FormalPara Key Summary Points

Biologics are cornerstones of treatment for patients with cancer, but the high cost can limit treatment access and negatively impact the health care system.

In the United States, six pegfilgrastim biosimilars have been approved for the prophylaxis of febrile neutropenia.

Though next-day pegfilgrastim is the FDA-approved administration method, same-day administration can be considered to minimize clinic visits in the context of patient preference and the COVID-19 pandemic.

Three pegfilgrastim administration options are available; selection should consider the individual patients’ needs and circumstances.

Introduction

Febrile neutropenia, defined as a temperature of > 38.3 °C or two consecutive readings of > 38.0 °C and absolute neutrophil count of < 0.5 × 109/L, is a serious complication of myelosuppressive chemotherapy with potentially fatal outcomes [1]. Febrile neutropenia can result in treatment delays and dose reductions, thereby limiting the efficacy of anticancer treatments and affecting patient survival rates [1, 2]. Febrile neutropenia also confers a substantial clinical and economic burden. Each year in the United States, more than 60,000 patients are hospitalized for neutropenia and more than 4000 patients die of febrile neutropenia. In 2012, prior to the introduction of filgrastim or pegfilgrastim biosimilars, neutropenia-related hospitalizations accounted for 5.2% of all cancer-related hospitalizations, with a mean hospital stay of up to 9.6 days and a total cost of $2.7 billion [3]. Granulocyte colony-stimulating factor (G-CSF) is recommended by international guidelines to reduce the incidence of febrile neutropenia in patients receiving myelosuppressive chemotherapy [1, 4, 5].

Filgrastim was the first myeloid growth factor approved for the prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy [6]. For the prophylaxis of febrile neutropenia, filgrastim is administered daily starting the day after chemotherapy until post-nadir recovery of absolute neutrophil count [6]. Filgrastim is indicated for up to 2 weeks of daily administration, but health database reviews report around 5–6 days as the most common duration of treatment for filgrastim as well as its commonly used biosimilar [7, 8]. Pegfilgrastim, a pegylated, long-acting form of filgrastim, was first approved in 2002 [9]. In contrast to filgrastim (nonpegylated G-CSF), pegfilgrastim is not prematurely eliminated from the circulation by the kidneys but is self-regulated by binding to the G-CSF receptor and is subsequently internalized by neutrophils and neutrophil precursor cells [10, 11]. Because of this prolonged activity, pegfilgrastim is required only once per cycle and is usually injected ≥ 24 h after chemotherapy [9]. Pegfilgrastim is the most commonly used G-CSF in the United States, with previous reports indicating its use in > 90% of patients [12, 13]. A recent meta-analysis suggested no statistically significant differences in outcomes between short-acting filgrastim and long-acting pegfilgrastim if their dosing followed recommended guidelines [14]. In clinical practice, however, short-acting filgrastim is commonly underdosed and bears the risk of lower adherence, as it can require daily administration for up to 2 weeks [15]. In the most recent iteration (v1.2022), the National Comprehensive Cancer Network (NCCN) hematopoietic growth factor guidelines recommend next-day administration of pegfilgrastim (i.e., US Food and Drug Administration [FDA]–recommended dosing); however, in acknowledgment of the growing body of evidence, the guidelines indicate that same-day administration may be used [4]. Any use of same-day administration must be weighed against the potential for increased risk of febrile neutropenia [16]. Because of the COVID-19 pandemic, the option of same-day administration is especially pertinent to minimize additional clinic visits and risks of SARS-CoV-2 exposure.

Biologic medications, such as pegfilgrastim, are associated with significant financial impact on patients and health care systems. This impact is so pronounced that the term “financial toxicity” is often applied to this situation, implying that the financial burden of biologics dramatically affects patients on both mental and physical levels and limits the medication’s usefulness. In 2019, the United States spent $212 billion on biologic drugs alone, which was 43% of the total medication spending for the year [17].

Biosimilar medications provide a more affordable option to reference product, as they enter the market as lower cost, competitive alternatives to the originator product. This can result in lower out-of-pocket cost for patients, offer significant cost savings to the health care system, and potentially increase drug accessibility for patients [18], all of which are particularly relevant in the time of the COVID-19 pandemic when financial stress is high.

