Inetetamab-based therapy in real-world treatment patterns with HER2-positive advanced breast cancer patients: a retrospective single-center study

Abstract

Background:

Inetetamab is a novel antibody targeting human epidermal growth factor receptor 2 (HER2) developed in China. Due to its optimized antibody-dependent cell-mediated cytotoxicity effect compared with trastuzumab, it has shown good efficacy and safety in the treatment of HER2-positive advanced breast cancer (ABC).

Objectives:

This study aimed to investigate the efficacy and safety of inetetamab combination therapy in the treatment of HER2-positive ABC in real-world clinical practice.

Design:

Retrospective study.

Methods:

A total of 133 patients with HER2-positive ABC who were treated with inetetamab-based regimens between March 2020 and January 2024 were retrospectively included in this study. The main endpoint was median progression-free survival (mPFS). The secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety.

Results:

The study included 133 HER2-positive ABC patients, and the median age was 55 years. The mPFS was 8.0 (6.7–9.3) months. The ORR was 50.4%, while the DCR was 88.7%. The mPFS for patients receiving inetetamab-based therapy as first to second, third to fourth, and later lines of metastatic treatment were 14.0, 7.0, and 6.0 months, respectively. Patients treated with inetetamab plus pyrotinib plus chemotherapy, especially with capecitabine, had the best outcomes (mPFS = 14.0 months). Multivariate analysis revealed that prior HER2-TKI treatment was significantly associated with worse PFS (hazard ratios 2.829, 95% confidence interval 1.265–6.328, p = 0.011). Subgroup analysis indicated that patients without visceral metastases had significantly better PFS (14.0 months vs 8.0 months, p = 0.003). The overall incidence of any grade adverse events (AEs) was 100%, with most being grades 1–2. Severe complications included neutropenia (37.6%) and leukopenia (33.1%).

Conclusions:

Inetetamab-based combination therapy shows promising efficacy and good safety in patients with HER2-positive ABC. It is one of the late-line treatment options for Chinese patients with HER2-positive ABC.

Introduction

As a major global public disease, breast cancer has become one of the most malignant tumors with the highest incidence rate worldwide. ¹ Among them, human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients account for about 15%–25% of all breast cancer, which is one of the most aggressive breast cancer subtypes. ² Since the advent of trastuzumab more than 20 years ago, many new anti-HER2 drugs have been developed, constantly rewriting the treatment pattern of HER2-positive breast cancer.^3–5 Unlike HER2-positive early breast cancer, which aims to cure, all treatments for HER2-positive advanced breast cancer (ABC) are aimed at prolonging survival, controlling disease symptoms, and improving quality of life.^6,7 The CLEOPATRA ⁸ and PHILA ⁹ studies have confirmed the cornerstone status of anti-HER2-targeted therapy, which includes large-molecule monoclonal antibodies and small-molecule tyrosine kinase inhibitors (TKIs), in the first-line treatment of HER2-positive ABC. Moreover, to address the therapeutic dilemmas faced by HER2-positive ABC patients in the past, where most second-line treatment options resulted in a progression-free survival (PFS) of less than 1 year following disease progression on standard first-line anti-HER2 therapy, ¹⁰ numerous scholars have promoted studies such as EMILIA ¹¹ and DESTINY-Breast 03, ¹² and have uncovered the potent efficacy of antibody–drug conjugates (ADCs). ⁵ As a result, the entire course of anti-HER2 therapy must be a priority at any stage of HER2-positive ABC. For HER2-positive ABC patients who have failed second-line therapy, the guidelines still recommend the preferential use of first-line drugs that have not been previously used. ¹³ Therefore, the choice of anti-HER2 drugs is particularly important.

The therapeutic landscape for HER2-positive ABC has evolved significantly with the introduction of various targeted agents. However, the relentless progression of the disease and the emergence of resistance to existing therapies necessitate the continuous exploration of novel treatment options. In the field of treating HER2-positive ABC, a series of emerging anti-HER2-targeted therapies is continuously emerging, providing patients with more treatment options. Currently, margetuximab, approved by both the U.S. Food and Drug Administration (FDA) and the National Medical Products Administration (NMPA) for use in combination with chemotherapy to treat adult patients with HER2-positive metastatic breast cancer (MBC), has been shown in phase III SOPHIA study to enhance the antibody-dependent cell-mediated cytotoxicity (ADCC) effect by increasing affinity for CD16A on the Fc region, thereby further improving the benefits of monoclonal antibody treatment for tumors.^14–16

Inetetamab (Cipterbin^®) is an innovative anti-HER2 monoclonal antibody whose Fc segment has been modified at two amino acid sites as well as optimized in the production process. Thus, it enhances ADCC and reduces immunogenicity and adverse effects compared to trastuzumab. ¹⁷ As another Fc-optimized anti-HER2 antibody, inetetamab demonstrates efficacy that is comparable to margetuximab. The HOPES study showed that the median progression-free survival (mPFS) for the first-line treatment subgroup was 11.2 months with an objective response rate (ORR) of 61.5% for the HER2-positive MBC patients in China with inetetamab in combination with chemotherapy, and the mPFS for the multiline treatment group was 9.2 months, and the ORR was still as high as 46.7%. ¹⁸ As a result, inetetamab was officially approved by the NMPA in June 2020 for the treatment of HER2-positive MBC in combination with chemotherapy.

