Abhijit Barve

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.

Importance Treatment with the anti-ERBB2 humanized monoclonal antibody trastuzumab and chemotherapy significantly improves outcome in patients with ERBB2 (HER2)–positive metastatic breast cancer; a clinically effective biosimilar may help increase access to this therapy. Objective To compare the overall response rate and assess the safety of a proposed trastuzumab biosimilar plus a taxane or trastuzumab plus a taxane in patients without prior treatment for ERBB2-positive metastatic breast cancer. Design, Setting, and Participants Multicenter, double-blind, randomized, parallel-group, phase 3 equivalence study in patients with metastatic breast cancer. From December 2012 to August 2015, 500 patients were randomized 1:1 to receive a proposed biosimilar or trastuzumab plus a taxane. Chemotherapy was administered for at least 24 weeks followed by antibody alone until unacceptable toxic effects or disease progression occurred. Interventions Proposed biosimilar (n = 230) or trastuzumab (n = 228) with a taxane. Main Outcomes and Measures The primary outcome was week 24 overall response rate (ORR) defined as complete or partial response. Equivalence boundaries were 0.81 to 1.24 with a 90% CI for ORR ratio (proposed biosimilar/trastuzumab) and −15% to 15% with a 95% CI for ORR difference. Secondary outcome measures included time to tumor progression, progression-free and overall survival at week 48, and adverse events. Results Among 500 women randomized, the intention-to-treat population included 458 women (mean [SD] age, 53.6 [11.11] years) and the safety population included 493 women. The ORR was 69.6% (95% CI, 63.62%-75.51%) for the proposed biosimilar vs 64.0% (95% CI, 57.81%-70.26%) for trastuzumab. The ORR ratio (1.09; 90% CI, 0.974-1.211) and ORR difference (5.53; 95% CI, −3.08 to 14.04) were within the equivalence boundaries. At week 48, there was no statistically significant difference with the proposed biosimilar vs trastuzumab for time to tumor progression (41.3% vs 43.0%; −1.7%; 95% CI, −11.1% to 6.9%), progression-free survival (44.3% vs 44.7%; −0.4%; 95% CI, −9.4% to 8.7%), or overall survival (89.1% vs 85.1%; 4.0%; 95% CI, −2.1% to 10.3%). In the proposed biosimilar and trastuzumab groups, 239 (98.6%) and 233 (94.7%) had at least 1 adverse event, the most common including neutropenia (57.5% vs 53.3%), peripheral neuropathy (23.1% vs 24.8%), and diarrhea (20.6% vs 20.7%). Conclusions and Relevance 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. Trial Registration clinicaltrials.gov Identifier: NCT02472964; EudraCT Identifier: 2011-001965-42

Long-term efficacy and safety of itolizumab in patients with moderate-to-severe chronic plaque psoriasis: A double-blind, randomized-withdrawal, placebo-controlled study

trial, and a trial by Ortonne et al. Table I summarizes their efficacy results. The PRESTA and PRISTINE trials found that the 50mg BIW/QWregimen resulted in statistically greater percentages of patients with disease improvement by week 12 and continuing through week 24. Ortonne et al did not statically compare the 2 dosing regimens, but nominally, the percentage of patients who achieved PASI 75 at week 24 is greater for the BIW/QW regimen. For adalimumab, Asahina et al evaluated dosing regimens of 40 mg EOW and 80 mg loading dose followed with 40 mg EOW. Two limitations for this study were (1) the loading dose plus maintenance regimen did not match the FDA-approved regimen and (2) the 2 dosing regimens were not statistically compared against each another. Both dosing regimens led to statistically greater percentages of patients achieving PASI 75 than patients in the placebo group. Table I illustrates that the loading dose plus maintenance regimen led to nominally greater proportions of patients with PASI 75 at every time point over the 40 mg EOW regimen. However, without appropriate statistical analysis, we cannot infer any difference in effect between these two dosing regimens. Currently, there is not sufficient evidence to conclude that there is a difference in effectiveness between the 2 dosing regimens. With regard to safety, all of the studies examined for both etanercept and adalimumab showed that the rates for adverse events were not statistically different between the differing dosing regimens. In conclusion, the etanercept data have shown that, startingwith a loading dose results in amore rapid and higherpercentageofpsoriatic skin improvement up to 24 weeks. For adalimumab, there are no data directly comparing the efficacy of loading dose plus maintenance andmaintenance-only dosing regimens, and future studies should address this gap.

A pharmacokinetics and pharmacodynamics equivalence trial of the proposed pegfilgrastim biosimilar, MYL-1401H, versus reference pegfilgrastim

PurposePegfilgrastim is a long-acting granulocyte colony-stimulating factor indicated for prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy by promoting neutrophil recovery.MethodsThis phase 1, randomized, double-blind, three-way crossover trial in healthy volunteers evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the proposed biosimilar, comparing MYL-1401H, reference pegfilgrastim (Neulasta®, Amgen Inc, Thousand Oaks, CA, USA) sourced from the European Union, and reference pegfilgrastim sourced from the USA. Primary PK end points were peak plasma concentration of pegfilgrastim (Cmax) and area under the plasma concentration–time curve from the time of dosing to infinity (AUC0−inf). Primary PD end points were area under the curve above baseline for absolute neutrophil counts (ANC AUC0−t) and maximum change from baseline for ANC (ANC Cmax). Adverse events were also recorded.ResultsThe primary PK and PD end points were similar across all groups. For the PK parameters, the 90% confidence intervals (CIs) of the ratios of geometric means ranged between 0.91 and 1.18, which were within the predefined bioequivalence interval of 0.8000 to 1.2500 for all comparisons. For the PD parameters, the 95% CIs of the ratios of geometric means ranged between 0.94 and 1.06 for all comparisons, which were within the predefined PD equivalence interval of 0.8500 to 1.1765. The safety profiles were similar, with the most common adverse events being back pain and headache.ConclusionsMYL-1401H demonstrated similar PK, PD, and safety to reference pegfilgrastim in healthy volunteers and may be an equivalent option for the prevention of febrile neutropenia.

A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL‐1401O vs. EU‐trastuzumab and US‐trastuzumab

Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2‐overexpressing breast cancer. MYL‐1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL‐1401O, reference EU‐trastuzumab and US‐trastuzumab.