With the growing acceptance of same-day pegfilgrastim administration and the ever-present financial burden of medications for patients, the preferred administration method and potential savings associated with biosimilar use are pertinent topics for discussion. Thus, the objective of this narrative review is to discuss pegfilgrastim and pegfilgrastim biosimilar administration options, focusing on those minimizing clinic visits in the context of patient preference and the COVID-19 pandemic, and to ultimately propose a patient-centric model of pegfilgrastim administration for prophylaxis of febrile neutropenia.

Methods

An initial thorough search of the literature was performed using PubMed and the following search terms: biosimilars AND oncology/human granulocyte colony-stimulating factors/GCSF/Neulasta/pegfilgrastim/chemo-induced neutropenia/supportive care. Articles in English from 2015 to 2021 were included in the nonsystematic review. This initial search produced 862 results. The results of this broad and expansive search were further refined, focusing on references concerning pegfilgrastim and related biosimilars. These results were screened by title and abstract, and full-text articles were reviewed for those of interest and relevance based on the authors’ expertise. As this review is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors, there is no ethics compliance to report.

Overview of Biosimilars

A biosimilar is a biologic medication that is highly similar in structure and function to the originator reference product. It must have no clinically meaningful differences in safety, purity, and potency compared with the originator [19,20,21]. To ensure that these criteria are met, biosimilars undergo an extensive review process prior to market authorization [20, 22]. For approval of a biosimilar candidate, the US FDA requires a totality-of-evidence approach that considers data and information collected from structural and functional characterization, nonclinical assessments, pharmacokinetic and pharmacodynamic analyses, clinical immunogenicity data, and, if deemed necessary, comparative clinical studies [19, 20]. The FDA requires postmarketing surveillance to monitor the safety of biosimilars. Since the introduction of biosimilars in the United States, there has been a 2–4% incremental increase in the overall use of biologics, including biosimilars and their originator products [17]. Over the next 5 years, the use of biosimilars is projected to result in savings exceeding $100 billion in US health care spending [17].

Economics of Biosimilars in Supportive Oncology Care

Although biosimilars for therapeutic monoclonal antibodies, such as rituximab, trastuzumab, and bevacizumab, have only recently been approved in oncology [23], biosimilars have been available for several years in supportive oncology care [15]. In 2015, filgrastim-sndz (ZARXIO®; Sandoz Inc., Princeton, NJ, USA) became the first approved biosimilar product in the United States [23]. Since June 2018, six biosimilars of pegfilgrastim have been approved in the United States [24,25,26,27,28]: pegfilgrastim-apgf (NYVEPRIA®; Pfizer Inc., New York, NY, USA), pegfilgrastim-bmez (ZIEXTENZO®; Sandoz Inc., Princeton, NJ, USA), pegfilgrastim-jmdb (FULPHILA®; Mylan, Rockford, IL, USA), pegfilgrastim-cbqv (UDENYCA®; Coherus BioSciences, Redwood City, CA, USA), pegfilgrastim-pbbk (FYLNETRA™, Amneal Pharmaceuticals LLC, Bridgewater, NJ, USA), and pegfilgrastim-fpgk (STIMUFEND, Fresenius Kabi USA LLC, Lake Zurich, IL, USA).

Use of these biosimilar products can result in significant savings, as biosimilars typically cost less than their reference product. The cost savings from biosimilar pegfilgrastim can potentially be used to expand treatment access to more patients. For example, economic modeling using the average sales price of originator and biosimilar pegfilgrastim in a population of 20,000 patients showed that cost savings of $326,744 (10% conversion from originator on-body injector [OBI] to biosimilar prefilled syringe for 1 cycle) to $22,286,640 (100% conversion from originator prefilled syringe to biosimilar prefilled syringe for six cycles) could be realized [29, 30]. These savings from converting 20,000 patients could be used to provide 1054 additional doses of biosimilar pegfilgrastim if all patients receive one cycle or 6322 additional doses if patients receive six cycles [29]. Savings could also be reallocated to other cancer treatments, such as antineoplastic or novel biologic-based treatments [31].

Cost savings can also have a significant impact on the financial stress experienced by patients with cancer, which is a prominent issue for these individuals. A systematic review found that up to 48% of cancer survivors experience financial toxicity [32], which can then cause survivors to forgo future medical treatments because of long-term, continued financial concerns [33]. Reduced medical costs can also directly impact patient quality of life, as financial burden has been found to be the strongest predictor of poor quality of life in patients with cancer [34]. Specific data are not available on the relationship between the impact of pegfilgrastim biosimilars on patients’ financial stress and quality of life. However, the availability of a G-CSF biosimilar in Europe (i.e., Germany, the United Kingdom, and The Netherlands) correlated with a 10–20% increase in G-CSF use, which was suggested to be related to increased patient access owing to affordability [35]. This evidence suggests a positive relationship between lower costs of biosimilars and treatment access, although a direct examination would be valuable to investigate whether decreased costs with biosimilars positively impact patients’ financial toxicity and quality of life.

