Biosimilars in Oncology Practice: A Multi-Site Health System Examination of the Use and Perception of Oncology Biosimilars

Biologic medications represent a diverse category of drugs, including therapeutic proteins and monoclonal antibodies, and account for a large cost burden in oncology practice.^1,2 The 2010 Biologics Price Competition and Innovation Act created an abbreviated pathway for the approval of biosimilars, with a goal of encouraging innovation while controlling costs.¹ The FDA defines a biosimilar as a biologic drug that is highly similar to, and has no clinically meaningful differences from, an existing FDA-approved reference drug.^1,2 For FDA approval, biosimilars focus on preclinical data that demonstrate comparable pharmacokinetic and pharmacodynamic properties to the reference drug.² Even with strict manufacturing processes for biologic drugs, different batches of drugs, whether reference or biosimilar, will have inevitable variability that can lead to subtle differences in effectiveness and safety.³ However, this allows for biosimilars to be developed at a much lower cost, which helps to introduce them to market at competitive price points to support healthy market competition.²

Over the past 10 years, several biosimilars for supportive care and the treatment of cancer have been approved. Despite approval, the widespread adoption of biosimilars has been limited because of a lack of knowledge of approval pathways, reimbursement concerns, and provider and patient perceptions on safety, efficacy, and immunogenicity.² However, biosimilars will reduce spending by approximately $54 billion between 2017 and 2026, an approximate 3% reduction of the total drug spending over this time period within the United States.⁴ Cost-savings have been projected at an institutional level. A single-center analysis of cost-savings at Intermountain Healthcare in Utah that assumed a 70% conversion of oncology reference drugs (pegfilgrastim, bevacizumab, trastuzumab, and rituximab) to biosimilars estimated a potential savings of $6 million for the institution.⁵ A buy-in to biosimilar use and addressing negative perceptions in practice from key stakeholders are critical to realizing the potential cost-savings for institutions, payers, and patients.

At the University of North Carolina Health System, several biosimilars for oncology are on formulary. We evaluated patients who received trastuzumab or bevacizumab and were later switched to a biosimilar to examine the safety and immunogenicity outcomes. In addition, we conducted a survey to characterize the providers’ perceptions of biosimilars and the considerations for changing a patient’s treatment from a reference drug to a biosimilar.

Methods

We conducted a retrospective chart review to evaluate the prescribing of bevacizumab and trastuzumab reference drugs and their biosimilars within a multi-site academic health system with 11 entities at the time of the evaluation. To be included, the patients must have received bevacizumab (Avastin) or trastuzumab (Herceptin) and then converted to a respective University of North Carolina Health System formulary–approved biosimilar of bevacizumab-awwb (Mvasi) or trastuzumab-dkst (Ogivri) for any reason. Although these agents are our formulary-preferred drugs, if there was a payer-preferred biosimilar that was not on formulary, it is a standard for us to allow that preferred drug to limit financial burden to the patient. Therefore, all patients were included in this review, including those who received formulary and nonformulary biosimilars.

The patients were identified via a medication administration record report documenting the administration of the reference drug and the biosimilar between October 2019 and February 2021; the majority of patients received treatment as an outpatient because most of the regimens containing these biosimilars are administered in infusion clinics. The information that was collected included the indication for treatment with bevacizumab or trastuzumab, the chemotherapy regimen with the reference drug and biosimilar (if part of a multi-agent regimen), the number of reference infusions before conversion to a biosimilar, the number of infusions after conversion to a biosimilar (through the data cutoff of February 1, 2021), the infusion time of the last reference drug’s administration, the infusion time of the first biosimilar’s administration, the incidence of new adverse events after conversion to a biosimilar, the type of adverse event after the conversion, the premedication adjustments that were required after the conversion, the hypersensitivity reactions after the conversion, the rate of biosimilar discontinuation, and the reason for treatment discontinuation (if applicable).

To determine the incidence of new adverse events after conversion to a biosimilar, we screened the progress notes for documented adverse events immediately before the date of conversion to a biosimilar and for the first 3 cycles after the conversion. Because bevacizumab was most often administered in combination with cytotoxic chemotherapy, only adverse events that were deemed specific to bevacizumab were collected to prevent inappropriate attribution of the adverse events to bevacizumab that were most likely related to the concomitant cytotoxic chemotherapy. Conversely, trastuzumab was most often administered as monotherapy or as part of a dual HER2-directed regimen. Thus, all documented adverse events were evaluated for patients who received trastuzumab.

To assess the adjustments in premedications after conversion to a biosimilar, the medication administration records were compared using the last reference drug’s administration encounter date and the first 3 administration encounters after conversion to the biosimilar. Premedications were analyzed for any adjustments of medications received before or after the conversion. Adjustments in premedications before or after the conversion were grouped into the 4 categories of no changes, medication or dose escalation-symptom management, medication or dose escalation-hypersensitivity management, and medication or dose de-escalation-symptom management. Switches to therapeutic equivalents were considered to be no change.

