Bridging the Knowledge Gap Between Biosimilars and Biologics in Breast Cancer

Since 2006, the European Medicines Agency has granted marketing authorization for more than 40 biosimilars, and, in less than 4 years, the FDA has approved 17, yet the knowledge gap in the understanding of biosimilarity poses a unique challenge to the agents’ assimilation into clinical practice and possible impact on access and cost savings, experts say.

Hope Rugo, MD

Since 2006, the European Medicines Agency has granted marketing authorization for more than 40 biosimilars, and, in less than 4 years, the FDA has approved 17,1,2 yet the knowledge gap in the understanding of biosimilarity poses a unique challenge to the agents’ assimilation into clinical practice and possible impact on access and cost savings, experts say.

Hope S. Rugo, MD, FASCO, a program cochair for the 36th Annual Miami Breast Cancer Conference® (MBCC), has been a leader in the effort to develop biosimilar versions of trastuzumab (Herceptin), the monoclonal antibody that has helped transform care for patients with HER2-positive breast cancer. The FDA has now approved 3 trastuzumab biosomilars: trastuzumab-dkst (MYL-1401O; Ogivri), trastuzumab-pkrb (CT-P6; Herzuma), and trastuzumab-dttb (SB3; Ontruzant) (Table).2

During a presentation Friday at MBCC, Rugo discussed how regulatory agencies evaluate proposed trastuzumab biosimilars, along with key issues such as whether biosimilars should extrapolate the same indications as the reference product and whether they should be interchangeable.

“Biosimilars are biologic agents that are highly similar to an approved biologic product, referred to as the reference product. Based on analytic, pharmacokinetic, pharmacodynamic, and clinical trial data, there are no clinically meaningful differences in terms of quality, safety, and effectiveness from the reference product,” Rugo said in an email interview in advance of her presentation. “As effective biologic agents go off patent in the United States and Europe, biosimilars have the potential to markedly reduce the cost of healthcare and improve access for patients who can benefit from these agents.”

Rugo, a professor of medicine and director of breast oncology and clinical trials education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, noted that supportive care medications such as filgrastim are being used routinely in clinical practice.

The first biosimilar versions of trastuzumab could enter the US market during the second half of 2019, according to Roche, which holds the patents on the drug.3 The introduction of biosimilars in other countries has resulted in lower prices for the reference product, according to Rugo.

Misconceptions Persist

“Biosimilars are here to stay,” Rugo said in a previous interview with OncLive®. “They’re being used in Europe and the rest of the world. They will come to the United States. My biggest hope for biosimilars is that they’ll improve access to lifesaving therapy.”Although the FDA has established extensive criteria to evaluate a potential biosimilar, myths about these products persist, Rugo and colleagues wrote in an article in Future Oncology.4 These include inaccurate perceptions that less clinical and nonclinical evidence is required for their approval, that there are differences in the primary structure between a biosimilar and a reference product, and that biosimilars must have clinical data for each indication to gain approval in that setting.4

In fact, regulatory approval is based on a “‘totality of evidence” substantiated by structural and functional classification, nonclinical evaluation, assessment of clinical pharmacokinetics and immunogenicity, and comparative clinical efficacy and safety data. For approval, biosimilars must demonstrate similarity with the reference drug “in terms of quality characteristics, biological activity, safety, and efficacy,” according to Rugo and colleagues.4

Efficacy Data Present for Approvals

“As increasing numbers of biosimilars achieve regulatory approval and are available for use in clinical practice, it is important for the medical community to understand the underlying concepts behind the evaluation of similarity and the approval of biosimilars for use in clinical settings,” the authors said.4MYL-1401O

In December 2017, MYL-1401O became the first trastuzumab biosimilar to receive FDA approval. Codeveloped by Mylan and Biocon, the biosimilar is indicated in similar settings as trastuzumab: HER2-positive patients with breast cancer or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The approval was based on structural and functional product comparisons, animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity, the FDA said in announcing the approval.5

The biologics license application included findings from the 2-part, double-blind, randomized Heritage trial, in which Rugo served as the principal investigator. Patients with measurable HER2-positive metastatic breast cancer who had not received prior chemotherapy or trastuzumab for metastatic disease were randomized to MYL- 1401O (n = 230) or trastuzumab with docetaxel or paclitaxel (n = 228).

In part 1 of the trial, trastuzumab was given for a minimum of 8 cycles and continued until progression, after which patients in part 2 with stable disease or better continued on MYL- 1401O or trastuzumab.

