Combined treatment of inetetamab plus pyrotinib and vinorelbine in managing advanced HER2-positive breast cancer patients (ILLUMINE): a multicenter, retrospective, real-world study

Introduction

Breast cancer (BC) remains a leading cause of cancer-associated death among global female populations (1). Each molecular subtype exhibits distinct biological characteristics and clinical prognosis, in accordance with the 2011 St. Gallen Consensus (2). Among advanced breast cancer (ABC) cases, overexpression or gene amplification of human epidermal growth factor receptor 2 (HER2) account for approximately 15–20% (3), featured by high invasiveness and poor prognosis. Advances in drugs specifically targeting HER2, represented by trastuzumab, have broaden the horizons of treatment (4-6). However, trastuzumab resistance remains a significant challenge. Further research is needed to better understand and address this issue.

Trastuzumab resistance in HER2-positive breast cancer is multifaceted, involving various factors such as epitope masking, activation of bypass signaling pathways, and inadequate response to HER2 (7). These factors interact and contribute to disease progression and treatment failure. The HER2CLIMB study has demonstrated that a combination of capecitabine, trastuzumab, and tucatinib exerted evident beneficial effects on both overall survival (OS) and progression-free survival (PFS) among patients HER2-positive metastatic breast cancer who have undergone extensive prior treatment (8). This enhanced antitumor effectiveness is attributed to the inhibitory effects through the complementary mechanisms of action at both extracellular and intracellular domains of the HER2, revealing the potential to overcome trastuzumab resistance. Likewise, the PHILA study showed the more comprehensive antitumor effect of a first-line treatment option utilizing two anti-HER2 agents compared to either agent alone (9).

Inetetamab is a recombinant monoclonal antibody targeting HER2 with an engineered fragment (Fc) designed to improve its antibody-dependent cellular cytotoxicity (ADCC), a key process mediating the antitumor activity of trastuzumab. Pyrotinib is a tyrosine kinase inhibitor (TKI) drug with potent HER2-antagonizing activity that enhances ADCC in a synergistic manner. This study explored the therapeutic effects and adverse events (AEs) of a combined regimen of inetetamb plus pyrotinib and vinorelbine as first to third-line treatment or HER2-positive ABC, aiming to optimize future treatment strategies. We present this article in accordance with the STROBE reporting checklist (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-7/rc).

Methods

Study design and oversight

This retrospective research (register number: NCT05764941) analyzed patient data collected from 17 institutions led by The First Affiliated Hospital of Nanjing Medical University. Data collection conformed to the ethics requirements of all institutions involved.

Patients

The participants were female patients diagnosed to have HER2-positive ABC histopathologically who received at least 2 cycles of the triple regimen, ranging from 18 to 80 years. Overexpression of HER2 determined by immunohistochemistry (IHC) as 3+, or IHC 2+ with fluorescence in situ hybridization (FISH) testing of amplification. An Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0–2, presence of at least one measurable lesion by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and sufficient organ function are necessary. Patients who had undergone ≤3 lines of chemotherapy to manage recurrent or metastatic disease were included. Patients were excluded if lost treatment information. Figure 1 shows the procedure of selecting eligible patients. Trastuzumab primary resistance refers to recurrence that was observed within the process or during the 12 months following the completion of trastuzumab-based adjuvant or neoadjuvant therapy, or disease progression identified during the initial radiological assessment (8–12 weeks), or within 3 months after administering first-line trastuzumab. Acquired trastuzumab resistance defines relapse that was diagnosed later than 12 months following adjuvant trastuzumab completion for early-stage disease or the progression that occurred following ≥2 lines of successful trastuzumab treatment which initially responded or stabilized during the first radiological assessment (10). A line of treatment denotes a scheduled treatment regimen cycles utilizing one or more anti-tumor drugs individually, sequentially, or in combination (11).

Figure 1 Trial profile. ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumors.

Treatment

The treatment regimen followed routine clinical practice and was tailored based on physician discretion. Patients received intravenous inetetamab at an initial dose of 8 mg/kg, with a maintenance dose of 6 mg/kg. Vinorelbine (25 mg/m²) was administered on the first and eighth days of each 3-week cycle, and oral pyrotinib (400 mg) was given daily. The treatment continued until disease progression, with adjustments made as per clinical judgment.

