Real-World Comparison of CT-P6 and Reference Trastuzumab for the Treatment of HER2-Positive Early-Stage and Metastatic Breast Cancer

Background: Here, we present the rst real-world comparison of CT-P6 versus reference trastuzumab (RTZ) for the neoadjuvant treatment of patients with HER2-positive EBC, and for the palliative rst-line treatment of patients with HER2-positive metastatic breast cancer (MBC). Methods: We retrospectively identied patients with HER2-positive EBC who had received neoadjuvant treatment with RTZ or CT-P6, plus pertuzumab, carboplatin, and docetaxel, followed by surgery, alongside patients with newly diagnosed HER2-positive MBC who had received palliative treatment with RTZ or CT-P6, plus pertuzumab and docetaxel. The primary endpoints were pathologic complete response (pCR) in the EBC cohort, and progression-free survival (PFS) in the MBC cohort. Results: A similar percentage of patients with EBC achieved a pCR with CT-P6 (74.4% [93/125]) and RTZ (69.8% [90/129]) (p=0.411). For patients with MBC, median PFS did not differ signicantly between the two groups (CT-P6: 13.9 months [95% condence intervals (CIs) not available]; RTZ: 18.4 months [95% CIs 12.5–24.3]; p=0.653). The cardiac safety proles of CT-P6 and RTZ were similar. Conclusions: These real-world data suggest that CT-P6 has similar effectiveness and cardiac safety to RTZ in patients with HER2-positive EBC and MBC, when administered as part of dual HER2-targeted therapy with pertuzumab plus chemotherapy in the neoadjuvant or palliative setting. propensity score matching (PSM) was performed using the nearest-neighbor matching method. Variables entered into the PSM included age, histologic type, histologic grade, estrogen receptor, progesterone receptor, subgroup, Ki67, clinical tumor stage, and clinical node stage. PFS and OS were evaluated using unadjusted log-rank tests and Cox proportional-hazards models. Differences in ORR or DCR between the treatment groups were evaluated using an adjusted Fisher’s exact test. The 95% condence intervals (CIs) for the ORRs were calculated using an asymptotic normal approximation. A two-tailed P-value < 0.05 was considered statistically signicant. The statistical analysis was performed using SPSS version 23 software (SPSS Inc., Chicago, IL, USA).


Background
Breast cancer is a heterogeneous disease that has multiple subtypes. Approximately 25% of breast cancers amplify the human epidermal growth factor receptor 2 (HER2) oncogene, resulting in a more aggressive phenotype with poorer prognosis. [1] The development of trastuzumab, a humanized monoclonal antibody that binds to the HER2 extracellular domain, has transformed the treatment of HER2-positive breast cancers. [2] In patients with operable or locally advanced HER2-positive disease, the addition of trastuzumab to chemotherapy improves clinical responses and event-free survival in the neoadjuvant setting [2][3][4] and long-term disease-free survival in the adjuvant setting. [5] Trastuzumab is also effective in metastatic HER2-positive breast cancer, with the addition of trastuzumab to standard chemotherapy shown to extend time to disease progression, as well as overall survival (OS). [6,7] However, the development of novel biologic agents is expensive, which can translate into high drug costs. [8] Despite their e cacy, the costs associated with these drugs can pose a burden on healthcare systems and create barriers to access. This di culty can be mitigated in part through the use of biosimilars. [8] A biosimilar is a drug that is highly similar to an existing drug -the originator or reference product -and which shows no clinically meaningful differences from the reference product in purity, safety, and e cacy. [8] Biosimilars are in general more affordable than their reference products, and their availability has the potential to improve patient access to safe and effective treatments.
Several biosimilars of trastuzumab have been developed, including CT-P6 (Herzuma®; Celltrion Inc., Incheon, Republic of Korea), [9,10] SB3 (Ontruzant®; Samsung Bioepis Co., Ltd, Incheon, Republic of Korea), [11] ABP 980 (Kanjinti®; Amgen, Thousand Oaks, CA, USA) [12] and PF-05280014 (Trazimera®; P zer, New York City, NY, USA). [13] CT-P6 binds with high a nity and speci city to the same HER2 epitope as the reference product, Herceptin® (Genentech, San Francisco, CA, USA). [9,10] In 2018, CT-P6 was approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of HER2-positive early-stage breast cancer (EBC) and metastatic breast cancer (MBC). [14,15] Approval was based in part on a phase III clinical trial in patients with operable HER2-positive EBC, which showed comparable safety and equivalent e cacy of CT-P6 and reference trastuzumab (RTZ) when administered in combination with docetaxel and uorouracil, epirubicin and cyclophosphamide (FEC). [16,17] Data from a 3-year follow-up study have subsequently con rmed that disease-free survival and OS are similar in patients treated with CT-P6 and RTZ. [18] Real-world studies are an important supplement to clinical trials, by revealing the long-term safety and effectiveness of drugs in broader patient populations, as well as in other settings and in combination with other treatments. For example, RTZ is now increasingly used in combination with pertuzumab (Perjeta®; Genentech) as part of dual HER2-targeted therapy. Pertuzumab is a monoclonal antibody that targets a different region of the HER2 receptor to trastuzumab, [19] and thus has a complementary mode of action. Dual HER2-targeting with trastuzumab and pertuzumab, plus chemotherapy, has been shown to improve clinical responses compared to trastuzumab plus chemotherapy alone in HER2-positive EBC [20,21] and MBC. [22] Here we present the results of the rst real-world comparison of the effectiveness of CT-P6 and RTZ when administered with pertuzumab plus chemotherapy in the neoadjuvant setting to patients with HER2positive EBC, and as palliative rst-line treatment to patients with HER2-positive MBC. As cardiotoxicity is a potentially serious adverse effect associated with the use of RTZ, [6] we also assessed the cardiac safety of CT-P6 and the reference product.