Furthermore, the efficacy of the three-drug combination regimen of utidelone + inetetamab + camrelizumab for the treatment of HER2-positive ABC was presented at the American Society of Clinical Oncology (ASCO) meeting 2023. ¹⁹ Its 3-month PFS rate was 71.84%, with an mPFS of 5.59 months, and it had a manageable safety profile with a favorable risk–benefit ratio. In the same year, the European Society for Medical Oncology (ESMO) meeting reported promising preliminary efficacy of the IPU study (inetetamab + pyrotinib + utidelone) for first to second-line treatment. ²⁰ Its ORR was 79.3% and disease control rate (DCR) was 93.1%. At the San Antonio Breast Cancer Symposium (SABCS) 2023, several studies also pointed to the encouraging efficacy and favorable safety profile of the inetetamab + pyrotinib + vinorelbine regimen in real-world and prospective studies. Therefore, a combination regimen based on inetetamab may be a reliable option for HER2-positive ABC patients.

In summary, this study aimed to explore the efficacy and safety of multiple combination regimens of inetetamab for the treatment of HER2-positive ABC in the real world, with a view to providing new insights and options for treatment planning.

Patients and methods

Study design and patients

The purpose of the retrospective study was to analyze the efficacy and safety of inetetamab-based therapy in the real world. From March 2020 to January 2024, 142 patients with pathologically confirmed HER2-positive (defined as 3+ for immunohistochemical (IHC) analysis or 2+ for gene amplification by fluorescence in situ hybridization staining) ABC received inetetamab-based therapy as the first or further lines of treatment across Cancer Hospital Chinese Academy of Medical Science. HER2 status was evaluated according to the American Society of Clinical Oncology/College of American Pathologists clinical practice guideline. Inclusion criteria: (1) Patients aged 18–80 years; (2) Advanced or MBC confirmed to be HER2-positive by histology; (3) Eastern Cooperative Oncology Group (ECOG) score ⩽ 2; (4) According to RECIST 1.1 criteria, measurable or non-measurable target lesions confirmed by CT or MRI; and (5) Patients treated with inetetamab. Exclusion criteria: (1) Patients with a second primary malignant tumor; (2) Patients with uncontrollable or severe cardiovascular diseases, such as intractable angina within 6 months before screening, congestive heart failure; history of myocardial infarction within 12 months before screening; any history of clinically significant ventricular arrhythmias, prolonged QT interval; history of cerebrovascular accident, symptomatic and medication-requiring coronary heart disease; (3) Significant clinical gastrointestinal functional abnormalities; intractable, persistent diarrhea of grade 2 or above; (4) Patients with severe concurrent diseases; and (5) Pregnant or lactating women were excluded.

Of these, 133 patients were eligible (aged ⩾18 years) for our analysis. The present study was approved by the Research and Ethics Committee of the National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College in China (Approval No. 18-174/1752). As this research was conducted retrospectively and involved the analysis of de-identified data, patient consent was not required. The reporting of this study conforms to the STROBE statement ²¹ (Supplemental Files).

Treatment

Inetetamab-based regimens were prescribed at the physician’s discretion. The initial dose of inetetamab was the loading dose of 8 mg/kg, then 6 mg/kg intravenously once every 3 weeks until disease progression or chemotherapy toxicity intolerance. Inetetamab was infused at an initial dose of 8 mg/kg and then at a maintenance dose of 6 mg/kg once every 3 weeks until disease progression or chemotherapy toxicity intolerance.

Regimens included inetetamab plus targeted medicine (anti-HER2 antibody (pertuzumab), anti-HER2 TKIs (pyrotinib) or antiangiogenic agents (bevacizumab)) ± chemotherapy (vinorelbine/capecitabine/abraxane/others), inetetamab with chemotherapy, and inetetamab with endocrine treatment ± CDK4/6i (palbociclib/dalpiciclib). Nonmandatory follow-up was conducted every 3 months.

Assessments

The characteristics of the patients (Table 1) at the time of initial diagnosis were extracted from the patient’s electronic medical records. Among them, disease-free interval (DFI) was defined as the time from surgery to diagnosis of metastasis. According to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the assessment variables included PFS, ORR, and DCR. Toxicity reports were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE version (5.0)), which provided a standardized framework for assessing and categorizing the severity of adverse events experienced by the study participants. The sources of safety data, such as medical records, pathology reports, laboratory test results, etc. The timing of safety evaluations was aligned with the routine clinical practice at our institution, with assessments typically conducted after every treatment cycle, and additionally as clinically indicated. The frequency of these evaluations was determined by the treating physician based on the patient’s condition and treatment response.

