Among the data presented to regulators for the product’s approval were those arising from a phase 1 pharmacokinetic and pharmacodynamic study in healthy volunteers and those from 2 phase 3 studies in patients with breast cancer undergoing chemotherapy.
Sandoz’s biosimilar pegfilgrastim, referencing Neulasta, was authorized in the European Union under the brand name Ziextenzo in November 2018. Among the data presented to regulators for the product’s approval were those arising from a phase 1 pharmacokinetic and pharmacodynamic study in healthy volunteers and those from 2 phase 3 studies in patients with breast cancer undergoing chemotherapy.
An analysis of those data, first presented in abstract form at the European Society for Medical Oncology 2018 Congress, held in October 2018 in Munich, Germany, have now been published in full in Future Oncology.
The analysis seeks to compare the safety data for the biosimilar across all 3 trials, and it compares the frequency of adverse events (AEs) for a single dose of the product in the phase 1 trial with AEs associated with the first treatment cycle of chemotherapy plus pegfilgrastim in the phase 3 trials.
In the phase 1 study, 92 volunteers received a 6-mg dose of the biosimilar and 92 received the same dose of the reference pegfilgrastim. Treatment-emergent adverse events (TEAEs) that were considered to be related to the study drug were observed in 95% of volunteers in the biosimilar arm and in 96% of volunteers in the reference arm. The most commonly reported drug-related TEAE was headache, followed by bone pain, myalgia, and back pain. TEAEs were generally mild; no serious AEs were reported in the phase 1 study.
In the first of the phase 3 studies, PROTECT-1, 159 patients received the biosimilar and 157 received the reference product together with chemotherapy. In total, 88.1% of patients in the biosimilar arm and 82.8% of patients in the reference arm had 1 or more TEAE. Alopecia, nausea, asthenia, vomiting, and neutropenia were the most commonly reported. TEAEs that were determined to be related to the study drug occurred in 11.9% of patients in the biosimilar arm and in 14.6% of patients in the reference arm. Treatment-related bone pain was reported by 4.4% and 3.8% of patients in each arm, respectively. A total of 6 patients (4 in the biosimilar arm and 2 in the reference arm) died during the study; none of the deaths were considered related to pegfilgrastim.
In the PROTECT-2 trial, 155 patients received the biosimilar and 153 received the reference product together with chemotherapy. In total, 96.1% of patients in the biosimilar arm and 95.4% of patients in the reference arm experienced at least 1 TEAE. The incidences of TEAEs related to the study treatment were 33.5% and 28.1% in the 2 arms, respectively. Bone pain was reported by 4.5% and 8.5% of patients, respectively, and serious TEAEs were reported by 2.6% and 0.7% of patients, respectively. A total of 5 deaths occurred, 3 in the biosimilar arm and 2 in the reference arm. Again, none were considered related to the study drug.
In the combined safety analysis, bone pain was the most frequent AE and was reported at similar incidences in the reference and biosimilar groups across all 3 studies. Bone pain is a known AE related to granulocyte colony-stimulating factor therapies, and it has previously been reported in 25% to 42% of patients enrolled in randomized double-blind studies. Differences in AEs reported by those enrolled in the phase 1 versus the phase 3 studies, write the authors, are likely related to differences in baseline health status, sex differences, and other patient factors.
According to the authors, no differences in AEs were observed between the biosimilar and its reference in the 3 studies, and “these findings support the matching clinical safety and efficacy of Sandoz proposed biosimilar pegfilgrastim and the reference biologic.”
Harbeck N, Wang J, Otto GP, Gattu S, Krendyukov A. Safety analysis of proposed pegfilgrastim biosimilar in phase I and phase III studies [published online March 5, 2019]. Future Oncol. doi: 10.2217/fon-2018-0878.