A trastuzumab biosimilar candidate (CT-P6) demonstrated therapeutic equivalence and similar safety to the reference drug, trastuzumab, in a double-blind, randomized phase 3 trial of women with HER2-positive, early-stage breast cancer.1 Therapeutic equivalence in the study was demonstrated by achievement of pathologic complete response (pCR) within a prespecified margin on an intent-to-treat basis. The data were presented in poster format by Justin Stebbing, MD, MA, FRCP, FRCPath, PhD, Professor of Cancer Medicine and Oncology/Senior Lecturer, Imperial College and Imperial College Healthcare NHS Trust, London, United Kingdom, at the 2017 meeting of the American Society of Clinical Oncology.
CT-P6 is a recombinant humanized monoclonal antibody that has an identical amino acid sequence and similar physiochemical and in vitro functional properties to reference trastuzumab. It was tested in a randomized, double-blind, active-controlled equivalence trial in which 549 women aged ≥18 years with stage I to IIIa operable HER2-positive breast cancer from 112 centers in 22 countries were recruited to participate.
Patients were randomly allocated in a 1:1 ratio to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (8 cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel, fluorouracil, epirubicin, and cyclophosphamide. The primary efficacy end point, analyzed in the per-protocol population, was pCR, defined as the absence of invasive cancer in the breast and axillary nodes, irrespective of ductal carcinoma in situ (DCIS) or nodal involvement.
Median age of patients was 53 years and characteristics were generally well-balanced between the 2 arms. The most common disease stages were IIb (38.7% of the CT-P6 group and 35.3% of the reference trastuzumab group) and IIIa (23.6% and 21.9%, respectively). Some 39.1% and 36.0% of the patients had estrogen receptor– and progesterone receptor–positive disease, respectively.
Following neoadjuvant treatment, patients underwent surgery, at which time pathologic response, pharmacokinetics, and immunogenicity were assessed. A total of 519 patients completed pCR assessment. The predefined 95% confidence interval (CI) for the risk ratio was 0.74 to 1.35, and the margin for the risk difference was −15% to +15%.
A similar proportion of patients achieved pCR with CT-P6 (46.8% of 248 patients) and trastuzumab (50.4% of 256 patients). The 95% CI of the estimated treatment outcome difference (−0.04% [95% CI, −0.12 to 0.05]) for the per-protocol set (PPS) was within the equivalence margin.
A breast pCR in the PPS was achieved in 51.6% of the CT-P6 arm and 55.1% of the trastuzumab arm. The proportion of pCR without DCIS was 39.9% and 41.4% in the CT-P6 and reference product arms, respectively, and the overall response rates were 88.3% and 89.5%, respectively.
Serum concentrations of trastuzumab and HER2-shed antigen levels were similar between the 2 treatment arms during the neoadjuvant period. None of the patients developed antidrug antibodies after study drug infusion.
The rates of treatment-emergent adverse events (TEAEs) were similar between the 2 arms—94.1% in the CT-P6 arm versus 95.0% in the trastuzumab arm. Neutropenia (39.9% vs 44.2%), anemia (19.2% vs 21.9%), and leukopenia (8.9% vs 13.7%) were the most common hematologic adverse events, and the rates were similar between arms. The most common nonhematologic adverse events in the CT-P6 and reference groups were alopecia (71.6% vs 76.6%), nausea (36.2% vs 31.7%), and fatigue (32.1% vs 34.2%). More than 90% of TEAEs were grade 1 or 2. The rates of severe (grade ≥3) TEAEs were similar between the 2 arms (8.6% vs 10.1%, respectively).
The relative dose intensity was >97% in each arm, “indicating good tolerability,” according to the investigators. One patient in each group had a grade ≥3 infusion reaction.
Data from a second trastuzumab biosimilar—SB3—in the neoadjuvant setting in HER2-positive, early-stage, or locally advanced breast cancer were also presented at ASCO 2017.2 This study included 875 women with newly diagnosed stage II to III breast cancer (including inflammatory breast cancer) with tumor size ≥2 cm who were randomly assigned to a loading dose of 8 mg/kg of SB3 or reference trastuzumab followed by a maintenance dose of 6 mg/kg every 3 weeks prior to surgery. All patients also received 4 cycles of docetaxel and 4 cycles of 5-fluorouracil, epirubicin, and cyclophosphamide.
The primary end point was breast pCR evaluated at the time of surgery. These rates were 51.7% for SB3 versus 42.0% for the reference product, which was within the 90% CI of the ratio of the equivalence margin. The 95% CI was 4.13 to 17.26; the lower margin was contained within the predefined equivalence margin but the upper margin was outside the range, said lead investigator Xavier B. Pivot, MD, from University Hospital Jean Minjoz, Besançon, France.
Overall safety was similar between the 2 drugs. There were 42 TEAEs in the SB3 group compared with 47 in the reference trastuzumab group, and 46 serious TEAEs in the SB3 group compared with 47 in the reference group.
The study “not only substantiates the biosimilarity of SB3 to trastuzumab 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,” said Dr Pivot.
One issue to consider with trastuzumab biosimilars is whether the 5 that have thus far been studied and submitted for approval in Europe or the United States will be approved for all trastuzumab indications although they have been evaluated in different settings—metastatic versus early-stage breast cancer, said Aleix Prat, MD, PhD, from the University of Barcelona, Spain. “Long-term toxicity might also be an issue, and pharmacovigilance here is important,” he said.
1. Stebbing J, Baranau YV, Baryash V, et al. Double-blind, randomized phase III study to compare the efficacy and safety of CT-P6, trastuzumab biosimilar candidate versus trastuzumab as neoadjuvant treatment in HER2 positive early breast cancer (EBC). J Clin Oncol. 2017;35(suppl):Abstract 510.
2. Pivot XB, Bondarenko I, Dvorkin M, et al. A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer. J Clin Oncol. 2017;35(suppl):Abstract 509.