Table 1.

Baseline characteristics of HER2-positive advanced breast cancer patients treated with inetetamab-based therapy.

Characteristics	Patients, no (%) (N = 133)
Age, median (range years)	55 (33–80)
ECOG performance status
0–1	111 (83.5)
⩾2	22 (16.5)
HER2 expression
IHC 2+ and FISH+	24 (18.0)
IHC 3+	109 (82.0)
HR status
Negative	62 (46.6)
Positive	71 (53.4)
Ki-67 level
⩽20%	22 (16.5)
>20%	96 (72.2)
NA	15 (11.3)
Surgery
No	25 (18.8)
Yes	108 (81.2)
Radiotherapy
No	75 (56.4)
Yes	58 (43.6)
DFI (month)
⩽12	25 (18.8)
>12	83 (62.4)
De novo IV stage	25 (18.8)
Previous trastuzumab treatment
Neoadjuvant therapy period	29 (21.8)
Adjuvant therapy period	46 (34.6)
Metastatic disease period	68 (51.1)
Previous anti-HER2 treatment
Pertuzumab	38 (28.6)
Pyrotinib	72 (54.1)
Lapatinib	15 (11.3)
Other TKIs	7 (5.3)
Angiogenesis inhibitors	5 (3.8)
TDM1	15 (11.3)
DS-8201	5 (3.8)
RC-48	8 (6.0)
Other ADCs	9 (6.8)
Metastatic sites
Lymph node	81 (60.9)
Liver	50 (37.6)
Lung	73 (54.9)
Bone	57 (42.9)
Brain	31 (23.3)
Others	30 (22.6)
Visceral metastases
No	26 (19.5)
Yes	107 (80.5)
Treatment lines
1 line	19 (14.3)
2 lines	36 (27.1)
3 lines	26 (19.5)
4 lines	25 (18.8)
⩾5 lines	27 (20.3)

ADC, antibody–drug conjugate; DFI, disease-free interval; FISH, Fluorescence in situ hybridization; HER2, human epidermal growth factor receptor 2; HR, hazard ratios; IHC, immunohistochemical; TKI, tyrosine kinase inhibitor.

The primary endpoint was PFS, which was defined as the time from the first inetetamab-based treatment to the first record indicating tumor progression or death from any cause. The secondary endpoints included ORR, DCR, and safety. ORR was defined as the proportion of patients with complete or partial response (CR + PR). DCR was defined as the proportion of patients with CR, PR, or stable disease (SD).

Statistical analysis

Statistical analysis was performed using SPSS 26.0 (IBM Corporation, Armonk, NY, USA) and R Studio (version 4.1.2, RStudio, PBC, Boston, MA, USA). Adobe Illustrator 2020 was used to construct graphics. Baseline characteristics, treatment patterns, tumor response, survival, and incidence of AEs were summarized using descriptive statistics in all enrolled patients. Categorical variables were expressed as frequency (percentage). Categorical variables in Supplemental Table 1 were assessed by Pearson’s chi-squared test. The Kaplan–Meier survival curve was used to analyze the mPFS of the patients and the difference in survival rate between the groups. In the analysis of the impact of metastatic sites on mPFS, taking liver metastasis as an example, all patients with liver metastasis were included in the analysis, regardless of other metastatic sites; the survival analysis for other metastatic sites was conducted in the same manner as for liver metastasis. In addition, Cox univariable model was employed to assess the covariate effects on PFS, and then Cox multivariate models were used to assess the factors with relative significant p-values in univariate analysis to PFS with hazard ratios (HR) and corresponding 95% confidence intervals (CIs). p-Value <0.05 was considered significant.

Results

Patients and treatment

A total of 142 patients receiving inetetamab-based treatment were enrolled in the study. After excluding the population with insufficient medical records, thus the evaluable population for the primary endpoint included 133 patients (Figure 1). Patient demographics are described in Table 1.

Figure 1.

Trial profile.

The median age of the group was 55 (33–80) years old, of which 53.4% were patients diagnosed with HR-positive/HER2-positive breast cancer (vs HR-negative/HER2-positive breast cancer: 53.4% vs 46.6%). Twenty-five patients (18.8%) had stage IV breast cancer as their first diagnosis, and 108 patients (81.2%) had undergone surgery (30 patients (22.6%) had received prior neoadjuvant treatment). Inetetamab-based treatment was in first to second lines, third line, fourth line, and beyond in 54 (40.6%), 26 (19.5%), 26 (19.5%), and 27 (20.3%) patients, respectively. The median number of administered lines was three (range, 1–10). Metastatic sites included 81 patients (60.9%) with lymph node metastasis, 50 patients (37.6%) with liver metastasis, 73 patients (54.9%) with lung metastasis, 57 patients (42.9%) with bone metastasis, 31 patients (23.3%) with brain metastasis, and others. Thus, most patients had visceral metastasis (107, 80.5%) and were more likely to be heavily pretreated. A total of 11 patients had not received prior anti-HER2 therapy. Furthermore, 115 patients (86.5%) had been exposed to trastuzumab-based therapy. Of those previously treated with other anti-HER2 drugs, 38 patients (28.6%) were prescribed pertuzumab, 72 patients (54.1%) used pyrotinib, and 37 patients (27.8%) used ADCs.

