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Cancer Research and Treatment > Volume 56(3); 2024 > Article
Zhang, Liu, Song, Zhang, and Li: Trastuzumab Biosimilar (HLX02), Pertuzumab Plus Chemotherapy in Patients with HER2-Positive Metastatic Breast Cancer after Progression of Trastuzumab: A Prospective, Phase II Study



This study aims to evaluate the efficacy and safety of trastuzumab biosimilar (HLX02) in combination with pertuzumab and chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) after progression of trastuzumab.

Materials and Methods

In this prospective, single-arm, phase II study, patients with HER2-positive MBC after progression of trastuzumab received pertuzuamb, HLX02, and chemotherapy in Beijing Cancer Hospital from March 2020 to December 2022. The primary endpoint was progression-free survival (PFS), and secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov (NCT05188495).


A total of 45 patients were included in this study. Twelve patients (26.7%) were treated in second-line and 33 patients (73.3%) were in third-line and later setting. Eighty percent and 15.5% patients had previously received pyrotinib/lapatinib and T-DM1, respectively. With a median follow-up of 24.4 months (range, 1.2 to 43.9 months), the median PFS was 7.6 months (95% confidence interval, 4.3 to 10.9), OS was not reached, the ORR was 31.1%, and DCR was 91.1%. The treatment was well tolerated.


The combination of trastuzumab biosimilar HLX02, pertuzumab, and chemotherapy exhibited promising efficacy and a favorable safety profile as second- and beyond-line treatment in HER2-positive MBC.


Trastuzumab-based targeted therapy has greatly improved the survival of human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer (MBC) in the past decades. CLEOPATRA study established the standard of first-line treatment of trastuzumab, pertuzumab combined with paclitaxel for HER2-positive MBC based on its significant overall survival (OS) advantage [1]. PUFFIN trial confirmed the survival benefit of dual anti-HER2 therapy in Chinese population [2].
The second-line treatment options for advanced breast cancer after progression of trastuzumab include antibody drug conjugates (ADC) like T-DM1, DS8201, and small molecule tyrosine kinase inhibitors (TKIs) including lapatinib, pyrotinib, tucatinib, and neratinib. However, not all people can afford ADCs due to expensive cost, and patients who used ADCs will also eventually experience disease progression. Up to now, there is no standard of care for third-line or later treatment [3-5].
Previous studies have shown that retaining trastuzumab in combination with other chemotherapy drugs after trastuzumab progression significantly prolongs OS compared to discontinuing trastuzumab [6-8]. However, whether the addition of pertuzumab to trastuzumab could achieve better efficacy in this population remains unclear. Trials evaluating the efficacy of dual anti-HER2 therapy with pertuzumab and trastuzumab in second- and beyond line setting are limited, and reported mixed conclusions [9-14]. Randomized phase III study PHEREXA reported that the addition of pertuzumab to trastuzumab plus capecitabine did not significantly improve progression-free survival (PFS) as second-line treatment, but an 8-month increase in median OS was observed [12]. Besides, randomized PRECIOUS study showed that pertuzumab retreatment in combination with trastuzumab and chemotherapy (TC) significantly improved PFS and showed a trend towards better OS than TC in patients previously treated with pertuzumab [10].
HLX02 (Zercepac) is the first manufactured trastuzumab biosimilar in China. It has been approved in China and some European countries based on its confirmed similar efficacy and safety in combination with chemotherapy compared with the reference drug in phase III study of first-line treatment for HER2-positive MBC. Nevertheless, data on whether HLX02 combined with pertuzumab and chemotherapy is safe and efficient in HER2-positive especially in trastuzumab pre-treated MBC patients is still lacking.
Therefore, we conducted this prospective study to evaluate the efficacy and safety of the trastuzumab biosimilar HLX02, pertuzumab plus chemotherapy (TPC) in patients with HER2-positive advanced breast cancer after trastuzumab progression. This study was approved by the Ethics Committee of Peking University Cancer Hospital (approval ID: 2020KT151) in Beijing, China, and was registered with ClinicalTrials.gov (NCT05188495).

