- Email: [email protected]
Biosimilars for HER2-Positive Breast Cancer
CHAPTER 14
Biosimilars for HER2-Positive Breast Cancer HOPE S. RUGO, MD
INTRODUCTION The use of trastuzumab, combined with the ability to identify breast cancers overexpressing HER2 or with HER2 gene amplification, has dramatically changed the outcome of both early- and late-stage HER2 positive (HER2þ) breast cancers, with improved response, duration of response, progression-free survival (PFS), and overall survival (OS).1 The success of trastuzumab is due to the ability to identify a subset of tumors that almost all appear to respond to this targeted biologic agent, as well as the synergy of trastuzumab with chemotherapy and continued response to antibody following progression. One of the challenges of success, and for biologics in general, is the significant cost associated with treatment, which limits access in many parts of the world. What is a biosimilar (Table 14.1)2? The concept of generic medications is familiar, whereby simple, small molecule chemicals are recreated, requiring only that the chemical structure and pharmacokinetics are similar to the original product. In contrast, biologics are large, complex molecules made in living cells, and due to variations in production and posttranslational modifications, even the current branded or reference product may be slightly different from the original agent depending on when and where it was produced.3 Biosimilars are “similar” to these originator biologic compounds, and due to their complexity, the European Medicines Agency (EMA), Food and Drug Administration (FDA), and World Health Organization have developed guidelines for their development.4 As the patent life ends or is close to ending on a number of novel biologic therapies for cancer therapy, the number of biosimilars in development has exploded, creating a new playing field important to providers, payers, and patients.5 The primary patent for trastuzumab expired in the European Union (E.U.) in July of 2014 and will expire in the United States (U.S.) in June of 2019.
A number of biosimilars are already in clinical use; in the U.S., the first oncology biosimilar to be approved was for the myeloid growth factor filgrastim, and several agents are in clinical use in Europe. As of early 2018, one trastuzumab biosimilar is approved in the U.S. and two are approved in the E.U.; none is yet in the clinic, and numerous applications are pending. Two other terms are used in reference to biologics: intended copies of biologic products (“me-too biologics”) and biobetters. Intended copies are copies of already licensed biologic products that have not met the regulatory criteria for biosimilars, and biobetters are biologic agents that have been structurally and/or functionally altered to improve or change clinical performance. Biobetters must go through the full biologic agent development and approval process.
REQUIREMENTS FOR BIOSIMILARITY The evaluation process of a proposed biosimilar is heavily weighted on proving similarity of structure, function, and biologic activity to the reference product6 (Fig. 14.1). Indeed, there should be “no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity and potency of the product.”7 Unlike the reference product, which must show improved outcome compared with accepted standard treatment and where both clinical efficacy and safety have already been confirmed, the biosimilar must demonstrate similarity in analytical and preclinical testing, as well as in pharmacodynamics and pharmacokinetics. The final step in proving biosimilarity is to confirm safety and efficacy in the appropriate target population, along with evaluation of immunogenicity. One of the major challenges is defining the optimal population to detect any clinically meaningful differences between the biosimilar and the reference product. The basis for the clinical guidelines 231
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TABLE 14.1
Difference Between Biologics and Generics Small Molecule Generics
Biologics
Produced by
Chemical synthesis
Living systems (cultured cells)
Characterization
Characterized with limited physicochemical methods
Comprehensive physicochemical analysis and bioassays
Manufacturing
Easy to reproduce
Manufacturing conditions are difficult and complicated by posttranslational modification
Safety considerations
Target-specific and off-target toxicity
Target-specific toxicity, off-target toxicity, characterization of immunogenicity (e.g., antidrug antibodies)
FIG. 14.1 Biosimilar development pathway. PD, pharmacodynamics; PK, pharmacokinetics.
for biosimilars is in demonstrating equivalence between short-term endpoints within a narrow margin to avoid the costly and larger trials required for approval of the reference product. It is important to ensure that a proposed biosimilarity has met strict regulatory guidelines, as some biologic biosimilars are in use in various countries around the world where the guidelines are much less strict and only a small trial assessing safety is required for approval.
identical, with drift seen even in the originator biologic.3 Next, analytic testing must demonstrate similar biologic activity by functional characterization; for trastuzumab biosimilars, this includes assessment of HER2 by cellular and Fcg receptor binding assays, antibodydependent cellular cytotoxicity, and inhibition of proliferation, among others. Safety studies are also conducted in cardiomyocytes, and pharmacokinetic and toxicology studies are performed in nonhuman primates.
ANALYTIC ASSESSMENT OF BIOSIMILARS Extensive analytic assessment of proposed biosimilars is required.8 This includes evaluation of primary (amino acid sequence), secondary, and tertiary structures, as well as posttranslational modifications (e.g., glycoforms, sialylation) and assessment of impurities. Similarity is required, as biologic products cannot be
CLINICAL STUDIES Assessment of biosimilarity starts with a comparison of pharmacokinetics between the proposed biosimilar and the originator biologic in a small number of patients. In the case of trastuzumab, U.S.- and E.U.-sourced trastuzumab is compared with the proposed biosimilar in
CHAPTER 14 Biosimilars for HER2-Positive Breast Cancer healthy adults.9,10 The final assessment of biosimilarity is a phase III trial comparing the proposed biosimilar with the originator product in a highly sensitive setting in which the primary endpoint is a marker of short-term efficacy. These trials must also include short- and longterm safety, evaluation of pharmacokinetics and immunogenicity with antidrug antibodies, and long-term measures of efficacy.11 There has been ongoing discussion about whether it is possible to define the optimal setting in which to evaluate a short-term efficacy endpoint with trastuzumab biosimilars. Centrally determined response rate is a generally acceptable end point that allows a smaller sample size and is a faster method of assessing drug activity. One concern has been the correlation of response with longer-term efficacy endpoints such as event-free survival (EFS) or PFS and OS. Two clinical settings are most relevant, either treatment of metastatic disease in the first-line setting with a primary endpoint of overall response rate (ORR) or as treatment in the neoadjuvant setting with a primary endpoint of pathologic complete response (pCR). For HER2þ disease, improvements in response in the first-line metastatic setting have generally correlated with both improved PFS and OS, and in the neoadjuvant setting, pCR correlates with disease-free survival and OS.12-14 Advantages can be found with evaluation of biosimilarity in both the neoadjuvant and metastatic settings. Patients treated in the neoadjuvant setting are naïve to prior therapy, whereas patients in the metastatic setting may have seen adjuvant or neoadjuvant trastuzumab. One metaanalysis of data from a number of clinical trials suggested smaller loss in long-term efficacy using pCR rather than ORR and concluded that the neoadjuvant setting could be the more optimal setting for
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the evaluation of biosimilars.15 However, treatment following surgery may vary significantly, which could impact the secondary endpoint of EFS for neoadjuvant biosimilar studies, and exposure to therapy is limited to 1 year. Biosimilar trastuzumab trials in the first-line metastatic setting include a population of patients with limited access to trastuzumab or even HER2 testing, quite similar to the patients enrolled in the original pivotal trials that led to approval of trastuzumab. In addition, patients with stable or responding metastatic disease stay on antibody therapy until progression, providing long-term safety and immunogenicity data. Response rates are a short-term, sensitive measure of the clinical activity of proposed trastuzumab biosimilars; regulatory guidelines support these endpoints. Indeed, both the neoadjuvant and first-line metastatic setting provide the data needed to assess trastuzumab biosimilarity and to support extrapolation of use.