In this study, most patients were treated with inetetamab in combination with chemotherapy and/or other anti-HER2-targeted therapies (Table 2). The most common chemotherapy regimens were vinorelbine (n = 53, 39.8%), abraxane (n = 39, 29.3%), and capecitabine (n = 15, 11.3%). Pyrotinib and pertuzumab were the most common target regimens in combination with inetetamab (n = 88/19, 66.2%/14.3%). Among them, inetetamab combined with pyrotinib plus vinorelbine (n = 45) was the most commonly used regimen, followed by inetetamab combined with pyrotinib plus capecitabine regimen (n = 16) and inetetamab combined with pyrotinib plus abraxane regimen (n = 14).

Table 2.

Summary of inetetamab-based regimens.

Regimen	n (%)
Chemotherapy regimens with inetetamab
Vinorelbine	53 (39.8)
Abraxane	39 (29.3)
Capecitabine	15 (11.3)
Other	20 (15.0)
None	5 (3.8)
Target regimens with inetetamab
Pertuzumab	19 (14.3)
Pyrotinib	88 (66.2)
Antiangiogenic agents	7 (5.3)
CDK4/6i	4 (3.0)
None	19 (14.3)

CDK4/6i, cyclin-dependent kinase 4/6 inhibitor.

Safety

Overall, the incidence of any grade AEs regardless of causality was 100% (Table 3). The most AEs were grades 1–2, with diarrhea, leukopenia, and neutropenia being the most common. In addition, neutropenia (37.6%), leukopenia (33.1%), diarrhea (6.0%), and aminotransferase increased (2.3%) were the severe complications (grade ⩾ 3 AEs). Diarrhea was mainly identified as related to anti-HER2 TKIs therapy such as pyrotinib. Hematological toxicity was mainly identified as related to chemotherapeutic agents. Peripheral neuropathy was primarily associated with the treatment of abraxane and capecitabine.

Table 3.

Treatment-emergent adverse events.

Event, n (%)	Any grade, n (%)	Grades 1–2, n (%)	Grades 3–4, n (%)
Neutropenia	118 (88.7)	68 (51.1)	50 (37.6)
Leukopenia	117 (88.0)	73 (54.9)	44 (33.1)
Anemia	47 (35.3)	46 (34.6)	1 (0.8)
Thrombocytopenia	29 (21.8)	27 (20.3)	2 (1.5)
Aminotransferase increased	69 (59.4)	66 (49.6)	3 (2.3)
Increased creatinine	6 (4.5)	6 (4.5)	0 (0.0)
Hypoalbuminemia	39 (29.3)	39 (29.3)	0 (0.0)
Peripheral neuropathy	42 (31.6)	42 (31.6)	0 (0.0)
Diarrhea	90 (67.7)	82 (61.7)	8 (6.0)
Rash	10 (7.5)	10 (7.5)	0 (0.0)

The physician determined that reactions related to inetetamab mainly included the following: 8.3% of patients (11/133) experienced infusion reactions during the first application of inetetamab; 3.8% of patients (5/133) had palpitations, but there were no signs of decreased cardiac function or other symptoms. No symptomatic cardiotoxicity events were observed in all enrolled patients. During the course of their inetetamab-based combination therapy, 32 patients (24.1%) have experienced prolonged dosing cycles or treatment interruptions due to hematologic toxicity (15/32), the COVID-19 (5/32), diarrhea (5/32), abnormal liver function (4/32), and elevated creatinine (3/32). Above all, there were no serious AEs related to treatment with inetetamab or treatment-related deaths.

Efficacy

By the data cutoff date in January 2024, the median follow-up time was 17 months (range, 1.5–46 months). The mPFS was 8.0 months in the overall cohort (Figure 2(a)). And the OS was immature. Of the total of 133 patients, 2 patients (1.5%) achieved CR, 65 (48.9%) had PR, 51 (38.3%) had SD, and 15 (11.3%) had PD. The ORR and the DCR were 50.4% and 88.7%, respectively.

Figure 2.

Kaplan–Meier plot for PFS in patients with inetetamab-based therapy. (a) Kaplan–Meier plot for PFS in all patients; (b) Kaplan–Meier plot for PFS of HER2 expression; (c) Kaplan–Meier plot for PFS of HR status; (d) Kaplan–Meier plot for PFS of treatment lines; (e) Kaplan–Meier plot for PFS of visceral metastasis; (f) Kaplan–Meier plot for PFS of liver metastasis; (g) Kaplan–Meier plot for PFS of lung metastatic; (h) Kaplan–Meier plot for PFS of bone metastasis; (i) Kaplan–Meier plot for PFS of brain metastatic.

