Evaluation of Biosimilar Trastuzumab MYL-1401O in HER2-Positive Breast Cancer

ABSTRACT

Objectives: The trastuzumab biosimilar MYL-1401O has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) as HER2 monotherapy.

Study Design: Here, we present the first real-world comparison of MYL-1401O vs RTZ as single/dual HER2-targeted therapy for the neoadjuvant, adjuvant, and palliative treatment of HER2-positive breast cancer in the first and second lines.

Methods: We retrospectively investigated medical records. We identified patients with HER2-positive early-stage breast cancer (EBC) (n = 159) who had received neoadjuvant chemotherapy with RTZ or MYL-1401O ± pertuzumab (n = 92) or adjuvant chemotherapy with RTZ or MYL-1401O plus taxane (n = 67) between January 2018 and June 2021, as well as patients with MBC (n = 53) who had received palliative first-line treatment with RTZ or MYL-1401O and docetaxel ± pertuzumab or second-line treatment with RTZ or MYL-1401O and taxane between January 2018 and June 2021.

Results: The rate of achieving pathologic complete response in patients receiving neoadjuvant chemotherapy was similar between those receiving MYL-1401O and RTZ (62.7% [37/59] and 55.9% [19/34], respectively; P = .509). Progression-free survival (PFS) at 12, 24, and 36 months was similar in the 2 cohorts of the EBC-adjuvant group: 96.3%, 84.7%, and 71.5%, respectively, in patients receiving MYL-1401O, and 100%, 88.5%, and 64.8% in patients receiving RTZ (P = .577). Median PFS was also similar in MBC, at 23.0 months (95% CI, 9.8-26.1) in patients receiving MYL-1401O and 23.0 months (95% CI, 19.9-26.0) in patients receiving RTZ (P = .270). The overall response rate, disease control rate, and cardiac safety profiles did not show significant differences in efficacy outcomes between the 2 groups.

Conclusions: These data suggest that biosimilar trastuzumab MYL-1401O has similar effectiveness and cardiac safety to RTZ in patients with HER2-positive EBC or MBC.

Am J Manag Care. 2023;29(2):e36-e42. https://doi.org/10.37765/ajmc.2023.89234

Takeaway Points

• The trastuzumab biosimilar MYL-1401O has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer (MBC) as HER2 monotherapy.
• Here, we present the first real-world comparison of MYL-1401O vs RTZ as single/dual HER2-targeted therapy for neoadjuvant, adjuvant, and palliative treatment of HER2-positive breast cancer in the first and second lines.
• These real-world data suggest that biosimilar trastuzumab MYL-1401O has effectiveness and cardiac safety similar to that of RTZ in patients with HER2-positive early-stage breast cancer or MBC.

Biologic drugs, also known as biologic therapeutics or biologics, are medications produced by living organisms, including human, animal, or microorganism cells. Today, they are usually produced through biotechnology. Biologics can include proteins, sugars, and nucleic acids, as well as living entities such as gene therapies. The development of new biological agents is difficult and very expensive, which can result in high drug costs.¹ Therefore, despite their effectiveness, the high costs of these drugs precludes their use by patients in need in some countries.1 These disadvantages can be partially mitigated by the administration of biosimilars.¹ A biosimilar is very similar (with only minor differences in clinically inactive components) to a drug already in use, and it has no clinically significant difference from the original or reference product in purity, safety, and efficacy.¹ However, biosimilars are generally more cost-effective than reference products.^2,3 Moreover, the applicability of biosimilars is likely to increase the accessibility of treatment that is safe and effective.

Breast cancer is the most frequent cancer and most frequent cause of cancer death in women around the world.^4-6 Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 25% to 30% of breast cancers.^7,8 Trastuzumab is a humanized immunoglobulin G1 monoclonal antibody targeting HER2.⁷ The combination of chemotherapy and trastuzumab has been demonstrated to increase disease-free survival and overall survival in HER2-positive early-stage breast cancer (EBC) and metastatic breast cancer (MBC).^9-12 Trastuzumab was also approved for metastatic gastric or gastroesophageal junction adenocarcinoma after it was approved for HER2-positive breast cancer.