CLINICAL TRIALS Five phase III trials have reported comparable efficacy using the regulatory guidelines defined by the FDA and EMA, two in the first-line metastatic setting (Table 14.2A) and three in the neoadjuvant setting (Table 14.2B). The first published trial evaluated the pharmaceutical company Mylan’s proposed biosimilar MYL0401O (trastuzumab-dkst, Ogivri) as first-line therapy for metastatic HER2þ breast cancer in a multicenter, doubleblind, randomized, parallel group, phase III equivalence study.16 Eligible patients were randomized to receive a taxane (84% received docetaxel) in combination with either the biosimilar or originator trastuzumab. Chemotherapy was administered for at least 24 weeks,
TABLE 14.2A
Biosimilar Phase III Trials With Primary Efficacy End Points. First-Line Therapy for Metastatic Breast Cancer Primary Endpoint
Results
Biosimilar
N
Treatment
Risk Difference
Risk Ratio
a
MYL-1401O16 Trastuzmab-dkst
500
Taxane plus trastuzumab or MYL-14101O
ORR (24 wk)
5.53 [95% CI 3.08% to 14.04%]
1.09 [90% CI 0.974 to 1.211]
b
707
Paclitaxel plus trastuzumab or PF-05280014
ORR (25 wk)
N/A
0.94 [95% CI 0.842 to 1.049]
PF-0528001418
ORR, overall response rate; wk, week. a Equivalence margins: risk difference [15%, 15%]; risk ratio [0.81, 1.24]. b Equivalence margin: risk ratio [0.8, 1.25].
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TABLE 14.2B
Biosimilar Phase III Trials With Primary Efficacy End Points. Neoadjuvant Therapy for Early-Stage Breast Cancer
Biosimilar
N
Treatment
a
549
D/FEC plus CT-P6 or trastuzumab 1 year
800
ABP 98023
c
19
CT-P6
b
SB-320
PF-0528001422
Primary Endpoint
Results Risk Difference
Risk Ratio
Total pCR
0.04% [95% CI 0.12% to 0.05%]
0.93 [95% CI 0.78, 1.11]
D/FEC plus SB-3 or trastuzumab 1 year
Breast pCR
10.70% [95% CI 4.13% to 17.26%]
1.259 [95% CI 1.08 to 1.460]
725
EC followed by paclitaxel with ABP-90 or trastuzumab 1 year
Total pCR
7.3% [90% CI 1.2% to 13.4%]
1.19 [90% CI 1.03 to 1.37]
226
D/Ca plus PF-05280014 or trastuzumab 6 cycles
PK at cycle 6, total pCR
NR
NR
D/Ca, docetaxel 75 mg/m2 plus carboplatin with area under the curve 6 IV every 3 weeks 6 cycles; D/FEC, docetaxel 75 mg/m2 IV every 3 weeks 4 cycles followed by 5-FU/epirubicin/cyclophosphamide (500 mg/m2/75 mg/m2/500 mg/m2) IV every 3 weeks 4 cycles with continuation of antibodies for 1 year; EC/paclitaxel, epirubicin 90 mg/m2 IV every 3 weeks 4 cycles followed by paclitaxel (weekly or every 3 weeks) 12 weeks combined with antibodies, followed with antibodies for 1 year with an additional randomization between antibodies in the trastuzumab arm (see text); NR, not reported; pCR, pathologic complete response; PK, pharmacokinetics; total pCR, pCR in breast and lymph nodes. a Equivalence margin: risk difference [e15%, 15%]; risk ratio [0$74, 1$35]. b Equivalence margin: risk difference [e13%, 13%]; risk ratio [0.785, 1.546]. c Equivalence margin: risk difference [e13%, 13%]; risk ratio [0.76, 1.32].