Data collection and assessment

Retrospective data extraction from electronic medical records (EMRs), encompassing both inpatient and outpatient documentation, captured demographic and clinicopathological characteristics, previous therapeutic regimens, clinical evaluation, and safety profiles. Tumor response was assessed using RECIST 1.1. Treatment-associated AEs (TAAEs) were assessed based on the Common Terminology Criteria for Adverse Events (CTCAE) 5.0.

Primary study endpoint is PFS, defined as the time from the first drug administration to the first recorded tumor progression or death due to any cause. Patients who are still alive and have not experienced progression at the last follow-up will be censored at the date of the last follow-up. The censoring date is October 31, 2023. Secondary endpoints include objective response rate (ORR), defined as the percentage of participants achieving complete response (CR) or partial response (PR); clinical benefit rate (CBR), defined as the percentage of participants achieving CR + PR + stable disease (SD) lasting for at least 6 months; OS, defined as the time from drug administration to death by any cause. Patients who are alive at the last follow-up will be censored at the date of the last follow-up. Safety will also be assessed throughout the study.

Statistical analyses

Baseline characteristics were summarized as descriptive statistics. Kaplan-Meier plots were employed for estimation of PFS for all patients and subgroups, while Cox regression models were used to assess the associations between baseline characteristics and the hazard of PFS. P<0.05 was deemed to signify statistical significance in two-sided tests. All treated patients were subjected to safety analyses. Survival analyses were conducted with SPSS 27.0 (IBM, Armonk, NY, USA) and RStudio 2023 (Posit Software, Boston, MA, USA). Plots were processed with Adobe Illustrator 2023 (Adobe Inc., San Jose, CA, USA).

Ethical declaration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The investigation received registration at ClinicalTrials.gov (NCT05764941) and approval from the Ethics Committee and Institutional Review Board of The First Affiliated Hospital of Nanjing Medical University (No. 2022-SR-652). The participants of this research offered written informed consent.

Results

Participants

From July 18, 2020 to October 31, 2023, 76 eligible HER2-positive ABC patients with an age range of 25–80 years (median, 53 years) were enrolled. The status of hormone receptor was ER and/or PR positive in 35 (46.1%) patients and negative in 41 (53.9%) patients. Baseline metastases included visceral metastases (53 patients, 69.7%), lymph node metastases (40 patients, 52.6%), bone metastases (30 patients, 39.5%), brain metastases (21 patients, 27.6%), and liver or lung metastases (29 patients each, 38.2%). Prior treatments included pertuzumab (34 patients, 44.7%), TKIs (30 patients, 39.5%), and trastuzumab emtansine (T-DM1) (4 patients, 5.3%). Table 1 summarizes the detailed clinicopathological characteristics of the study cohort before treatment. The median number of prior treatment regimens for advanced-stage illness was one.

Efficacy

The study followed all participants until October 31, 2023. At a median follow-up of 20.8 months, 52 patients experienced disease progression and 3 patients died. No event was observed within the first 3 months of follow-up. At the time of data cutoff, 24 patients remained on treatment. The median PFS (mPFS) for the entire cohort was 10.03 months (95% CI: 6.80 to 13.27), with the median OS not yet reached at the end of follow-up (Figure 2A). The mPFS was 12.27 months (95% CI: 5.26 to 19.28) for first-line treatment patients, 11.37 months (95% CI: 7.31 to 15.43) for second-line, and 9.43 months (95% CI: 6.95 to 11.91) for third-line. In the entire cohort, the ORR was 61.8%, with 3 patients achieving CR and 44 patients achieving PR. The CBR was 97.4% (74 of 76 patients) (Figure 2B).

Figure 2 Patient response to treatment. Kaplan-Meier plots of PFS via RECIST 1.1 in (A) the entire and (C) brain metastases cohorts. Waterfall plots were used to display treatment duration and key clinical events for each patient in (B) the entire and (D) brain metastases cohorts. CBR, clinical benefit rate; CI, confidence interval; CR, complete response; mPFS, median progression-free survival; ORR, objective response rate; PD, progression disease; PFS, progression-free survival; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

Furthermore, we focused on the efficacy in the brain metastases cohort. Brain metastasis was diagnosed in 21 patients, with a mPFS of 10.03 months (95% CI: 4.24 to 15.82) (Figure 2C). Five patients were still receiving treatment. Three patients received simultaneous radiotherapy. The ORR was 57.1%, with 11 and 1 patients respectively exhibiting PR and CR. The CBR reached 100% (21 of 21 patients) (Figure 2D).

