07 (0.94-1.21)	
 n (%)	141 (59.7)	133 (56.1)		
 95% CI	53.2-66.1	49.5-62.5		
 Best overall response category at week 24, n (%)				
 CR	5 (2.1)	7 (3.0)	—	
 PR	136 (57.6)	126 (53.2)	—	
 Non-CR/non-PD	3 (1.3)	3 (1.3)	—	
 SD	72 (30.5)	80 (33.8)	—	
 PD	15 (6.4)	16 (6.8)	—	
 Unknown	5 (2.1)	5 (2.1)	—	
Secondary endpoints per investigator				
 24-week ORR			0.97 (0.85-1.11)	
 n (%)	130 (55.1)	135 (57.0)		
 95% CI	48.5-61.5	50.4-63.4		
 Best overall response category at week 24, n (%)				
 CR	5 (2.1)	5 (2.1)	—	
 PR	125 (53.0)	130 (54.9)	—	
 SD	78 (33.1)	72 (30.4)	—	
 PD	22 (9.3)	25 (10.5)	—	
 Unknown	6 (2.5)	5 (2.1)	—	
 DCR				
 6-month DCR			1.14 (0.97-1.33)	
 n (%)	120 (50.8)	106 (44.7)		
 95% CI	44.3-57.4	38.3-51.3		
 12-month DCR			0.96 (0.74-1.24)	
 n (%)	59 (25.0)	62 (26.2)		
 95% CI	19.6-31.0	20.7-32.2		
 TTR			0.87 (0.71-1.06)	
 Median, months	2.9	2.8		
 95% CI	2.8-4.1	2.7-2.9		
 DoR			1.00 (0.75-1.33)	
 Median, months	9.8	11.1		
 95% CI	7.0-12.0	8.2-13.1		
 PFS			1.00 (0.82-1.21)	
 Median, months	8.3	8.4		
 95% CI	7.2-10.9	7.0-9.8		
 OS			0.90 (0.61-1.34)	
 Median, months	NR	NR		
 1-year OS, %	95.1	93.3		
 95% CI	91.4-97.3	89.2-95.9		
Non-CR/non-PD referred to the presence of target lesions as assessed by investigators at enrollment whereas absence as assessed by the IRC.

CI, confidence intervals; CR, complete response; DCR, disease control rate; DoR, duration of response; FAS, full analysis set; HR, hazard ratio; IRC, independent review committee; NR, not reached; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; RR, risk ratio; SD, stable disease; TTR, time to response.

Secondary efficacy endpoints

Secondary efficacy endpoints in the FAS population per investigators are summarized in Table 2. The 24-week ORRs per investigator were similar in the two groups (55.1% versus 57.0%; RR = 0.97; 90% CI 0.85-1.11; P = 0.648). The median TTR was 2.9 months (95% CI 2.8-4.1 months) for QL1701 and 2.8 months (95% CI 2.7-2.9 months) for reference trastuzumab, with an HR of 0.87 (90% CI 0.71-1.06; P = 0.195; Figure 2A). Besides, there were no notable differences in the 6-month DCR (50.8% versus 44.7%; RR = 1.14; 90% CI 0.97-1.33; P = 0.178) and 12-month DCR (25.0% versus 26.2%; RR = 0.96; 90% CI 0.74-1.24; P = 0.792) between the two groups. The median DoR (9.8 versus 11.1 months; HR = 1.00; 90% CI 0.75-1.33; P = 0.996; Figure 2B) and median PFS (8.3 versus 8.4 months; HR = 1.00; 90% CI 0.82-1.21; P = 0.951; Figure 2C) were also comparable between the QL1701 and reference trastuzumab groups. As of the data cut-off date, the median OS had not been reached. The estimated 1-year OS rates were 95.1% (95% CI 91.4% to 97.3%) in the QL1701 group and 93.3% (95% CI 89.2% to 95.9%) in the reference trastuzumab group (HR = 0.90; 90% CI 0.61-1.34; P = 0.570; Figure 2D), respectively. Results of all secondary efficacy endpoints were consistent in the FAS and PPS populations (Supplementary Table S2 and Supplementary Figure S4, available at https://doi.org/10.1016/j.esmoop.2024.103682).Figure 2 Kaplan–Meier curves in the FAS population. (A) Kaplan–Meier curves of TTR as assessed by investigators. (B) Kaplan–Meier curves of DoR as assessed by investigators. (C) Kaplan–Meier curves of PFS as assessed by investigators. (D) Kaplan–Meier curves of OS as assessed by investigators. DoR, duration of response; FAS, full analysis set; OS, overall survival; PFS, progression-free survival; TTR, time to response.

