Biologics is an umbrella term for therapeutic agents at least partially derived from living organisms such as yeast, bacteria, plant, or animal cells. Typically, biologics are large, complex molecules and include vaccines, gene therapies, and cellular therapies, often made using recombinant DNA technology. Insulins, erythropoietin, and an increasing number of cancer drugs are in this class of therapies. In 2005, biologics accounted for 32% of the $9.5 billion Medicare Part B drug spending; by 2014, these products constituted 62% of the $18.5 billion total.1
Generic drugs duplicate the structure of chemically synthesized drugs, whereas biosimilars are “close enough” imitations of biologics. To encourage competition in the biologics market and create a pathway for regulatory approval of biosimilar drugs, the US Congress passed the Biologics Price Competition and Innovation Act as part of the Affordable Care Act of 2010. A biosimilar is a product that would be “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and would have “no clinically meaningful differences” in terms of safety or activity.2 From a regulatory point of view, a biosimilar drug is neither a generic drug—presumed to have chemical identity with the original product—nor a “new” biological product, but a related entity proven sufficiently alike to the original biological drug that it can be marketed based on its biosimilarity. The result would be 2 branded but highly similar products—like Coke or Pepsi, but not a generic “cola.”
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) may approve biosimilar agents based on the “totality of the evidence” from preclinical (structural, functional, mechanism of action, and animal toxicity) and clinical (pharmacological, immunogenicity, and efficacy) end points.2 If approved as a biosimilar for 1 specific indication, a product might subsequently be approved for clinical use across multiple indications of the original drug by extrapolation and might foster market competition that could lower the costs of biological therapies.
The EMA defined a regulatory strategy for scientific review of biosimilars more than a decade ago, and many biosimilar products are now in widespread use across the European Union, with few reported safety concerns. To date, 4 biosimilar proteins have received FDA approval in the United States: first a biosimilar for granulocyte colony-stimulating factor in 2015, followed by the anti-inflammatory agents infliximab, etanercept, and adalimumab approved in 2016. With more biologics in development, regulators, drug purchasers, patients, and physicians face the challenge of determining when and whether the evidence base supports substitution of a biosimilar product for its branded reference product.
In this issue of JAMA, Rugo and colleagues3 describe the results of the Heritage Study, the first report of a biosimilar intended as a cancer treatment. The investigation represents a head-to-head comparison of a proposed trastuzumab biosimilar vs the “branded” or “reference” trastuzumab (Herceptin), the humanized anti–ERBB2 (formerly HER2 or HER2/neu) antibody. The study is of particular note because trastuzumab is a targeted therapy that improves survival in both early- and advanced-stage, ERBB2-positive breast cancer.4- 6 About 15% to 20% of the nearly 2 million women diagnosed with breast cancer each year worldwide have ERBB2-positive tumors, and trastuzumab is included on the World Health Organization’s list of essential cancer medications.7,8 Thus, a trastuzumab biosimilar has the opportunity to extend biosimilars into the high-stakes arena of treating and curing cancer, including breast cancer and possibly gastric cancer, clinical entities for which patients and clinicians would understandably demand powerful assurance that the biosimilar was indeed just as good.
Carefully following the FDA roadmap, the investigators compared outcomes in 458 women with ERBB2-positive metastatic breast cancer receiving first-line taxane chemotherapy (docetaxel or paclitaxel) in combination with trastuzumab, either branded or biosimilar. Taxane-based chemotherapy is the backbone for trastuzumab treatment in both the adjuvant and first-line metastatic settings. In the United States and Europe, first-line therapy for metastatic disease often additionally includes another anti-ERBB2 antibody, pertuzumab, whereas use of trastuzumab and taxanes is standard in the adjuvant setting. The Heritage Study began before pertuzumab was regularly used in first-line treatment of ERBB2-positive breast cancer, and the accrual of patients exclusively from developing countries in Europe, Asia, Africa, and South America meant that pertuzumab was not a therapeutic consideration and that few (<10%) had received adjuvant trastuzumab.