To evaluate the perceptions about and level of comfort with biosimilars, we administered a survey to hematology/oncology providers throughout the health system. All nondemographic survey responses were based on a 5-point Likert scale (full survey available in the Appendix, available Here).

Descriptive statistics were used for all end points in this study. Categorical data were represented as counts and percentages, whereas continuous data were represented as medians with associated interquartile ranges.

Results

Between October 1, 2019, and February 1, 2021, 185 patients were included in this retrospective chart review. A total of 88 patients received bevacizumab (Avastin) before transitioning to the biosimilar bevacizumab-awwb (Mvasi), whereas 97 patients received trastuzumab (Herceptin) before transitioning to the biosimilar trastuzumab-dkst (Ogivri). The patients’ demographic information and clinical characteristics surrounding the reference drugs and biosimilars are shown in Table 1. Bevacizumab was most frequently indicated for gastrointestinal malignancies. Reference bevacizumab and biosimilar bevacizumab were often prescribed in combination with cytotoxic chemotherapy (67% and 57%, respectively). Trastuzumab was most often indicated for breast malignancies. Reference trastuzumab was often prescribed with cytotoxic chemotherapy (47%), whereas after the conversion biosimilar trastuzumab was more frequently prescribed as monotherapy (41%) or in combination with other HER2 therapies (53%). The median infusion time of bevacizumab was 20 minutes, which did not change after conversion to the biosimilar. The median trastuzumab infusion time increased by only 2 minutes after conversion, from 34 minutes with the reference drug to 36 minutes with the biosimilar. For most patients who received bevacizumab or trastuzumab, <4 months passed between receiving the reference drug and biosimilar use.

In the bevacizumab group, 69% of the patients had no changes to their premedication within 3 cycles after conversion to a biosimilar, 11% had de-escalation of their premedication, 17% had escalation for symptom management, and only 2% required escalation as a result of hypersensitivity. In the trastuzumab group, 88% of patients had no changes to their premedication, and only 8% required escalation for symptom management (Table 1).

New adverse events after biosimilar conversion occurred in 25% of patients who received bevacizumab and in 23% of patients who received trastuzumab. Within the bevacizumab group, hypertension, kidney dysfunction/proteinuria, and bleeding were the most frequent new adverse events. Of the patients who received bevacizumab with new adverse events, 17 (77%) were receiving bevacizumab in combination with cytotoxic chemotherapy. Within the trastuzumab group, peripheral neuropathy, headache, and arthralgia/myalgia were the most frequent new adverse events. Of the patients who received trastuzumab and had new adverse events after conversion to a biosimilar, 5 (23%) were receiving trastuzumab in combination with cytotoxic chemotherapy. All other patients were receiving trastuzumab monotherapy or trastuzumab in combination with other HER2 therapy (Table 1).

Only 2 (2%) patients in the bevacizumab group had hypersensitivity reactions after conversion to a biosimilar. Both patients were able to continue receiving bevacizumab-aawb with escalation in premedication and did not require transition back to the reference drug. Two (2%) patients who received bevacizumab did transition from a biosimilar back to the reference drug, of which 1 was for unclear reasons and 1 was a result of differences in validated treatment plans in the inpatient and outpatient setting (a reference drug was received inpatient and a biosimilar was received outpatient). A total of 6 (6%) patients in the trastuzumab group transitioned from the biosimilar back to the reference drug. Only 1 (1%) patient in the trastuzumab group had a hypersensitivity reaction after conversion to the biosimilar and was subsequently transitioned back to the trastuzumab reference drug. A total of 3 additional patients were switched back to the reference drug because of intolerable adverse events with the biosimilar. One patient was switched back because of unknown reasons, and another received the reference drug during an inpatient admission (Table 1).

The biosimilar was discontinued in 57% of the patients who received bevacizumab and in 51% of the patients who received trastuzumab. Bevacizumab was discontinued most often because of disease progression or death (39%), and only 6 (7%) patients discontinued treatment with bevacizumab as a result of intolerability or adverse events. Trastuzumab was primarily discontinued because of therapy completion (69%), followed by disease progression or death (18%). Only 3 (6%) patients discontinued treatment with trastuzumab as a result of intolerability or adverse events (Table 1).

A total of 41 physicians responded to the survey between March 5, 2021, and April 2, 2021, and evaluated the perceptions of, level of comfort with, and potential barriers to biosimilar prescribing in clinical practice. The responses to the survey questions are shown in Table 2. Most providers surveyed (73%) practiced within oncology and 24% practiced in hematology. The 2 most common responses for the length of the providers’ practice experience were 1 to 5 years (41%) and >20 years (24%).