Although biosimilars provide an encouraging potential for economic benefit, they can be hindered by several factors. One is drug rebate walls, where competitors offer financial rebates to buyers that act as a barrier to the new market entry of biosimilars [36]. Confusion around interchangeability between an originator and biosimilar can also be a hurdle. To gain interchangeable status, a switching study with the biosimilar must be performed to prove switching is not associated with decreased efficacy or increased safety risk; some health care professionals may incorrectly perceive this FDA requirement to imply that a biosimilar is not clinically the same as the reference product and, as a result, be hesitant to prescribe a biosimilar product [36]. To further complicate interchangeability/switching, policies vary between the FDA and European Medicines Agency. Medicare reimbursement for biosimilars also presents a challenge. Generic drugs are billed under the same billing code as the brand-name version, with the average sales price representing a weighted average of the molecules. This differs from biosimilars, where each biosimilar receives its own billing code and is paid based on its own average sales price; this can limit price competition between the biosimilar and reference product [37]. Despite these potential economic barriers, a 2021 report suggests that, in the absence of biosimilar competition, the average sales price of reference pegfilgrastim would have been expected to increase by 96.2%; thus, the introduction of biosimilar pegfilgrastim products has lowered the estimated price of reference pegfilgrastim [38].

Administration Options for Pegfilgrastim

The FDA-approved, and NCCN-supported, indication for pegfilgrastim administration for febrile neutropenia prophylaxis is next-day administration at the clinic [9]. Based on recently published evidence, the NCCN also supports same-day administration [4], which is particularly important for minimizing clinic visits during the COVID-19 pandemic. Same-day administration may be preferable for patients who find returning to the clinic burdensome, especially for those who live far from the clinic or want to minimize visits because of the emotional and physical exhaustion following chemotherapy [39].

There are three approaches to pegfilgrastim administration that minimize clinic visits: same-day administration of pegfilgrastim after chemotherapy, use of the FDA-approved OBI that delivers pegfilgrastim ~ 27 h after application, or self-administration of pegfilgrastim by the patient or caregiver > 24 h after chemotherapy. Consideration of each option should be based on the individual patient-specific needs and comfort level (Fig. 1).

Fig. 1
figure 1

Patient-centric decision tree for determining the appropriate method of pegfilgrastim administration. HCP health care provider, OBI on-body injector

Full size image

Self-administration of pegfilgrastim reduces the number of clinic visits and may improve quality of life for patients and their families [40]. However, correct self-injection techniques are crucial for safe and effective self-administration. Although self-injection has been taught successfully across some patient populations (e.g., insulin injection in patients with diabetes) [41], it remains important for advanced practitioners to revisit these techniques across follow-up appointments to minimize risks associated with incorrect self-injection [41, 42]. Furthermore, several barriers to self-injection have been identified and include aversions to injections, fear, anxiety, needle phobia, anticipated pain, and impaired manual dexterity [43]. For pegfilgrastim, patient age and comorbidities often limit the ability to self-administer, resulting in the requirement (and additional burden) for a caregiver who would need to be trained in safe injection techniques.

The pegfilgrastim OBI, an FDA-approved delivery device that is applied the same day as chemotherapy and delivers the standard dose of pegfilgrastim ~ 27 h after application [44], is an alternative for patients who are unable to self-administer G-CSF or who may be unable to return to the hospital the next day for other reasons. Similar OBI-delivery devices that provide biosimilar pegfilgrastim at a lower cost are not currently available, but a pegfilgrastim-cbqv OBI is in development [45]. Complicating reliable febrile neutropenia prophylaxis, OBI failure rates of 1.7–6.9% have been reported and not all patient populations accept the OBI device [46,47,48,49,50,51]. Patient education may be required to ensure the effectiveness of pegfilgrastim OBI and to handle device failure [52]. OBIs and prefilled syringes with originator pegfilgrastim (Neulasta) are currently available at the same price, but both are more expensive than biosimilar products [29]. Compared with originator pegfilgrastim (single-dose syringe or OBI), the average wholesale acquisition cost is approximately 33–37% higher and the average sales price is 5–6% higher than the price of biosimilar pegfilgrastim products [53] (Table 1), which are currently only available as prefilled syringes.