Univariate Cox regression analyses identified several factors associated with differences in PFS. In our cohort, patients without prior T-DM1 exposure demonstrated longer PFS (P<0.001). However, this comparison is limited by the small number of patients with T-DM1 exposure (n=4) and the approval timing of T-DM1 in China during the study period, which may have introduced selection bias. This limitation aligns with prior reports suggesting that early real-world studies on T-DM1 may reflect a selection bias—patients with more aggressive disease who progressed rapidly after first-line therapy were more likely to receive T-DM1 shortly after its approval. As T-DM1 and other anti-HER2 agents were introduced sequentially in clinical practice, this approval timeline may have disproportionately affected treatment sequencing and patient selection in real-world settings (12) (Table 2). Patients with ECOG ≥1 and ECOG =0 respectively had a mPFS of 8.47 months (95% CI: 5.69 to 11.25) and 12.63 months (95% CI: 8.37 to 16.90) [hazard ratio (HR), 1.794; 95% CI: 1.024 to 3.144; P=0.041] (Figure 3A). Hormone receptor-negative patients had a mPFS of 11.37 months (95% CI: 8.27–14.47), compared to 7.67 months (95% CI: 5.64–9.70) in hormone receptor-positive patients (HR, 1.798; 95% CI: 1.040–3.108; P=0.04) (Figure 3B).

Figure 3 Kaplan-Meier plots of PFS via RECIST 1.1 in (A) the ECOG, (B) hormone receptor status, and (C) type of resistance to trastuzumab cohorts. ^†, relapse during or within 12 months of completion of trastuzumab-based therapy in the adjuvant or neoadjuvant setting, or disease progression identified during the initial radiological assessment (8–12 weeks), or within 3 months after administering first-line trastuzumab. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; mo, months; mPFS, median progression-free survival; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors.

In the multivariate Cox proportional-hazards regression model, variables with univariate association with clinical outcomes (ECOG, lymph node metastases, lung metastases, bone metastases, hormone receptor status) were included. The type of resistance to trastuzumab was also incorporated considering the association with clinical benefit of patients received anti-HER2 treatment to a substantial extent. In the final model, hormone receptor status (HR, 2.056; 95% CI, 1.062 to 3.981; P=0.03) and type of resistance to trastuzumab (HR, 1.913; 95% CI, 1.010 to 3.621; P=0.046) were independently associated with overall PFS (Figure 4). A mPFS of 8.57 months (95% CI: 6.92 to 10.22) was noted for patients with primary resistance to trastuzumab, while that for those with acquired resistance was 11.37 months (95% CI: 8.06 to 14.69) (HR, 1.374; 95% CI: 0.788 to 2.396, P=0.26) (Figure 3C).

Figure 4 Multivariate analyses of factors predicting PFS. ^†, relapse during or within 12 months of completion of trastuzumab-based therapy in the adjuvant or neoadjuvant setting, or disease progression identified during the initial radiological assessment (8–12 weeks), or within 3 months after administering first-line trastuzumab. *, P<0.05. CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; PFS, progression-free survival.

Safety

AEs observed during the treatment period were consistent with the known toxicity profiles of the included agents. The most frequent treatment-related AEs included diarrhea (77.6%), leukopenia (75.0%), neutropenia (69.7%), nausea (28.9%), anemia (27.6%), and fever (27.6%). Other reported AEs included fatigue (23.7%), vomiting (22.4%), transferase increase (19.7%), stomachache (14.5%), rash (13.2%), peripheral sensory neuropathy (9.2%), lactate dehydrogenase increase (6.6%), creatinine increased (1.3%), hair loss (1.3%), and heart failure (1.3%). Grade III or worse AEs included leukopenia (19.7%), neutropenia (19.7%), and diarrhea (17.1%). No treatment discontinuation, dose reductions, or interruptions due to AEs were reported. Additionally, no serious AEs (SAEs) or treatment-related deaths were recorded during the study period. A detailed summary of observed AEs is provided in Table 3.