Most providers (78%) routinely prescribe biosimilars in their clinical practice. The providers most often described their knowledge of biosimilars as moderate (59%) or high (27%), with only 2% describing it as very low. No providers described their knowledge as very high. At least 50% of providers stated that they were likely to prescribe a biosimilar most times or always for front-line (51%), second-line (50%), and palliative (51%) treatments. Most providers felt comfortable or very comfortable prescribing a biosimilar instead of the reference drug for an FDA-approved indication (68%) and switching established patients from a reference drug to a biosimilar for an FDA-approved indication (69%). When switching a patient’s treatment from a reference drug to a biosimilar, most providers were not at all concerned or minimally concerned about potential loss of efficacy (85%), potential for adverse events (88%), or potential for an increased risk for an immune reaction (86%; Table 2). The providers’ ranked concerns when transitioning between the reference drug and a biosimilar is shown in Supplementary Figure S1 (available at Here). Insurance coverage was most often ranked as the top concern (30%). The most common second concern was level of knowledge or comfort with biosimilars (20%). Efficacy was also frequently listed as the providers’ first (15%) or second (10%) concern, whereas several providers (7%) had no concerns at all.

Discussion

Biosimilars play an essential role in cancer care in helping to control the cost of therapy.^5-7 The Biologics Price Competition and Innovation Act creates an efficient approval pathway that encourages innovation with cost in mind. Although biosimilars are not structurally identical to their reference drug counterpart, to support interchangeability between the reference drug and the biosimilar the FDA requires that a biosimilar has no clinically meaningful differences from the reference drug.^1,8 Organizations such as the American Society of Clinical Oncology and the European Society for Medical Oncology have issued statements that support the Biologics Price Competition and Innovation Act but that emphasize that providers should always be consulted before a biosimilar is substituted for a reference drug.^1,9,10 However, there are varying degrees of provider understanding of biosimilars and comfort with their prescribing because of efficacy and safety concerns.¹¹ Considering these expert recommendations to consult providers, it is critically important for providers to have an accurate understanding of biosimilars and their role in cancer care. This includes educating providers that although biosimilars are highly similar to the reference drugs, they are not chemically identical and thus there are production differences that can lead to variability in response and tolerability.³ Thus, this study set out to evaluate the safety of biosimilars in patients who transition from a reference drug to a biosimilar as well as to characterize providers’ understanding of and comfort level with biosimilars.

Our retrospective review indicates that 25% and 23% of patients receiving bevacizumab and trastuzumab, respectively, had new adverse events after switching from the reference drug to a biosimilar. Approximately 79% of the patients who switched from trastuzumab to the trastuzumab biosimilar received HER2-directed therapy alone or HER2 dual therapy without cytotoxic chemotherapy. Thus, the adverse events after the transition from the reference drug to the biosimilar were most likely attributed to HER2-directed therapy (trastuzumab-dkst monotherapy or HER2 dual therapy). Most of the reported side effects with the trastuzumab biosimilar were typical adverse events for patients with breast cancer who receive HER2 therapy.^12-19 Similarly, most side effects with the bevacizumab biosimilar were frequent adverse events of bevacizumab therapy.^20-25

More than 50% of the patients did not require any changes to premedication or dose changes for symptom management, suggesting that the tolerability of biosimilar and reference drugs is comparable. In addition, some of the observed adverse events with bevacizumab and trastuzumab can be cumulative adverse events that present with additional cycles of therapy. Considering that there was a median of 12 infusions of the reference drug in both groups before switching to the biosimilar, many of the observed adverse events could have very well been cumulative in nature and eventually could have been observed with additional infusions of the reference drug had it been continued.

Hypersensitivity reactions after conversion to a biosimilar were low in both biosimilar groups (2 patients receiving bevacizumab and 1 patient receiving trastuzumab). A total of 2 (2%) patients in the bevacizumab group and 6 (6%) in the trastuzumab group switched back to the reference drug. The 2 patients receiving bevacizumab who had hypersensitivity reactions were able to continue therapy with the biosimilar with an adjustment in premedications. Of the 2 patients who received the bevacizumab biosimilar and switched back to the reference drug, 1 had a hypersensitivity reaction related to carboplatin treatment that required inpatient administration for desensitization therapy. The bevacizumab reference drug was ordered as part of the desensitization regimen. The other patient who received bevacizumab was switched for unknown reasons. Of the 6 patients who received a trastuzumab biosimilar, only 1 switched because of a hypersensitivity reaction related to trastuzumab-dkst. The median infusion times were similar between the formulations, which supports the tolerability of biosimilars as a result of their low rates of hypersensitivity reactions and no need for infusion interruptions.