followed by antibody alone in patients with responding or stable disease until evidence of disease progression or toxicity mandated treatment discontinuation. Of the 458 eligible patients, less than 10% had received adjuvant trastuzumab. The primary outcome was ORR at week 24, and secondary endpoints included time to tumor progression (TTP), PFS, and OS at week 48, as well as development of antieantibody drug antibodies (ADA) and safety. The ORR at 24 weeks was 69.6% (95% CI 63.62%e75.51%) and 64% (95% CI 57.81%e70.26%) for trastuzumab-dkst and trastuzumab, respectively. The ORR ratio and difference were within the predefined equivalence margins (Table 14.2A). At 48 weeks, there was no statistically significant difference between the biosimilar and trastuzumab in TTP (41.3% vs. 43.0%; 1.7%; 95% CI 11.1% to 6.9%), PFS (44.3% vs. 44.7%; 0.4%; 95% CI 9.4% to 8.7%), or OS (89.1% vs. 85.1%; 4.0%; 95% CI 2.1% to 10.3%). Of note, due to the low number of events, survival data are still immature. There was no clinically significant difference in toxicity, including cardiac events, and ADA were detected in a small number of patients in each arm. Based on this data, Mylan’s proposed biosimilar was approved in the U.S. using “comparisons of extensive structural and functional product characterization,
animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity between Ogivri and U.S.-licensed Herceptin.”17 Furthermore, the FDA approval states that “these data demonstrate that Ogivri is highly similar to U.S.-licensed Herceptin and that there are no clinically meaningful differences between the products.” Approval was granted for all indications currently held for trastuzumab, including HER2þ gastric cancer and early- and late-stage breast cancer, although it will not be available in the clinic until the U.S. patent expires in mid-2019. Another randomized, double-blind, phase III trial has been conducted in the first-line metastatic setting comparing the proposed trastuzumab biosimilar PF05280014 with trastuzumab given in combination with weekly paclitaxel for at least 33 weeks, followed by antibody therapy alone until progression or toxicity.18 About 10% of the 707 randomized patients had previous exposure to adjuvant trastuzumab. The primary endpoint of ORR was similar between the two arms at 62.5% (95% CI 57.2%e67.6%) and 66.5% (95% CI 61.3%e71.4%) for the biosimilar and originator, respectively. The risk ratio for response was within the equivalence margin (Table 14.2A), and secondary endpoints, including 1 year PFS (56% vs.
CHAPTER 14 Biosimilars for HER2-Positive Breast Cancer 52%) and OS (88.84% vs. 87.96%), were also similar. There was no difference in safety or immunogenicity, and applications for approval are pending. Three trastuzumab biosimilars have been tested in the neoadjuvant setting, and two are now approved for use in the E.U. The first study to be published, and the first biosimilar to trastuzumab to be approved in the E.U., is CT-P6.19 In a randomized, double-blind, active-controlled, phase III equivalence trial, patients with stage IeIII HER2þ breast cancer were treated with docetaxel 75 mg/m2 IV every 3 weeks for 4 cycles followed by 5-FU 500 mg/m,2 epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 IV every 3 weeks 4 cycles (D/FEC) and were randomized to receive either concurrent CT-P6 or trastuzumab. Following chemotherapy, patients underwent surgery followed by infusions of the originally assigned antibody every 3 weeks to complete 1 year of therapy. The primary endpoint was pCR in breast and axillary nodes with secondary endpoints including long-term safety and efficacy 3 years after the last patient started therapy. Efficacy met the predetermined equivalence margin for both risk difference and risk ratio (Table 14.2B) with pCR rates of 46% (95% CI 40.4e53.2) and 50.4% (95% CI 44.1e56.7) for CT-P6 and trastuzumab, respectively. There were no differences in safety or immunogenicity (negative ADAs). Long-term followup is ongoing. The second trastuzumab biosimilar to gain approval in the E.U. is SB-3. In this phase III, randomized, double-blind study, 800 patients with stage IIeIII HER2þ breast cancer were treated with D/FEC with either SB-3 or trastuzumab followed by surgery and the assigned antibody to complete 1 year.20 The primary endpoint was breast pCR. Secondary endpoints included pCR in breast and axillary nodes, safety, and EFS and OS at 1 year. Breast pCR was similar between the two arms (51.7% vs. 42.0% in the SB-3 and trastuzumab arms, respectively), and both the risk difference and risk ratio met the equivalence margins (Table 14.2B). pCR in breast and node was also similar (45.8% vs. 35.8%, respectively), and there were no differences in safety endpoints, including cardiac function and immunogenicity. At a median follow-up of just over 1 year, the incidence of treatment-emergent adverse events was comparable between the two arms, and only three patients in each arm had evidence of ADAs. EFS was also similar with a hazard ratio of 0.94 (92.2% and 91.6%, SB-3 vs. trastuzumab; 95% CI 0.59e1.51), as was OS (99.8% and 98.9%).21 Two additional neoadjuvant trials have been reported; both agents have applications pending for
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biosimilar approval. The neoadjuvant PF-0520014 trial randomized 226 patients with early-stage HER2þ disease to receive docetaxel 75 mgm2 plus carboplatin (area under the curve ¼ 6) IV every 3 weeks 6 with either the proposed biosimilar or trastuzumab, followed by surgery.22 The primary endpoint for this trial was noninferiority in the percentage of patients with cycle 5 trough concentration >20 mg/mL, which was achieved in 92.1% and 93.3% of patients receiving PF-0520014 and trastuzumab, respectively, meeting the noninferiority margin for the difference between the two groups of 12.5% (lower limit of 95% CI, 8.02% to 6.49%). Efficacy, measured by pCR in breast and node, was also similar (47.0%, 95% CI 36.9%e57.2% for PF-05280014; and 50.0%, 95% CI 80.2%e93.7% for trastuzumab). Adverse events were similar in number, and ADA rates were very low in both arms. The ABP-90 phase III neoadjuvant trial has an additional design plan that incorporates switching between the biosimilar and originator antibody.23 Patients with 2 cm HER2þ early-stage breast cancer were treated with epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 IV every 3 weeks 4 cycles, followed by either ABP-90 or trastuzumab with every 3 week or weekly paclitaxel (taxane schedule per investigator choice) for 12 weeks followed by surgery. After surgery, patients initially randomized to ABP-90 continued on this antibody to complete 1 year. Patients initially randomized to trastuzumab were re-randomized to receive either ABP-90 or trastuzumab for their remaining treatment. The primary endpoint was pCR in breast and nodes, which was similar between the two arms at 48% and 40.5% for ABP-90 or trastuzumab, respectively. Both the risk difference and risk ratio fell within the prespecified equivalency margins (Table 14.2B). Patients who switched from trastuzumab to ABP-90 had no difference in safety or efficacy compared with those who stayed on trastuzumab or those who stayed on ABP-90 with short follow-up.24,25 All five biosimilars described above have submitted applications for regulatory approval in both the U.S. and E.U. As noted, one biosimilar is approved in the U.S. and two in the E.U. Several other biosimilars have been evaluated in small, randomized trials primarily focusing on safety.
