Real-world clinical scenarios during introduction of trastuzumab biosimilar for HER2-positive breast cancer in the European Union

HER2 amplification (HER2+) occurs in approximately a fifth of breast cancer cases and had been associated with a poor prognosis prior to the availability of trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of HER2 [1–3]. Intravenous (iv.) trastuzumab (Herceptin^®; Genentech) was approved by the US FDA in September 1998 and by the European Medicines Agency (EMA) in August 2000 for treatment of HER2+ metastatic breast cancer [4,5]. Over the past few decades, prolonged survival of patients with HER2+ breast cancer in pivotal trials and real-world settings has been attributed to treatment with trastuzumab [3,6,7]. Trastuzumab is approved for the treatment of HER2+ adjuvant and metastatic breast cancer and HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma [4], and for HER2+ metastatic and early breast cancer as well as HER2+ metastatic gastric cancer in the European Union [5]. A subcutaneously (SC) administered formulation of trastuzumab (Herceptin Hylecta™ [trastuzumab and hyaluronidase-oysk]; Genentech), indicated only for HER2+ breast cancer, was approved in 2013 and 2019 by the EMA and FDA, respectively [8,9].

Despite improved survival with trastuzumab treatment of HER2+ breast cancer, observational studies from the USA, the UK and European Union spanning the years between 2000 and 2015 suggested that up to approximately 60% of patients with HER2+ breast cancer might not have received anti-HER2 therapy at some point during their course of treatment [10].

Trastuzumab use in early and curative disease stages can be limited by high patient out-of-pocket expenses and reimbursement denials discouraging its use [8]. The trastuzumab SC formulation has been shown to reduce costs of drug administration time in Europe [11,12], but this benefit has been disputed based on arguments that costs associated with different adverse events between formulations have not been factored into these analyses [13]. The cardiac adverse events associated with trastuzumab also discourage use by patients and physicians [8,14].

Biosimilars provide access to more cost-effective treatments [15]. Indications for biosimilars can be extrapolated, based on the extension of clinical data for reference products (RPs) to biosimilars, to garner approval for all RP indications without multiple individual comparator studies. These savings can contribute to reducing healthcare costs [16]. The approval of trastuzumab biosimilars are contingent on extensive analytical and clinical studies that demonstrate no meaningful difference in safety, purity and potency compared with RP (trastuzumab) [17–19]. Currently, five biosimilars to trastuzumab are available in the USA and European Union [8].

Among barriers to biosimilar uptake is a lack of real-world characterization of their use [20]. A systematic review of studies investigating current USA and EU healthcare provider knowledge, perceptions and prescribing patterns of biosimilars reported gaps in knowledge about biosimilars that foster concerns about their safety, efficacy, extrapolation and pharmacy-driven substitution [20]. The American Society of Clinical Oncology (ASCO) recommends that, to educate oncologists, real-world clinical use data should be collected and disseminated to help establish practice guidelines for how biosimilars are prescribed, administered and dispensed [21]. Similar education recommendations in oncology have been proposed by country healthcare providers and industry experts in the European Union [22,23].

Trastuzumab-anns (iv.) (Kanjinti^®; Amgen) the first marketed biosimilar to trastuzumab, demonstrated no clinically meaningful difference in risk difference and risk ratio of pathological complete response from the RP in the phase III LILAC study and in other comparisons with RP [24–27]. Trastuzumab-anns was approved by the EMA on 16 May 2018 [28], and by the FDA on 13 June 2019, for treatment of HER2+ early and metastatic breast cancer as well as metastatic gastric cancer [29,30]. The first insight into trastuzumab-anns uptake and use, after the July 2019 launch in the USA, was obtained from a retrospective, observational analysis of cancer patients using structured data from the Flatiron Health electronic health record-derived database [31]. Trastuzumab-anns was used within the first 4 days after market entry, and 2997 patients with recorded use of trastuzumab-anns were eligible for the study during the following 12 months, suggesting rapid and robust uptake of trastuzumab-anns. Most patients treated with trastuzumab-anns had a breast cancer diagnosis and more than half of patients had been treated with RP prior to initiating trastuzumab-anns. Most of these patients received trastuzumab-anns within 28 days of last treatment with RP.

The current descriptive, observational chart review expands knowledge regarding treatment characteristics of patients who received trastuzumab-anns to real-world clinical practice settings in seven countries in the European Union.