HER2, human epidermal growth factor receptor 2; HR, hazard ratios; PFS, progression-free survival.

Patients who received inetetamab-based therapy as first to second, third to fourth, and later lines of metastatic treatment had a median PFS of 14.0, 7.0, and 6.0 months, respectively (Figure 2(b)). In addition, we compiled the PFS data from the first-line and second-line treatments to clarify the treatment expectations of inetetamab-based regimens compared to the current standard treatments. The results showed that the first-line treatment group had a mPFS of 14.0 months (95% CI: 10.2–17.8), while the second-line treatment group had a mPFS of 15.0 months (95% CI: 4.4–25.6; Supplemental Figure S1(G)). The mPFS of patients with HER2 expression (7.0 months vs 8.0 months, p = 0.198) or hormone receptor status (8 months vs 10.5 months, p = 0.324) are shown in Figure 2(c) and (d). Further analysis, the mPFS was 8.0 and 14.0 months in patients with/without visceral metastases (p = 0.003; Figure 2(e)). We also looked at some subgroups of interest in different metastatic sites. A total of 50 patients with liver metastases, 73 patients with lung metastases, 57 patients with bone metastases, and 31 patients with brain metastases had mPFS of 6.0, 8.0, 8.0, and 6.0 months, respectively (Figure 2(f)–(i)). Furthermore, survival outcomes in subgroups by DFI, prior trastuzumab therapy or prior anti-HER2 therapy (the mPFS of prior pertuzumab, anti-HER2 TKIs, and ADCs = 8.0, 6.0, and 6.0 months) are shown in Figure 3(a) and Supplemental Figure S1.

Figure 3.

Kaplan–Meier plot for PFS of subgroup in patients with inetetamab-based therapy. (a) Kaplan–Meier plot for PFS of DFI; (b) Kaplan–Meier plot for PFS in patients with inetetamab + chemotherapy; (c) Kaplan–Meier plot for PFS in patients with inetetamab + pertuzumab + chemotherapy; (d) Kaplan–Meier plot for PFS in patients with inetetamab + pyrotinib + chemotherapy; (e) Kaplan–Meier plot for PFS in patients with inetetamab + pyrotinib + vinorelbine; (f) Kaplan–Meier plot for PFS in patients with inetetamab + pyrotinib + abraxane; (g) Kaplan–Meier plot for PFS in patients with inetetamab + pyrotinib + capecitabine; (h) Kaplan–Meier plot for PFS in patients with prior anti-HER2 TKIs; (i) Kaplan–Meier plot for PFS in patients with inetetamab + pyrotinib + chemotherapy in the context of prior anti-HER2 TKIs patients.

DFI, disease-free interval; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.

Further analysis of the efficacy of treatment regimens combining inetetamab with chemotherapy revealed that the mPFS for the groups receiving inetetamab plus chemotherapy (11.3%), inetetamab plus pertuzumab plus chemotherapy (14.3%), and inetetamab plus pyrotinib plus chemotherapy (62.4%) all reached 8.0 months (Figure 3(b)–(d)). Furthermore, we performed analysis for the three main treatment regimens in the inetetamab + pyrotinib + chemotherapy group, with baseline characteristics in Supplemental Table 1. Inetetamab combined with pyrotinib plus capecitabine was the best combination among the three groups (mPFS = 14.0 months) (Figure 3(e)–(g)). The ORR of this subgroup of patients was 75.0% and the DCR was 93.8%, with 1 CR, 11 PR, and 3 SD (Supplemental Table 2). However, the many patients previously treated with pertuzumab in the group of inetetamab + pyrotinib + capecitabine regimen and the imbalance in baseline ki-67 levels among the three groups resulted in a mismatch in the baseline characteristics of the three cohorts. What is more important, the interpretive value of the sub-analyses for various pyrotinib combination groups is constrained due to their limited sample sizes.

Based on the univariate analysis, ECOG performance status, liver metastasis, lung metastasis, brain metastasis, visceral metastasis, number of metastasis sites before inetetamab, number of inetetamab therapy lines, prior trastuzumab-targeted regimens in the period of metastatic disease, and history of ADCs or HER2-TKIs treatment may be related to a poorer PFS (Table 4). Further analysis of multivariate demonstrated that patients with a history of HER2-TKIs treatment had a worse PFS (HR 2.829, 95% CI 1.265–6.328, p = 0.011). However, the median treatment line for this group of patients is relatively late. In all, 76 patients received anti-HER2-TKI therapy prior to inetetamab-based therapy. The mPFS was 7.0 and 14.0 months pretreated with and without anti-HER2 TKIs therapy, respectively (p < 0.0001) (Figure 3(h)). This suggests that the history of anti-HER2 TKIs treatment has a significant impact on efficacy.