PHARMACOVIGILANCE Postregulatory approval pharmacovigilance is a critical and required component of the incorporation of biosimilars into clinical practice with guidelines in place
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in the U.S. and E.U. Pharmacovigilance includes focused monitoring and careful safety reporting with ongoing assessment of the adverse effects to generate postmarketing surveillance data.
meaningless initials to avoid association with specific companies. For example, Mylan’s trastuzumab biosimilar is named trastuzumab-dkst (brand name Ogivri).
FUTURE STEPS EXTRAPOLATION AND INTERCHANGEABILITY Extrapolation means that the use of an approved biosimilar in one setting could be extrapolated to any setting in which the originator is approved and for which there is sufficient scientific justification for use.26 Does equivalency in one setting mean that clinicians can be confident in similar effectiveness across indications? Extrapolation is a critical component of biosimilar development and is based on demonstrating comparability of safety, efficacy, and immunogenicity without clinically relevant differences in a sensitive and key clinical indication. It is only with extrapolation that development can be streamlined to reduce the marketed cost of the biosimilar and improve access. Indeed, Mylan’s trastuzumab biosimilar was approved for HER2-overexpressing breast cancer and metastatic gastric or gastroesophageal junction adenocarcinoma. Given the efficacy and safety of trastuzumab across indications and with multiple different combinations (including the antibody pertuzumab) without unexpected safety or pharmacokinetic concerns,14 extrapolation for agents that meet the strict criteria for regulatory approval seems reasonable and safe without additional data.27 The FDA has issued draft guidance on biosimilar interchangeability, a designation that would allow pharmacy substitution for biosimilars without concern about safety or efficacy. A biologic product must be tested in a dedicated switching study evaluating pharmacokinetics, pharmacodynamics, immunogenicity, and safety, although demonstration of efficacy is not required for the switch, given that the study designs would not allow this. No product has yet received this designation. A study evaluating the safety of switching from the originator trastuzumab to a biosimilar in the adjuvant setting24 is the first step in approaching interchangeability. It is not clear which trials or how much data will be required to obtain this designation. In general, physicians as prescribers should be involved in these decisions on an individual patient level.
Naming The naming of biosimilars follows regulatory guidelines and differs between the U.S. and E.U., as well as other countries. The U.S. FDA has determined that biosimilars will use the generic name followed by a series of four
The good news is that there are now approved trastuzumab biosimilars in oncology that are expected to be available for clinical use in the near future. One trastuzumab biosimilar is approved in the U.S. and two are approved in the E.U., with many applications pending. It is encouraging to see similar efficacy and safety at the completion of adjuvant therapy, as well as after maintenance therapy in the metastatic setting. Use of biosimilar trastuzumab with extrapolation was recently endorsed by the St. Gallen International Expert Consensus Conference.28 Biosimilars of trastuzumab, a life-saving biologic therapy, are expected to reduce cost and to improve access to biologic therapy worldwide.29 It has been estimated that use of biosimilars will result in at least a 20%e30% cost reduction, and this may increase with increasing competition. Given that breast cancer is the most common cancer diagnosis in women worldwide and that HER2þ disease comprises about 20% of those cases, the availability of lowercost trastuzumab biosimilars also has the potential to significantly improve disease outcomes. In countries where the originator product is readily available, availability of lower-cost alternatives that have been rigorously tested following international regulatory guidelines will help defray the overall increasing costs of oncologic care with an expanding range of biologic therapies.
REFERENCES 1. Jiang H, Rugo HS. Human epidermal growth factor receptor 2 positive (HER2þ) metastatic breast cancer: how the latest results are improving therapeutic options. Ther Adv Med Oncol. 2015;7(6):321e339. 2. Buske C, Ogura M, Kwon HC, Yoon SW. An introduction to biosimilar cancer therapeutics: definitions, rationale for development and regulatory requirements. Future Oncol. 2017;13(15s):5e16. 3. Kim S, Song J, Park S, et al. Drifts in ADCC-related quality attributes of Herceptin(R): impact on development of a trastuzumab biosimilar. MAbs. 2017;9(4):704e714. 4. Coiffier B. Preparing for a new generation of biologic therapies: understanding the development and potential of biosimilar cancer therapeutics. Future Oncol. 2017; 13(15s):1e3. 5. Reinke T. The biosimilar pipeline seams seem to Be bursting. Manag Care. 2017;26(3):24e25.
CHAPTER 14 Biosimilars for HER2-Positive Breast Cancer 6. Rugo HS, Linton KM, Cervi P, Rosenberg JA, Jacobs I. A clinician’s guide to biosimilars in oncology. Cancer Treat Rev. 2016;46:73e79. 7. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product; 2015. http://www.fda.gov/downloads/DrugsGuidanceCompliance RegulatoryInformation/Guidances/UCM291128.pdf. 8. Hurst S, Ryan AM, Ng CK, et al. Comparative nonclinical assessments of the proposed biosimilar PF-05280014 and trastuzumab (Herceptin(R)). BioDrugs. 2014;28(5):451e459. 9. Yin D, Barker KB, Li R, et al. A randomized phase 1 pharmacokinetic trial comparing the potential biosimilar PF-05280014 with trastuzumab in healthy volunteers (REFLECTIONS B327-01). Br J Clin Pharmacol. 2014;78(6): 1281e1290. 10. Esteva FJ, Stebbing J, Wood-Horrall RN, Winkle PJ, Lee SY, Lee SJ. A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab. Cancer Chemother Pharmacol. 2018. 11. Markus R, Liu J, Ramchandani M, Landa D, Born T, Kaur P. Developing the totality of evidence for biosimilars: regulatory considerations and building confidence for the healthcare community. BioDrugs. 2017;31(3):175e187. 12. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938): 164e172. 13. Slamon D, Eiermann W, Robert N, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011; 365(14):1273e1283. 14. Swain SM, Kim SB, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14(6):461e471. 15. Jackisch C, Scappaticci FA, Heinzmann D, et al. Neoadjuvant breast cancer treatment as a sensitive setting for trastuzumab biosimilar development and extrapolation. Future Oncol. 2015;11(1):61e71. 16. Rugo HS, Barve A, Waller CF, et al. 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):37e47. 17. FDA. FDA Approves Ogivri as a Biosimilar to Herceptin; 2017. https://www.fda.gov/Drugs/InformationOnDrugs/Approved Drugs/ucm587404.htm. 18. Pegram M, Tan-Chiu E, Freyman A, et al. A randomized, double-blind study of PF-05280014 (a potential trastuzumab biosimilar) vs trastuzumab, both in combination with paclitaxel, as first-line treatment for HER2-positive metastatic breast cancer. ESMO Conf Proc. 2017: Abstr #238PD.