Safety

The safety profile was similar between the two groups (Table 3). There were 98.3% (232/236) and 97.0% (230/237) of patients who reported at least one TEAE of any grade in the QL1701 and trastuzumab groups, respectively. Grade ≥3 TEAEs were reported in 158 (66.9%) and 156 (65.8%) patients, respectively. TRAEs of any grade were observed in 187 (79.2%) and 194 (81.9%) patients in the QL1701 and trastuzumab groups, of which grade ≥3 TRAEs occurred in 91 (38.6%) versus 86 (26.3%) patients in the two groups, respectively. The most frequently observed TRAEs of any grade in the QL1701 and trastuzumab groups, respectively, were leukopenia (43.2% versus 40.5%), neutropenia (43.2% versus 42.2%), anemia (25.4% versus 19.8%), elevated alanine aminotransferase (ALT; 15.7% versus 18.1%), elevated aspartate aminotransferase (14.8% versus 16.0%), and alopecia (14.4% versus 11.8%). Besides, the most common grade ≥3 TRAEs were neutropenia (32.2% versus 28.3%) and leukopenia (20.8% versus 18.1%). Serious TEAEs were observed in 41 (17.4%) and 32 (13.5%) patients in the QL1701 and trastuzumab groups, of whom 23 (9.7%) and 13 (5.5%) reported TRSAEs, respectively. The most common TRSAEs were neutropenia (1.3% versus 1.3%) and liver dysfunction (0.8% versus 1.3%). Treatment discontinuation due to TRAEs occurred with a similar incidence in the QL1701 (1.7%) and trastuzumab (1.3%) groups. TEAEs leading to death occurred in one (0.4%) patient in the QL1701 group and four (1.7%) patients in the trastuzumab group, of which one (0.4%; dyspnea) versus one (0.4%; unknown) were considered as treatment-related.Table 3 Summary of adverse events in the SS population

	QL1701 group (n = 236)	Trastuzumab group (n = 237)	
TEAEs, n (%)			
 Any grade	232 (98.3)	230 (97.0)	
 Grade ≥ 3	158 (66.9)	156 (65.8)	
 Serious TEAEs	41 (17.4)	32 (13.5)	
 TEAEs leading to treatment discontinuation	4 (1.7)	4 (1.7)	
 TEAEs leading to death	1 (0.4)	4 (1.7)	
TRAEs, n (%)			
 Any grade	187 (79.2)	194 (81.9)	
 Grade ≥ 3	91 (38.6)	86 (26.3)	
 TRSAEs	23 (9.7)	13 (5.5)	
 TRAEs leading to treatment discontinuation	4 (1.7)	3 (1.3)	
 TRAEs leading to death	1 (0.4)	1 (0.4)	
TRAEs reported in ≥5% of either group, n (%)	
 Leukopenia	102 (43.2)	96 (40.5)	
 Neutropenia	102 (43.2)	100 (42.2)	
 Anemia	60 (25.4)	47 (19.8)	
 Elevated ALT	37 (15.7)	43 (18.1)	
 Elevated AST	35 (14.8)	38 (16.0)	
 Alopecia	34 (14.4)	28 (11.8)	
 Diarrhea	32 (13.6)	24 (10.1)	
 Nausea	29 (12.3)	22 (9.3)	
 Fatigue	25 (10.6)	25 (10.5)	
 Infusion-related reactions	20 (8.5)	26 (11.0)	
 Lymphopenia	19 (8.1)	9 (3.8)	
 Fever	19 (8.1)	22 (9.3)	
 Elevated weight	17 (7.2)	14 (5.9)	
 Hyperuricemia	17 (7.2)	15 (6.3)	
 Urinary tract infection	14 (5.9)	22 (9.3)	
 Dizziness	14 (5.9)	10 (4.2)	
 Constipation	14 (5.9)	6 (2.5)	
 Hypertriglyceridemia	14 (5.9)	15 (6.3)	
 Thrombocytopenia	12 (5.1)	11 (4.6)	
 Sinus tachycardia	12 (5.1)	5 (2.1)	
 Elevated GGT	10 (4.2)	20 (8.4)	
 Vomiting	10 (4.2)	12 (5.1)	
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; SS, safety set; TEAEs, treatment-emergent adverse events; TRAEs, treatment-related adverse events; TRSAEs, treatment-related serious adverse events.

