The safety and efficacy of trastuzumab (TRZ) biosimilars for neoadjuvant breast cancer therapy demonstrated comparable safety and efficacy, according to two studies presented on June 4.
Biosimilar SB3 Compared With Trastuzumab
A randomized, double-blind phase III trial compared the biosimilar SB3 to TRZ (Abstract 509). The objective of the trial was to demonstrate comparable clinical efficacy of neoadjuvant SB3 and TRZ in HER2-positive, early-stage or locally advanced breast cancer.
Xavier B. Pivot, of University Hospital Jean Minjoz, in France, said the trial “not only substantiates the biosimilarity of SB3 to TRZ, but also thoroughly demonstrates the evaluation of a biosimilar based on the ‘totality of evidence’ approach, with comprehensive assessments including clinical efficacy, safety, pharmacokinetics, and immunogenicity.”
The trial included patients from 97 sites in 14 countries. The major eligibility criteria were age 18 to 65; ECOG performance status of 0 or 1; nonmetastatic, unilateral, newly diagnosed stage II-III breast cancer including inflammatory breast cancer with tumor size 2 cm or larger; and known estrogen receptor and progesterone receptor status.
A total of 875 patients were randomly assigned to treatment, and the per-protocol set (which completed eight cycles of neoadjuvant therapy and surgery) included 402 patients in the SB3 group and 398 patients in the TRZ group. Median age was 51 in the SB3 group and 50 in the TRZ group.
Patients received a loading dose of 8 mg/kg of either SB3 or TRZ followed by a maintenance dose of 6 mg/kg every 3 weeks prior to surgery. All patients also received four cycles of docetaxel and four cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC). The primary endpoint was breast pathologic complete response (pCR), which was evaluated at the time of surgery. After surgery, the two groups received 10 cycles of SB3 or TRZ.
Safety and immunogenicity were comparable between the groups, with neutropenia, alopecia, and nausea the most commonly reported adverse events. The pharmacokinetics of the two drugs was also similar. “Equivalence was demonstrated between SB3 and TRZ based on the ratio of breast pCR rates in patients treated with neoadjuvant therapy for HER2-positive, early-stage breast cancer,” Dr. Pivot said.
Overall safety was similar between the two drugs, he said. In the SB3 group, there were 42 treatment-emergent adverse events compared with 47 in the TRZ group. There were 46 serious treatment-emergent adverse events in the SB3 group compared with 47 in the TRZ group. Treatment-emergent adverse events of special interest included congestive heart failure and left ventricular systolic dysfunction; the most common were infusion-related reactions, with 36 in the SB3 group and 44 in the TRZ group. Treatment-emergent adverse events with incidence of at least 15% included alopecia, neutropenia, nausea, leukopenia, diarrhea, increased alanine aminotransferase, anemia, and fatigue.
Biosimilar CT-P6 Compared With Trastuzumab
Results from another randomized, double-blind phase III study, which compared the efficacy and safety of another TRZ biosimilar, were also reported (Abstract 510). The comparison of biosimilar CT-P6 to TRZ also demonstrated similar efficacy when used as neoadjuvant therapy in HER2-positive, early-stage breast cancer.
According to Justin Stebbing, MD, PhD, of Imperial College Healthcare NHS Trust, in the United Kingdom, the trial was a parallel group, active-controlled study and is ongoing. Patients were recruited from 112 centers in 22 countries between August 2014 and May 2016. Women with stage I-IIIA operable HER2-positive breast cancer were randomly selected 1:1 to receive intravenous neoadjuvant CT-P6 or TRZ in eight cycles for 24 weeks.
Patients received CT-P6 therapy as an 8 mg/kg loading dose and then 6 mg/kg every 3 weeks or an 8 mg/kg loading dose of TRZ followed by 6 mg/kg every 3 weeks for eight cycles. That therapy was given in conjunction with neoadjuvant docetaxel during cycles one through four and FEC during cycles five through eight.
Randomization was stratified by clinical stage, hormone receptor status, and country. Among the 781 patients who were screened, 549 were randomly assigned, with 271 given CT-P6 therapy and 278 given TRZ.
Surgery was followed by an adjuvant treatment period of up to 1 year, and long-term safety and efficacy were monitored for 3 years from the last enrollment. The primary efficacy endpoint was pCR, which was assessed through specimens obtained during surgery and analyzed by a central review of local histopathology reports.
In the per-protocol population, which included 248 patients treated with CT-P6 and 256 treated with the reference drug, a similar proportion achieved pCR (46.8% vs. 50.4%, respectively). Serious treatment-emergent adverse events were reported by 6.6% of the 271 patients in the CT-P6 group and 7.6% in the reference product group. Serious adverse events of grade 3 or higher that were considered related to treatment occurred in 8.6% of the patients in the CT-P6 group compared with 10.1% in the reference drug group; neutropenia was the most frequently reported hematologic adverse event. Median left ventricular ejection fraction (LVEF) at baseline was 66.0%, and the median lowest LVEF was 62% with CT-P6 and 62.8% with the reference drug.
Dr. Stebbing said that the availability of TRZ biosimilars “could increase access to this targeted therapy for HER2-positive, early-stage cancer with savings for health care systems around the world.”
Discussant Aleix Prat, MD, PhD, of the University of Barcelona, in Spain, reviewed the safety and efficacy results of the trials comparing the two biosimilars with TRZ, and noted that survival data are pending. Five proposed TRZ biosimilars have shown positive phase III results in equivalence studies, two for metastatic disease, and three, including CT-P6 and SB3, in the neoadjuvant setting, he said.
The primary patent for Herceptin (TRZ) expired in Europe in 2014 and is set to expire in the United States in 2019, Dr. Prat said. The potential cost savings of a biosimilar, anticipated to be about 30% of the cost of the brand name drug, could be substantial, given that the brand name drug’s worldwide sales are about $6.7 billion, he said.
–Kathy Holliman, MEd