Table 1 WAC and ASP of pegfilgrastim biosimilars at launch, relative to reference pegfilgrastim [53]
Full size table

Same-day injection of pegfilgrastim (off-label) at the end of chemotherapy is another administration option that minimizes the risk associated with an additional outpatient clinic visit. Same-day administration may be a preferrable option for patients who are unable to self-inject pegfilgrastim and who are not comfortable having a device (i.e., an OBI) attached to their skin. Concern over same-day administration is rooted in observations that administration of nonpegylated, shorter-acting filgrastim may exacerbate neutropenia in certain therapeutic settings [54, 55]. For longer-acting pegfilgrastim, a retrospective evaluation found that patients receiving prophylactic pegfilgrastim on the same day as chemotherapy or 4–5 days after chemotherapy had a significantly higher incidence of febrile neutropenia compared with patients receiving pegfilgrastim on days 1–3 following chemotherapy [56]. However, same-day administration of pegfilgrastim is not uncommon in clinical practice, and an increasing number of studies across various tumor types have not detected differences in outcomes compared with next-day administration [16, 57,58,59]. In a large meta-analysis, the incidence of grade 4 neutropenia was equal between patients receiving same-day or standard next-day pegfilgrastim [57]. In another meta-analysis of 23 studies, rates of febrile neutropenia reduction were low with same- or next-day administration, and no increase in risk of grade 3/4 chemotherapy-induced neutropenia was observed [58]. A retrospective study in patients with gastrointestinal cancers receiving FOLFOX or FOLFIRI concluded that same-day administration of pegfilgrastim was a safe, effective alternative in this patient population [59]. A similar retrospective study in patients with lung cancer also reported low rates of febrile neutropenia and grade 3/4 neutropenia with same-day pegfilgrastim administration [60]. A recent review showed that the efficacy of same-day pegfilgrastim appears to be dependent on the chemotherapy regimen administered [16]. Overall, as acknowledged in the NCCN guidelines [4], the growing body of available data show that same-day pegfilgrastim can be considered for the prophylaxis of chemotherapy-induced neutropenia and febrile neutropenia. Any decision on same-day administration should take into account the prescribed chemotherapy regimen, patient-specific risk factors, and outpatient visit–associated risks [16].

Pegfilgrastim Administration in the Context of COVID-19

Patients with cancer are generally at an increased risk of infection compared with healthy individuals [61]. Frequent hospital visits may further increase the risk of contracting COVID-19 during the current pandemic, especially in immunocompromised older patients with poor functional status [61]. During the pandemic, outpatient visits for patients with cancer should therefore be minimized without compromising adequate patient care [61]. The risk–benefit ratio for therapeutic and supportive oncology care may be altered, as hospital visits to receive treatment and treatment-induced immunosuppression may increase the risk of contracting COVID-19. Although the benefits of same-day pegfilgrastim treatment options have not been exclusively studied in the context of the COVID-19 pandemic, these methods were successfully used before the COVID-19 pandemic and may provide risk-minimization opportunities [16]. Reducing patient visits can also reduce the workload for health care workers, who are currently overburdened and overworked because of COVID-19 [62].

COVID-19 has also resulted in a huge health-related financial burden. The American Hospital Association estimates $202.6 billion in lost revenue for health care systems and hospitals because of the COVID-19 pandemic [63]. Specific data are lacking on the financial benefits of pegfilgrastim biosimilar use during the COVID-19 pandemic; however, as biosimilars are established as lower-cost alternatives, the use of biosimilar pegfilgrastim can mitigate part of the economic impact associated with COVID-19. Beyond pegfilgrastim in supportive oncology care, lower-cost biosimilar alternatives to expensive biologic medicines may provide health care systems and hospitals with an opportunity to balance the significant revenue reduction and cost increase associated with the COVID-19 pandemic [63]. COVID-19 has also significantly impacted the finances of patients, particularly the marginalized and vulnerable populations who may not have comprehensive insurance coverage [64]. Therefore, cost savings to these patients through biosimilar use could improve patients’ financial situation and treatment access.

Conclusions

Several G-CSF same-day administration options are available to avoid or minimize additional health care visits and the associated risk of COVID-19 exposure while also accommodating specific patient needs and preferences. Pegfilgrastim biosimilars can play a key role in minimizing the treatment-associated financial burden on patients, payers, and health care systems during the COVID-19 pandemic and beyond.