The overall cardiac-related TEAEs of special interest was low. There were no notable differences between the QL1701 and trastuzumab groups in the incidences of cardiac-related TEAEs of special interest, including cardiac failure (0.4% versus 0.0%) and decreased ejection fraction (1.7% versus 1.7%). Treatment-related cardiac failure and decreased ejection fraction were reported in 0.4% and 0.8% of patients in the QL1701 group and 0.0% and 1.7% of patients in the trastuzumab group, respectively.

PK and immunogenicity

A total of 451 patients were included in the PK and immunogenicity population (QL1701 group, n = 224; trastuzumab group, n = 227). The serum concentration-time profiles were comparable in the QL1701 and trastuzumab groups, with the Ctrough remaining stable throughout cycles 3-9. The immunogenicity profiles were also similar in the two groups (Supplementary Figure S5, available at https://doi.org/10.1016/j.esmoop.2024.103682). Only one patient in the QL1701 group was ADA-positive at baseline. One (0.4%) patient in each group showed treatment-induced ADA positivity and only the patient in the QL1701 group was further confirmed Nab-positive.

Discussion

In the randomized, double-blinded, phase III trial, the proposed trastuzumab biosimilar QL1701 demonstrated equivalent efficacy to the reference trastuzumab, each combined with docetaxel, resulting in 24-week ORRs of 59.7% (95% CI 53.2% to 66.1%) for QL1701 and 56.1% (95% CI 49.5% to 62.5%) for reference trastuzumab in patients with HER2-positive metastatic breast cancer. The efficacy equivalence was validated in the PPS population and subgroup analysis according to stratification. Furthermore, QL1701 demonstrated a similar safety profile, PK, and immunogenicity to the reference trastuzumab.

In this study, the efficacy equivalence of QL1701 to the reference trastuzumab was validated by the RR for the primary endpoint of 24-week ORR (RR = 1.07), and the 90% CI (0.94-1.21) was within the pre-specified equivalence margin of 0.80-1.25. The ORR at week 24 was 59.7% (95% CI 53.2% to 66.1%) for QL1701 and 56.1% (95% CI 49.5% to 62.5%) for reference trastuzumab, with a median PFS of 8.3 months and 8.4 months, respectively. By contrast, previous studies reported a similar ORR (61.0%-72.7%) for first-line treatment of metastatic breast cancer with trastuzumab or a trastuzumab biosimilar in combination with a taxane, but with higher PFS (10.6-12.8 months).6,25,26,28, 29, 30 Considering that efficacy outcomes may be influenced by variations in patient characteristics, prior treatment patterns, and methodology factors (such as dosing schedules and efficacy outcomes assessments), cross-trial comparisons should be made with caution. Of note, the median number of treatment cycles was 11.5 for QL1701 and 9.0 for reference trastuzumab, which was lower than that observed in other studies, which might partly explain the slightly lower PFS in our study.25,26,29

