Table 2.
Phase III trials evaluating trastuzumab biosimilars
| Agent | Company | Phase | n | Indication | Endpoint | Study design | Trial status | Results | Drug status |
|---|---|---|---|---|---|---|---|---|---|
| CT-P6 (Herzuma®) | Celltrion Healthcare(Incheon, ROK)/ TevaPharmaceuticals(Petach Tikwa, Israel) | pooledI/IIB–III | 475 | first line mBC |
ORR | equivalence | completed | CT-P6 vs. trastuzumab RPa: ORR 57 vs. 62%; mTTP 11.07 vs. 12.52 months [14] | marketed in South Korea following approval in January 2014; submitted to FDA in July 2017 and rejected in April 2018; resubmitted to FDA in May 2018 |
| III | 549 | eBC (NAT) |
pCR | equivalence | completed | non-inferior pCR (ypt0/is ypN0); 46.8% (95% CI 40.4–53.2) vs. 50.4% (95% CI 44.1–56.7) (CT-P6 vs. trastuzumab RP); 95% CI of the estimated treatment outcome difference (−0.04 (95% CI −0.12 to 0.05)) was within the equivalence margin, RR 0.92 [15] | |||
| PF-05280014 (Trazimera®) | Pfizer (New York, NY, USA)/Hospira (Lake Forest, IL, USA) | III | 707 | mBC | ORR | equivalence | completed | RR 0.940 (95% CI 0.842–1.049) over trastuzumab; 95% CI within the prespecified equivalence margin of 0.80–1.25; ORR 62.5% (95% CI 57.2–67.6%) for PF-05280014 vs. 66.5% (95% CI 61.3–71.4%) for trastuzumab RP; | phase I study completed; phase III study ongoing, expected to be completed March 2018; positive phase III results reported in November 2016 and September 2017; submitted to EMA and FDA for approval in September 2017; rejected by FDA in April 2018; approved by EMA in June 2018 |
| PFS (median 12.16 months for PF-05280014 vs. 12.06 months for trastuzumab; 1-year rate 54 vs. 51%) or OS (median: not reached in either group; 1-year rate 89.31 vs. 87.36%) [16] | |||||||||
| III | 226 | eBC (NAT) |
PK endpoints |
non-inferiority | completed | PF-05280014 vs. trastuzumab RP: non-inferior pCR 47 vs. 50%; lower limit of 95% CI (−8.02, 6.49%) for the stratified difference between groups was above the non-inferiority margin (−12.5%) (NCT02187744) [17] | |||
| ABP980 (Kanjinti®) | Amgen (Thousand Oaks, CA, USA) | III | 827 | eBC (NAT) |
pCR | equivalence | completed | non-inferior pCR 48% (95% CI 43–53) for ABP 980 41%, (95% CI 35–46) for trastuzumab RP (RD 7.3, 90% CI 1.2–13.4; RR 1.188, 90% CI 1.033–1.366); central assessed pCR 48 vs. 42% (RD 5.8, 90% CI −0.5 to 12.0 and RR 1.142, 90% CI 0.993–1.312) [18] | approved by EMA in March 2018; submitted to FDA for approval in July 2017; rejected by FDA in June 2018 |
| SB3 (Ontruzant®, EU; Samfenet®, R.O.K.) | Samsung Bioepis (Biogen/Samsung) (Incheon, ROK)/Daewoong Pharmaceuticals (Seoul, ROK)/Merck (MSD)(Kenilworth, NJ, USA) | III | 875 | eBC | pCR | equivalence | completed | SB3 vs. trastuzumab RP: equivalent bpCR 51.7 and 42% with SB3 and trastuzumab RP; adjusted ratio of bpCR: 1.259 (95% CI 1.085–1.460), within the predefined equivalence margins; adjusted difference: 10.70% (95% CI 4.13–17.26%), with the lower limit contained within and the upper limit outside the equivalence margin; tpCR: 45.8 and 35.8% | approved by EMA in November 2017; approved by Korea's MFDS in November 2017; submitted to FDA for approval in December 2017 |
| ORR 96.3% for SB3 vs. 91.2% for trastuzumab RP, adjusted ratio 1.259 (95% CI 1.085–1.460) [19]; | |||||||||
| EFS: comparable between groups, HR (SB3/trastuzumab RP) 0.94 (95% CI 0.59–1.51); 12-month EFS 93.7% for SB3 vs. 93.4% for trastuzumab RP; final analysis after 438 days: EFS rate for SB3 (92.2%) vs. trastuzumab RP (91.6%) [20] | |||||||||
| MYL-1410 (Ogivri®) | Mylan (Canonsburg, PA, USA)/Biocon (Bangalore, India) | III | 458 | mBC | ORR | equivalence | completed | MYL-1410 vs. trastuzumab RP: non-inferior ORR: 69.6 vs. 64% (HR 1.09; 95% CI 0.95–1.24); ORR difference (5.53; 95% CI −3.08 to 14.04) 48-week PFS (44.3 vs 44.7%; −0.4%; 95% CI −9.4 to 8.7%), OS (89.1 vs. 85.1%; 4.0%; 95% CI −2.1 to 10.3%; p = 0.13) [21] | received approval from FDA December 2017; submitted to EMA for approval in November 2016; withdrawn from EMA August 2017; resubmitted to EMA for approval in December 2017; |
| BCD-022 (HERtiCAD®) | Biocad (Saint Petersburg, Russia) | III | 126 | mBC | ORR | non-inferiority | completed | BCD-022 vs. trastuzumab RP: ORR 53.6 vs. 53.7%; progression rate not different: 21.45 vs. 20.4%) | received approval from Russian regulatory body January 2016 |
aGenentech, San Francisco, CA, USA.
RP, reference product; PK, pharmacokinetics; RD, risk difference; RR, risk ratio; pCR, pathologic complete response; bpCR, breast pathologic complete response; tpCR, total pathologic complete response; eBC, early breast cancer; mBC, metastatic breast cancer; EFS, event-free survival; HR, hazard ratio; CI, confidence interval; ORR, overall response rate; OS, overall survival; mTTP = median time to progression; ROK, Republic of Korea; EU, European Union; FDA, Federal Drug Administration; EMA, European Medicines Agency; MFDS, Ministry of Food and Drug Safety; NAT, neoadjuvant treatment; PFS, progression-free-survival.