Several biosimilars of trastuzumab have been developed and are currently in use. These include MYL-1401O (Ogivri; Viatris Inc),¹³ CT-P6 (Herzuma; Celltrion Healthcare),^14,15 SB3 (Ontruzant; Samsung Bioepis Co, Ltd),¹⁶ ABP 980 (Kanjinti; Amgen),¹⁷ and PF-05280014 (Trazimera; Pfizer).¹⁸ MYL-1401O (trastuzumab-dkst) has the same amino acid sequence as trastuzumab (Herceptin; Genentech).¹⁹ The similarity between MYL-1401O and reference trastuzumab (RTZ), sourced from both the United States and Europe, was demonstrated in physicochemical, preclinical, and pharmacokinetic studies.^20,21 The combination of MYL-1401O and taxane-based chemotherapy as first-line therapy in MBC was compared against trastuzumab with taxane-based chemotherapy in the phase 3 HERITAGE trial (NCT02472964).¹³ The overall response rate (ORR) at 24 weeks, which was the primary end point, was equivalent between the biosimilar and RTZ groups¹³; thus, MYL-1401O is approved in the United States and Europe. At the end of 24 weeks, patients with stable or responsive disease continued on maintenance monoclonal antibody monotherapy until progression in the HERITAGE trial.¹³

Demonstrating the long-term safety and efficacy of biosimilar drugs in larger patient populations, including results in neoadjuvant/adjuvant 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, dual HER2 targeting with trastuzumab and pertuzumab plus chemotherapy has been demonstrated to induce better clinical responses compared with trastuzumab plus chemotherapy alone.^22-24 However, there is no clinical study of MYL-1401O in a single/dual combination in early-stage disease and a dual combination in advanced disease.

The purpose of our study is to contribute to the literature by assessing real-world efficacy and safety data on the use of MYL-1401O in patients with early and advanced stages of breast cancer being treated at 2 academic oncology centers in Mersin, Turkey.

MATERIALS AND METHODS

In this study, medical data were collected retrospectively from the Department of Medical Oncology, Mersin University Faculty of Medicine, and the Department of Medical Oncology, Mersin City Training and Research Hospital. Patients with nonmetastatic HER2-positive breast cancer received neoadjuvant (mostly patients with locally advanced disease) or adjuvant (mostly patients with early-stage disease) chemotherapy between January 2018 and June 2021. HER2-positive MBC was defined as newly diagnosed de novo or recurrent disease in patients who received palliative chemotherapy between January 2018 and June 2021. Our study was approved by Mersin University Ethics Committee with the number of 2021/789.

In the American Joint Committee on Cancer [AJCC] Cancer Staging Manual, Seventh Edition, EBC was classified as clinical stage II to III. MBC was classified to include eligible patients, both those who had previously received and those who did not receive palliative therapy for advanced disease.

Procedures

In the nonmetastatic group, 2 different protocols were applied in those receiving neoadjuvant therapy. After 4 cycles of AC (doxorubicin 60 mg/m2, cyclophosphamide 600 mg/m2; 21-day cycle), patients received either (1) 4 cycles of taxane plus trastuzumab (8 mg/kg in first cycle, 6 mg/kg in cycles 2-4) or (2) 4 cycles of taxane plus trastuzumab (8 mg/kg in first cycle, 6 mg/kg in cycles 2-4) plus pertuzumab (840 mg in first cycle, 420 mg in cycles 2-4). Then, both groups completed 1 year of trastuzumab, with or without pertuzumab. Adjuvant therapy consisted of 4 cycles of AC followed by 4 cycles of taxane plus trastuzumab followed by 1 year of trastuzumab.

The metastatic group included patients receiving either (1) taxane plus trastuzumab after 4 cycles of AC or (2) taxane plus trastuzumab plus pertuzumab. Pertuzumab and MYL-1401O or RTZ were given until disease progression or until intolerability developed. Pertuzumab, docetaxel, and RTZ or MYL-1401O were given at the same doses in the metastatic group as in the neoadjuvant group.