Materials and Methods

1. Key eligibility criteria

Eligible patients aged 18years or older with histologically confirmed HER2-positive invasive breast cancer. HER2-positive status confirmed by immunohistochemistry 3+ and/or fluorescence in situ hybridization confirmed gene amplification (HER2/CEP17 ratio ≥ 2). Other criteria are as follows: (1) Patients with MBC previously treated with trastuzumab (during neo/adjuvant setting or metastatic setting) and have experienced disease progression while or after receiving trastuzumab-based therapy; (2) Measurable disease as defined per Response Evaluation Criteria in Solid Tumor v.1.1 criteria. Patients with only central nervous system diseases are not suitable for inclusion; (3) Eastern Cooperative Oncology Group performance status 0-2; (4) Adequate organ and bone marrow function; (5) Left ventricular ejection fraction (LVEF) ≥ 50%, determined by echocardiography; (6) Patients who have received pertuzumab for metastatic diseases are excluded (if used during adjuvant or neo-adjuvant, the time from the last medication to recurrence or metastasis should be more than 12 months); (7) Untreated symptomatic progressive brain metastases occurred within 30 days before randomization are excluded.

2. Trial design

This is a prospective single-arm, single-center, phase II clinical trial. Eligible patients were assigned at baseline to receive trastuzumab (HLX02), pertuzumab, and chemotherapy based on physician’s choice. Trastuzumab (HLX02) was given intravenously as an 8 mg/kg loading dose followed by 6 mg/kg maintenance doses every 3weeks. Pertuzumab was given intravenously as an 840mg loading dose followed by 420 mg maintenance doses every 3 weeks. Physician’s choice of chemotherapy agents including taxels (docetaxel, paclitaxel, and nab-paclitaxel), gemcitabine, eribulin, capecitabine, or vinorelbine monotherapy. The administration approach referred to the recommendations in the 2020 Chinese Society of Clinical Oncology (CSCO) Guidelines for the Diagnosis and Treatment of Breast Cancer.

3. Assessment

Tumor assessment was carried out every 6 weeks with a computed tomography scan of the chest with or without a scan of the abdomen (depends on the presence of abdominal metastases), and if the disease had not progressed after 6 months, the investigator decided whether to continue chemotherapy. Trastuzumab and pertuzumab continued to be applied until the disease progressed or toxicity became intolerable, hormone receptor–positive patients were allowed to receive endocrine therapy as maintenance therapy. Responses were evaluated using Response Evaluation Criteria in Solid Tumor 1.1 criteria.
The primary endpoint was PFS, secondary endpoints included OS, objective response rate (ORR), disease control rate (DCR), and safety. PFS was calculated from the time of first administration to the time of disease progression or death, OS was calculated from the time of first administration to the time of death due to any cause. ORR was defined as the proportion of patients with measurable disease whose best overall response was evaluated as either complete remission (CR) or partial remission (PR). DCR was defined as the proportion of patients who achieved CR, PR, and stable disease (SD). LVEF was monitored at baseline and every three months with an echocardiogram during targeted therapy. Adverse events (AEs) were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, ver. 5.0 (NCI CTCAE 5.0).

4. Statistical analysis

The sample size was calculated using one-sample log-rank test based on the primary endpoint of PFS. According to the data of previous studies (TH3RESA and SOPHIA trial), we assume that PFS shorter than 4.5 months is not ideal, and not shorter than 7.5 months is promising, with a target hazard ratio of 0.60, two-sided alpha level of 5%, and power of 80%, the enrollment time and follow-up time were both 12 months, a Weibull distribution shape parameter of k=1, estimate 39 evaluable subjects, the expected number of events during the study is 31. Considering the actual possible shedding (calculated by 15%), a total of 45 patients was required in this study.
Kaplan-Meier method was used to analyze PFS, OS, and inter-group comparisons were performed using the log-rank test. SPSS ver. 26.0 (IBM Corp., Armonk, NY) was used for all statistical analyses, and p < 0.05 was considered statistically significant.


