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Clinical review of biosimilars approved in oncology

Biosimilars/Research | Posted 09/10/2020 0 Post your comment

As cancer therapeutics constitutes a large proportion of the biologicals market, and patents have begun to expire, biosimilars have an important role in optimizing patient access and reducing costs in the oncology therapeutic area. Authors Ngo and Chen from the City of Hope National Medical Center, Los Angeles, USA, give an overview of the US Food and Drug Administration (FDA)-approved biosimilars in oncology and their impact on the healthcare system in the Annals of Pharmacotherapy [1]. A summary of the main findings from that article follows.

Biosimilar clinical trial design
At a minimum to pursue FDA approval, a pharmacokinetic (PK) and/or immunogenicity study needs to be carried out comparing the proposed biosimilar and the reference product. Per FDA guidance for biosimilars, sponsors should provide scientific justification for whether patients or healthy subjects are chosen for pharmacology trials. FDA recommends that sponsors collect immunogenicity data in all clinical studies when possible. In most cases, a comparative clinical study will need to be done to clarify any residual uncertainty that could not be resolved from the PK/pharmacodynamic (PD) studies and immunogenicity assessment.

FDA-approved biosimilars in oncology
Clinical trials of FDA-approved biosimilars for bevacizumab, rituximab and trastuzumab showed no significant differences with respect to efficacy, safety and PKs when compared to their reference products. For additional details and an in-depth review of the data, see Table 1, [1].

Bevacizumab
The patent on bevacizumab expired in the US in July 2019 and will expire in the European Union (EU) in January 2022 [2], which has led many drug companies to seek approval for their biosimilars [3]. There have been two biosimilars approved in the US, bevacizumab-awwb (Mvasi) in September 2017 and bevacizumab-bvzr (Zirabev) in June 2019 [4]. Both have also received approval by the European Commission (EC) in January 2018 and February 2019, respectively [5].

Rituximab
The patent for rituximab expired in 2016 in the US (and in 2013 in Europe) [2], which has led to development of the biosimilars Truxima (rituximab-abbs) and Ruxience (rituximab-pvvr) [6], which were approved by FDA in November 2018 and July 2019, respectively [4]. In Europe, Truxima and Ruxience was approved in January 2017 and April 2020, respectively [5].

Trastuzumab
Many companies have pursued trastuzumab biosimilars in anticipation of the patent expiring in 2019 [2]. Currently, there are five FDA-approved trastuzumab biosimilars with the indications in breast cancer and metastatic gastric cancers: trastuzumab-dkst (Ogivri) in December 2017, trastuzumab-pkrb (Herzuma) in December 2018, trastuzumab-dttb (Ontruzant) in January 2019, trastuzumab qyyp (Trazimera) in March 2019, and trastuzumab-anns (Kanjinti) in June 2019 [4]. All of these biosimilars have been approved in Europe as well [5].

