Σάββατο, 10 Δεκεμβρίου 2016

TRASTUZUMAB BIOSIMILAR NEAR MARKET

In part 1 of a phase III equivalence trial reported in JAMA, Rugo et al found that treatment with trastuzumab (Herceptin) or a proposed trastuzumab biosimilar in combination with a taxane produced similar overall response rates in patients with previously untreated metastatic HER2-positive breast cancer.
Study Details
In the double-blind trial, 500 women from 95 sites in Bulgaria, Chile, Czech Republic, Georgia, Hungary, India, Latvia, Philippines, Poland, Romania, Russia, Serbia, Slovakia, South Africa, Thailand, and Ukraine were randomized between December 2012 and August 2015 to receive trastuzumab or a proposed biosimilar (MYL-1401O) combined with site choice of docetaxel or paclitaxel. An early protocol amendment excluding patients who had already received first-line treatment resulted in exclusion of 23 trastuzumab and 19 biosimilar patients, leaving an intent-to-treat population of 458 patients (230 in the trastuzumab group, 228 in the biosimilar group).
Trastuzumab and the proposed biosimilar were given via infusion every 3 weeks with an initial 8 mg/kg loading dose over 90 minutes followed every 3 weeks with 6 mg/kg over 30 minutes. Docetaxel was given at 75 mg/m2 every 3 weeks and paclitaxel was given at 80 mg/m2 weekly; paclitaxel could be omitted for 1 week every 4 weeks. Chemotherapy was administered for ≥ 24 weeks followed trastuzumab or the biosimilar alone until unacceptable toxicity or disease progression. The primary endpoint was overall response rate at week 24.
After completing a minimum of 8 cycles (24 weeks), patients with at least stable disease were eligible for part 2 of the trial, during which they continued to receive originally allocated treatment until disease progression, unacceptable toxicity, or death. The results of part 2 are to be presented in a future publication.
Patients in the trastuzumab and biosimilar groups had mean ages of 53 and 54 years; 68% and 69% were white and 32% and 31% were Asian; and the assigned taxane was docetaxel in 84% in both, paclitaxel in 14% and 15%, and none in 2% and 1%.
Response Rates
At week 24, the overall response rate was 69.6% (95% confidence interval [CI] = 63.62%–75.51%) for the proposed biosimilar group vs 64.0% (95% CI = 57.81%–70.26%) for the trastuzumab group. The overall response rate ratio (1.09, 90% CI = 0.974–1.211) and the overall response rate difference (5.53, 95% CI = −3.08 to 14.04) were within the prespecified equivalence boundaries. Stable disease was observed in 20.9% vs 21.5%.
There were no significant differences between biosimilar and trastuzumab groups at week 48 in terms of the time to tumor progression (41.3% vs 43.0%; difference = −1.7%, 95% CI = −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; difference = −0.4%, 95% CI = −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; difference = 4.0%, 95% CI = −2.1% to 10.3%).
Adverse Events
Adverse events of any grade occurred in 98.6% of the biosimilar group vs 94.7% of the trastuzumab group by 24 weeks. Any grade hematologic adverse events included neutropenia in 57.5% vs 53.3%, leukopenia in 17.0% vs 20.7%, and anemia in 16.2% vs 16.3%. Hematologic adverse events of grade ≥ 3 occurred in 63.3% of all patients, with the most common being neutropenia (44.8%) and leukopenia (14.0%).
The most common nonhematologic adverse events of any grade were peripheral neuropathy (23.1% vs 24.8%), diarrhea (20.6% vs 20.7%), asthenia (21.9% vs 16.3%), and nausea (19.8% vs 13.8%); these adverse events were of grade ≥ 3 in < 2% of patients. Changes in median left-ventricular ejection fraction values at 24 weeks were −1.0% (range = −13% to 21%) vs −1.0% (range = −19% to 13%). Serious adverse events occurred in 38.1% vs 36.2% of patients, with the most common being neutropenia (27.5% vs 25.2%) and neutropenia with fever (4.5% vs 4.1%).
The investigators concluded: “Among women with ERBB2-positive metastatic breast cancer receiving taxanes, the use of a proposed trastuzumab biosimilar compared with trastuzumab resulted in an equivalent overall response rate at 24 weeks. Further study is needed to assess safety and long-term clinical outcome.”
The study was funded and sponsored by Mylan Inc and Biocon Research Limited.

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