Table 5.

Phase 3 safety results for the trastuzumab biosimilar(s) (candidates)

Biosimilar (candidate)	Adverse events	Cardiotoxicity	Antidrug antibody detection	Ref.
ABP 980 (Amgen/Allergan)	≥ 1 AE: 80.2% vs 79.5%, Grade ≥ 3 AE: 14.8% vs 14.1% for ABP 980 and RP, respectively°	Six patients in the ABP 980 group and one in the RP group had cardiac failure adverse events. All events were grade 1 or 2, and patients completed planned doses with no worsening of the cardiac failure event°	Two patients in each group developed binding antibodies. Neither tested positive for neutralising antibodies°	55,56
	AE: 52.0% vs 57.3% for RP-RP group and switch group, Grade ≥ 3 AE: 10 in each group°°	One patient (0.6%) with cardiac failure in each group°°	One patient with binding, non-neutralising ADA (switch group)°°	82
BCD-02+ (Biocad)	No statistically significant difference in AEs, including SAEs, between groups	Tachycardia (34.92% vs 19.67%), arterial hypertension (20.63 vs 18.03%) atrial fibrillation (0% vs 3.28%), extrasystoles (0% vs 1.64%), aggravated myocardiodystrophy (1.59% vs 0%)	Neutralising ADA in one patient in each group	57
CT-P6x (Celltrion)	AEs comparable between groups*	Cardiotoxicity in 8 (3.3%) and 10 (4.3%) patients in biosimilar and RP group, respectively*	NR*	66
	STEAE: 7% vs 8% for CT-P6 and RP group Grade ≥ 3 TEAE: 6% vs 8% for CT-P6 and RP group**	TEAEs owing to heart failure in 2% vs 1% for CT-P6 and RP group, respectively. Of these, one patient (RP group) withdrawn from study (confirmed decrease in LVEF). One grade 1 heart failure (CT-P6 group), but no substantial decrease in LVEF**	All post infusion ADA tests were negative**	67
MYL-1401O (Mylan/Biocon)	TEAEs and SAEs similar between groups	No difference in median LVEF between groups	ADA similar between groups	61,62
PF-05280014 (Pfizer)~	SAEs similar in both arms*	NR*	One patient developed ADA (EU-RP)*	65
	Grade 3–4 TEAEs: 38.1% vs 45.5% for PF-05280014 and RP**	No TEAEs of congestive heart failure or clinically significant LVEF abnormalities were reported in either arm. No notable differences between the treatment groups in mean LVEF results.**	No patients with ADA for PF-05280014 vs one patient for RP**	64
SB3 (Samsung Bioepis)	SAEs: 10.5% vs 10.7% for SB3 and RP**	Two patients in SB3 group presented with CHF**	ADA 0.7% vs 0.0% for SB3 and RP**	54
	TEAEs (97.5% vs 96.1% for SB3 and RP) similar between groups***	14 LVSD events in 11 (2.5%) patients in biosimilar group, 9 LVSD events in 8 (1.8%) patients in RP group. Four patients (three in SB3, one in RP) reported CHF***	0.7% in both groups***	63

ADA antidrug antibodies; AE adverse event; CHF congestive heart failure; LVEF left ventricular ejection fraction; LVSD asymptomatic left ventricular systolic dysfunction; NR not reported; RP reference product; SAE serious adverse event; TEAE treatment emergent serious adverse event

Data are derived from published scientific literature (full text or abstract)

^°Results from neoadjuvant setting

^°°Results from the single switch treatment arm vs continuing arm in adjuvant phase of the study

^*Reported results are safety results of the phase 3 trial in metastatic breast cancer population

^**Reported results are safety results of the phase 3 trial in early breast cancer patients (neoadjuvant period)

^***Reported results are safety results of the phase 3 trial in early breast cancer patients (neoadjuvant + adjuvant period)

⁺BCD-022 is authorised in Russia, but has not been submitted to FDA or EMA and most likely would not be considered as a biosimilar following stringent FDA or EMA requirements

^xThe phase 3 data in MBC for CT-P6 were not submitted to EMA as part of the marketing authorisation application and were thus not evaluated when assessing the totality of evidence for biosimilarity⁵⁰

^~The pivotal phase 3 trial for PF-05280014 was conducted in the MBC setting. Supportive efficacy data have been gathered in a phase 3 clinical trial in patients with early breast cancer in the neoadjuvant setting (PK endpoint as primary endpoint)⁵²