Table 4.

Univariate and multivariate analyses of factors predicting progression-free survival in patients treated with inetetamab-based treatment.

Items	Univariate			Multivariate
	HR	95% CI	p	HR	95% CI	p
Age
<50	—	—	—
⩾50	0.790	0.503–1.241	0.307
ECOG performance status
0–1	—	—	—	—	—	—
⩾2	2.309	1.353–3.939	0.002	1.850	0.964–3.553	0.064
HER2 expression
IHC 2+ and FISH+	—	—	—
IHC 3+	0.706	0.403–1.235	0.222
HR status
Negative	—	—	—
Positive	0.818	0.539–1.243	0.348
Ki-67 expression
⩽20%	—	—	—
>20%	0.854	0.486–1.502	0.854
NA	0.744	0.347–1.595	0.744
Surgery
No	—	—	—
Yes	0.677	0.398–1.152	0.151
Radiotherapy
No	—	—	—
Yes	1.524	0.994–2.338	0.055
DFI (month)
⩽12	—	—	—
>12	1.265	0.725–2.208	0.408
De novo IV stage	1.766	0.888–3.511	0.105
Liver metastasis
No	—	—	—	—	—	—
Yes	1.751	1.145–2.678	0.010	1.383	0.824–2.322	0.220
Lung metastasis
No	—	—	—	—	—	—
Yes	1.550	1.007–2.385	0.046	0.978	0.532–1.799	0.943
Bone metastasis
No	—	—	—
Yes	1.281	0.843–1.946	0.246
Brain metastasis
No	—	—	—	—	—	—
Yes	1.693	1.061–2.701	0.027	0.932	0.550–1.581	0.794
Lymph nodes metastasis
No	—	—	—
Yes	1.358	0.877–2.103	0.171
Visceral metastasis
No	—	—	—	—	—	—
Yes	2.391	1.270–4.504	0.007	1.401	0.578–3.398	0.456
Number of metastasis sites before inetetamab
1	—	—	—	—	—	—
⩾2	2.361	1.283–4.342	0.006	1.379	0.676–2.814	0.376
Number of inetetamab therapy lines
1–2 lines	—	—	—
3–4 lines	1.919	1.162–3.167	0.011	0.661	0.282–1.552	0.342
⩾5 lines	3.816	2.135–6.822	0.000	0.824	0.303–2.243	0.704
Previous trastuzumab treatment
Neoadjuvant therapy period (no vs yes)	0.907	0.540–1.522	0.711
Adjuvant therapy period (no vs yes)	1.101	0.703–1.723	0.674
Metastatic disease period (no vs yes)	1.860	1.209–2.861	0.005	1.137	0.664–1.949	0.639
Previous anti-HER2 treatment
Pertuzumab (no vs yes)	0.924	0.578–1.476	0.740
Anti-HER2 TKIs (no vs yes)	2.857	1.789–4.562	0.000	2.829	1.265–6.328	0.011
ADCs (no vs yes)	2.550	1.505–4.321	0.001	1.800	0.927–3.497	0.083
Treatment strategy
Inetetamab + chemotherapy	—	—	—
Inetetamab + pertuzumab + chemotherapy	0.834	0.375–1.853	0.656
Inetetamab + pyrotinib + chemotherapy	0.819	0.427–1.572	0.548
Others	1.110	0.469–2.628	0.813

ADC, antibody–drug conjugate; DFI, disease-free interval; HER2, human epidermal growth factor receptor 2; IHC, immunohistochemical. p-Value <0.05 was considered significant (boldface).

In the group of inetetamab + pyrotinib + capecitabine regimen, only five patients had a history of anti-HER2 TKIs treatment. So, we also analyzed the mPFS of the patients pretreated with pyrotinib in the inetetamab + pyrotinib + chemotherapy regimen group. A total of 33 patients were included in this subgroup analysis. Patients with inetetamab + pyrotinib + capecitabine regimen had significantly longer PFS (8.0 months) than those exposed to inetetamab + pyrotinib + vinorelbine/abraxane agents (6.0 months) (p = 0.046) (Figure 3(i)).

Discussion

In the treatment of ABC, the main goal is to prolong the OS and improve the quality of life of patients. The treatment of patients with HER2-positive ABC is a comprehensive treatment based on anti-HER2-targeted drugs, and anti-HER2-targeted therapy throughout the treatment is the key to benefit patients. In recent years, the treatment of HER2-positive breast cancer has undergone rapid development, and new therapeutic drugs and treatment modalities have emerged in an endless stream. Inetetamab is the first innovative anti-HER2 macromolecular monoclonal antibody independently developed in China. ¹⁷ As an innovative anti-HER2 monoclonal antibody modified by the Fc segment, it has the same mechanism of action as trastuzumab, it can be used in conjunction with chemotherapy for the treatment of HER2-positive MBC. According to the results of the CLEOPATRA ⁸ and PHILA ⁹ studies, dual-targeted regimens are gradually replacing trastuzumab as the mainstream choice for first-line treatment regimens, and the use of TKIs in first-line therapy is gradually increasing. An increasing number of patients in second-line therapy are in the dual-target therapy combined with chemotherapy and TKI-treated population, which is not included in most second-line studies (EMILIA, ¹¹ PHOEBE, ²² etc.). Therefore, the research evidence for previous standard second-line and even back-line treatments does not meet actual clinical needs. In clinical practice, there is an urgent need for new treatment options to better respond to the evidence-based medical evidence of later-line treatment.