Methods

Study design

This was a single-arm, observational, serial chart review of adult patients with HER2+ breast cancer who received trastuzumab-anns in routine clinical practice sites in selected countries in Europe (France, Italy, Spain, Greece, The Netherlands, Poland and Romania). Sites included in the study had a focus on treating subjects with breast cancer. A range of center types within a given country were selected to take part in the study including academic, local, and, where relevant, private offices. Sites were selected to ensure a good geographical spread within each country. Inclusion of specific country sites in the study were dependent on local feasibility, regulatory and ethics committee requirements and were conducted in seven countries. Site selection was based on interest in study participation, and willingness and capacity to comply with protocol and data entry conventions. Within each country, sites were selected to ensure a representative geographical spread.

The study started at enrollment of the first subject, on 28 October 2019, and continued until closing on 13 October 2021, 12 months after enrollment of the last subject. The overall study duration was approximately 24 months (Figure 1). After enrollment, patients could be followed for up to 24 months until withdrawal of consent, death, loss to follow-up, entry into interventional trial, or end of study (12 months after last patient enrolled), whichever occurred first. Data pertaining to the interval between trastuzumab-anns initiation and study enrollment were collected retrospectively. From enrollment onward, data were abstracted prospectively from the medical records on a quarterly basis until the follow-up period ended.

Patient population

All patients enrolled in the study were ≥18 years of age, had metastatic or early HER2+ breast cancer at any stage of disease or phase of treatment, and had initiated to trastuzumab-anns. Patients were excluded from the study if they had any other cancer types concurrent with breast cancer, were currently participating in a concurrent interventional trial, or whose medical chart was not available for data extraction. With respect to prior trastuzumab use, patients were categorized as switchers if they had been administered any trastuzumab brand prior to trastuzumab-anns initiation. All other patients were categorized as trastuzumab treatment-naive. A patient's informed consent to participate (where required per country regulation) was requested only after the patient had initiated trastuzumab-anns.

Outcomes & procedures

The primary objectives of this study were to describe characteristics of patients with HER2+ breast cancer receiving trastuzumab-anns and whether patients were trastuzumab-treatment naive or had switched from a different trastuzumab brand. For patients who had previously received trastuzumab RP, the study investigated the route of administration (iv. or SC). Other objectives of the study were to describe use of concurrent anticancer therapies given with trastuzumab-anns and to describe reasons for trastuzumab-anns discontinuation.

Primary outcome variables of the study were the trastuzumab-anns regimen details, reasons for trastuzumab-anns discontinuation, and post trastuzumab-anns treatment. Regimen details included treatment setting (neoadjuvant, adjuvant, or metastatic), line of therapy, concomitant anticancer therapy and trastuzumab-anns dose. Exploratory outcome variables included evidence of documentation in patient charts of patient education or information on the biosimilar; overall safety and adverse events of interest, including cardiac dysfunction, administration/infusion-related reactions, neutropenia, pulmonary disorders and infections; cardiac assessments; breast cancer stage at follow-up; disease response assessments, together with time from trastuzumab-anns initiation to these disease responses; and Eastern Cooperative Oncology Group Performance Status during follow-up. Data for this study, which were collected at least quarterly, were derived from medical records that were kept per routine clinical practice to document decision-making for a patient's care. Abstracted data from the medical records were transcribed by trained site staff onto an electronic case report form to make a longitudinal cohort of subjects for analysis.

Treatment-emergent adverse events (TEAEs) were analyzed and included events starting on or after trastuzumab-anns initiation up to 30 days after the last trastuzumab-anns dose. Treatment-related adverse events were determined by investigators.

Statistical analysis

The statistical analysis for this study was descriptive. No formal hypothesis was tested. Data were presented for the full analysis set, which included all subjects who received trastuzumab-anns and who met all eligibility criteria. Analyses were presented by treatment setting and trastuzumab initiation status.

Results

Patient population

A total of 488 trastuzumab-anns-treated subjects were enrolled, sequentially, from 42 participating sites in seven countries. Most patients in the study were from Spain, France and Poland (Figure 2). The vast majority of treatment sites (92.9%, n = 39) were hospitals, more than half were nonacademic (n = 24, 57.1%), and almost two-thirds were publicly funded (n = 27, 64.3%; Supplementary Table 1). Hospital policy on biosimilar use was documented in just over a third of sites (n = 15, 35.7%); most patients (n = 309, 63.3%) had no documentation in the medical record of having been informed they would receive a trastuzumab biosimilar (Supplementary Figure 1).