Outcome Measures

The primary end points were pathological complete response (pCR) in the neoadjuvant group and progression-free survival (PFS) in the adjuvant and metastatic groups, and pCR was examined locally at the hospital surgery center. The absence of invasive tumor cells in the primary tumor and in the axillary lymph node was defined as pCR. Median PFS is the time from the start of palliative systemic therapy containing MYL-1401O or RTZ to the day the progression is documented. Because the EBC-adjuvant group did not progress sufficiently to determine the median PFS, the PFS rates at 12, 24, and 36 months were measured.

The secondary end points in the metastatic group were the ORR and the disease control rate (DCR). ORR is the sum of complete response (CR) and partial response (PR) according to RECIST 1.1 criteria. DCR is the sum of CR, PR, and stable disease according to RECIST 1.1 criteria.

Cardiac safety was a secondary end point in the neoadjuvant, adjuvant, and metastatic groups. A decrease of at least 10 percentage points in left ventricular ejection fraction (LVEF) from baseline in any condition or a reduction in LVEF to less than 50% at any time was defined as a cardiac adverse effect.

Statistical Analysis

Differences in pCR, ORR, and DCR between the RTZ and MYL-1401O treatment groups were evaluated by χ² or Fisher exact test. For calculating PFS, generating survival curves, and log-rank testing, the Kaplan-Meier method was used. The difference was considered significant when the P value was less than .05.

RESULTS

Our study had 212 total patients; all were women. Of a total of 159 patients with HER2-positive EBC, 92 patients received neoadjuvant therapy followed by surgery, and 67 patients received adjuvant therapy after surgery (eAppendix [available at ajmc.com]). In neoadjuvant therapy, baseline characteristics were similar between patients receiving MYL-1401O (n = 59; 64.1%) and patients receiving RTZ (n = 33; 35.9%). In adjuvant therapy, patients receiving MYL-1401O (n = 27; 40.2%) and patients receiving RTZ (n = 40; 59.8%) had similar baseline characteristics (Table 1).

We also followed a total of 53 patients with HER2-positive MBC with recurrent or de novo stage IV disease (eAppendix). MBC patients who received palliative treatment between January 2018 and June 2021 received chemotherapy containing trastuzumab in the first line or second line. Those who received treatment in the first line received docetaxel, trastuzumab, and pertuzumab, and those who received treatment in the second line received taxane and trastuzumab. These rates were similar in the MYL-1401O (first line, 16.0%; second line, 84.0%) and RTZ (first line, 17.9%; second line, 82.1%) groups. The baseline characteristics of patients with MBC receiving MYL-1401O (n = 28; 52.9%) and RTZ (n = 25; 47.1%) were similar. Distant lymph nodes, bone, lung, and liver were the most common sites of metastasis.

Effectiveness in EBC and MBC Groups

The rate of achieving pCR in the group receiving neoadjuvant chemotherapy was similar between MYL-1401O and RTZ, with no significant difference between them (Figure 1). The pCR rate was 62.7% (37/59) in the group receiving MYL-1401O and 55.9% (19/34) in the group receiving RTZ (P = .509). The pCR rate in the hormone receptor (HR)–positive group receiving neoadjuvant therapy was similar in the groups receiving MYL-1401O (58.1%; 18/31) and RTZ (52.6%; 10/19). The pCR rate in the HR-negative group receiving neoadjuvant therapy was similar in the groups receiving MYL-1401O (67.9%; 19/28) and RTZ (64.3%; 9/14).

PFS rates at 12, 24, and 36 months were similar in both groups. In the EBC-adjuvant group, they were 96.3%, 84.7%, and 71.5%, respectively, in patients receiving MYL-1401O, vs 100%, 88.5%, and 64.8% in patients receiving RTZ (P = .577).

The median PFS was similar in both metastatic groups: 23.0 months (95% CI, 9.8-26.1) in patients receiving MYL-1401O vs 23.0 months (95% CI, 19.9-26.0) in patients receiving RTZ (P = .270) (Figure 2). In the HR-positive group, PFS was not reached vs 26 months (95% CI, 23.9-28.0) in those receiving MYL-1401O and RTZ, respectively, with no statistically significant difference (P = .387). In the HR-negative group, there was no statistically significant difference in median PFS in patients receiving MYL-1401O and RTZ at 16 months (95% CI, 12.7-19.2) vs 12 months (95% CI, 8.6-15.3), respectively (P = .376). There was no statistically significant difference in terms of ORR between those receiving MYL-1401O (84.0%) and RTZ (78.6%) (P = .555), nor in terms of DCR (MYL-1401O; 92.0%, vs RTZ; 89.3%) (P = .555) (Table 2).