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19. Stebbing J, Baranau Y, Baryash V, et al. CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial. Lancet Oncol. 2017. 20. 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: JCO2017740126. 21. Pivot X, Bondarenko I, Nowecki Z, et al. A phase III study comparing SB3 (a proposed trastuzumab biosimilar) and trastuzumab reference product in HER2-positive early breast cancer treated with neoadjuvant-adjuvant treatment: final safety, immunogenicity and survival results. Eur J Cancer. 2018;93:19e27. 22. Lammers PE, Dank M, Masetti R, et al. A randomized, double-blind study of PF-05280014 (a potential biosimilar) vs trastuzumab, both given with docetaxel (D) and carboplatin (C), as neoadjuvant treatment for operable human epidermal growth factor receptor 2positive (HER21) breast cancer. ESMO Conf Proc. 2017: Abstr # 154PD. 23. von Minckwitz G, Ponomarova O, Morales S, Zhang N, Hanes V. Efficacy and safety of biosimilar ABP 980 compared with trastuzumab in HER2 positive early breast cancer. ESMO Conf Proc. 2017: Abstr #151PD. 24. von Minckwitz G, Turdean M, Zhang N, Santi P, Hanes V. Biosimilar ABP 980 in patients with early breast cancer: results of single switch from trastuzumab to ABP 980. SABCS Conf Proc. 2017: Abstr #P5-20-13. 25. Kolberg H-C, Demetriou GS, Zhang N, Tomasevic Z, Hanes V. Safety results from a randomized, doubleblind, phase 3 study of ABP 980 compared with trastuzumab in patients with breast cancer. SABCS Conf Proc. 2017: Abstr #PD3e10. 26. Declerck P, Danesi R, Petersel D, Jacobs I. The language of biosimilars: clarification, definitions, and regulatory aspects. Drugs. 2017;77(6):671e677. 27. Cohen HP, Blauvelt A, Rifkin RM, Danese S, Gokhale SB, Woollett G. Switching reference Medicines to biosimilars: a systematic literature review of clinical outcomes. Drugs. 2018. 28. Curigliano G, Burstein HJ, Winer EP, et al. De-escalating and escalating treatments for early-stage breast cancer: the St. Gallen international Expert Consensus Conference on the primary therapy of early breast cancer 2017. Ann Oncol. 2017;28(8):1700e1712. 29. Yu B. Greater potential cost savings with biosimilar use. Am J Manag Care. 2016;22(5):378.
Biosimilars for HER2-Positive Breast Cancer HOPE S. RUGO, MD
INTRODUCTION The use of trastuzumab, combined with the ability to identify breast cancers overexpressing HER2 or with HER2 gene amplification, has dramatically changed the outcome of both early- and late-stage HER2 positive (HER2þ) breast cancers, with improved response, duration of response, progression-free survival (PFS), and overall survival (OS).1 The success of trastuzumab is due to the ability to identify a subset of tumors that almost all appear to respond to this targeted biologic agent, as well as the synergy of trastuzumab with chemotherapy and continued response to antibody following progression. One of the challenges of success, and for biologics in general, is the significant cost associated with treatment, which limits access in many parts of the world. What is a biosimilar (Table 14.1)2? The concept of generic medications is familiar, whereby simple, small molecule chemicals are recreated, requiring only that the chemical structure and pharmacokinetics are similar to the original product. In contrast, biologics are large, complex molecules made in living cells, and due to variations in production and posttranslational modifications, even the current branded or reference product may be slightly different from the original agent depending on when and where it was produced.3 Biosimilars are “similar” to these originator biologic compounds, and due to their complexity, the European Medicines Agency (EMA), Food and Drug Administration (FDA), and World Health Organization have developed guidelines for their development.4 As the patent life ends or is close to ending on a number of novel biologic therapies for cancer therapy, the number of biosimilars in development has exploded, creating a new playing field important to providers, payers, and patients.5 The primary patent for trastuzumab expired in the European Union (E.U.) in July of 2014 and will expire in the United States (U.S.) in June of 2019.
A number of biosimilars are already in clinical use; in the U.S., the first oncology biosimilar to be approved was for the myeloid growth factor filgrastim, and several agents are in clinical use in Europe. As of early 2018, one trastuzumab biosimilar is approved in the U.S. and two are approved in the E.U.; none is yet in the clinic, and numerous applications are pending. Two other terms are used in reference to biologics: intended copies of biologic products (“me-too biologics”) and biobetters. Intended copies are copies of already licensed biologic products that have not met the regulatory criteria for biosimilars, and biobetters are biologic agents that have been structurally and/or functionally altered to improve or change clinical performance. Biobetters must go through the full biologic agent development and approval process.
REQUIREMENTS FOR BIOSIMILARITY The evaluation process of a proposed biosimilar is heavily weighted on proving similarity of structure, function, and biologic activity to the reference product6 (Fig. 14.1). Indeed, there should be “no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity and potency of the product.”7 Unlike the reference product, which must show improved outcome compared with accepted standard treatment and where both clinical efficacy and safety have already been confirmed, the biosimilar must demonstrate similarity in analytical and preclinical testing, as well as in pharmacodynamics and pharmacokinetics. The final step in proving biosimilarity is to confirm safety and efficacy in the appropriate target population, along with evaluation of immunogenicity. One of the major challenges is defining the optimal population to detect any clinically meaningful differences between the biosimilar and the reference product. The basis for the clinical guidelines 231
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TABLE 14.1
Difference Between Biologics and Generics Small Molecule Generics
Biologics
Produced by
Chemical synthesis
Living systems (cultured cells)
Characterization
Characterized with limited physicochemical methods
Comprehensive physicochemical analysis and bioassays
Manufacturing
Easy to reproduce
Manufacturing conditions are difficult and complicated by posttranslational modification
Safety considerations
Target-specific and off-target toxicity
Target-specific toxicity, off-target toxicity, characterization of immunogenicity (e.g., antidrug antibodies)
FIG. 14.1 Biosimilar development pathway. PD, pharmacodynamics; PK, pharmacokinetics.