In this study, we revealed the real-world clinical practice of inetetamab in HER2-positive MBC patients. A total of 133 patients were enrolled in this study with a median number of treatment lines of three. In all, 118 patients (86.5%) had previously applied trastuzumab in the adjuvant (mPFS = 9.0 months), neoadjuvant (mPFS = 8.0 months), or advanced treatment phase (mPFS = 7.0 months) (Supplemental Figure S1). Furthermore, 38 patients (28.6%) had previously received pertuzumab (mPFS = 8.0 months), 72 patients (54.1%) had received pyrotinib, and 15 patients (11.3%) patients had received lapatinib. In addition, some patients also received treatment with ADCs, including Trastuzumab emtansine (T-DM1) (11.3%), Trastuzumab deruxtecan (DS-8201) (3.8%), Disitamab Vedotin (RC-48) (6.0%), and other ADCs (6.8%). Twelve patients (9.0%) who did not receive any anti-HER2 drugs were enrolled. It can be concluded that the baseline population characteristics of the patients in this study are more in line with the current clinical reality of HER2-positive ABC patients in China, and that inetetamab still has superior survival benefits in prior anti-HER2 treatment (https://tbcr.amegroups.com/article/view/61051/html).

In the study of inetetamab-based treatment in Chinese patients with HER2-positive MBC, Liu et al. ²³ found that it had both efficacy and safety benefits. The median PFS of the entire cohort (n = 141) was 7.1 months. And the toxicity was tolerable. In addition, in a small sample study, Yu et al. ²⁴ also found that the mPFS of 64 patients with HER2-positive ABC treated with inetetamab-based therapy was 5.6 months. Among the combination regimens, patients treated with inetetamab + pyrotinib + vinorelbine had the most benefit, with an mPFS of up to 9.3 months (p = 0.048). In our study, the mPFS for the total population was 8.0 months. The mPFS for the first to second, third to fourth, and post to fifth lines populations was 14.0, 7.0, and 6.0 months, respectively (p < 0.0001). In terms of safety, most patients experienced grade 1–2 AEs. Hematologic toxicity was the most common grade ⩾ 3 AEs but was primarily associated with chemotherapy. No cardiac-toxic effects related to treatment with inetetamab were noted. Overall, inetetamab demonstrated good efficacy and safety across different treatment regimens. In patients with HER2-positive ABC who were heavily pretreated with anti-HER2 therapy, pyrotinib probably accounted for most of the benefit of inetetamab plus pyrotinib plus chemotherapy.

In the context of the era of dual-targeted therapy, this retrospective study delves into a comparative analysis of efficacy among three treatment groups: inetetamab combined with chemotherapy, inetetamab + pertuzumab + chemotherapy, and inetetamab + pyrotinib + chemotherapy. Notably, there was no significant difference observed in mPFS among these groups (8.0 months). However, given potential discrepancies in baseline characteristics and variations in group sizes, further exploration with an expanded sample size is warranted in future investigations. In addition, the landscape of HER2-positive breast cancer treatment is rapidly transforming, driven by the swift progress in integrating large and small-molecule-targeted therapies with chemotherapy for more effective treatments. Notably, the HER2CLIMB study ²⁵ demonstrated significant improvements in mPFS (7.6 months vs 4.9 months) and mOS (24.7 months vs 19.2 months) with tucatinib + trastuzumab + capecitabine compared to placebo + trastuzumab + capecitabine, highlighting the efficacy of this regimen. Consequently, our study conducted a thorough analysis of the three most common regimens within the inetetamab + pyrotinib + chemotherapy group. We observed varying mPFS outcomes: 14.0 months with inetetamab + pyrotinib + capecitabine, 9.0 months with inetetamab + pyrotinib + abraxane, and 8.0 months with inetetamab + pyrotinib + vinorelbine in subgroup analyses.

