Real-World Outcomes With Inetetamab-Based Regimens for HER2-Positive Metastatic Breast Cancer: A Multicenter Retrospective Analysis in China.

Introduction
According to the GLOBOCAN 2022, breast cancer (BC) ranks second in incidence globally, only surpassed by lung cancer.
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In 2022, there were 2.3 million newly diagnosed cases of BC (11.6%) among women worldwide.
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The mortality cases reached 0.66 million (6.9%), ranking fourth in cancer mortality; by 2050, new cases and deaths will have increased by 38% and 68%, respectively.
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Notably, BC remains the most prevalent malignancy among women globally, with HER2-positive subtype accounting for 20%-30% of cases.3–5 HER2-positive BC shows more aggressive clinical behavior and poorer prognosis.
The continuous emergence of anti-HER2 drugs, ranging from monoclonal antibodies to tyrosine kinase inhibitors (TKIs) and antibody-drug conjugates (ADCs), has improved the prognosis of patients with HER2-positive metastatic breast cancer (MBC). Trastuzumab plus pertuzumab is the first-line standard, achieving prolonged survival, while subcutaneous formulations improve convenience.
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TKIs mainly include neratinib, pyrotinib, and tucatinib. Pyrotinib, which has achieved a complementary mechanism between large-molecule and small-molecule combination therapy, offers a new treatment option for first-line treatment of HER2-positive MBC.
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Tucatinib demonstrate efficacy in brain metastases, and the intracranial response rate reaches 47.3% when it is combined with trastuzumab.
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Trastuzumab deruxtecan (T-DXd) surpasses T-DM1 with a median progression-free survival (PFS) of 28.8 months, and extends benefits to HER2-low disease.9,10 For patients with multiple lines of resistance, RC48 alone can achieve partial response. Emerging strategies such as bispecific antibodies, immune checkpoint inhibitors, and HER2-targeted vaccines are under clinical investigation, offering novel strategies for HER2-positive MBC. These advancements highlight progress while underscoring the necessity for personalized approaches in refractory HER2-positive MBC.
Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody developed in China. Although its Fab domain is identical to that of trastuzumab, its Fc domain contains specific amino acid substitutions in the heavy chain constant region—specifically, D359 (aspartic acid) and L361 (leucine) instead of E359 (glutamate) and M361 (methionine), respectively.
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These modifications amplify antibody-dependent cellular cytotoxicity, improving immune-mediated tumor cell clearance and survival benefits. Previous studies have shown that inetetamab has higher level of sialylation, longer half-life, and lower immunogenicity risk. The HOPES study a multicenter prospective randomized Phase III trial, demonstrated that inetetamab plus vinorelbine significantly prolonged PFS compared with vinorelbine alone.
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Therefore, inetetamab has been approved for the treatment of HER2-positive MBC, providing a new therapeutic option for patients.
Currently, real-world evidence is playing an increasingly important role in clinical decision-making.
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By analyzing multicenter data on inetetamab-treated HER2-positive MBC patients, we have explored the efficacy and safety of inetetamab-based regimens, aiming to identify optimal therapeutic strategies and strengthen evidence-based medical practice.

Methods

Patients and Treatments
Between November 2020 and April 2023, this retrospective, multicenter, real-world study included patients with HER2-positive metastatic breast cancer who received inetetamab-based regimens at four institutions in China, including: Shandong Cancer Hospital and Institute, the Affiliated hospital of Jining medical university, Tengzhou Central People’s hospital, and Linyi Cancer Hospital.
Inclusion criteria: (1) Female BC patients aged more than or equal to 18 years. (2) HER-2 positive tissue samples were defined as 3+ staining intensity by immunohistochemistry, or 2+ and a positive by fluorescence in situ hybridization (FISH). (3) According to the response evaluation criteria in solid tumors (RECIST) version 1.1, patients had at least one measurable lesion, defined as a lesion with a longest diameter of ≥10 mm on contrast-enhanced CT or MRI (or ≥20 mm on chest radiography). (4) Patients who received therapy based on inetetamab (Cipterbin®) were treated with medication manufactured by Sunshine Guojian Pharmaceutical, Inc., Shanghai, China. The initial infusion dose was 8 mg/kg, followed by a maintenance dose of 6 mg/kg, administered once every 3 weeks until disease progression or intolerable chemotherapy-related toxicity. (5) Patients with complete medical records.
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Shandong Cancer Hospital and Institute (Approval No. 2020012003; Date: March 2021). All participants provided written informed consent prior to enrollment. It has been registered with the Chinese Clinical Trial Registry under the number ChiCTR2200061413.