Patients were predominantly (n = 483, 99%) female, and the median age was 56 years. Most patients (n = 327, 67%) had estrogen receptor/progesterone receptor-positive breast cancer at diagnosis (Table 1).

Treatment setting

Most patients initiated trastuzumab-anns as naive new starters (n = 344, 71%) compared with switchers (n = 144, 30%; Figure 3). Approximately 33% of the 488 patients at the time of trastuzumab-anns initiation were treated in each of the adjuvant, neoadjuvant and metastatic settings. Among patients who were in the metastatic setting prior to initiating trastuzumab-anns (n = 20, 4.1%), 19 patients initiated trastuzumab-anns in the metastatic setting and of those, 52.6% (n = 10) initiated trastuzumab-anns in the first line while 21.1% (n = 4) initiated trastuzumab-anns in fifth or later lines (Table 2). Among patients in the metastatic setting prior to initiating trastuzumab-anns, and who switched from another trastuzumab (n = 18, 12.5%), 50% (n = 9) initiated trastuzumab-anns in the first-line and 22.2% (n = 4) initiated trastuzumab-anns in the fifth or higher line.

Most naive new starters initiated trastuzumab-anns in the neoadjuvant setting (91.2%, n = 145), whereas most switchers initiated trastuzumab-anns in the metastatic setting (59.3%, n = 96; Table 3). Among the switcher population, 63.2% (n = 91) of patients switched to trastuzumab-anns from RP (iv. or SC).

Regimens

Trastuzumab-anns as a single agent was the third most common regimen (n = 40, 8.2%). Most patients initiated trastuzumab-anns at the standard dosing schedule (n = 280, 57.4%) and most were treated with trastuzumab-anns every 3 weeks (n = 394, 80.7%), including metastatic (n = 146, 90.1%) and switcher patients (n = 132, 91.7%).

At the end of the study, 50% (n = 244) of patients had discontinued trastuzumab-anns and, among the discontinued, 96 (39%) patients were metastatic (Figure 4). The most common reasons for discontinuation were a switch to another biosimilar trastuzumab (34.8%, n = 85) or switch to RP (15.6%, n = 38). Disease progression was the reason for discontinuation of trastuzumab-anns in 11.5% (n = 28) of patients.

Trastuzumab-anns was most commonly used in combination with other agents, with the rates of single-agent trastuzumab ranging from 15% of patients in the metastatic setting to 25% in the neoadjuvant setting. The agents most commonly used in combination with trastuzumab-anns were: 1) taxanes, 2) additional Her-2 neu blockade and 3) hormonal therapy. Trastuzumab-anns was used in combination with a taxane (with or without other agents) in 80% of patients in the adjuvant setting, 82% of patients in the neoadjuvant setting and 49% of patients in the metastatic setting.

TEAEs

Overall, 111 patients (22.7%) had a TEAE, ranging from a low of 31 (18.6%) patients in the adjuvant setting to a high of 42 (26.4%) patients in the neoadjuvant setting (Table 4). Among TEAEs of interest, the most common was infections (n = 29, 5.9%), of which only one (0.2%) was considered treatment related. The next most common TEAE of interest was neutropenia (including febrile neutropenia; n = 28, 5.7%). Overall, 33 (6.8%) patients had investigator-determined treatment-related TEAEs, which were reported in 30 (8.7%) patients among trastuzumab-anns naive new starters compared with three (2.1%) patients among switchers. Percentages of patients with treatment-related TEAEs were lowest in the adjuvant group (n = 7, 4.2%) and highest in the neoadjuvant group (n = 16, 10.1%). Serious TEAEs were reported in 31 (6.4%) patients overall and were deemed serious treatment-related TEAEs in seven (1.4%) of those patients. The lowest percentage of patients with serious TEAEs were reported among adjuvant subjects (n = 8, 4.8%), and the highest percentage were reported among metastatic subjects (n = 15, 9.3%; Table 4). TEAEs of interest associated with RP were reported in 69 (14.1%) patients overall. TEAEs of interest occurred in <10% of subjects in trastuzumab-anns naive new user or switcher groups. Treatment-related TEAEs of interest were each reported in ≤2.5% of patients overall; however, 11 (3.2%) patients in the naive new starter group had neutropenia compared with one (0.7%) patient in the switcher group. This report includes only adverse events starting from initiation date of trastuzumab-anns up to 30 days after last dose of subjects' trastuzumab-anns dose. Events occurring more than 30 days after last trastuzumab-anns dose or those occurring during treatment with the RP, prior to trastuzumab-anns initiation, are not included.