The phase III PHOEBE study established the efficacy (mPFS 12.5 months) of pyrotinib combined with capecitabine in the second-line treatment of HER2-positive ABC. ²² Even in later-line treatment, our study corroborates the survival benefits of inetetamab combined with pyrotinib plus capecitabine. However, the inclusion of only 16 patients in this group necessitates cautious interpretation due to potential limitations associated with the small sample size. In addition, Jin et al. ²⁶ prospectively enrolled 30 patients with prior trastuzumab-treated HER2-positive ABC treated with inetetamab + pyrotinib + vinorelbine, with a median PFS of 8.63 months. Similarly, findings from the 2023 ESMO meeting even revealed that 77 patients with HER2-positive MBC treated with inetetamab in combination with pyrotinib and vinorelbine had an mPFS of up to 10.03 months (95% CI 6.66–13.41 months) and had an ORR of 62.3% (48/77) and a clinical benefit rate (CBR) of 77.9% (60/77). ²⁷ It further validated the efficacy potential of this regimen, which aligns with our study’s observations.

The PRETTY study, a real-world investigation, demonstrated a median real-world PFS of 8.4 months for patients receiving pyrotinib in combination with chemotherapy other than capecitabine (n = 87) and 8.5 months for those receiving pyrotinib in combination with vinorelbine (n = 33). ²⁸ Compared with our study, it reaffirmed the therapeutic advantage of inetetamab in HER2-positive ABC. While inetetamab combined with pyrotinib plus paclitaxel may yield lower therapeutic benefits compared to first-line treatments observed in the PHILA study (mPFS 24.3 months), it remains a well survival benefit in later-line treatment. Nevertheless, direct comparability among the three treatment regimens may be challenging due to small subgroup sizes and imbalances in baseline characteristics, such as prior pertuzumab treatment and Ki-67 levels, leading to baseline feature mismatches (Supplemental Table 1). In summary, the combination of inetetamab with pyrotinib and chemotherapy presents a viable treatment option for patients with HER2-positive ABC in China, highlighting the evolving landscape of treatment modalities in this setting.

Determining the optimal curable population by clinical and pathologic characteristics is an important step in escalating the survival benefit in clinical care. It is known that highly HER2-dependent HER2-driven tumors (HER2 IHC 3+), low tumor burden, oligo-metastasis, and non-visceral metastasis are associated with better long-term prognosis in HER2-positive ABC. ²⁹ By Kaplan–Meier survival analysis, we found that DFI, HER2 expression, and HR status were not significantly associated with survival benefit. Visceral metastasis (14.0 months vs 8.0 months, p = 0.003), liver metastasis (11.0 months vs 6.0 months, p = 0.006), lung metastasis (12.0 months vs 8.0 months, p = 0.035), brain metastasis (9.0 months vs 6.0 months, p = 0.019), and the history of anti-HER2 TKIs treatment (14.0 months vs 6.0 months, p< 0.0001) significantly reduced mPFS. However, by uni- and multivariate analyses, only the history of anti-HER2 TKIs therapy was significantly associated with worse PFS (Table 4). One possible factor is the late median number of treatment lines (fourth line) in this group of patients (n = 76). Furthermore, it may be influenced by various aspects such as the sample size, tumor heterogeneity, ³⁰ activation of compensatory signaling pathways, immune escape, and so on. ⁵ To find the superior benefit population of inetetamab treatment, we further performed survival analysis on the subgroup of pyrotinib retreatment based on inetetamab treatment. We found that the group of inetetamab in combination with pyrotinib and capecitabine still prolonged the mPFS by 2.0 months compared with that of the group of abraxane and vinorelbine (p = 0.046) (Figure 3(i)).

Real-world research and evidence are becoming increasingly integral to medical decision-making processes. However, it is important to acknowledge the strengths and limitations of this cohort analysis in our study’s context. While our retrospective design allowed for an exploration of real-world treatment patterns, it is worth noting that some AE data may have been lost during follow-up. Nonetheless, this did not compromise the evaluation of the safety profiles of the inetetamab-based treatment regimens. Moreover, the inclusion of inetetamab in medical insurance coverage in China only began in March 2021. As a result, our study’s sample size was relatively small. Despite these constraints, our findings offer valuable insights into clinical practice for patients with HER2-positive ABC. Moving forward, it is imperative to expand the sample size in future studies. This expansion would facilitate a deeper exploration of optimal sequencing strategies for anti-HER2 agents throughout the treatment course for HER2-positive breast cancer. Notably, patients with a history of anti-HER2-TKI therapy in our study exhibited significantly lower survival benefits, underscoring the importance of refining treatment strategies to maximize patient outcomes. In conclusion, while our study has inherent limitations, it serves as a springboard for further research and highlights the importance of ongoing investigation into the optimal management of HER2-positive ABC in real-world settings.

Conclusion

In conclusion, our study suggests that inetetamab-based regimens demonstrate favorable efficacy and tolerable toxicity profiles in patients with HER2-positive ABC. Particularly, inetetamab combined with pyrotinib and chemotherapy shows promise as a reliable treatment option. Moving forward, larger prospective studies are warranted to delve deeper into the efficacy and safety profiles of inetetamab in combination with various treatment strategies. Such studies will contribute to reshaping the treatment landscape of HER2-positive ABC, ultimately improving patient outcomes, and enhancing the quality of care provided to this patient population.