Patients
We retrospectively reviewed the medical records in the EBC and MBC cohort from Severance Breast Cancer Registry at the Yonsei Cancer Center and Gangnam Severance Hospital in Seoul, Republic of Korea (Additional le 1).
We identi ed patients with HER2-positive EBC who had undergone neoadjuvant chemotherapy between April 2015 and October 2019, as well as patients with newly diagnosed de novo or recurrent HER2positive MBC who had undergone palliative chemotherapy between May 2014 and December 2019. For both the EBC and MBC cohorts, eligible patients were women aged > 19 years with a histologically con rmed diagnosis of HER2-positive breast cancer. EBC was de ned as clinical stage II-III, classi ed according to the American Joint Committee on Cancer Breast Cancer Staging seventh edition. In the EBC cohort, eligible women had received neoadjuvant treatment with docetaxel (T)-carboplatin (C)-RTZ or CT-P6 (H)-pertuzumab (P) (TCHP) chemotherapy followed by surgery, and had a primary tumor > 2 cm in diameter or clinically metastatic axillary lymph node-positive cancer. Patients were excluded from the EBC cohort if they had bilateral breast cancer or a history of ductal carcinoma in situ (DCIS) or invasive breast cancer.
Patients with MBC were still eligible if they had received chemotherapy with or without trastuzumab in the neoadjuvant or adjuvant setting, provided there was a minimum 12-month interval between completion of all therapy and the diagnosis of metastatic disease.
Patients were excluded from the MBC cohort if they had received RTZ and docetaxel as rst-line palliative treatment, or if they had switched from RTZ to CT-P6 during treatment.

Procedures
In the EBC cohort, neoadjuvant TCHP treatment was administered via intravenous infusion every 3 weeks, for a total of six cycles, in accordance with procedures in the TRYPHAENA trial. [23] Study drugs were given consecutively on the same day in the following sequence: CT-P6 or RTZ, followed by pertuzumab, carboplatin, and docetaxel. CT-P6 or RTZ were administered at a loading dose of 8 mg/kg on day 1 of cycle 1, and at a maintenance dose of 6 mg/kg on day 1 of cycles 2-6. Pertuzumab was administered at a loading dose of 840 mg, then a maintenance dose of 420 mg in subsequent cycles. Carboplatin was administered at area under the curve 5 or 6 and docetaxel at 75 mg/m 2 , in all cycles.
In the MBC cohort, palliative rst-line treatment with THP was administered via intravenous infusion every 3 weeks, in accordance with procedures in the CLEOPATRA trial. [24] Pertuzumab was given on day 1 of each cycle, at a loading dose of 840 mg in cycle 1, decreasing to a maintenance dose of 420 mg in subsequent cycles. RTZ or CT-P6 were administered on day 1 of each cycle at a loading dose of 8 mg/kg, and then a maintenance dose of 6 mg/kg in subsequent cycles. Docetaxel was given on day 1 of the rst cycle at 75 mg/m 2 . Pertuzumab and RTZ or CT-P6 were given until disease progression or unmanageable toxic effects, and docetaxel was given for at least six cycles. If chemotherapy was discontinued due to toxic effects, pertuzumab and RTZ or CT-P6 were continued until disease progression, or occurrence of unacceptable adverse events.