1. Patient characteristics

A total of 45 patients were enrolled in this study from March 2020 to December 2022. The median age was 56 years (range, 35 to 70 years). The baseline characteristics of the population are provided in Table 1.
Among them, 24 patients (53.3%) had hormone receptor–positive disease, 38 patients (84.4%) had visceral metastases, the median number of previous lines of treatment for metastatic disease was two with a range of one to six, 12 patients (26.7%) were treated in second line and 33 patients (73.3%) were treated in third-line and later setting. The occurrence of relapse was observed in nine patients either during or within 12 months after the completion of adjuvant trastuzumab therapy. Thirty-six patients (80%) had previously received pyrotinib or lapatinib, and seven patients (15.5%) had previously received both T-DM1 and TKIs. Taxanes and vinorelbine were the most common chemotherapy agents combined. Notably, granulocyte colony-stimulating factor (G-CSF) was used prophylactically after chemotherapy in 25 patients (55.6%).

2. Efficacy

At a median follow-up period of 24.4 months (range, 1.2 to 43.9 months), 35 patients (77.8%) in 45 patients had PFS events. The median PFS was 7.6 months (95% confidence interval [CI], 4.3 to 10.9) (Fig. 1), OS was not reached due to short follow-up time. The subgroup analysis of PFS was conducted based on hormone receptor status, presence of liver metastasis, prior treatment line and combined chemotherapy regimen. No statistically significant differences were observed in the subgroup analysis for PFS (Table 2).
The 45 patients had the best clinical response as follows: 14 (31.1%) had a PR, 27 (60%) had SD, four patients (8.9%) had progressive disease, and no patients had CR. The ORR was 31.1%, DCR was 91.1% (Table 3).

3. Safety

The safety profile is summarized in Table 4. AEs of all grades shown had a frequency of 10% or higher. Most toxicities were grade 1–2 and manageable, including neutropenia (20 patients [44.4%]), anemia (nine [20.0%]), diarrhea (nine [20.0%]), alanine aminotransferase/aspartate aminotransferase elevation (eight [17.8%]), grade 3 or higher AEs were mainly neutropenia (three patients [6.7%]) which was considered to be associated with chemotherapy, not with trastuzumab and pertuzumab. No infusion related reaction and no clinical significant decline in LVEF was observed. Overall, the study regimen was generally well tolerated, exhibiting no unexpected toxicities.