for biosimilars is in demonstrating equivalence between short-term endpoints within a narrow margin to avoid the costly and larger trials required for approval of the reference product. It is important to ensure that a proposed biosimilarity has met strict regulatory guidelines, as some biologic biosimilars are in use in various countries around the world where the guidelines are much less strict and only a small trial assessing safety is required for approval.
identical, with drift seen even in the originator biologic.3 Next, analytic testing must demonstrate similar biologic activity by functional characterization; for trastuzumab biosimilars, this includes assessment of HER2 by cellular and Fcg receptor binding assays, antibodydependent cellular cytotoxicity, and inhibition of proliferation, among others. Safety studies are also conducted in cardiomyocytes, and pharmacokinetic and toxicology studies are performed in nonhuman primates.
ANALYTIC ASSESSMENT OF BIOSIMILARS Extensive analytic assessment of proposed biosimilars is required.8 This includes evaluation of primary (amino acid sequence), secondary, and tertiary structures, as well as posttranslational modifications (e.g., glycoforms, sialylation) and assessment of impurities. Similarity is required, as biologic products cannot be
CLINICAL STUDIES Assessment of biosimilarity starts with a comparison of pharmacokinetics between the proposed biosimilar and the originator biologic in a small number of patients. In the case of trastuzumab, U.S.- and E.U.-sourced trastuzumab is compared with the proposed biosimilar in
CHAPTER 14 Biosimilars for HER2-Positive Breast Cancer healthy adults.9,10 The final assessment of biosimilarity is a phase III trial comparing the proposed biosimilar with the originator product in a highly sensitive setting in which the primary endpoint is a marker of short-term efficacy. These trials must also include short- and longterm safety, evaluation of pharmacokinetics and immunogenicity with antidrug antibodies, and long-term measures of efficacy.11 There has been ongoing discussion about whether it is possible to define the optimal setting in which to evaluate a short-term efficacy endpoint with trastuzumab biosimilars. Centrally determined response rate is a generally acceptable end point that allows a smaller sample size and is a faster method of assessing drug activity. One concern has been the correlation of response with longer-term efficacy endpoints such as event-free survival (EFS) or PFS and OS. Two clinical settings are most relevant, either treatment of metastatic disease in the first-line setting with a primary endpoint of overall response rate (ORR) or as treatment in the neoadjuvant setting with a primary endpoint of pathologic complete response (pCR). For HER2þ disease, improvements in response in the first-line metastatic setting have generally correlated with both improved PFS and OS, and in the neoadjuvant setting, pCR correlates with disease-free survival and OS.12-14 Advantages can be found with evaluation of biosimilarity in both the neoadjuvant and metastatic settings. Patients treated in the neoadjuvant setting are naïve to prior therapy, whereas patients in the metastatic setting may have seen adjuvant or neoadjuvant trastuzumab. One metaanalysis of data from a number of clinical trials suggested smaller loss in long-term efficacy using pCR rather than ORR and concluded that the neoadjuvant setting could be the more optimal setting for
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the evaluation of biosimilars.15 However, treatment following surgery may vary significantly, which could impact the secondary endpoint of EFS for neoadjuvant biosimilar studies, and exposure to therapy is limited to 1 year. Biosimilar trastuzumab trials in the first-line metastatic setting include a population of patients with limited access to trastuzumab or even HER2 testing, quite similar to the patients enrolled in the original pivotal trials that led to approval of trastuzumab. In addition, patients with stable or responding metastatic disease stay on antibody therapy until progression, providing long-term safety and immunogenicity data. Response rates are a short-term, sensitive measure of the clinical activity of proposed trastuzumab biosimilars; regulatory guidelines support these endpoints. Indeed, both the neoadjuvant and first-line metastatic setting provide the data needed to assess trastuzumab biosimilarity and to support extrapolation of use.
CLINICAL TRIALS Five phase III trials have reported comparable efficacy using the regulatory guidelines defined by the FDA and EMA, two in the first-line metastatic setting (Table 14.2A) and three in the neoadjuvant setting (Table 14.2B). The first published trial evaluated the pharmaceutical company Mylan’s proposed biosimilar MYL0401O (trastuzumab-dkst, Ogivri) as first-line therapy for metastatic HER2þ breast cancer in a multicenter, doubleblind, randomized, parallel group, phase III equivalence study.16 Eligible patients were randomized to receive a taxane (84% received docetaxel) in combination with either the biosimilar or originator trastuzumab. Chemotherapy was administered for at least 24 weeks,
TABLE 14.2A
Biosimilar Phase III Trials With Primary Efficacy End Points. First-Line Therapy for Metastatic Breast Cancer Primary Endpoint
Results
Biosimilar
N
Treatment
Risk Difference
Risk Ratio
a
MYL-1401O16 Trastuzmab-dkst
500
Taxane plus trastuzumab or MYL-14101O
ORR (24 wk)
5.53 [95% CI 3.08% to 14.04%]
1.09 [90% CI 0.974 to 1.211]
b
707
Paclitaxel plus trastuzumab or PF-05280014
ORR (25 wk)
N/A
0.94 [95% CI 0.842 to 1.049]
PF-0528001418
ORR, overall response rate; wk, week. a Equivalence margins: risk difference [15%, 15%]; risk ratio [0.81, 1.24]. b Equivalence margin: risk ratio [0.8, 1.25].
