How can biosimilars change the trajectory of breast cancer therapy?

KEYWORDS:

• Biosimilars
• breast cancer
• trastuzumab
• similar biotherapeutic products
• SBP
• UHC
• cancer policy

1. Introduction

The clinical development and use of biologic agents, or biologics, has successfully improved outcomes in several life-threatening diseases, including malignancies. In cancer medicine, the development of biologics has significantly expanded the availability of valuable options of treatments for the curable and advanced setting, along with indications of supportive care to control treatment-related toxicities [1]. However, the cost of biologics used in oncology represents one major barrier to the global uptake of cancer treatments, resulting in disparities in the affordable access to therapy for patients, especially in but not limited to low-middle income countries (LMIC), implying large survival gaps in the world. With the expiration of the patents of biological agents, room for affordable and sustainable production has been pushed, and several industries have established programs of biosimilar development. The relevance of biosimilars is to drive the development of sustainable cancer programs in LMIC, as envisioned by the World Health Organization (WHO), endorsing their value to enhance the pharmacological development and clinical uptake of biosimilars as functional to the commitment of improving the affordable access to essential medicines for patients with cancer [2]. In 2019, WHO included the biosimilars of the essential medicines rituximab and trastuzumab in the WHO essential list of medicines (EML), integrating the previous mention of the biosimilars of erythropoietin agents and of filgrastim. The EML Secretariat recognized the value of biosimilars as therapeutically equivalent alternatives capable of leading greater market competition, improved patient access and reduced costs for health systems. Stating the interchangeability of biosimilar products as a very important rule for wider access and a crucial aspect to foster competition [3]. The WHO Committee considered that where biosimilars of listed essential medicines exist, these must also be considered therapeutically equivalent for procurement purposes – tackling a key issue in the selection of medicines. The uptake of biosimilars is included among the strategies to improve efficiency in health systems, pertaining resource selection and utilization, expected to reduce waste of resources and improve the cost-effectiveness of medical interventions.

2. Facts and perspectives in biosimilars for breast cancer

2.1. The current landscape of development of biosimilars of trastuzumab for breast cancer: a case study for priority setting in research and health policy for cancer care

To understand the landscape of biosimilars in breast cancer, we reviewed the registration trials for the FDA and EMA approved biosimilars and proposed biosimilars under development from ClinicalTrials.gov (US National Library of Medicine). In a preliminary research, we failed to identify other biosimilars developed or under development for breast cancer other than trastuzumab; we excluded the multiple tumor cohorts of patients and the agents for supportive care (e.g. peg-filgrastim biosimilars). Similarly, we excluded bevacizumab, as the indication for breast cancer is FDA withdrawn. Data for the approved biosimilars ABP 980, CT-P6, MYL-1401O, PF-05280014, SB3 were retrieved; thereafter, we systematically searched for the ongoing clinical trials of proposed biosimilars of trastuzumab on ClinicalTrials.gov.

Our research identified 17 ongoing trials assessing approved or proposed biosimilars in clinical investigations. We excluded the studies were biosimilars were used as an alternative to trastuzumab to test new combinations of experimental compounds (n = 10), to assure to paint the landscape of ongoing development of biosimilars, reducing the possible selection bias related to other workstreams of companies. Truly, we enjoyed to learn that several pharmaceutical companies acknowledge the total interchangeability of trastuzumab and its approved biosimilars in drug development. Thus, we identified seven proposed biosimilars, three tested in enrolling clinical trials (AryoTrust, SIBP-01 [CN-Trastuzumab] and TX05) and four in trials closed to enrollment (HLX02, BCD-022, ALT02, HD201). Table 1. All the trials but one were phase 3 randomized non-inferiority clinical trials, assessing trastuzumab or its proposed biosimilar in combination with chemotherapy – none with pertuzumab – in early and advanced settings, designed to comply with the clinical exercise of similarity and complement the totality of the evidence for the registration, approval for human use and extrapolation; ALT02 is the only one tested in a phase 1 trial of pharmacokinetics and pharmacodynamics, on healthy male volunteers.

Table 1. The clinical landscape of drug development and regulatory status of approved and proposed biosimilars.