To our knowledge, this is the first study to evaluate the efficacy and safety of the trastuzumab biosimilar (HLX02) combined with pertuzumab as second line and beyond treatment in patients with advanced HER2-positive breast cancer after progression of trastuzumab. The median PFS was 7.6 months (95% CI, 4.3 to 10.9), which achieved its priori target promising outcome: 7.5 months. The study regimen was generally well tolerated, no clinical significant decline in LVEF was observed.
The chemotherapy regimens in our study included a variety of physician-selected drugs, most commonly taxanes and vinorelbine, the PFS was 7.6 months, and no significant differences were observed between taxane and non-taxane regimen groups. Furthermore, 73.3% of patients had received at least two lines of therapy, 85% of patients had received pyrotinib, and 15% of patients had received T-DM1 before enrollment.
In the TH3RESA trial, which targeted the later-line population, the median number of previous treatment lines was four, and 100% of the patients were treated with lapatinib, median PFS for T-DM1 and physician’s choice were 6.2 months vs. 3.3 months (p < 0.0001) [15]. In SOPHIA study for margetuximab (M), 91% of the enrolled population had received T-DM1, 65.8% of the patients had received ≤ 2 previous lines of treatment in the metastatic setting, and the investigator-assessed median PFS was 5.7 months with M+chemotherapy vs. 4.4 months with H+ chemotherapy (hazard ratio, 0.70 [95% CI, 0.56 to 0.87]; p=0.001) [16]. Although we cannot compare our data directly with the data from previous studies, a median PFS of 7.6 months is also favorable and promising.
Notably, prior treatment with pertuzumab in the metastatic phase was not allowed in our study. In fact, pertuzumab was not available in China until 2019, and until now, medical insurance only covers the use of pertuzumab in the early stage, not in the metastatic phase, as a result, many patients were treated with single target therapy of trastuzumab in the first-line setting. In PRECIOUS study, median PFS was 5.3 months with TPC and 4.2 months with TC as third- or fourth-line therapy for patients with prior pertuzumab treatment (p=0.022) [10]. And another single-arm study reported a similar PFS of 5.5 months with gemcitabine, pertuzumab, and tratuzumab as second-line and beyond therapy after prior treatment with pertuzumab [8]. Without previous exposure of pertuzumab may contributed to the longer PFS in our study than in the two aforementioned studies. It was mentioned that the recently published PHILA study in China has shown that the first-line treatment with pyrotinib combined with trastuzumab and docetaxel has achieved a PFS of more than 2 years (24.3 months), which is longer than the PFS of THP in CLEOPATRA (18.7 months) [17]. Therefore, pyrotinib has been approved by the China Food and Drug Administration for the first-line treatment of HER2-positive MBC in April 2023. This will lead to new changes in the antiHER2 treatment landscape in China, and pertuzumab may lose its standard position in first-line treatment. Thus this study exploring the efficacy of pertuzumab in the posterior line of treatment has important realistic clinical implications in China.
In Destiny-Breast 03 trial, the median PFS of DS8201 in second-line therapy has reached 28 months [18], and Destiny-Breast 09 trial is ongoing to compare the first-line efficacy of DS8201 and TPC, if it can confirm that DS8201 is superior to the H+P dual-antiHER2 therapy in the first-line treatment, pertuzumab will lose its status as the standard of care in the first-line treatment in the worldwide and may only be used in the later-line treatment after T-DM1 and TKIs by then. Our study provides new data and evidence regarding the efficacy and safety of pertuzumab plus trastuzumab in the treatment of patients beyond the second-line setting.
Regarding to safety, grade 3 and higher AEs were mainly neutropenia, which was lower than reported in previous studies, due to prophylactic use of G-CSF in a significant number of patients. In contrast to other anti-HER2 drugs, most of which have a significant incidence of AE of special interest, such as thrombocytopenia with T-DM1 [15,19,20], diarrhea with TKIs [21-23], higher infusion-related reactions with margetuximab compared with trastuzumab (13.3% vs. 3.4%) [16], interstitial lung disease and gastrointestinal effects with DS8201 [18,24,25], the dual-targeted therapy of trastuzumab and pertuzumab had a lower incidence of perceived toxicity and was better tolerated.
The main limitations of this study are the single arm and single-center study design. Multi-center, and randomized controlled trials could be conducted in the future to address these limitations. Furthermore, the follow-up time was not long enough to allow for OS analysis, additional survival data will be reported with further enrollment and longer follow-up.
In conclusion, this study demonstrated promising efficacy and confirmed favorable safety profile of the combination of trastuzumab biosimilar HLX02, pertuzumab, and chemotherapy as second- and beyond-line treatment in HER2-positive MBC, these findings provide new evidence for use of dual-antibody therapy in late-line setting of HER2-positive MBC.


Ethical Statement

This study was approved by the Ethics Committee of Peking University Cancer Hospital (Approval ID: 2020KT151), all the participants provided written informed consent.

Author Contributions

Conceived and designed the analysis: Zhang R, Li H.

Collected the data: Zhang R, Song G.

Contributed data or analysis tools: Zhang R, Liu X, Song G, Zhang Y.