One potential area of resistance to biosimilar adoption is providers’ perception of and level of comfort with biosimilars. A systematic review completed in 2020 analyzed 23 studies related to providers’ perceptions regarding the uptake of biosimilars.¹¹ The results showed that familiarity with biosimilars varied from 49% to 76% and that confidence in prescribing biosimilars for patients who were biologic-naïve was 54% to 94%.¹¹ Most providers also had negative perceptions related to pharmacist-led substitution of biologics.¹¹ A 19-question survey to assess the current level of knowledge, understanding, and comfort of prescribing biosimilars conducted by the European Society for Medical Oncology demonstrated that only 49% of providers who specialized in oncology prescribed biosimilars regularly in practice.⁹ These data highlight that barriers remain related to the acceptance of biosimilars in routine practice.

Overall, providers’ perceptions of biosimilar safety and efficacy within our institution were generally positive. Of the 41 providers who responded to our survey, most indicated that they were comfortable prescribing biosimilars, with only 1 provider indicating that they were not at all comfortable with prescribing biosimilars. The providers who were the most comfortable with prescribing biosimilars were those with 1 to 5 years of experience (75%) and those with >20 years of experience (50%). There was also a similar distribution of responses for the prescription of biosimilars in the first-line, second-line, and palliative care treatment settings. When asked to rank their concerns with prescribing biosimilars, the providers noted that the most common barrier was insurance coverage, with 30% ranking this as their primary concern. However, it is worth mentioning that this analysis includes all patients, regardless of the formulary status of the biosimilar received, and therefore these results should be generalizable to other institutions that may have different formularies.

Because biosimilars have become an integral part of cancer care, it is essential to continue to support the uptake of biosimilars. Education for healthcare professionals as well as national guideline recommendations are needed to help support their use. The findings in our study demonstrate that switching a patient from a reference drug to a biosimilar did not lead to a significant emergence of additional adverse events. Furthermore, our survey showed encouraging levels of prescriber knowledge of and comfort with prescribing biosimilars. Other studies of biosimilars, such as by Yang and colleagues, have suggested that switching from bevacizumab to a biosimilar for bevacizumab in combination with chemotherapy are accepted in real-world practice.²⁶ A strength of this evaluation is that responses were across a multi-hospital health system, representing an academic medical center and several community centers of varying sizes.

Limitations

Our study has limitations. The retrospective design of our study introduces some selection bias that is inherent to this type of evaluation. The documentation of tolerability within the electronic medical record was not standardized among the providers. Thus, the assessment of adverse events was limited to what was in the electronic medical record. Rituximab is another biosimilar that is frequently prescribed within our health system and was not included in our evaluation because we specifically assessed patients who switched drugs in the middle of their treatment course. The introduction of the rituximab biosimilar at our institution allowed for patients who were receiving reference rituximab to complete their course of therapy with the reference drug and for any new patients who started treatment with the biosimilar. Thus, there were very few patients who switched during therapy.

Nonetheless, the study characterizes the adverse events that were observed on switching drugs and provides insight into the perception of oncologists regarding biosimilars. Furthermore, considering that this analysis involved a retrospective chart review, insights into deciding which biosimilar a patient received and why were not accurately captured. Subsequent studies are needed to assess the perceptions regarding biosimilars over time, the resulting uptake and acceptance of their use, and the associated cost implications.

Conclusion

The future direction of cancer involves effective and safe cancer treatments as well as greater access to affordable therapies. Biosimilars introduce an opportunity to control the costs of cancer care. As identified through our provider survey, the common barriers to biosimilar conversion include a concern about payer coverage, clinical efficacy compared with the reference drug, and varying levels of knowledge and comfort among providers. Our data offer evidence that treatment conversions to biosimilars are safe in regard to adverse events.

Additional data are needed to better characterize the real-world clinical efficacy of biosimilars. The coverage of certain biosimilars by different payers creates a complex payer landscape for these drugs. Payers should simplify the coverage guidelines and institutions should establish workflows that help facilitate the selection of biosimilar based on the payer’s status. In addition, greater education of healthcare providers regarding the use of biosimilars could help with the uptake of these drugs in practice. By identifying, examining, and sharing the current influences on biosimilar adoption, there is a great opportunity to further promote the conversion of treatment for established patients to biosimilar drugs.

Author Disclosure Statement
Dr Czech is currently employed at Exelixis, which began after submission of the manuscript. Dr Alexander is currently employed at Merck & Co., Inc., and has previously served on Advisory Boards at Merck & Co., Inc., Omeros, EUSA Pharma, AcelRx, and Teva Pharmaceuticals; during the research and writing of this paper, he was at the University of North Carolina Medical Center, and the opinions or perspectives expressed here do not represent the opinions or perspectives of Merck & Co., Inc. Dr Chen, Dr Dennison, Dr Palmer, Dr Eberwein, Dr Pappas, Dr Vest, and Dr Laundon have no conflicts of interest to report.

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