Outcome Measurements
The primary endpoint was PFS, defined as the time from treatment initiation to disease progression or death from any cause. Secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. ORR was defined as the proportion of patients with a complete response (CR) or partial response (PR) as the best objective tumor response. DCR was defined as the proportion of patients achieving CR, PR, or stable disease (SD) for at least 4 consecutive weeks.
Tumor responses were evaluated according to RECIST version 1.1, based on CT, MRI, and physical examinations assessed at 6-week intervals. Adverse events (AEs) were assessed using the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, with severe AEs defined as grade ≥3. Data on AEs were collected retrospectively from medical records and supplemented by follow-up contacts via telephone or WeChat. The final follow-up was conducted on March 25, 2024. Patients who were lost to follow-up were censored at the date of their last known contact. For PFS calculation, censoring events included completion of the study without progression, or loss to follow-up.

Statistical Analysis
The study included all eligible patients and employed descriptive analyses to characterize their clinical features. Categorical variables were expressed as frequency (percentage). The PFS was estimated using Kaplan–Meier curves, with corresponding 95% confidence intervals (CIs), and the differences in PFS between groups were compared using the log-rank test. Additionally, associations between potential prognostic factors and PFS were assessed using univariate and multivariate Cox proportional hazards models, with variables selected for multivariate analysis based on statistical significance (P < 0.05) in univariate analysis or clinical relevance. A two-sided P-value of less than 0.05 was considered statistically significant. All statistical analyses were conducted with SPSS (version 25.0) and GraphPad Prism (version 8.0).

Results

Patient Characteristics
A total of 140 patients were included (Table 1), with a median age of 53 years (range, 27-90). The cohort was predominantly composed of patients with recurrent disease (88.6%); only 11.4% presented with de novo stage IV cancer. Nearly half (46.4%) were hormone receptor (HR)-positive, specifically 39.3% were estrogen receptor (ER)-positive and 29.3% were progesterone receptor (PR)-positive. Among these patients, 65.7% had visceral metastases, most commonly in the brain, bone, liver, and lung; 55.0% had at least two metastatic lesions. The median number of prior treatment lines was 3 (range, 1-11). All patients were included: 42 (30.0%) received inetetamab as ≤second-line therapy, and 98 (70.0%) as ≥third-line therapy. Prior anti-HER2 therapy was common: 95.0% received trastuzumab, 27.9% received trastuzumab and pertuzumab, and 67.9% (95/140) received trastuzumab plus HER2-TKIs.

Treatment Administration
Inetetamab was most commonly combined with HER2-TKIs (pyrotinib) and chemotherapy (59/140, 42.1%). Other regimens included: inetetamab with chemotherapy alone (44/140, 31.4%); inetetamab plus pertuzumab and chemotherapy (21/140, 15.0%); and inetetamab with endocrine therapy (9/140, 6.4%). Regarding concomitant chemotherapy, vinorelbine (87/140, 62.1%) and nab-paclitaxel (42/140, 30.0%) were the most common choices.