Regulatorystatus ^a	Drug	Interventions	Setting	Gender	Sponsor/Collaborators	NCT Number; phase of development
Proposed biosimilars	AryoTrust	AnC-> T + D	(Neo)A	Female	AryoGen Pharmed Co.	NCT03425656 [TRA.ARY.RS.95 (III)]; 3
	SIBP-01 (CN-Trastuzumab)	CarboD + T	(Neo)A	Female	Shanghai Institute Of Biological Products|Fudan University	NCT03989037 [SIBP-01-3]; 3
	TX05	AnC-> T + D	(Neo)A	Female	Tanvex BioPharma USA, Inc.	NCT03556358 [TX05-03]; 3
	HLX02^b	T + D	ABC	All	Shanghai Henlius Biotech	NCT03084237 [HLX02-BC01|2016-000206-10]; 3
	BCD-022	T + D	ABC	Female	Biocad	NCT01764022 [BCD-022-02]; 3
	ALT02	T	NA^a	Male (healthy volunteer)	Alteogen, Inc.|Cristália Produtos Químicos Farmacêuticos Ltda	NCT03242239 [ALT02]; 1
	HD201	AnC-> T + D	(Neo)A	Female	Prestige Biopharma Pte Ltd	NCT03013504 [TROIKA]; 3
Approved biosimilars	ABP 980	AnC-> T + D	(Neo)A	Female	Amgen/Actavis Inc.	NCT01901146 [Lilac]; 3
	CT-P6	FAnC -> T + D	(Neo)A	Female	Celltrion/Nippon Kayaku Co., Ltd.	NCT02162667; 3
	MYL-1401O	T + D	ABC	All	Mylan Inc./Mylan GmbH	NCT02472964 [HERiTAge]; 3
	PF-05280014	A: T + D; B: CarboD + T	A: ABD; B: (Neo)A	All	Pfizer	A: NCT01989676 [REFLECTIONS B327-02]; 3 B: NCT02187744 [REFLECTIONS B327-04]; 3
	SB3	FAnC -> T + D	(Neo)A	Female	Samsung Bioepis Co., Ltd.	NCT02149524; 3

aAs per November 2019. ^bthe phase 3 trial met the primary endpoint and the registration has been requested for human use.

An, anthracycline; C, cyclophosphamide; T, trastuzumab or trastuzumab biosimilar; D, taxane; (Neo)A, neoadjuvant or adjuvant regimen; Carbo, carboplatin; ABC, advanced breast cancer; NA, not applicable; F, 5-fluorouracil.

We identified the countries involved in the clinical development of the biosimilars, as reported from the online database, collecting the centers where the trials were or had been performed (n = 825 centers). The clinical development of the approved and proposed biosimilars mainly represented in LMIC, where 77% (n = 633) of the centers were described. The LMIC- oriented distribution was conserved for approved and proposed biosimilars, with no major divergencies (Figure 1).

Figure 1. The global distribution of institutions involved in the clinical development of proposed (a) or approved (b) biosimilars of trastuzumab.

For the approved biosimilars, we analyzed the lists of the authors of the published publications, to define if the implementation of trials in developing countries results in appropriate acknowledgment of the participating centers [4–9]. We identified 81 authors across 6 clinical trials; half of the authors belonged to institutions in LMIC (n = 41). The proportion of authors affiliated to an institution in LMIC was higher for trials run by companies or partners based in Asia (SB3, CT-P6). However, the first and senior authorship was never found for an investigator from LMIC.

2.2. The instrumental role of biosimilars in changing the trajectory of breast cancer research and treatment

The global analysis of the clinical development of biosimilars for breast cancer paved the way for innovative perspectives in the research implementation in oncology, serving as a case study. Trastuzumab is a WHO essential medicine for breast cancer treatment, and the only biologic agent in the WHO essential medicine list for this indication, both in early and advanced setting. In the perspective to understand the decision-making process in setting health priorities, this case study has strategically been selected for the purpose. So far, this is the first study painting a global landscape of drug development of biosimilars, as previous reports have generally focused on the clinical uptake and use of them. Overall, the knowledge of cancer research priorities in LMIC is widely obscure, especially when framed in public–private partnerships, where regulations for transparency have been invoked but inhomogeneously formulated, often within ample margins of contractual discretion.