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TABLE 14.2B
Biosimilar Phase III Trials With Primary Efficacy End Points. Neoadjuvant Therapy for Early-Stage Breast Cancer
Biosimilar
N
Treatment
a
549
D/FEC plus CT-P6 or trastuzumab 1 year
800
ABP 98023
c
19
CT-P6
b
SB-320
PF-0528001422
Primary Endpoint
Results Risk Difference
Risk Ratio
Total pCR
0.04% [95% CI 0.12% to 0.05%]
0.93 [95% CI 0.78, 1.11]
D/FEC plus SB-3 or trastuzumab 1 year
Breast pCR
10.70% [95% CI 4.13% to 17.26%]
1.259 [95% CI 1.08 to 1.460]
725
EC followed by paclitaxel with ABP-90 or trastuzumab 1 year
Total pCR
7.3% [90% CI 1.2% to 13.4%]
1.19 [90% CI 1.03 to 1.37]
226
D/Ca plus PF-05280014 or trastuzumab 6 cycles
PK at cycle 6, total pCR
NR
NR
D/Ca, docetaxel 75 mg/m2 plus carboplatin with area under the curve 6 IV every 3 weeks 6 cycles; D/FEC, docetaxel 75 mg/m2 IV every 3 weeks 4 cycles followed by 5-FU/epirubicin/cyclophosphamide (500 mg/m2/75 mg/m2/500 mg/m2) IV every 3 weeks 4 cycles with continuation of antibodies for 1 year; EC/paclitaxel, epirubicin 90 mg/m2 IV every 3 weeks 4 cycles followed by paclitaxel (weekly or every 3 weeks) 12 weeks combined with antibodies, followed with antibodies for 1 year with an additional randomization between antibodies in the trastuzumab arm (see text); NR, not reported; pCR, pathologic complete response; PK, pharmacokinetics; total pCR, pCR in breast and lymph nodes. a Equivalence margin: risk difference [e15%, 15%]; risk ratio [0$74, 1$35]. b Equivalence margin: risk difference [e13%, 13%]; risk ratio [0.785, 1.546]. c Equivalence margin: risk difference [e13%, 13%]; risk ratio [0.76, 1.32].
followed by antibody alone in patients with responding or stable disease until evidence of disease progression or toxicity mandated treatment discontinuation. Of the 458 eligible patients, less than 10% had received adjuvant trastuzumab. The primary outcome was ORR at week 24, and secondary endpoints included time to tumor progression (TTP), PFS, and OS at week 48, as well as development of antieantibody drug antibodies (ADA) and safety. The ORR at 24 weeks was 69.6% (95% CI 63.62%e75.51%) and 64% (95% CI 57.81%e70.26%) for trastuzumab-dkst and trastuzumab, respectively. The ORR ratio and difference were within the predefined equivalence margins (Table 14.2A). At 48 weeks, there was no statistically significant difference between the biosimilar and trastuzumab in TTP (41.3% vs. 43.0%; 1.7%; 95% CI 11.1% to 6.9%), PFS (44.3% vs. 44.7%; 0.4%; 95% CI 9.4% to 8.7%), or OS (89.1% vs. 85.1%; 4.0%; 95% CI 2.1% to 10.3%). Of note, due to the low number of events, survival data are still immature. There was no clinically significant difference in toxicity, including cardiac events, and ADA were detected in a small number of patients in each arm. Based on this data, Mylan’s proposed biosimilar was approved in the U.S. using “comparisons of extensive structural and functional product characterization,
animal data, human pharmacokinetic and pharmacodynamic data, and clinical studies including clinical immunogenicity between Ogivri and U.S.-licensed Herceptin.”17 Furthermore, the FDA approval states that “these data demonstrate that Ogivri is highly similar to U.S.-licensed Herceptin and that there are no clinically meaningful differences between the products.” Approval was granted for all indications currently held for trastuzumab, including HER2þ gastric cancer and early- and late-stage breast cancer, although it will not be available in the clinic until the U.S. patent expires in mid-2019. Another randomized, double-blind, phase III trial has been conducted in the first-line metastatic setting comparing the proposed trastuzumab biosimilar PF05280014 with trastuzumab given in combination with weekly paclitaxel for at least 33 weeks, followed by antibody therapy alone until progression or toxicity.18 About 10% of the 707 randomized patients had previous exposure to adjuvant trastuzumab. The primary endpoint of ORR was similar between the two arms at 62.5% (95% CI 57.2%e67.6%) and 66.5% (95% CI 61.3%e71.4%) for the biosimilar and originator, respectively. The risk ratio for response was within the equivalence margin (Table 14.2A), and secondary endpoints, including 1 year PFS (56% vs.
CHAPTER 14 Biosimilars for HER2-Positive Breast Cancer 52%) and OS (88.84% vs. 87.96%), were also similar. There was no difference in safety or immunogenicity, and applications for approval are pending. Three trastuzumab biosimilars have been tested in the neoadjuvant setting, and two are now approved for use in the E.U. The first study to be published, and the first biosimilar to trastuzumab to be approved in the E.U., is CT-P6.19 In a randomized, double-blind, active-controlled, phase III equivalence trial, patients with stage IeIII HER2þ breast cancer were treated with docetaxel 75 mg/m2 IV every 3 weeks for 4 cycles followed by 5-FU 500 mg/m,2 epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 IV every 3 weeks 4 cycles (D/FEC) and were randomized to receive either concurrent CT-P6 or trastuzumab. Following chemotherapy, patients underwent surgery followed by infusions of the originally assigned antibody every 3 weeks to complete 1 year of therapy. The primary endpoint was pCR in breast and axillary nodes with secondary endpoints including long-term safety and efficacy 3 years after the last patient started therapy. Efficacy met the predetermined equivalence margin for both risk difference and risk ratio (Table 14.2B) with pCR rates of 46% (95% CI 40.4e53.2) and 50.4% (95% CI 44.1e56.7) for CT-P6 and trastuzumab, respectively. There were no differences in safety or immunogenicity (negative ADAs). Long-term followup is ongoing. The second trastuzumab biosimilar to gain approval in the E.U. is SB-3. In this phase III, randomized, double-blind study, 800 patients with stage IIeIII HER2þ breast cancer were treated with D/FEC with either SB-3 or trastuzumab followed by surgery and the assigned antibody to complete 1 year.20 The primary endpoint was breast pCR. Secondary endpoints included pCR in breast and axillary nodes, safety, and EFS and OS at 1 year. Breast pCR was similar between the two arms (51.7% vs. 42.0% in the SB-3 and trastuzumab arms, respectively), and both the risk difference and risk ratio met the equivalence margins (Table 14.2B). pCR in breast and node was also similar (45.8% vs. 35.8%, respectively), and there were no differences in safety endpoints, including cardiac function and immunogenicity. At a median follow-up of just over 1 year, the incidence of treatment-emergent adverse events was comparable between the two arms, and only three patients in each arm had evidence of ADAs. EFS was also similar with a hazard ratio of 0.94 (92.2% and 91.6%, SB-3 vs. trastuzumab; 95% CI 0.59e1.51), as was OS (99.8% and 98.9%).21 Two additional neoadjuvant trials have been reported; both agents have applications pending for