Efficacy
The median follow-up time was 25.4 months (range, 24.2-26.6). The median PFS (mPFS) of the entire cohort was 6.1 months (95% CI, 5.0-7.2, Figure 1A). In the best response assessment during inetetamab therapy, one patient (0.7%) achieved a CR, while 48 patients (35.6%) had a PR. SD was reported in 59 patients (43.7%), and progressive disease (PD) was detected in 32 patients (23.7%) (Table 2). The ORR was 35.0% (49/140) and the DCR was 77.1% (108/140). The mPFS was significantly longer with first-line inetetamab (22.2 months; 95% CI, 21.7-22.7) than with second-line treatment (12.9 months; 95% CI, 10.1-15.7; P = 0.022; Figure 1B). Similarly, mPFS was better in the ≤second-line group (14.5 months; 95% CI, 9.5-19.5;) than the ≥third-line group (4.8 months; 95% CI, 4.2-5.3; P < 0.0001; Figure 1C). A trend of decreasing ORR was observed with later lines of therapy: 76.9% in first-line, 48.3% in second-line, and 25.5% in third-line or beyond (Table 2).
Patients with prior trastuzumab but no TKI exposure had a significantly longer median mPFS of 12.8 months (95% CI, 10.5-15.2) compared with those who had received both trastuzumab and TKIs (mPFS, 5.7 months; 95% CI, 4.8-6.5; P = 0.001; Figure 2A). We next evaluated the efficacy of different inetetamab-based combination regimens. Treatment with inetetamab plus HER2-TKIs and chemotherapy was associated with the longest PFS, with a median of 8.4 months. This was longer than the mPFS observed with inetetamab plus pertuzumab and chemotherapy (4.2 months), inetetamab plus chemotherapy alone (6.0 months), or inetetamab plus endocrine therapy (6.1 months). Furthermore, patients receiving inetetamab combined with HER2-TKIs and chemotherapy had a significantly longer mPFS of 8.4 months (95% CI, 5.7 to 11.1) than those receiving other inetetamab-based regimens, who had a median PFS of 5.7 months (95% CI, 4.5 to 6.9; P = 0.023; Figure 2B).
In Table 3, we summarize the results of univariate and multivariate Cox proportional hazards regression analyses, identifying factors associated with PFS. On univariate analysis, the lines of systematic treatment of inetetamab, prior exposure to HER2-TKIs, and inetetamab-based regimens (inetetamab plus HER2-TKIs plus chemotherapy vs others) were significantly correlated with PFS (P < 0.05). In the multivariate model, earlier treatment line (1-2 vs ≥3) was independently associated with prolonged PFS (HR = 0.330; 95% CI, 0.211-0.517; P < 0.001).
At baseline, 91 patients (65%) had visceral metastases. The mPFS in these patients was 6.2 months, compared with 6.1 months in those without visceral metastases (P = 0.553; Figure 2C). Among patients with brain metastases, the mPFS was 5.8 months (95% CI: 2.4-9.2), which was not significantly different from the mPFS of 6.2 months (95% CI: 5.0-7.4) observed in patients without brain metastases (P = 0.33, Figure 2D). The ORR of patients with brain metastases was 20.0% (5/25), and the DCR was 56.0% (14/25). Although both ORR and mPFS appeared numerically lower in patients with brain metastases, those who achieved at least SD experienced a notably longer mPFS of 8.9 months.

Safety and Tolerability
Safety assessments of inetetamab-based therapy are detailed in Table 4. Among 140 patients, the most common adverse events included leukopenia (43/140, 30.7%), neutropenia (39/140, 27.9%), and diarrhea (28/140, 20.0%). Notably, grade 3 or 4 leukopenia (23/140, 16.4%), neutropenia (18/140, 12.9%), and diarrhea (12/140, 8.6%) were observed; no treatment-related deaths occurred.