Despite a rhetorical neglection of cancer care in developing countries, related to the unaffordability of cancer interventions along with unpreparedness of health systems to efficiently deliver quality care, the paradigm of cancer as a disease of westernized societies has no reason to exist anymore. In 2018, more than 2 millions of women and men were diagnosed with breast cancer in the world, causing 630 000 deaths [10]. Of them, more than one-half of patients were living in LMIC, where 70% of the global breast cancer deaths were registered. Women and men die of breast cancer in the world, and the burden of the problem is actually shifted toward LMIC, where the poor access to screening and treatment worsened by weak health system capacity and scarce value-based regulatory systems for selection, procurement, and pricing of cancer medicines – especially biologics – weights on patients and their families as a death sentence or, in the worst case, an unaffordable hope at the cost of bankruptcy. Securing the access to the best quality and valuable care for cancer patients ensuring financial protection is the driving element of Universal Health Coverage (UHC), committed to shield people from financial hardship and not threaten living standards. According to WHO, between 7% and 15% of the world population across the Regions mobilized large household income for health and were pushed under the threshold of poverty as a result of catastrophic health expenditure [11]. Based on the estimations from the Global Burden of Diseases, the major gap determining inequalities in the outcome of cancer patients in LMIC is the inadequate access to cancer services [12].

Taken together, the data suggest that the trajectory of breast cancer care has been tracked around high-income countries for too long, and that the current priority is to reorient the research agenda in an LMIC perspective, to address the current relevant unmet needs and tackle the disparities – aligning to the global commitment of the United Nations (UN) Sustainable Development Goals (SDG), to sustainably reduce the mortality for cancer of one-third by 2030, prioritizing essential medicines, medical devices, and technologies whilst ensuring financial protection to all [13]. This is the current mandate of UN and WHO, pursuing UHC for a better society, addressing social equality and justice.

In this context, the possibility to access affordable care becomes a priority instrument for the cure and care of breast cancer patients – emphasizing the critical role of biosimilars in realizing UHC. Stagnating improvements experienced in some LMIC for cancer control may reflect the complex and resource-intense efforts in reorienting and building services for cancer care, that must be based on a value-based priority-setting framework to choose wisely [14,15]. Accordingly, quality assured biosimilars of essential medicines are functional in pursuing UHC for cancer, representing a wise choice.

However, cogent issues must be addressed and resolved. The misperception around biosimilars as cheap options for poorer patients recalls the urgent need to optimize the training and education of both oncologists and policymakers, to clarify that biosimilars were never supposed to be developed as special regulatory exceptions based on fragile evidence to authorize suboptimal medicines for resource-limited health settings. Biosimilars must be the antineoplastic therapeutics of choice in all the settings. All the prejudices on biosimilars and their value can potentially worsen the survival gaps of patients and widen the inequalities, thus dampen the achievement of UHC.

The strategic prioritization of valuable health interventions must ensure value for money, the key principle of health planning that links the efficient allocation of resources, and the significant improvement of the clinical outcomes, trait d’union of the governance, and clinical level across the cancer continuum. Pushing for health equalities, tackling unjust and avoidable differences in people’s health across the population and between specific population groups, primarily the most vulnerable strata, can be catalyzed by the policies of choosing wisely, where the role of biosimilars is prominent. As the policy formulation for biosimilars intersects the selection and prioritization of medicines for cancer, within significant budget implications, and touches the governmental sensitive aspects of public–private negotiations (price setting) as well as the policies for reimbursement and patients’ co-payments, it cannot be neglected what instrumental role biosimilars can play to realize UHC: at the crossroads of justice, fairness, and egalitarianism, built upon the conditions of relevance, publicity, appeals, and enforcement – in one word, upon the accountability for reasonableness ethic approach.

In the  context  of value-based healthcare, where the need of choosing wisely the health interventions, improve efficiency in budget allocation, disengage from wastefulness and prioritize essential medicines and medical technologies represent the most powerful operational model to inform decision-making in healthcare as in high- as in low-middle income countries, the misrecognition of the value of biosimilars is a failure in culture, science, policy, and medicine.

Expert Opinion

The implementation of clinical trials must align with national priorities and contextualized to the health system structure and capacity, meeting population needs while framing a patient- centered care. In the perspective of changing the trajectory of breast cancer care worldwide, the bedrock of the change can pass through the drug development of biosimilars, prioritizing the development of a research field with an immediate possible translation into the clinical practice, embracing the perspectives of economic and financial benefits. Only advocating for population public health, we can secure the appropriate positioning of biosimilar development into the broader context of healthcare, thus assuring the catalyzation of priority access to the most valuable medicines for breast cancer patients, orienting the health funding and resource allocation – ultimately setting priorities across the continuum of care.

Declaration of interest

Giuseppe Curigliano has received honoraria from Pfizer, Novartis, Lilly, Roche; fees for expert testimony and medical education from Pfizer; and has participated in advisory boards for Pfizer, Roche, Lilly, Novartis, Seattle Genetics, Celltrion. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper received no funding.