Discussion

The application of drugs targeting HER2 leads to significant improvement of prognosis of HER2-positive breast cancer, greatly prolonging the survival for patients with ABC (4-6). Both international and domestic guidelines recommend a combined regimen of taxane, trastuzumab, and pertuzumab for first-line HER2-positive ABC treatment, based on the excellent outcomes of CLEOPATRA and PUFFIN trials (13,14). However, many patients develop primary or acquired resistance to trastuzumab over time. In the EMILIA trial, T-DM1 displayed durable anticancer efficacy, with an ORR of 43.6% (95% CI: 38.6% to 48.6%) and a mPFS of 9.6 months in patients previously received trastuzumab with taxane (15). The series of DESTINY-BREAST trials redefined the role of trastuzumab deruxtecan (T-DXd) in treating HER2-positive ABC. The DESTINY-BREAST 03 trial demonstrated the significant survival advantage of T-DXd over T-DM1 in HER2-positive ABC patients who progressed after previous trastuzumab treatment (HR, 0.28; 95% CI: 0.22 to 0.37; P<0.001) (16). The superior PFS and ORR along with a favorable safety profile of T-DXd render it as the standard second-line treatment in place of T-DM1, but the high economic cost restricts its application in China. More seriously, it has been observed in clinical practice that approximately 11.4% of patients develop T-DXd-induced interstitial lung disease (ILD) (17). The PHENIX and PHOEBE trials established capecitabine plus pyrotinib to be a conventional second-line therapy in China. Against the considerable therapeutic effect, severe negative events such as diarrhea and hand-foot syndrome impact the quality of life, leading to dose reduction even treatment discontinuation. Although anti-HER2 agents have already diversified in recent years, a highly effective and more affordable treatment option is urgently needed (18,19).

Trastuzumab resistance can develop through various mechanisms. The most common explanation is inadequate binding of the HER family receptors owing to downregulation or loss of HER2 expression, which could be overcome by antibody drug conjugates (ADCs) with potent payload or dual HER2 inhibitors. Apart from HER2 amplification or overexpression, HER2 mutation also conferred tumorigenesis and primary resistance to prior trastuzumab. Second-generation TKIs have been demonstrated the ability to overcome resistance in HER2 tumors harboring the HER2 + L755S mutation, the most common alteration associated with reduced sensitivity to T-DM1 (20). The combination of pan-HER TKIs such as neratinib or pyrotinib, a more complete blockade of HER family, has the potential of overcoming the acquired resistance derived from amplified epidermal growth factor receptor (EGFR) signaling (6). Additionally, activation of compensatory pathways such as PI3K-AKT-mTOR pathway and bidirectional crosstalk between HER2 and ER offer tumor cells an escape from trastuzumab as well (21-24). Other vulnerabilities in resistant tumor cell have been implicated include HER2 epitope loss or masking, HER2 heterogeneity, and weakened ADCC due to an immune suppressive tumor microenvironment (25-27). These complexities necessitate ongoing development of new therapies on the basis of existing and/or novel platforms.

Incorporating pyrotinib may enhance HER2 signaling inhibition through dual HER2 blockade. The HER2CLIMB trial showcased that adding tucatinib to capecitabine and trastuzumab significantly reduced disease progression or death (HR, 0.54; 95% CI: 0.42 to 0.71; P<0.001), and converted to OS benefit (median OS, 21.9 vs. 17.4 months, P=0.005) (8). The PHILA trial showed significant improvements of trastuzumab, pyrotinib and docetaxel as the first-line treatment for HER2-positive ABC (HR, 0.41; 95% CI: 0.32 to 0.53; P<0.001), leading to its inclusion in the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines 2023 (9).

Inetetamab is an artificial recombinant monoclonal antibody targeting HER2, sharing the same Fab segment as trastuzumab which offers the ability to suppress HER2-positive BC cell proliferation through hindering the HER2 cascades. Additionally, inetetamab has a modified Fc segment that enhances its ability to bind to innate immune cells, inducing more robust ADCC and intensive tumor cell lysis (28). A preclinical study indicates that inetetamab can increase ADCC effects by approximately 11.1% compared to trastuzumab. Vinorelbine could exhibit a better synergistic effect than other chemotherapy compounds when combined with trastuzumab (29). Moreover, the combination with vinorelbine yields a favorable toxicity profile, with fewer grade III/IV AEs compared to docetaxel, especially regarding neuropathy (30). In the phase III HOPES study, inetetamab combined with vinorelbine markedly prolonged mPFS relative to vinorelbine monotherapy in participants without undergoing anti-HER2 therapeutics previously (39.1 vs. 14.0 weeks; HR, 0.24; 95% CI: 0.16–0.36; P<0.001) (31). Subgroup analysis exhibited a remarkable efficacy of inetetamab equivalent to trastuzumab as first-line treatment for HER2-positive ABC, with a mPFS of 11.1 months and an ORR of 61.5% (32). Our previous phase II trial of inetetamab plus oral vinorelbine and pyrotinib (NCT05823623) has shown moderate efficacy in HER2-positive ABC patients, although the sample size is limited (33).

