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Biosimilar may provide affordable, effective trastuzumab alternative
Women with HER-2–positive metastatic breast cancer responded equally to a trastuzumab biosimilar and its reference product, according to a multicenter, double blind phase 3 equivalence study published in JAMA.
This biosimilar may be more accessible and potentially more affordable than branded trastuzumab (Herceptin, Genentech).
“Trastuzumab is not widely available around the world,” Hope S. Rugo, MD, clinical professor in the department of medicine (hematology/oncology) and director of the breast oncology clinical trials program at University of California San Francisco Helen Diller Family Comprehensive Cancer Center, and colleagues wrote. “A biosimilar treatment option may increase global access to biologic cancer therapies, provided, among other issues, that the price of the biosimilar is sufficiently inexpensive to enable women in non–high-income countries to access this therapy.”
Suggested equivalency
A biosimilar drug is a biological product highly similar to a licensed biological product, with no clinically meaningful differences in safety, purity or potency.
Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves PFS and OS in patients with HER-2–positive metastatic breast cancer. Because of its prohibitive cost — approximately $64,000 for one year of treatments — researchers compared branded trastuzumab plus a taxane with a proposed biosimilar drug (14010; Mylan Inc, Biocon Research Limited) plus a taxane.
From December 2012 to August 2015, researchers randomly assigned 458 patients (mean age, 53.6 years, standard deviation, 11.11 years) previously untreated for HER-2–positive metastatic breast cancer to receive a proposed biosimilar (n = 230) or branded trastuzumab (n = 228). Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred.
Overall response rate, defined as complete or partial response at 24 weeks, served as the study’s primary endpoint. Researchers set equivalency boundaries for the proposed biosimilar vs. branded trastuzumab of 0.81 to 1.24 with a 90% CI for ORR ratio, and of –15% to 15% with a 95% CI for ORR difference.
Secondary endpoints included time to tumor progression, PFS and OS at 48 weeks, and adverse events.
The ORR for proposed biosimilar (69.6%; 95% CI, 63.62-75.51) compared favorably with the ORR for branded trastuzumab (64%; 95% CI, 57.81-70.26). The ORR ratio (1.09; 90% CI, 0.97-1.21) and ORR difference (5.53; 95% CI, –3.08 to 14.04) also were within equivalent boundaries.
At week 48, there remained no statistically significant difference between proposed biosimilar and branded trastuzumab for time to tumor progression (41.3% vs. 43%; difference, –1.7%; 95% CI, –11.1 to 6.9), PFS (44.3% vs. 44.7%; difference, –0.4%; 95% CI, –9.4 to 8.7) or OS (89.1% vs. 85.1%; difference, 4%; 95% CI, –2.1 to 10.3).
The proportion of patients who experienced at least one adverse event was 98.6% (n = 239) in the biosimilar arm and 94.7% (n = 233) in the branded trastuzumab arm. The most common adverse events were neutropenia (57.5% vs. 53.3%), peripheral neuropathy (23.1% vs. 24.8%) and diarrhea (20.6% vs. 20.7%).
Researchers noted that ongoing follow-up will assess longer term efficacy and safety information to evaluate the use of the proposed trastuzumab biosimilar alone during the maintenance phase.
Influence of publication
Because Mylan Inc., a co-developer of the proposed biosimilar trastuzumab, has recently attracted attention due to its pricing, promotion and involvement in school health policies regarding one of its other products, injectable epinephrine (EpiPen), editors of JAMA had consider “whether concerns about the behavior of one of the study sponsors with respect to pricing of a product should influence the decision to publish a research report sponsored by that company about a different product,” Howard Bauchner, MD, the editor in chief of JAMA, and colleagues wrote in a corresponding editorial.
“There has been substantial criticism of the company by patients, physicians and politicians about the recent price increase and the subsequent introduction of a generic epinephrine product by the same company,” Bauchner and colleague wrote.
The editors ultimately decided to publish the study due to its scientific merit and potential to contribute meaningful clinical information, although they noted it remains to be seen whether this study will prove to be truly practice changing.
“These drugs are a potential solution to the substantially increasing costs of cancer treatment, and introduction of these agents is expected to expand affordability,” Bauchner and colleagues wrote. “Accordingly, the proposed trastuzumab biosimilar will need to be priced at a level at which patients who otherwise would not have access to expensive therapies such as trastuzumab could receive needed therapy. ... The manufacturers must ensure that the pricing of this biosimilar product is responsible and fair and provides access to this important therapy at an affordable price.”
In another accompanying editorial, Harold Burstein, MD, PhD, associate professor of medicine at Harvard Medical School, and Deborah Schrag, MD, PhD, professor of medicine at Harvard Medical School, chief of the division of population sciences at Dana-Farber Cancer Institute and associate editor of JAMA, pointed out that an increasing amount of cancer drugs are biologics, accounting for 62% of the $18.5 billion spent on Medicare Part B drugs.
Burstein and Schrag suggested FDA approval of biosimilars might foster market competition that could lower the costs of biological therapies. They also noted that biosimilar drugs are now in widespread use in European countries, with few reported safety concerns.
“Unless the price of 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,” Burstein and Schrag wrote. “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.” – by Chuck Gormley
Disclosure: The study was funded by Mylan Inc and Biocon Research Limited. Rugo reports research support and travel expenses from Genentech/Roche and MacroGenics. Four researchers report stock ownership in Mylan Inc., and one other reports stock ownership in Biocon Research Limited. Two researchers report consulting fees from Mylan Inc. Bauchner and colleagues, and Burstein and Schrag report no relevant financial disclosures.