Study objectives and assessments
The study objective was to compare the effectiveness and cardiac safety of CT-P6 and RTZ in patients with HER2-positive EBC and MBC, when administered as part of a chemotherapy regimen containing pertuzumab in the neoadjuvant or rst-line palliative setting, respectively.
In the EBC cohort, tumor assessments were performed at baseline and after completion of cycle 6 of the neoadjuvant regimen prior to surgery, by ultrasonography or magnetic resonance imaging and clinical breast examination. In the MBC cohort, tumor assessment was performed every 9 weeks based on the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Left ventricular ejection fraction (LVEF) was measured either by echocardiography or a multiple-gated acquisition scan every 3 months, with the same method always used for individual patients.

Outcome measures
The primary endpoints were pathologic complete response (pCR) in the EBC cohort, and progression-free survival (PFS) in the MBC cohort. pCR was assessed locally at the time of surgery and was de ned as the absence of invasive tumor cells during a microscopic assessment of the primary tumor (ypT0/is) and axilla (ypN0). Median PFS was de ned as time from the date of rst-line palliative systemic treatment to the rst documented disease progression or death from any cause.
The secondary endpoints in the MBC cohort were median overall survival (mOS), overall response rate (ORR) and disease control rate (DCR). mOS was the time from the date of rst-line palliative systemic treatment to death from any cause. ORR was de ned as the proportion of patients who achieved a complete response (CR) or con rmed partial response (cPR) per RECIST 1.1. DCR was de ned as the proportion of patients who achieved a CR, cPR, or stable disease (SD) per RECIST 1.1.
Cardiac safety was a secondary endpoint in both the EBC and MBC cohorts. An adverse event related to cardiac safety was de ned as a decline in investigator-assessed LVEF of ≥ 10 percentage points from baseline at any time, or an LVEF of < 50% at any time.

Statistical analysis
Standard descriptive and analytic methods were used to describe the patient population and their baseline characteristics. pCR rate was compared between treatment groups using the chi-square test or Fisher's exact test. To reduce baseline confounders between the CT-P6 group and RTZ group, one-to-one propensity score matching (PSM) was performed using the nearest-neighbor matching method. Variables entered into the PSM included age, histologic type, histologic grade, estrogen receptor, progesterone receptor, subgroup, Ki67, clinical tumor stage, and clinical node stage. PFS and OS were evaluated using unadjusted log-rank tests and Cox proportional-hazards models. Differences in ORR or DCR between the treatment groups were evaluated using an adjusted Fisher's exact test. The 95% con dence intervals (CIs) for the ORRs were calculated using an asymptotic normal approximation. A two-tailed P-value < 0.05 was considered statistically signi cant. The statistical analysis was performed using SPSS version 23 software (SPSS Inc., Chicago, IL, USA).

EBC cohort
Study population A total of 258 women with HER2-positive EBC were identi ed who underwent neoadjuvant treatment with TCHP, followed by surgery, between April 2015 and October 2019 (Additional le 1).
Four patients were excluded owing to the presence of bilateral breast lesions (n = 3) or a history of DCIS/invasive breast cancer (n = 1). The remaining 254 women were analyzed in this study.

Effectiveness
The percentage of patients who achieved a pCR did not differ between the two treatment groups (Fig. 1A) In both groups, the most common sites of metastasis were distant lymph nodes, followed by bone, lung, and liver.

Effectiveness
The median follow-up time was 9.  . 2B and 2C). mOS was 30.0 months in patients who received treatment with CT-P6, and was not reached in the RTZ group (P = 0.880). There was no signi cant difference in mOS between the two treatment groups regardless of HR status (data not shown).

Cardiac safety
Both CT-P6 and RTZ showed a manageable cardiac safety pro le, assessed on the basis of LVEF (Additional le 4). Thirteen out of 38 (34.2%) patients in the CT-P6 group experienced a decline in LVEF of ≥ 10 percentage points from baseline, compared with 25/65 (38.5%) patients in the RTZ group (P = 0.695). Among those who received treatment with CT-P6, 2/38 (5.3%) patients experienced a reduction in LVEF to < 50% at any time. One of these patients discontinued CT-P6 for 1 month before re-starting; the other continued treatment but later discontinued after 3 months owing to progressive disease. Among the patients who received treatment with RTZ, 4/65 (6.2%) experienced a reduction in LVEF to < 50% at any time. Two of these patients discontinued treatment with RTZ, one discontinued for 1 month before restarting, and the other continued treatment with RTZ.

