Evaluation of biosimilar trastuzumab MYL-1401O in HER2-positive early-stage and metastatic breast cancer in real-life data

Background The trastuzumab biosimilar MYL-1401O has demonstrated equivalent ecacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) as non-dual HER2 therapy. Here, we present the rst real-world comparison of MYL-1401O versus RTZ with single/dual HER2-targeted therapy for the neoadjuvant, adjuvan and palliative rst-/second-line treatment with HER2-positive early breast cancer (EBC) and metastatic breast cancer (MBC) patients in two tertiary hospitals in Turkey. Methods We retrospectively investigated medical records in the Severance Breast Cancer Registry in Turkey. We identied patients with HER2-positive EBC (n=159) who had received neoadjuvant chemotherapy (n= 92) with RTZ or MYL-1401O±pertuzumab and adjuvant chemotherapy (n=67) with RTZ or MYL-1401O plus taxan between january 2018 and jun 2021. Stage IV MBC (n=53) who had received palliative rst-line treatment with RTZ or MYL-1401O, and docetaxel±pertuzumab (THP) or second-line treatment with RTZ or MYL-1401O, and taxan between january 2018 and jun 2021. Primary endpoints were pathological complete response in neoadjuvant grup (pCR) and progression-free survival (PFS) in adjuvant and metastatic grup. Secondary endpoints in the metastatic patient group (MBC) was overall response rate (ORR), disease control rate (DCR) and cardiac safety. Results similar between in patients with RTZ (95% CI p=0.577). Median PFS similar in metastatic group, 23.0 (9.8-16.1) months in patients with MYL-1401O and 23 (19.9-26.0) months in patients with RTZ (95% CI p=0.270). The ORR, DCR, and cardiac safety proles did not also show signicant difference ecacy outcomes between two groups. Conclusion These real-world data suggest that biosimilar trastuzumab MYL-1401O has similar effectiveness and cardiac safety to RTZ in HER2-positive EBC and MBC patients when administered as part of single/dual HER2-targeted therapy with chemotherapy in the neoadjuvant, adjuvant or palliative setting.


Introduction
Development of new biological agents di cult and pricey, which can result in high drug costs [1]. Therefore, despite their effectiveness, these drugs cannot be used for patients in need in some countries due to the high costs [1]. These disadvantages can be partially reduced by the administration of biosimilars [1]. A biosimilar is very similar to a drug already in use, in addition, it has no clinically signi cant difference with the original or reference product in purity, safety and e cacy [1]. However, biosimilars are generally more cost-effective than reference products. Moreover, the applicability of biosimilar is likely to increase the accessibility of the treatments safety and effectively Breast cancer is the most frequently cancer and most frequently reason of cancer death in women around the world [2][3][4]. Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 25% to 30% of breast cancers [5,6]. Trastuzumab is a humanized IgG1 mAb targeting HER2 [5]. The combination of chemotherapy (CT) and trastuzumab has been demonstrated to increase disease-free survival (DFS) and overall survival (OS) in HER2-positive early stage and metastatic breast cancer (mBC) [7][8][9][10]. Trastuzumab is also approved for metastatic gastric or gastroesophageal junction adenocarcinoma after con rmation of HER2 positive breast cancer.
Demonstrating long-term safety and e cacy of biosimilar drugs in larger patient populations, including results in neo/adjuvan settings and in combination with other treatments makes real-world studies an important complement to clinical studies. A good example is the increasing use of RTZ in combination with pertuzumab (Perjeta®; Genentech) as part of dual HER2-targeted therapy. In HER2-positive EBC and MBC double HER2-targeting with trastuzumab and pertuzumab plus CT has been demonstrated to develop clinical responses compared to trastuzumab plus CT alone [20][21][22]. However, there is no clinical study with MYL-1401O in single/dual combination in early stage disease and dual combination in advanced disease.
The purpose of our study is to contribute to the literature to complete the missing data (e cacy and safety data) in the early and advanced stages, as well as to present the real-life data of myl-1401O.