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biosimilar approval. The neoadjuvant PF-0520014 trial randomized 226 patients with early-stage HER2þ disease to receive docetaxel 75 mgm2 plus carboplatin (area under the curve ¼ 6) IV every 3 weeks 6 with either the proposed biosimilar or trastuzumab, followed by surgery.22 The primary endpoint for this trial was noninferiority in the percentage of patients with cycle 5 trough concentration >20 mg/mL, which was achieved in 92.1% and 93.3% of patients receiving PF-0520014 and trastuzumab, respectively, meeting the noninferiority margin for the difference between the two groups of 12.5% (lower limit of 95% CI, 8.02% to 6.49%). Efficacy, measured by pCR in breast and node, was also similar (47.0%, 95% CI 36.9%e57.2% for PF-05280014; and 50.0%, 95% CI 80.2%e93.7% for trastuzumab). Adverse events were similar in number, and ADA rates were very low in both arms. The ABP-90 phase III neoadjuvant trial has an additional design plan that incorporates switching between the biosimilar and originator antibody.23 Patients with 2 cm HER2þ early-stage breast cancer were treated with epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 IV every 3 weeks 4 cycles, followed by either ABP-90 or trastuzumab with every 3 week or weekly paclitaxel (taxane schedule per investigator choice) for 12 weeks followed by surgery. After surgery, patients initially randomized to ABP-90 continued on this antibody to complete 1 year. Patients initially randomized to trastuzumab were re-randomized to receive either ABP-90 or trastuzumab for their remaining treatment. The primary endpoint was pCR in breast and nodes, which was similar between the two arms at 48% and 40.5% for ABP-90 or trastuzumab, respectively. Both the risk difference and risk ratio fell within the prespecified equivalency margins (Table 14.2B). Patients who switched from trastuzumab to ABP-90 had no difference in safety or efficacy compared with those who stayed on trastuzumab or those who stayed on ABP-90 with short follow-up.24,25 All five biosimilars described above have submitted applications for regulatory approval in both the U.S. and E.U. As noted, one biosimilar is approved in the U.S. and two in the E.U. Several other biosimilars have been evaluated in small, randomized trials primarily focusing on safety.
PHARMACOVIGILANCE Postregulatory approval pharmacovigilance is a critical and required component of the incorporation of biosimilars into clinical practice with guidelines in place
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in the U.S. and E.U. Pharmacovigilance includes focused monitoring and careful safety reporting with ongoing assessment of the adverse effects to generate postmarketing surveillance data.
meaningless initials to avoid association with specific companies. For example, Mylan’s trastuzumab biosimilar is named trastuzumab-dkst (brand name Ogivri).
FUTURE STEPS EXTRAPOLATION AND INTERCHANGEABILITY Extrapolation means that the use of an approved biosimilar in one setting could be extrapolated to any setting in which the originator is approved and for which there is sufficient scientific justification for use.26 Does equivalency in one setting mean that clinicians can be confident in similar effectiveness across indications? Extrapolation is a critical component of biosimilar development and is based on demonstrating comparability of safety, efficacy, and immunogenicity without clinically relevant differences in a sensitive and key clinical indication. It is only with extrapolation that development can be streamlined to reduce the marketed cost of the biosimilar and improve access. Indeed, Mylan’s trastuzumab biosimilar was approved for HER2-overexpressing breast cancer and metastatic gastric or gastroesophageal junction adenocarcinoma. Given the efficacy and safety of trastuzumab across indications and with multiple different combinations (including the antibody pertuzumab) without unexpected safety or pharmacokinetic concerns,14 extrapolation for agents that meet the strict criteria for regulatory approval seems reasonable and safe without additional data.27 The FDA has issued draft guidance on biosimilar interchangeability, a designation that would allow pharmacy substitution for biosimilars without concern about safety or efficacy. A biologic product must be tested in a dedicated switching study evaluating pharmacokinetics, pharmacodynamics, immunogenicity, and safety, although demonstration of efficacy is not required for the switch, given that the study designs would not allow this. No product has yet received this designation. A study evaluating the safety of switching from the originator trastuzumab to a biosimilar in the adjuvant setting24 is the first step in approaching interchangeability. It is not clear which trials or how much data will be required to obtain this designation. In general, physicians as prescribers should be involved in these decisions on an individual patient level.
Naming The naming of biosimilars follows regulatory guidelines and differs between the U.S. and E.U., as well as other countries. The U.S. FDA has determined that biosimilars will use the generic name followed by a series of four
The good news is that there are now approved trastuzumab biosimilars in oncology that are expected to be available for clinical use in the near future. One trastuzumab biosimilar is approved in the U.S. and two are approved in the E.U., with many applications pending. It is encouraging to see similar efficacy and safety at the completion of adjuvant therapy, as well as after maintenance therapy in the metastatic setting. Use of biosimilar trastuzumab with extrapolation was recently endorsed by the St. Gallen International Expert Consensus Conference.28 Biosimilars of trastuzumab, a life-saving biologic therapy, are expected to reduce cost and to improve access to biologic therapy worldwide.29 It has been estimated that use of biosimilars will result in at least a 20%e30% cost reduction, and this may increase with increasing competition. Given that breast cancer is the most common cancer diagnosis in women worldwide and that HER2þ disease comprises about 20% of those cases, the availability of lowercost trastuzumab biosimilars also has the potential to significantly improve disease outcomes. In countries where the originator product is readily available, availability of lower-cost alternatives that have been rigorously tested following international regulatory guidelines will help defray the overall increasing costs of oncologic care with an expanding range of biologic therapies.
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