Discussion
To our knowledge, this is the rst real-world study to show that CT-P6 has similar effectiveness and cardiac safety to RTZ in patients with HER2-positive EBC and MBC, when administered as part of dual HER2-targeted therapy with pertuzumab and docetaxel in the neoadjuvant or palliative setting.
Almost 75% of patients with HER2-positive EBC who received CT-P6 achieved a pCR, compared with ~ 70% of patients who received RTZ. In the EBC cohort, a signi cantly greater percentage of patients in the CT-P6 versus RTZ treatment group had a Ki67 index ≥ 14 at baseline (87.5% versus 70.5%; P = 0.005).
Notably, the Ki67 index is known to be a predictive marker for pCR in patients with breast cancer who receive neoadjuvant chemotherapy. [25,26] Therefore, we implemented PSM to reduce confounding bias: in the PSM cohort, there was no difference in response to treatment between the two groups, similar to the ndings for the whole EBC cohort.
In the phase III randomized controlled trial that established the equivalence of CT-P6 and the reference product, no pertuzumab was added to the neoadjuvant regimen. [16] However, since the dual HER2targeted approach may further improve pCR rates compared with use of either monoclonal antibody alone, [20,24,27,28] most patients with HER2-positive breast cancer who received neoadjuvant chemotherapy at our institution were treated with TCHP from 2018, when CT-P6 was approved. For this reason, we compared the e cacy of CT-P6 and RTZ among patients with HER2-positive EBC who received TCHP in the neoadjuvant setting. The current results con rm for the rst time in routine clinical practice that CT-P6 is at least as effective as RTZ when administered as part of dual HER2-targeted therapy with pertuzumab.
Our study also provides the rst real-world evidence that CT-P6 is as effective as RTZ in patients with While not statistically signi cant, the numerical difference in PFS between the treatment groups may re ect the shorter follow-up time for the CT-P6 group than RTZ (9.1 versus 32.3 months, respectively). However, since a relatively large number of censored events occurred early in the follow-up period for CT-P6, but later in the follow-up period for RTZ, a longer-term follow-up analysis will be required to con rm the equivalence of CT-P6 and RTZ with respect to median PFS.
Use of trastuzumab has historically been associated with an increased risk of cardiotoxicity, [6] most often in the form of an asymptomatic decline in LVEF. In the current study, neither CT-P6 nor RTZ showed serious cardiac toxicity pro les. No patients with EBC experienced a reduction in LVEF of < 50% in either treatment group, consistent with the low cardiotoxicity observed in patients with EBC treated with RTZ or CT-P6 in the neoadjuvant [16,21] and adjuvant [17,21] settings. In the current study, 2/38 (5.3%) patients with MBC experienced a decline in LVEF to < 50% with CT-P6, as did 4/65 (6.2%) patients in the RTZ group. A similar decline in LVEF was observed in 6.1% of patients treated with pertuzumabtrastuzumab-docetaxel in the CLEOPATRA trial. [22] One strength of our study is that it included a broader patient population, that is more representative of the patient population as a whole, than the highly selected individuals recruited into clinical trials. This is also the rst study to compare the e cacy and safety of CT-P6 and RTZ in both EBC and MBC based on data from two cancer centers in Korea. There were also limitations: rstly, the study had a retrospective design and a relatively small sample size. Therefore, further prospective and larger studies are warranted. Secondly, the follow-up time for patients who received CT-P6 was shorter than for those who received RTZ. While the analysis found no signi cant difference in median PFS with CT-P6 versus RTZ, a longer follow-up period will be required to con rm their equivalence with respect to PFS, as well as OS.
Despite the established safety and e cacy pro le of RTZ, the high cost of the drug remains a barrier to access, particularly in healthcare systems with fewer resources.
For example, a study in China found that patients with HER2-positive EBC who lived in areas with a relatively high gross domestic product were more likely to receive RTZ than those in areas with a lower gross domestic product. [30] The same study reported better survival outcomes in patients with EBC or MBC who received treatment with RTZ, illustrating how the high cost of RTZ can deprive patients of effective treatments.
Biosimilars can provide treatment that is as safe and effective as RTZ, but at a signi cantly reduced cost. [8] Conclusion This real-world study suggests that the biosimilar CT-P6 has similar e cacy and cardiac safety to RTZ in HER2-positive EBC and MBC, when administered as part of dual HER2-targetd therapy with pertuzumab and chemotherapy in the neoadjuvant or palliative rst-line setting. CT-P6 was well tolerated, with a cardiac safety pro le similar to that of the reference product. The increased use of biosimilars such as CT-P6 has the potential to boost access to life-extending treatments for women with HER2-positive breast cancer.