Overall response rate (ORR) served as the primary endpoint of the trial, with secondary endpoints of progression-free survival (PFS), overall survival (OS), time to progression, safety, and tolerability. After 24 weeks, the rates of ORR were 69.9% and 64% among women who received MYL-1401O and trastuzumab in combination with a taxane, respectively.6

The ratio of ORR for MYL-1401O to trastuzumab was 1.09—both 90% CI (0.974-1.211); the difference in ORR between the 2 arms was 5.53% (95% CI, —3.08% to –14.04%). At the week-48 cutoff, there was no statistically significant difference for time to progression, PFS, or OS. The adverse event (AE) profile also was similar.

Updated findings that Rugo presented at the 2018 American Society of Clinical Oncology Annual Meeting correlated with the earlier results. Through 48 weeks, the PFS was nearly identical between the 2 arms at 11.1 months (P = .842), with similar CIs (MYL-1401O, 8.81- 11.20; trastuzumab reference, 8.60-11.20). HR stratified by assigned taxane, tumor progression, and tumor endocrine status for 48-week PFS was 0.95 (95% CI, 0.714-1.251; P = .694).7


CT-P6 was approved in December 2018 as a treatment for patients with HER2-overexpressing breast cancer. The label includes clinical trial findings for studies as adjuvant therapy in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, or as part of a regimen with docetaxel and carboplatin. The approval also includes frontline treatment of HER2-overexpressing metastatic breast cancer either in combination with paclitaxel or as monotherapy for patients who have received ≥1 chemotherapy regimen for metastatic disease.8

The clinical evidence supporting the application included findings from a phase III trial in which CT-P6 exhibited long-term diseasefree survival (DFS) and OS similar to the reference product in the treatment of patients with HER2-positive early breast cancer.

Data presented at the 2018 San Antonio Breast Cancer Symposium demonstrate that CT-P6 outcomes remained consistent with the efficacy and safety findings previously reported for the 1-year mark. In the trial, 549 patients with HER2-positive stage I to IIIa breast cancer were randomized to receive anthracyclineand taxane-based chemotherapy in combination with either trastuzumab or CT-P6. After patients underwent surgery, they continued to receive trastuzumab or CT-P6 to complete 1 year of therapy.9

At a median follow-up of 27 months, 259 patients in the CT-P6 arm and 269 in the trastuzumab arm were included in the follow-up evaluation. Among the intent-to-treat (ITT) population, the rate of 2-year DFS was 86% (95% CI, 80%-90%) in the CT-P6 arm and 90% (95% CI, 85%-93%) in the trastuzumab arm.

Moreover, 2-year OS was 97% (95% CI, 93%- 98%) in the CT-P6 arm and 98% (95% CI, 96%-99%) in the trastuzumab arm. The rates of 3-year OS indicated a consistent similarity in the ITT analysis at 92% (95% CI, 86%-96%) and 93% (95% CI, 87%-96%) in the CT-P6 and trastuzumab arms, respectively.

Regarding safety, patients sustained an average ventricular ejection fraction (LVEF) >55% during both the 1 year on treatment and the follow-up period. Over the course of treatment, the average worst LVEF value was 60 in both the CT-P6 (95% CI, 38-70) and trastuzumab (95% CI, 30-76) arms. Overall, 29.5% of patients in the CT-P6 arm and 25.2% of those in the trastuzumab arm had a decrease in LVEF of ≥10 points.

The rates of cardiac toxicity observed over the course of treatment and follow-up period were similar, at 11.8% and 13.7% in the CT-P6 and trastuzumab arms, respectively. The rates of cardiac disorders that were linked to the study medication were closer in nature, at 8.1% in the CT-P6 arm and 8.6% in the trastuzumab arm. Notably, the rate of unrelated cardiac disorders was slightly lower in the CT-P6 arm at 5.2% compared with 6.8% in the trastuzumab arm.


In January 2019, SB3 became the third trastuzumab biosimilar to receive FDA approval, with indications for the treatment of patients with HER2-overexpressing breast cancer or metastatic gastric or GEJ junction adenocarcinoma.10

The approval was based on a compilation of data from 7 clinical trials, all of which demonstrated similarity in survival outcomes and safety between SB3 and reference trastuzumab in patients with HER2-positive adjuvant and metastatic breast cancer, in addition to HER2- positive metastatic gastric cancer.