Cardiac and Drug Reaction Safety

In the EBC cohort, the rate of LVEF did not differ between the 2 treatment groups before neoadjuvant chemotherapy (mean [95% CI] LVEF, 60.4% [50.0%-65.0%] for MYL-1401O vs 61.8% [60.0%-68.0%] for RTZ; P = .134) (Table 3). After neoadjuvant chemotherapy, 5 of 59 (8.4%) patients showed a decrease in LVEF of at least 10 percentage points from baseline in the MYL-1401O group compared with 6 of 33 (18.1%) patients in the RTZ group (P = .193). One patient receiving RTZ and 1 patient receiving MYL-1401O showed a decrease in LVEF to less than 50%, and both of these decreases were reversible.

In the EBC cohort, the rate of LVEF did not differ between the 2 treatment groups before adjuvant chemotherapy (mean [95% CI] LVEF, 60.8% [52.0%-65.0%] for MYL-1401O vs 62.5% [60.0%-68.0%] for RTZ; P = .150) (Table 3). After adjuvant chemotherapy, 3 of 27 (11.1%) patients showed a decrease in LVEF of at least 10 percentage points from baseline in the MYL-1401O group compared with 3 of 40 (7.5%) patients in the RTZ group (P = .679) (Table 3). One patient in the RTZ treatment group showed a decrease in LVEF to less than 50%, but it was reversible.

In the metastatic group, LVEF decreased by more than 10% in 5 of 25 (20.0%) patients in the MYL-1401O group and 4 of 28 (14.2%) patients in the RTZ group (P = .71) (Table 3). In this cohort, no patient experienced a decrease of LVEF to less than 50%, either in the MYL-1401O or RTZ group.

Skin reactions accounted for most of the infusion-related drug reactions (IRDRs) in our trial. The incidence of IRDRs in the neoadjuvant group was similar between MYL-1401O (5/59; 8.4%) and RTZ (1/33; 3.0%) (P = .41) (Table 3). The incidence of IRDRs in the adjuvant group was similar between MYL-1401O (3/27; 11.1%) and RTZ (4/40; 10.0%) (P = .59) (Table 3). The incidence of IRDRs in the metastatic group was similar between MYL-1401O (2/25; 8.0%) and RTZ (2/28; 7.1%) (P = .41) (Table 3).

DISCUSSION

To our knowledge, this is the first study to include real-world data on treatment with MYL-1401O. A phase 3 randomized controlled trial of MYL-1401O did not include patients in the neoadjuvant and adjuvant settings and included only patients with metastatic disease (additionally, none received pertuzumab combination therapy).¹³ In biosimilar therapy, showing similar treatment response efficacy in metastatic disease is sufficient to obtain approval for use.25 Our retrospective study is the first in the literature on MYL-1401O that includes efficacy and safety data from the neoadjuvant and adjuvant settings in addition to the metastatic disease setting. The results of the study help to reduce the current literature gap on the real-world use of oncology biosimilars among women with breast cancer being treated in Turkey.

In our study, the pCR rates 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 the MYL-1401O and RTZ groups, two-thirds of our patients received AC plus taxane and one-third received AC plus taxane plus pertuzumab. The pCR rates in our patients were similar to those in the study of the chemotherapy combination in the relevant literature (64.7% without pertuzumab, 61.8% with pertuzumab in different trials).^26,27

In addition to reflecting real-world data, our study shows that MYL-1401O is as effective as RTZ in combination treatment with pertuzumab in patients with HER2-positive MBC. In the CLEOPATRA study (NCT00567190), the addition of pertuzumab to first-line trastuzumab-docetaxel palliative treatment in HER2-positive MBC was compared against docetaxel-trastuzumab, and PFS was 18.5 months vs 12.4 months (P < .001), whereas OS was 56.5 months vs 40.8 months (P < .001), respectively. The ORR in the CLEOPATRA study was 80.1% with pertuzumab and 69.3% without pertuzumab.²⁴ Most patients in our study received treatment with pertuzumab. This is consistent with the proportion of patients who received the combination of pertuzumab plus MYL-1401O (82%) or pertuzumab plus RTZ (80%) in our study.