Notwithstanding these distinctive clinical features of the patient population in the Heritage Study, the trial design is a fair comparison, and by all clinically important measures, the proposed trastuzumab biosimilar in combination with taxane chemotherapy met prespecified criteria for equivalence compared with branded trastuzumab combined with taxane therapy. The overall response rate (including complete or partial clinical response) at 24 weeks was 69.6% (95% CI, 63.62%-75.51%) for the proposed trastuzumab biosimilar group compared with 64.0% (95% CI, 57.81%-70.26%) for the trastuzumab group.3 Data on time to tumor progression also overlapped, with median time to progression of approximately 1 year. Exploratory findings of outcomes for the secondary efficacy analysis revealed no significant differences at week 48 between the proposed trastuzumab biosimilar group and the trastuzumab group in tumor progression (41.3% vs 43.0%), progression-free survival (44.3% vs 44.7%), or overall survival (89.1% vs 85.1%). Importantly, the toxicity profile was identical for the brand and biosimilar treatment groups. There were no significant differences in adverse effects, either those most associated with chemotherapy such as neutropenia or those linked to the antibody such as immunogenicity or cardiac dysfunction. In addition, the outcomes in the Heritage Study are comparable to those in recent multicenter trials involving first-line treatment of patients with ERBB2-positive breast cancer receiving taxanes and brand-name trastuzumab; clinical response rates in these trials ranged from 55% to 69% with median times to progression between 11.3 and 12.4 months.6,9,10
The data from the Heritage Study demonstrate that the proposed trastuzumab biosimilar meets the criteria for establishing equivalence with trastuzumab. In answer to the proverbial question “Would you use the trastuzumab biosimilar for your mother if she had ERBB2-positive breast cancer?” the answer should be yes. Nonetheless, pharmacovigilance is warranted with tracking systems that distinguish between branded and biosimilar drug versions. Once this drug is marketed, safety monitoring should build confidence that encourages substitution of the biosimilar for the branded drug. A more difficult question is whether the evidence from the Heritage Study could support extrapolation to use of the proposed trastuzumab biosimilar for treatment of ERBB2-positive gastric cancer, which accounts for about 10% to 20% of the annual 1 million global diagnoses.7,11 Although the answer is also likely to be yes, based on the current data, a “trust but verify” approach is necessary, including pharmacovigilance studies evaluating both safety and efficacy.
The Heritage Study experience is likely to support approval to move the proposed trastuzumab biosimilar into the market for patients with ERBB2-positive breast cancer and possibly gastric cancer and could serve as a blueprint for development of other biosimilar products across the spectrum of cancer care. However, it remains to be seen how the market availability of therapeutic biosimilars will affect the cost of cancer drugs. To date, biosimilars have had less of an effect on drug prices than might have been anticipated, perhaps because both brand and biosimilar manufacturers have an interest in maintaining price margins even in the setting of market-driven competition. Given the escalating costs of biological cancer treatments, the rapid evolution of second- or third-generation agents that target the same pathways, and the expanding number of clinical situations for which multiple biological products are used in combination therapy, modest price effects on the order of 25% or less achieved through a biosimilar approval may not realize the hoped-for savings or the expanded access to innovative therapy that was the goal of the Biologics Price Competition and Innovation Act.
What is at stake for patients with cancer depends on where they live. In Europe, trastuzumab went off patent in 2014, and, were the EMA review to lead to approval of the biosimilar product, Roche’s annual $2 billion European market for trastuzumab (of the nearly $7 billion global total of the trastuzumab market) will face competition. Bulk purchasing by European Union governments offers leverage to negotiate discounts from manufacturers of both branded and biosimilar products. Individual European Union nations will make their own policies that will influence market penetration of the trastuzumab biosimilar such as whether substitution is automatic or whether it requires individual patient disclosure.
In the United States, the trastuzumab biosimilar will probably reduce prices, although this will not take full effect until the patent on trastuzumab expires in 2019. Under the prevailing “buy and bill” system of Medicare Part B, oncology practices are reimbursed for chemotherapy based on a drug’s average sales price plus a 6% margin intended to cover overhead and inventory management. To mitigate the financial disincentive to prescribe inexpensive alternatives, the Centers for Medicare & Medicaid Services has wisely pegged reimbursement for biosimilar products to the average sales price of the biosimilar plus 6% of the branded version, that is, the 6% is based on the cost of the more expensive drug.12
The greatest potential value of the proposed trastuzumab biosimilar would be facilitating access to treatment for patients with ERBB2-positive breast cancer and gastric cancer around the world who now are untreated because of prohibitive costs. Unless the price of the trastuzumab biosimilar is set considerably lower than the 25% to 30% discounts typically seen during the last decade for biosimilars entering European markets, treatment will remain inaccessible for far too many patients. It is morally indefensible to foster a clinical trials system that recruits participants from low- and middle-resource countries primarily to benefit market competition in richer countries. The ethical conduct of biosimilar trials requires ensuring that the communities of trial participants should have realistic access to drugs they have helped to develop.
The Heritage Study opens the pathway to therapeutic biosimilars in oncology and should facilitate market forces that lead to lower drug prices. Hopefully, this competition will be sufficient to make trastuzumab and other biologics more affordable and thereby make cancer care both more effective and more equitable around the world.
Corresponding Author: Deborah Schrag, MD, MPH, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215 (firstname.lastname@example.org).
Published Online: December 1, 2016. doi:10.1001/jama.2016.18979
Conflict of Interest Disclosures: Both authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Burstein HJ, Schrag D. Biosimilar Therapy for ERBB2 (HER2)–Positive Breast CancerClose Enough?. JAMA. Published online December 01, 2016. doi:10.1001/jama.2016.18979