Table 1: Summary of clinical data of FDA-approved biosimilars compared to the reference product
Product Name/ Manufacturer		Study Design	Dose	ORR	PFS	Comments
ABP-215 (Amgen/ Allergan)	Bevacizumab-awwb (Mvasi®)	Phase III, randomized, double-blind. Advanced NSCLC (N = 642). With carboplatin/paclitaxel x 4‒6 cycles.	15 mg/kg	ABP-215 39% vs BEV-EU 41.7% (RR 0.93, 90% CI 0.80‒1.09).	ABP-215 6.6 months vs BEV-EU 7.9 months	Median doses received: ABP215 4.8 doses vs BEV-EU 5 doses. Duration of response ABP 215 5.8 months vs BEV-EU 5.6 months. With no differences in PK, safety, or immunogenicity.
ABP-215 (Amgen/ Allergan)	Bevacizumab-awwb (Mvasi®)		15 mg/kg	ABP-215 39% vs BEV-EU 41.7% (RR 0.93, 90% CI 0.80‒1.09).	ABP-215 6.6 months vs BEV-EU 7.9 months
PF-06439535 (Pfizer)	Bevacizumab-bvzr (Ziravev®)	Phase III, double-blind, parallel-group. Advanced NSCLC (N = 719). With carboplatin /paclitaxel x 4‒6 cycles.	15 mg/kg	PF-06439535 45.3% vs BEV-EU 44.6% (RR 1.015, 95% CI 0.863‒1.193)	1-yr PFS: PF-06439535 33.1% vs BEV-EU 30.9%	Both arms received a median of 11 doses. Duration of response PF-06439535 8.3 months vs BEV-EU 6.6 months with no differences in PK, safety, or immunogenicity.
CT-P10 (Celltrion)	Rituximab-abbs (Truxima®)	Phase III, double-blind, parallel-group. Untreated LTB-FL (N = 258). Weekly x 4 doses.	375 mg/m²	CT-P10 83% vs RX-US 81%. ∆+1.8% (95% CI -8.22- 11.53).	N/A	Both arms received up to 2 years of maintenance. CR at 24 weeks: CT-P10 30% vs RX-US 22%. PK results similar. ≥1 treatment-emergent serious AE: CT-P10 23% vs RX-US 13%. No differences in PK and immunogenicity.
CT-P10 (Celltrion)	Rituximab-abbs (Truxima®)	Phase III, double-blind, parallel-group. Untreated LTB-FL (N = 258). Weekly x 4 doses.	375 mg/m2	CT-P10 83% vs RX-US 81%. ∆+1.8% (95% CI -8.22‒11.53).	N/A	Both arms received up to 1‒2 years of maintenance. CR at month 7: CT-P10 28% vs RX-US 34%. No differences in PK, safety, immunogenicity.
PF-05280586 (Pfizer)	Rituximab-pvvr (Ruxience®)	Phase III, randomized, double-blind. Previously untreated CD-20 positive, LTB-FL (N = 394). Weekly x 4 doses.	375 mg/m²	PF-05280856 75.5% vs RX-EU 70.7%. ∆+4.66% (95% CI -4.16‒13.47).	1-yr PFS: PF-05280856 78.2% vs RXEU 83.0% (HR 1.39, p = 0.189)	Similar rates of CR: PF05280586 29.3% vs 31% for RX-EU. No differences in PK, safety, immunogenicity.
MYL-1401O (Mylan)	Trastuzumab-dkst (Ogivri®)	Phase III, randomized, double-blind, parallel group in HER2-positive metastatic breast cancer (N = 500). In combination with a taxane.	8 mg/kg loading then 6 mg/kg	MYL-1401O 69.6% vs TRA 64.0% (RR 1.09, 90% CI 0.974‒1.211)	48-weeks: MYL-1401O 44.3% vs TRA 44.7% (HR 0.97, p = 0.84)	Similar OS rates at 48 weeks: MYL-1401O 89.1% vs TRA 85.1% (HR 0.67, p = 0.13). No differences in PK, safety or immunogenicity.
CT-P6 (Celltrion)	Trastuzumab-pkrb (Herzuma®)	Phase III, randomized, double-blind, equivalence in HER2-positive operable breast cancer (N = 549). With neoadjuvant docetaxel /adjuvant FEC x 8 cycles.	8 mg/kg loading then 6 mg/kg	CT-P6 87.1% vs TRA-US 86.3%	N/A	pCR CT-P6 46.8% vs TRA-US 50.4% (RR 0.93, 95% CI 0.78‒1.11). No differences in PK, safety or immunogenicity.
SB3 (Samsung Bioepsis)	Trastuzumab-dttb (Ontruzant®)	Phase III, randomized, double-blind, parallel group in HER2-positive operable breast cancer (N = 800). With neoadjuvant (docetaxel/ FEC) x 8 cycles then adjuvant SB3/TRA x 10 cycles.	8 mg/kg loading then 6 mg/kg	SB3 96.3% vs TRA-EU 91.2% (RR 1.055, 95% CI 1.017‒1.095)	N/A	bpCR SB3 51.7% vs TRA-EU 42.0% (RR 1.259, 95% CI 1.085‒1.460). No differences in PK, safety or immunogenicity.
PF-05280014 (Pfizer)	Trastuzumab-qyyp (Trazimera®)	Phase III, randomized, double-blind in HER-2 positive metastatic breast cancer (N = 707). With weekly paclitaxel x 6 cycles.	4 mg/kg loading then 2 mg/kg	PF-05280014 62.5% vs TRA-EU 66.5 % (RR 0.94, 95% CI 0.842‒1.049)	1-yr PFS: PF-05280014 54% vs TRAEU 51%	Median time to PFS: PF05280014 12.16 months vs TRA-EU 12.06 months (HR 1.00, p = 0.505). 1-yr OS: PF05280014 89.31% vs TRA-EU 87.36% (HR 1.004, p = 0.507). Duration of response: PF05280014 11.27 months vs TRA-EU 10.58 months. (HR 0.92, p = 0.304). No differences in PK, safety or immunogenicity.
PF-05280014 (Pfizer)	Trastuzumab-qyyp (Trazimera®)	Phase III, randomized, double-blind, non-inferiority in HER2-positive operable breast cancer (N = 226). With neoadjuvant docetaxel/ carboplatin x 6 cycles.	8 mg/kg loading then 6 mg/kg	PF-05280014 88.1% vs TRA-EU 82.0% (∆+5.96, 95% CI -4.01‒15.94)	N/A	pCR PF-05280014 47.0% vs TRA-EU 50.0% (∆-2.81, 95% CI-16.58‒10.96). No differences in PK, safety or immunogenicity.
ABP-980 (Amgen)	Trastuzumab-anns (Kanjinti®)	Phase III, randomized, double-blind, equivalence in HER2-positive operable breast cancer (N = 725). With neoadjuvant EC-T then adjuvant ABP 980/TRA x 1 year.	8 mg/kg loading then 6 mg/kg	N/A	N/A	pCR ABP-980 48% vs TRA-EU 40.5% (RR 1.1877, 90% CI 1.0327‒1.3660)
AE: adverse events; BEV-EU: bevacizumab reference product sourced from the European Union; bpCR: breast pathological complete response; CI: confidence interval; CR: complete response; CVP: cyclophosphamide/vincristine/ prednisone; EC→T: epirubicin/cyclophosphamide then paclitaxel; FEC: fluorouracil/ epirubicin/cyclophosphamide; FL: follicular lymphoma; HER2: human epidermal growth factor receptor 2; HR: hazard ratio; LTB: low tumor burden; N/A: not applicable; NSCLC: non-squamous non-small cell lung cancer; ORR: overall response rate; OS: overall survival; pCR: pathological complete response; PFS: progression-free survival; PK: pharmacokinetics; RR: relative risk; RX-US: rituximab reference product sourced from the European Union; RX-US: rituximab reference product sourced from the United States; TRA: trastuzumab reference product; TRA-EU: trastuzumab reference product sourced from the European Union; TRA-US: trastuzumab reference product sourced from the United States.