Discussion

This is the third retrospective study to report trastuzumab-anns real-world uptake – the first study, based on the Flatiron database, focused on uptake of trastuzumab-anns in US oncology practices [31]. The second retrospective study recorded measures of quality assurance following the switch from trastuzumab to trastuzumab-anns for treatment of early and metastatic HER2-positive breast cancer in more than 200 patients at four Bavarian university clinics [33]. In addition to confirming comparable efficacy and safety between RP and biosimilar, the study also demonstrated that patient acceptance was high when preceded by education about biosimilar clinical performance. The current study represents the most substantial summary of real-world data from patients with breast cancer treated with trastuzumab-anns in seven countries in the European Union. 488 patients were enrolled equally across the adjuvant, neoadjuvant and metastatic settings. Results of this study confirm findings of the US study that suggested robust uptake of trastuzumab-anns in trastuzumab-naive patients and in patients originally treated with RP. As an observational chart review eligibility criteria for this study were selected to ensure inclusion of appropriate participants to reflect real-world data. A limitation of the study is that as such the descriptive analyses of the patient sample may not reflect the European situation.

Baseline demographic and breast cancer data for the adjuvant and neoadjuvant subjects in this study are similar to those from trastuzumab-anns-treated subjects in the phase III LILAC study [24]. In the LILAC study, 73% of patients were hormone receptor positive and, in this study, 73.7 and 66.7% of patients in the adjuvant and neoadjuvant settings were hormone receptor positive. In this study, most patients with HER2+ breast cancer who initiated trastuzumab-anns were naive new starters (71%) and most patients were in stage II or stage IV, suggesting minimal physician reservation in initiating therapy with trastuzumab-anns.

The most common reason for discontinuation (34.8%) of trastuzumab-anns was to switch to another trastuzumab biosimilar. Switching was unlikely due to a lack of efficacy, as the percentage of patients who discontinued trastuzumab-anns because of disease progression was low (11.5%). Reasons for switching from trastuzumab-anns to another trastuzumab brand or treatment refusal were not collected and may have been due to medical or contractual (i.e., change in trastuzumab procurement) reasons.

The observations that 30% of patients initiating trastuzumab-anns in this study did so after treatment with either RP iv. or SC (Table 3) and that 34.8% of 244 patients overall who discontinued trastuzumab-anns during the study switched to another trastuzumab biosimilar (Figure 4) suggests a fluid treatment choice pattern of trastuzumab therapy in HER2+ breast cancer in these EU countries. It will be important for future studies to investigate the reasons underlying frequent pricing negotiations and to demonstrate whether the potential reason, unlikely to be driven by efficacy differences, is due to lower cost that may serve to continue to drive down the costs of breast cancer therapy.

The incidence of TEAEs of interest were lower among both adjuvant and neoadjuvant patients in this study (Table 4) compared with corresponding patients treated with trastuzumab-anns in the LILAC study [24]. There were no new safety findings during this study summary of results.

Uptake of trastuzumab biosimilars in real-world settings have been reported in the USA, Italy and Denmark [34–36]. In the USA, analysis of real-world drug administration involving prescribing behavior for five trastuzumab biosimilars found that 80.5% of patients initiating first-line trastuzumab began treatment with a biosimilar during a the first 3-month period in 2020, a year after the launch of the first biosimilar to trastuzumab [34]. A survey from the National Cancer Institute in Italy reported that from 1 January 2019, through 31 December 2020, biosimilars were used in 34.3% of trastuzumab-based treatments [35]. The trastuzumab biosimilars used in Italy were trastuzumab-anns in the neoadjuvant setting, and trastuzumab-pkrb and trastuzumab-dttb in the recurrent metastatic setting. In Denmark, the market share of biosimilar trastuzumab had increased to 90% within the first 3 months of market availability; currently, it is the only European country to cross the 90% market share boundary [36]. Biosimilars to trastuzumab are included in National Comprehensive Cancer Network 2023 and ASCO 2022 Guidelines for treatment of HER2+ breast cancer, each stating that an FDA-approved biosimilar is an appropriate substitute for RP for invasive breast cancer [37,38].

Conclusion

Biosimilars to trastuzumab provide an additional treatment option for enabling patient access across three different cancer types. Clinicians will benefit from information about biosimilars and their use to inform themselves and answer patient questions with knowledge that may cultivate patient confidence. Future observational studies should explore the reasons/rationale for switching to another RP or biosimilar.