Trastuzumab’s potential cardiotoxicity is well known¹²; it often causes an asymptomatic decrease in LVEF. Serious cardiac toxicity was not observed in any patient in our study. Two patients who received neoadjuvant therapy (1 receiving MYL-1401O, 1 receiving RTZ) and 1 who received adjuvant therapy (with MYL-1401O) had LVEF decrease to less than 50%. This low cardiotoxicity is comparable with the cardiotoxicity rate of RTZ observed in a neoadjuvant study with and without pertuzumab.²⁶

No patients with metastatic disease had LVEF decrease to less than 50% in our study. This rate is better than those seen in the HERITAGE (12%) and CLEOPATRA (6.1%) studies.^24,28

In our study, there was no significant difference in IRDRs among patients in the neoadjuvant, adjuvant, and metastatic groups who received MYL-1401O (8.4%, 11.1%, and 8%, respectively) and RTZ (3%, 10%, and 7.1%; P = .41, P = .59, and P = .55). Rugo et al reported IRDR rates (foremost, rash) of 8.9% and 10.2% in the MYL-1401O and RTZ groups, respectively,²⁸ which are similar to our rates.

One of the important aspects of our study is the examination of large patient populations and different stages of breast cancer. This study adds unique data to the literature because of the previous absence of neoadjuvant and adjuvant studies of MYL-1401O and of pertuzumab combination studies in metastatic disease.

Limitations

One of our study’s limitations is its retrospective nature; another is the heterogeneity of the patients in the treatment arms. Because patients were evaluated separately in 3 groups (neoadjuvant, adjuvant, and metastatic), the numbers of patients per group were relatively small. Because of these small numbers, patients receiving HER2 monotherapy vs dual HER2 therapy could not be evaluated separately in the neoadjuvant group and the metastatic group. Therefore, prospective studies with larger patient populations are required. Another limitation is the short follow-up period in the metastatic group.

CONCLUSIONS

A biosimilar is a biological product that is highly similar in safety, efficacy, and potency to the original product. The development of the biosimilar pharmaceutical industry is necessary due to rising drug prices and difficulty of global access to reference drugs.²⁹ A study conducted in China showed that the use of RTZ is higher in rich countries than in poor countries, and accordingly, survival among patients with both early-stage and metastatic cancer is better in wealthier nations.³⁰ As have previous studies,^1,13,28,31 our study shows that biosimilar drugs are as effective and safe as RTZ. If biosimilar uptake increases, drug expenditure will decrease and access to effective treatments will be easier. Our real-world study has shown that MYL-1401O has similar efficacy and safety as RTZ in neoadjuvant, adjuvant, and metastatic settings as first- or second-line therapy for breast cancer, with or without pertuzumab combination therapy.

Acknowledgments

Medical writing support was provided by Kenan Turgutalp, Prof Dr, and Halil Çelik, PhD.

Author Affiliations: Department of Medical Oncology, Mersin University Faculty of Medicine (KE, ES, VE), Mersin, Turkey; Department of Medical Oncology, Mersin City Education and Research Hospital (Aİ), Mersin, Turkey.

Source of Funding: None.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (KE, VE, Aİ); acquisition of data (KE, VE); analysis and interpretation of data (KE, VE, Aİ); drafting of the manuscript (KE, VE, Aİ); critical revision of the manuscript for important intellectual content (KE, ES); statistical analysis (KE, ES); provision of patients or study materials (ES, Aİ); administrative, technical, or logistic support (KE); and supervision (ES).

Address Correspondence to: Kadir Eser, MD, Department of Medical Oncology, Mersin University Faculty of Medicine, Çiftlikköy Campus, 33343, Yenişehir/Mersin, Turkey.

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