Cost comparison and impact on healthcare landscape
A full comparison of the wholesale acquisition costs between the biosimilars and their reference products for bevacizumab, rituximab and trastuzumab is shown in Table 2. As can be observed in the table, the discounts on a price basis are not as high (10% to 25%) when compared to generics price discounts (39% to 95%). However, given the scale and magnitude of drug pricing for complex biological molecules, even small price reductions can result in significant cost savings. It is important to note that the wholesale acquisition costs do not account for discounts, rebates, and other incentives provided by manufacturers. Price negotiations between payors, institutions and manufacturers will guide decision-making and impact the potential cost savings of a biosimilar. If there is a large proportion of patients with private insurance, the choice of which biosimilar to carry at an institution will depend on what product is preferred by each of the different insurance companies. Currently, there are no interchangeable biosimilars available in the US, but a biosimilar with interchangeability status will control more market share for a specific biological.

Table 2: Comparison of wholesale acquisition costs between biosimilars and their reference products for bevacizumab, rituximab and trastuzumab
Product Name/Manufacturer		Biosimilar Wholesale Acquisition Cost (US$)	Reference Product Wholesale Acquisition Cost (US$)
ABP-215 (Amgen/ Allergan)	Bevacizumab-awwb (Mvasi®)	100 mg/4 mL vial: $677.40 400 mg/16 mL vial: $2,709.60	Bevacizumab (Avastin®) 100 mg/4 mL vial: $796.94 400 mg/16 mL vial: $3,187.76
PF-06439535 (Pfizer)	Bevacizumab-bvzr (Ziravev®)	100 mg/4 mL vial: $613.40 400 mg/16 mL vial: $2,453.60
CT-P10 (Celltrion)	Rituximab-abbs (Truxima®)	100 mg/10 mL vial: $845.55 500 mg/50 mL vial: $4,227.75	Rituximab (Rituxan®) 100 mg/10 mL vial: $939.52 500 mg/50 mL vial: $4,697.60
PF-05280586 (Pfizer)	Rituximab-pvvr (Ruxience®)	100 mg/10 mL vial: $716.80 500 mg/50 mL vial: $3,584.00
ABP-980 (Amgen)	Trastuzumab-anns (Kanjinti®)	150 mg vial: $1,320.45 420 mg vial: $3,697.26	Trastuzumab (Herceptin®) 150 mg vial: $1,558.42
MYL-1401O (Mylan)	Trastuzumab-dkst (Ogivri®)	150 mg vial: $1,324.66 420 mg vial: $3,697.26	420 mg vial: discontinued
SB3 (Samsung Bioepsis)	Trastuzumab-dttb (Ontruzant®)	150 mg vial: $1,324.66 420 mg vial: $3,709.04
CT-P6 (Celltrion)	Trastuzumab-pkrb (Herzuma®)	150 mg vial: $1,402.50 420 mg vial: $3,927.00
PF-05280014 (Pfizer)	Trastuzumab-qyyp (Trazimera®)	420 mg vial: $3,391.08

The authors therefore concluded that, although there are still ‘many questions to be answered, biosimilars have the potential for significant cost savings in the US health care system’.

The authors of the research paper [1] did not provide any conflict of interest statement.

Abstracted by Jason Chen, Clinical Pharmacist at the City of Hope National Medical Center, Duarte, CA, USA.

Biosimilars in oncology in the US

References
1. Ngo D, Chen J. A clinical review of biosimilars approved in oncology. Ann Pharmacother. 2020;1060028020944596.
2. GaBI Online - Generics and Biosimilars Initiative. Patent expiry dates for biologicals: 2018 update [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 9]. Available from: www.gabi-journal.net/patent-expiry-dates-for-biologicals-2018-update.html
3. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of bevacizumab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 9]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-of-bevacizumab
4. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in the US [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 9]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-the-US
5. GaBI Online - Generics and Biosimilars Initiative. Biosimilars approved in Europe [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 9]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-approved-in-Europe
6. GaBI Online - Generics and Biosimilars Initiative. Biosimilars of rituximab [www.gabionline.net]. Mol, Belgium: Pro Pharma Communications International; [cited 2020 Oct 9]. Available from: www.gabionline.net/Biosimilars/General/Biosimilars-of-rituximab

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