Performed the analysis: Zhang R, Liu X, Zhang Y.

Wrote the paper: Zhang R, Li H.

Conflicts of Interest

Conflict of interest relevant to this article was not reported.


This work was supported by the WU JIEPING medical foundation (Grant number:320.6750.2020-20-37). We would like to thank all patients and the staff of Peking University Cancer Hospital who participated in our study.

Fig. 1.
Progression-free survival of 45 patients. CI, confidence interval; mPFS, median progression-free survival.
Table 1.
Baseline characteristics of 45 patients
Characteristic No. (%) (n=45)
Age (yr), median (range) 56 (35-70)
ECOG performance status
 0-1 40 (88.9)
 2 5 (11.1)
Hormone receptor
 Positive 24 (53.3)
 Negative 21 (46.7)
Visceral disease involvement 38 (84.4)
 Liver 23 (51.1)
 Lung 25 (55.6)
 Brain 5 (11.1)
Previous trastuzumab exposure
 (Neo)adjuvant setting 17 (37.8)
De novo stage IV 11 (24.4)
 Metastatic setting 30 (66.7)
Previous other anti-HER2 therapy for metastatic disease
 TKI (pyrotinib or lapatinib) 36 (80.0)
 T-DM1+TKI 7 (15.5)
Previous treatment line for metastatic disease, median (range) 2 (1-6)
 1 12 (26.7)
 2 18 (40.0)
 ≥ 3 15 (33.3)
Combined chemo-regimens
 Taxanes 22 (48.9)
  Nab-paclitaxel 17 (37.8)
  Docetaxel 3 (6.7)
  Paclitaxel 2 (4.4)
 Vinorelbine 13 (28.9)
 Capecitabine 4 (8.9)
 Gemcitabine 4 (8.9)
 Eribulin 2 (4.4)

ECOG, Eastern Cooperative Oncology Group; HER2, human epidermal growth factor receptor 2; TKI, tyrosine kinase inhibitor.

Table 2.
PFS of subgroups for 45 patients
Subgroup No. (events) Median PFS (mo) (95% CI) p-value
Hormone receptor
 Negative 21 (15) 10.3 (6.1-14.5) 0.199
 Positive 24 (20) 5.8 (4.0-7.5)
Liver metastasis
 Yes 23 (18) 6.2 (4.0-8.4) 0.460
 No 22 (17) 8.2 (6.0-10.4)
Prior treatment lines
 1 12 (8) 6.2 (0-18.9) 0.492
 ≥ 2 33 (27) 7.6 (4.8-10.3)
Chemotherapy regimen
 Taxanes 22 (17) 7.6 (3.1-12.1) 0.721
 Non-taxanes 23 (18) 7.4 (4.5-10.3)

CI, confidence interval; PFS, progression-free survival.

Table 3.
Best overall response of 45 patients
Best overall response No. (%) (n=45)
CR 0
PR 14 (31.1)
SD 27 (60.0)
PD 4 (8.9)
ORR (CR+PR) 14 (31.1)
DCR (CR+PR+SD) 41 (91.1)

CR, complete response; DCR, disease control rate; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Table 4.
Adverse events of 45 patients
Adverse event No. (%) (n=45)
Grade ≥ 3 adverse event 3 (6.7)
LVEF (< 50% or ≥ 15% reduction from baseline) 0
Infusion-related reaction 0
Most common adverse eventsa)b)
 Diarrhea 9 (20.0)/9 (20.0)/0
 Neutropenia 20 (44.4)/17 (37.8)/3 (6.7)
 Anemia 9 (20.0)/9 (20.0)/0
 ALT/AST elevation 8 (17.8)/8 (17.8)/0

ALT, alanine aminotransferase; AST, aspartate aminotransferase; LVEF, left ventricular ejection fraction.

a) Reported in ≥ 10% of patients,

b) All grade/grade 1-2/grade 3-4.


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