Discussion
In the multicenter, real-world study retrospectively reported that inetetamab-based regimens were effective in patients with HER2-positive MBC, with an ORR of 35.0%, a DCR of 77.1%, and a mPFS of 6.1 months. These findings suggest that inetetamab-based therapy is a viable treatment option in this patient population, particularly when integrated into earlier lines of therapy or in combination with HER2-targeted tyrosine kinase inhibitors (TKIs) and chemotherapy.
Inetetamab represents a targeted optimization of the trastuzumab Fc domain, though its broader clinical utility and potential superiority require further investigation.13–15 Unlike trastuzumab, which has validated efficacy both early and metastatic HER2-positive breast, the current evidence and indications for inetetamab-based therapy remain more confined, primarily to the MBC setting.16–18 Our results are consistent with prior retrospective studies evaluating inetetamab in real-world settings. For instance, Liu et al.
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reported an mPFS of 7.1 months and ORR of 36.9% in a similar cohort of 141 Chinese patients with HER2-positive MBC, and the DCR was 80.9%.Another single-center study by Zhang et al demonstrated an mPFS of 8.0 months and ORR of 50.4% among 133 patients.
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A mPFS of 14.0 months was achieved with inetetamab, pyrotinib, and chemotherapy, while mPFS across the first-to second-line, third-to fourth-line, and fifth-line or later populations was 14.0, 7.0, and 6.0 months, respectively. The safety profile was favorable, dominated by grade 1-2 AEs. The observed variance in efficacy outcomes is likely influenced by differences in patient characteristics, prior therapies, and specific drug combinations. Notably, our study and others consistently show that combining inetetamab with a TKI and chemotherapy is associated with favorable PFS, with a mFPS of 8.4 months in our cohort, consistent with the 8.2 months reported by Liu et al.
Furthermore, in our study, the significant difference in mPFS between patients receiving inetetamab in earlier (≤second-line) vs later (≥third-line) treatment lines (14.5 vs 4.8 months; P < 0.0001) underscores the importance of treatment sequencing in HER2-positive MBC. This is further supported by multivariate analysis, which identified treatment line as an independent predictor of PFS (HR 0.330; 95% CI 0.211-0.517; P < 0.001). These findings align with those of Wu et al for 52 patients, who reported a mPFS of 17 months in second-line settings compared to 5 months in later lines. Wu et al.
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Reported the efficacy and safety of inetetamab and pyrotinib in combination with vinorelbine for second-line therapy and beyond in HER2-positive MBC. Interestingly, patients with prior exposure to trastuzumab without TKIs derived greater benefit from inetetamab than those who had received both trastuzumab and TKIs (mPFS 12.8 vs 5.7 months; P = 0.001). This suggests that inetetamab may retain efficacy in patients with resistance to trastuzumab but not necessarily to TKIs, highlighting a potential niche for its use in sequencing strategies.
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The safety profile of inetetamab was acceptable; the most common AEs were leukopenia, neutropenia, and diarrhea. Leukopenia and neutropenia were primarily attributed to concomitant chemotherapy, while diarrhea was predominantly associated with HER2-TKIs. No treatment-related deaths were reported, consistent with previous studies.
In the current landscape of HER2-targeted therapy, T-DXd and tucatinib-based regimens have become standard treatments for HER2-positive MBC, with remarkable efficacy.
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However, as tucatinib is not yet approved or accessible in China, combination regimens incorporating alternative TKIs are commonly employed in clinical practice. During the enrollment period of this study, ADCs had not been included in the National Reimbursement Drug List (NRDL), leading to a low rate of prior ADC exposure in patients. Thus, the efficacy of the “ADC → anti-HER2 monoclonal antibody” sequential strategy cannot be evaluated. In this context, inetetamab, a novel anti-HER2 monoclonal antibody with a favorable safety profile and no known pulmonary toxicity, may serve as an important complementary option for patients’ ineligible for T-DXd.
This study has limitations, including its retrospective design, the potential for selection bias, heterogeneity in treatment regimens across participating centers, and lack of a formal sample size calculation. Although the sample size of 140 patients was substantial, it may still be inadequate to detect subtle differences in subgroup analyses. In addition, overall survival data were immature at the time of analysis, limiting our ability to assess long-term outcomes.

Conclusions
This real-world analysis confirms the inetetamab-based therapy as an effective treatment option for HER2-positive MBC, particularly in earlier lines or combined with TKIs and chemotherapy. These results thereby affirm its value in clinical practice, while also highlighting the necessity of prospective research to optimize treatment strategies.