Preliminary phase III data on the biosimilar were published in January 2018 and showed similar rates of breast pathologic complete response (bpCR) in patients with HER2- positive breast cancer for SB3 and reference trastuzumab.11

Eligible patients enrolled in the trial were randomized to 8 cycles of SB3 (n = 402) or trastuzumab (n = 398) in combination with 4 cycles of docetaxel, after which patients received 4 cycles of fluorouracil, epirubicin, and cyclophosphamide. Patients then underwent surgery, followed by 10 cycles of adjuvant SB3 or trastuzumab.

Patients were well balanced between treatment arms with regard to both demographics and baseline disease characteristics. A high proportion of patients had T2 disease (52.8%) and lymph node involvement (79.5%). Less than half of patients (40.9%) had negative estrogen receptor (ER) and progesterone receptor (PR) tumors.

According to the statistical design of the study, if the 95% CI of the ratio fell within 0.785 to 1.546, SB3 was considered equivalent for bpCR. The median follow-up was 337 days in the SB3 arm and 338 days in the trastuzumab arm.

In the per-protocol populations, consisting of all patients who completed 8 cycles of neoadjuvant therapy and surgery without major deviations from the trial design, 51.7% of patients in the SB3 arm and 42.0% in the trastuzumab arm achieved bpCR. That translated into an adjusted bpCR ratio for responses to SB3 compared with reference trastuzumab of 1.259 (95% CI, 1.085-1.460).

Among all patients who were randomly assigned to treatment, the bpCR rate was 49.0% in the SB3 arm and 39.7% in the trastuzumab arm. The adjusted ratio of the bpCR rate was 1.243 (95% CI, 1.070-1.444), and the adjusted difference in the bpCR rate was 9.59% (95% CI, 3.26-15.91). The rates of total pathologic complete response rate were 45.8% in the SB3 arm and 35.8% in the trastuzumab arm, respectively, in the per-protocol population.

Treatment-emergent AEs were similar between the SB3 and reference trastuzumab, with the most frequently reported being neutropenia (67.0% vs 63.7%), alopecia (67% vs 63.2), nausea (31.1% vs 30.4%), and leukopenia (27.9% vs 24.4%).


  1. Biosimilar medicines: overview. European Medicines Agency website. overview. Accessed February 24, 2019.
  2. Biosimilar product information. FDA website. DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ ucm580432.htm. Updated January 18, 2019. Accessed February 24, 2019.
  3. Finance report 2018. Roche website. 4564-4b17-a29b-246ac7e617d5/en/fb18e.pdf. Published 2019. Accessed February 24, 2019.
  4. Rugo HS, Rifkin RM, Declerck P, Bair AH, Morgan G. Demystifying biosimilars: development, regulation and clinical use [published online November 30, 2018]. Future Oncol. doi: 10.2217/fon-2018-0680.
  5. FDA approves Ogivri as a biosimilar to Herceptin. FDA website. www. htm. Updated December 1, 2017. Accessed February 24, 2019.
  6. Rugo HS, Barve A, Waller CF, et al; Heritage Study Investigators. Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: a randomized clinical trial. JAMA. 2017;317(1):37-47. doi: 10.1001/jama.2016.18305.
  7. Manikhas A, Pennella EJ, Bondarenko I, et al. Biosimilar trastuzumab- dkst monotherapy versus trastuzumab monotherapy after combination therapy: toxicity, efficacy, and immunogenicity from the phase 3 Heritage trial. J Clin Oncol. 2018;36(suppl; abstr 110). meetinglibrary.
  8. Celltrion and Teva announce FDA approval of Herzuma (trastuzumab- pkrb), a biosimilar to Herceptin, for the treatment of HER2- overexpressing breast cancer for certain indications [news release]. Incheon, South Korea, and Jerusalem, Israel: Celltrion, Inc; December 14, 2018. Accessed February 24, 2019.
  9. Esteva FJ, Lee S, Yu S, Kim M, Kim N, Sebbing J. 24 months results from a double-blind, randomized phase III trial comparing the efficacy and safety of neoadjuvant then adjuvant trastuzumab and its biosimilar candidate CT-P6 in HER2 positive early breast cancer (EBC). In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract P6-17-03. cancerres.
  10. Ontruzant [prescribing information]. Incheon, Korea, and Whitehouse Station, NJ: Samsung Bioepis and Merck; 2019. www.accessdata. Accessed February 24, 2019.
  11. Pivot X, Bondarenko I, Nowecki Z, et al. Phase III, randomized, double- blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2—positive early breast cancer. J Clin Oncol. 2018;36(10):968- 974. doi: 10.1200/JCO.2017.74.0126.