To better reflect real-world clinical scenarios, the largest multicenter study to date was carried out in a Chinese population to assess the efficacy and safety of triple regimen among patients from diverse regions using routine clinical practice data. In the current study utilizing real clinical data from a retrospectively collected cohort, the treatment regimen demonstrated durable anticancer efficacy in HER2-positive ABC participants, resulting in a mPFS of 10.03 months (95% CI: 6.80 to 13.27), a confirmed ORR of 61.8%, and a CBR of 97.4%, comparable to the EMILIA trial. The Cox multivariate analysis indicated that negative hormone receptor status and acquired resistance to trastuzumab were associated with better outcomes in the triple-exposed cohort. Conversely, positive hormone receptor status was linked to less favorable clinical outcomes, likely due to the interaction between the ER and HER2 pathways. Nevertheless, our data must be cautiously explained due to the limited number of patients included and further validated by trials with bigger sample sizes. The triple regimen also displayed desirable safety profile, as the incidence and severity of TAAEs were consistent with those reported previously and no unreported TAAEs were observed. Most AEs were grade I/II and manageable, with leukopenia, neutropenia, and diarrhea being the most common grade III/IV AEs, all of which were controllable with careful monitoring. While the efficacy of triple regimen was inferior to T-DXd, its higher cost-effectiveness and better tolerance could empower it more clinical accessibility.

Patients with brain metastases generally experience shorter survival and poorer quality of life (34). TKIs are continually investigated because of their ability to penetrate the blood-brain barrier. Yan et al. reported a mPFS of 11.3 months for the combination of capecitabine and pyrotinib in individuals with radiotherapy-naive HER2-positive brain metastases in the PERMEATE study (35). Our study reported a mPFS of 10.03 months for patients with brain metastases, comparable to the PERMEATE study and the 9.9 months observed in participants suffering from brain metastases in the HER2CLIMB trial (8). This high level of therapeutic activity in patients with brain metastases supports the clinical application of the inetetamb, pyrotinib, and vinorelbine, despite the limited sample size.

Our study had some potential limitations due to vulnerabilities in research design and data. Firstly, the small sample size and retrospective nature resulted in inherent analysis biases and the inability to conduct depth analysis. Secondly, the absence of randomized grouping may have led to persistent differences between groups despite the fact that we employed advanced statistical methods to address known confounders. Lastly, only 5 of the 76 enrolled patients received ADCs in prior treatment: 4 (5.3%) with T-DM1 and 1 (1.3%) with disitamab vedotin (RC48). Therefore, the therapeutic efficacy of the triple regimen in HER2-positive BC patients after ADCs failure warrant further validation.

Conclusions

The combination of inetetamab with vinorelbine plus pyrotinib demonstrated desirable therapeutic effects and safety for HER2-positive ABC patients.

Acknowledgments

The authors express their gratitude to the patients, investigators, and their institutions for the time and effort put into this study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-7/rc

Data Sharing Statement: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-7/dss

Peer Review File: Available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-7/prf

Funding: This research was supported by the National Natural Science Foundation of China (Nos. 81902704 and 81972484) and the Beijing Life Oasis Public Service Center (No. cphcf-2022-225).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tbcr.amegroups.com/article/view/10.21037/tbcr-25-7/coif). Y.Y. serves as an unpaid editorial board member of Translational Breast Cancer Research from March 2024 to February 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The investigation received registration at ClinicalTrials.gov (NCT05764941) and approval from the Ethics Committee and Institutional Review Board of The First Affiliated Hospital of Nanjing Medical University (No. 2022-SR-652). The participants of this research offered written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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