Material And Method
In this study, medical data were collected retrospectively from Mersin University Medical Faculty Medical Oncology Department and Mersin City Training-Research Hospital Medical Oncology Department.
Patients with HER2 positive EBC as those who received neoadjuvant/adjuvant chemotherapy between January 2018 and June 2021. HER2-positive MBC was de ned as newly diagnosed de novo or recurrently patients who received palliative chemotherapy between January 2018 and June 2021.
American Joint Cancer Breast Cancer Staging Committee according to the seventh edition classi cation, EBC were de ned as clinical stage II-III. In the MBC group, eligible patients had previously received and did not receive palliative therapy in advanced disease were included.

Prosedures
In the non-metastatic group, 2 different protocols were applied in those receiving neoadjuvant therapy: patients who received taxan+trastuzumab(8mg/kg at rst cycle, 6 mg/kg at 2-4. cycles) after 4 cycles of AC(Adriamicin 60 mg/m2, Cyclophosphamide 600 mg/m2, 21 day cycle) or patients who received 4 cycles taxan+trastuzumab (8mg/kg at rst cycle, 6 mg/kg at 2-4. cycles)+pertuzumab (840 mg at rst cycle, 420 mg at 2-4. cycle) after 4 cycles of AC. There was no statistical difference between the groups in terms of MYL-1401O and RTZ usage rates. Adjuvant therapy was applied as 4 cycles AC followed by 4 cycles of taxan+trastuzumab followed by a single trastuzumab completion to 1 year.
In the metastatic group: patients receiving taxan+trastuzumab after 4 AC or patients receiving taxan+trastuzumab+pertuzumab. There was no statistical difference between the groups in terms of MYL-1401O and RTZ usage rates. Pertuzumab and MYL-1401O or RTZ were given until disease progression or unmanaged toxic state. Pertuzumab, docetaxel and RTZ or MYL-1401O were given in the same doses in the metastatic group as in the neoadjuvant group.

Outcome Measures
Primary endpoints were pathological complete response in neoadjuvant grup (pCR) and progression-free survival (PFS) in adjuvant and metastatic grup, pCR was examined locally at the center of surgery.
Absence of invasive tumor cells in the primary tumor and in the axillary lymph node was de ned as pCR. Median PFS is the time from the start of palliative systemic therapy containing MYL or RTZ to the day the progression is documented.
Secondary endpoints in the metastatic patient group (MBC) was overall response rate (ORR), and disease control rate (DCR). ORR is the sum of complete response (CR) and partial response (PR) according to RECIST 1.1. DCR is the sum of CR, PR, stable disease (SD) according to RECIST 1.1.
Cardiac safety was a secondary endpoint in neoadvuvant, adjuvant and metastatic grup. ≥10 percentage point decrease in LVEF from baseline in any condition or <50% LVEF reduction at any time was de ned as an cardiac side effect.

Statistical Analysis
Differences in pCR, ORR, and DCR between the RTZ and MYL-1401O treatment groups were evaluated by chi-square or scher's exact test. For calculating PFS, generating survival curves and log-rank testing, Kaplan-Meier method was used. The statistical difference was considered signi cant when the P-value was <0.05.

Results
The total number of patients in our study is 212. Of a total of 159 female patients with HER2 positive EBC, 92 patients received neoadjuvant therapy followed by surgery and 67 patients received adjuvant therapy after surgery. In neoadjuvant therapy patients receiving MYL (n=59, 64.1%) and patients receiving RTZ (n=33, 35.9%) baseline characteristics were similar. In adjuvant therapy, patients receiving MYL (n=27, 40.2%) and patients receiving RTZ (n=40, 59.8%) baseline characteristics were similar.
In our study, we followed a total of 53 HER2 positive metastatic patients with recurrent or de novo stage IV. MBC patients who received palliative treatment between January 2018 and June 2021, chemotherapy containing trastuzumab some of in the 1st line or some in the 2nd line. Those who received treatment in the 1st line received THP, those who received treatment in the 2nd line received TH. These rates were similar in the MYL (1. line 16%, 2. line 84%) and RTZ(1. line 17.9%, 2. line 82.1%) groups. Patients receiving MYL (n=28, 52.9%) and patients receiving RTZ (n=25, 47.1%) baseline characteristics were similar. Distant lymph nodes, bone, lung and liver are the most common sites of metastasis.