The strength and robustness of the equivalence was validated in the following aspects. Firstly, this study was conducted using the combination regimen of trastuzumab and docetaxel in patients with HER2-positive metastatic breast cancer, which was considered to be a well-established and globally accepted regimen for equivalence clinical studies of trastuzumab biosimilars.26,28 Secondly, patients in the two groups were well balanced regarding the baseline demographic and pathological status of the disease. Thirdly, although eligible patients were recruited from 73 centers in China, the primary endpoint was centrally assessed by IRC to minimize bias. Besides, the methods of imaging assessments were kept consistent for individual patients, i.e. CT or MRI, to assess tumor response accurately. Fourthly, the primary and secondary efficacy endpoints were analyzed in FAS and PPS populations, and the results were consistent to demonstrate the equivalence of QL1701 to the reference trastuzumab. The efficacy equivalence of QL1701 to the reference trastuzumab was further supported by supplementary analyses based on re-assessment of HER2-positive status by a central laboratory, subgroup analyses, or investigator-assessed secondary efficacy endpoints. Thus, these findings indicated that the efficacy of QL1701 was equivalent to the reference trastuzumab as a first-line treatment for patients with HER2-positive metastatic breast cancer.

In this study, both QL1701 and the reference trastuzumab were generally well tolerated, and only a few patients (1.7% versus 1.3%) discontinued treatment due to TRAEs. There were no notable differences between the two groups with regard to the type, incidence, or severity of TRAEs. Additionally, the safety profile of QL1701 was also generally consistent with historical data on trastuzumab.26,30,31 No new safety signal was observed. The incidences of cardiac-related TEAEs of special interest were low and comparable in both groups. Cardiac failure and decreased ejection fraction were reported in 0.4% and 1.7% of patients in the QL1701 group and 0.0% and 1.7% of patients in the trastuzumab group, respectively, which was consistent with that observed in a similar equivalence trial of trastuzumab.30 Moreover, QL1701 and the reference trastuzumab also had comparable immunogenicity profiles, with a low incidence of treatment-induced ADA positivity. The low immunogenic potential was consistent with published data with trastuzumab.28,30 Overall, the safety findings of QL1701 in the present study were consistent with those expected for the reference trastuzumab, with no notable differences between groups.

However, there were several limitations in the current study. Firstly, we adopt trastuzumab plus chemotherapy as a treatment regimen, not dual HER2 blockade with pertuzumab (a humanized monoclonal antibody that binds to the extracellular domain II of HER2) plus chemotherapy, which is currently the standard of care as first-line therapy for HER2-positive metastatic breast cancer.4,32 The reason lies in that pertuzumab is not considered as cost-effective, which confines its accessibility.33,34 Secondly, the short-term efficacy endpoint of 24-week ORR as the primary objective to assess clinical similarity as well as maintenance therapy at a maximum of 12 months could support short-/intermediate-term efficacy data but prevent reliable assessment of long-term survival.23 Finally, this trial was conducted with the Chinese population, and the equivalence of QL1701 to the reference trastuzumab in other populations should be validated in further studies.

Conclusions

This randomized phase III trial demonstrated the efficacy equivalence between QL1701 and the reference trastuzumab in combination with docetaxel as first-line therapy for HER2-positive metastatic breast cancer. Safety, PK, and immunogenicity profiles were also comparable between the two groups. Additionally, QL1701 provides a novel anti-HER2 treatment option for HER2-positive metastatic breast cancer upon its approval.

Supplementary data

Supplementary Appendix

Supplementary Figure S1

Supplementary Figure S2

Supplementary Figure S3

Supplementary Figure S4

Supplementary Figure S5

Acknowledgements

The authors thank all patients and their families, investigators, and staff from all participating study centers.

Funding

This work was supported by Qilu Pharmaceutical Co., Ltd. (no grant number).

Disclosure

CJL, BHZ, and XYK were employees of Qilu Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.

Data sharing

The Qilu Pharmaceutical Co., Ltd. will provide the study protocol and data with publication of this manuscript as required.
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