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Trastuzumab Biosimilar Found Safe, Effective in Pretreated HER2-Positive Breast Cancer


A study from the Republic of Korea confirmed the safety and efficacy of Herzuma (CT-P16) in patients with heavily pretreated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer.

Results of a study in the Republic of Korea suggest the trastuzumab biosimilar Herzuma combined with treatment of physician’s choice (TPC) was effective and safe in 109 patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who had failed 2 or more HER2-targeted chemotherapies.

The study also investigated genetic biomarkers, and found that duration of response to previous anti-HER2 therapy and mutations in PIK3CA and ERBB2 were associated with duration of progression-free survival (PFS).

The investigators noted that HER2 is overexpressed in approximately 20% of breast cancers. Although HER2-targeting chemotherapy is the main treatment strategy in these cancers, treatment options are limited after progression despite anti-HER2 therapies. According to the authors, continued anti-HER2 therapy is the clinical standard. “Therefore, trastuzumab beyond progression should be considered for patients when other anti-HER2 therapies have been exhausted or are not available,” they wrote.

Although the trastuzumab biosimilar Herzuma (Celltrion) has demonstrated comparable efficacy and safety to the reference product and is already used in many countries for the same indications as the reference product, the authors said that the efficacy and safety of Herzuma re-administration after previous trastuzumab therapy has not yet been studied.

Patients had an average of 3 previous anti-HER2 therapies (range, 2-8), with 61% receiving more than three previous lines of chemotherapy. The median age of the 109 patients was 55 years, and just over half (54.1%) had hormone receptor positive tumors. Treatments of physicians’ choice (TPC) included eribulin (48.6%), vinorelbine (29.4%), nab-paclitaxel (15.6%), and gemcitabine (6.4%). About half of patients (49.5%) had a prior duration of response to anti-HER2 therapy of 6 months or less.

The investigators conducted a single-arm study and used a historical control: the chemotherapy only group in the TH3RESA trial. The primary endpoint of the study was PFS, with objective response rate (ORR), overall survival (OS), safety, and quality of life (QoL) as secondary endpoints.

Median Progression-free Survival Was 4.6 Months, Greater Than Hypothesized

After the median 13.3 month follow-up, the ORR was 18.7% and median PFS was 4.6 months (95% CI, 2.8-7.2), which the authors noted surpassed their hypothesized PFS of 3.8 months based on their historical control.The median OS was 18.6 months.

Subgroup analyses revealed that median PFS was greater in patients 55 or older (5.6 vs. 4.2 months) and in patients who had a response duration to previous anti-HER2 therapy of more than 6 months (5.8 vs. 3.3 months). Also, patients with liver metastasis had a non-statistically significant shorter PFS.

Genetic Biomarkers Associated With Progression-free Survival

Genetic biomarkers in tumor tissue or circulating tumor DNA were analyzed in the 100 patients for whom tumor tissues or blood samples were available. The most common gene alterations, PIK3CA, TP53, and ERBB2, were evaluated. Overall, mutation rates were 23% for PIK3CA (35.4% in tumor tissue, 11.5% in ctDNA), 41% for TP53 (50% in tumor tissue, 32.7% in ctDNA), and 7.0% for ERBB2 (8.3% in tumor tissue, 5.8% in ctDNA).

Significantly shorter PFS was observed in patients with PIK3CA or ERBB2 mutations. These associations were more pronounced based on circulating tumor DNA compared to tumor tissue.

The authors cited previous studies suggesting PIK3CA mutations may be a resistance mechanism to anti-HER2 therapies. Most ERBB2 mutations, they said, have been reported in HER2-negative breast cancers, and ERBB2 mutations may be acquired due to anti-HER2 therapy. They wrote that “these mutations could be good targets to improve the clinical efficacy of anti-HER2 therapy.”

The investigators also carried out multivariable analysis, in which the response duration to previous anti-HER2 therapy greater than 6 months was a predictor of longer PFS, and PIK3CA and ERBB2 mutations predicted shorter PFS.

Most Adverse Events Were “Mild and Tolerable”

During the study, 1 patient experienced a grade 3 cardiac event (heart failure). Decreased left ventricular ejection fraction (grade 2) and diastolic dysfunction (grade 2) were also experienced by 1 patient each. The most common adverse events (AE) were hematologic toxicities such as neutropenia and thrombocytopenia. The authors said that 2 of the patients who developed cardiac AEs discontinued the study treatment, but all cardiac AEs resolved. Most AEs were “mild and tolerable,” according to the investigators. The primary reason for discontinuing treatment was disease progression.

The authors concluded the combination of chemotherapy of the physician’s choice with Herzuma was effective and safe in patients with heavily pre-treated HER2-positive metastatic breast cancer. Progression-free survival was longer in patients with 6 months or more response duration to previous anti-HER2 therapy, and shorter in patients with mutations of PIK3CA and ERBB2. They discussed the limitations of their study, in particular the use of a historical control, the nonrandomized single-arm study design, and small sample size.


Sim SH, Kim JE, Kim MH, et al. Phase II study to investigate the efficacy of trastuzumab biosimilar (Herzuma®) plus treatment of physician's choice (TPC) in patients with heavily pretreated HER-2+ metastatic breast cancer (KCSG BR 18-14/KM10B). Breast. 2022;65:172-178. doi:10.1016/j.breast.2022.08.002

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