Effectiveness of EBC and MBC Groups
The rate of achieving pCR in the group receiving neoadjuvant chemotherapy was similar between MYL and RTZ, there was no statistical difference ( Figure 1)

Discussion
To our knowledge, this is the rst study to include real-life data on the treatment of MYL-1401O. Phase 3 randomized controlled trial of MYL-1401O did not include neoadjuvant and adjuvant patients, only includes metastatic patients (they also did not receive pertuzumab combination therapy) [11]. In biosimilar therapy, showing similar treatment response e cacy in metastatic disease is su cient to obtain approval for use [23]. Our study is the rst in the literature in that MYL-1401O includes neoadjuvant/adjuvant therapy similarity e cacy and safety data in addition to metastatic disease.
In our study, the PCR ratio of those who received MYL-1401O (62.7%) and RTZ (55.9%) were similar in neoadjuvant treatment. PCR rates differ according to the chemotherapy combination received by the patients. In both MYL-1401O and RTZ group, 2/3 of our patients received AC+taxan, 1/3 AC+taxan+pertuzumab. The PCR rates in our patients are similar to the study of the chemotherapy combination in the relevant literature (without pertuzumab 64.7%, with pertuzumab 61.8% in different trials) [24,25].
In addition to re ecting real-life data, our study shows that MYL-1401O is as effective as RTZ in the combination treatment with pertuzumab in metastatic HER2 positive patients. In the CLEOPATRA study, the addition of pertuzumab to rst-line trastuzumab-docetaxel palliative treatment in HER2 positive metastatic BC was compared docetaxel-trastuzumab, PFS was 18.5 months vs 12.4 months (p<0.001), OS was 56.5 months vs 40.8 months (p<0.001), respectively was found. The ORR rate in CLEOPATRA study was 80.1% with pertuzumab, 69.3% without pertuzumab [22]. Most of the patients in our study received treatment with pertuzumab. This is consistent with the proportion of patients who received the combination of pertuzumab+MYL-1401O (82%) or +RTZ (80%) in our study.
The cardiotoxic effect of trastuzumab use has been known for a long time [10], and it often causes an asymptomatic decrease in LVEF. Serious cardiac toxicity was not observed in any patient in our study. 2 of the patients who received neoadjuvant (1 MYL-1401O, 1 RTZ) and 1 adjuvant therapy (with MYL-1401O) had LVEF <50. This low cardiotoxicity is comparable to the rate of RTZ in the neoadjuvant study without pertuzumab and the study with pertuzumab [24].
No patients had LVEF <50 in metastatic patients in our study. This rate is better than the HERİTAGE (12%) and the CLEOPATRA (6.1%) study [22,26].
One of the important aspects of our study is the examination of large patient populations and different stages of BC disease. This study is the only and unique data in the literature due to the absence of neoadjuvant and adjuvant studies of MYL-1401O and absance of pertuzumab combination study in metastatic disease.
One of the limitations of our study is retrospective nature and the heterogeneity of the patients in the treatment arms. Therefore, prospective studies with larger patient populations are required. The second limitation is the short follow-up period in metastatic patient groups.
Biosimilars are biological products that are highly similar in safety, e cacy, and potency to the original product. The development of the biosimilar pharmaceutical industry is necessary due to rising drug price costs and global reach [27]. A study conducted in China showed that the use of RTZ is higher in rich countries than in poor countries, and accordingly, survival is better in both the early and metastatic stages [28]. As in previous studies [1,11,26,29], our study has shown that biosimilar drugs are as effective and safe as RTZ. In this way, drug-expenditure will decrease and access to effective treatments will be easier.
Our real-life study has shown that MYL-1401O has similar e cacy and safety as RTZ in neoadjuvant, adjuvant, and metastatic therapy as rst-or second-line therapy, with or without pertuzumab combination therapy.   Percentage of patients with HER2-positive early-stage (neoadjuvant) breast cancer who achieved a pCR following MYL-1401O or RTZ treatment, strati ed by HR status for all patients. HER2, human epidermal growth factor receptor 2; HR, hormone receptor; pCR, pathologic complete response; RTZ, reference trastuzumab