Dataset Information

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

ABSTRACT:

Background

Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC).

Patients and methods

We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m² paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety.

Results

Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%).

Conclusions

Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.

SUBMITTER: Kim M

PROVIDER: S-EPMC10485395 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

Kim M M Lee J L JL Shin S J SJ Bae W K WK Lee H J HJ Byun J H JH Choi Y J YJ Youk J J Ock C Y CY Kim S S Song H H Park K H KH Keam B B

ESMO open 20230627 4

<h4>Background</h4>Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC).<h4>Patients and methods</h4>We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m<sup>2</sup> paclitaxel on d ...[more]

PMID: 37385153

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Project description:BACKGROUND:This randomised, double-blind study compared PF-05280014 (a trastuzumab biosimilar) with reference trastuzumab (Herceptin®) sourced from the European Union (trastuzumab-EU), when each was given with paclitaxel as first-line treatment for HER2-positive metastatic breast cancer. METHODS:Between 4 April 2014 and 22 January 2016, 707 participants were randomised 1:1 to receive intravenous PF-05280014 plus paclitaxel (PF-05280014 group; n = 352) or trastuzumab-EU plus paclitaxel (trastuzumab-EU group; n = 355). PF-05280014 or trastuzumab-EU was administered weekly (first dose 4 mg/kg, subsequent doses 2 mg/kg), with the option to change to a 3-weekly regimen (6 mg/kg) from Week 33. Treatment with PF-05280014 or trastuzumab-EU could continue until disease progression. Paclitaxel (starting dose 80 mg/m2) was administered on Days 1, 8 and 15 of 28-day cycles for at least six cycles or until maximal benefit of response. The primary endpoint was objective response rate (ORR), evaluating responses achieved by Week 25 and confirmed by Week 33, based on blinded central radiology review. RESULTS:The risk ratio for ORR was 0.940 (95% CI: 0.842-1.049). The 95% CI fell within the pre-specified equivalence margin of 0.80-1.25. ORR was 62.5% (95% CI: 57.2-67.6%) in the PF-05280014 group and 66.5% (95% CI: 61.3-71.4%) in the trastuzumab-EU group. As of data cut-off on 11 January 2017 (using data up to 378 days post-randomisation), there were no notable differences between groups in progression-free survival (median: 12.16 months in the PF-05280014 group vs. 12.06 months in the trastuzumab-EU group; 1-year rate: 54% vs. 51%) or overall survival (median: not reached in either group; 1-year rate: 89.31% vs. 87.36%). Safety outcomes and immunogenicity were similar between the treatment groups. CONCLUSION:When given as first-line treatment for HER2-positive metastatic breast cancer, PF-05280014 plus paclitaxel demonstrated equivalence to trastuzumab-EU plus paclitaxel in terms of ORR. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov, NCT01989676.

Project description:BackgroundThe trastuzumab biosimilar CT-P6 has demonstrated equivalent efficacy and comparable safety to reference trastuzumab (RTZ) in clinical trials of human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC). Here, we present the first real-world comparison of CT-P6 versus RTZ with dual HER2-targeted therapy for the neoadjuvant and palliative first-line treatment with HER2-positive EBC and metastatic breast cancer (MBC) patients in two tertiary hospitals in Korea.MethodsWe retrospectively investigated medical records in the Severance Breast Cancer Registry in Korea. We identified patients with HER2-positive EBC (n=254) who had received neoadjuvant chemotherapy with RTZ or CT-P6, plus pertuzumab, carboplatin and docetaxel (TCHP) and untreated stage IV MBC (n=103) who had received palliative first-line treatment with RTZ or CT-P6, plus pertuzumab and docetaxel (THP) between May 2014 and December 2019. The primary endpoints were pathologic complete response (pCR) in the EBC and progression-free survival (PFS) in the MBC cohort. Overall survival (OS), overall response rate (ORR), disease control rate (DCR), and cardiac safety were secondary endpoints.ResultsA similar percentage of EBC patients achieved a pCR with CT-P6 versus RTZ (74.4% [93/125]) vs 69.8% [90/129], p=0.411). For patients with MBC, median follow-up duration was 23.0 and 41.0 months for CT-P6 and RTZ groups, respectively; median PFS did not differ significantly between two groups (13.0 vs 18.0 months, 95% confidence intervals (CIs) 0.0-26.6 vs 11.3-24.7, p=0.976). The ORR, DCR, and cardiac safety profiles did not also show significant difference efficacy outcomes between two groups.ConclusionsThese real-world data suggest that biosimilar trastuzumab CT-P6 has similar effectiveness and cardiac safety to RTZ in HER2-positive EBC and MBC patients, when administered as part of dual HER2-targeted therapy with pertuzumab plus chemotherapy in the neoadjuvant or palliative setting.

Project description:Background and objectiveTrastuzumab targets human epidermal growth factor receptor 2 (HER2) receptors and is indicated for treating HER2-positive metastatic breast cancer. BP02, a recombinant IgG1 kappa humanized monoclonal antibody, is being developed as a trastuzumab biosimilar. The objective of this study was to evaluate the equivalence of BP02 with reference trastuzumab (RT: Herceptin®-EU) in patients with HER2-positive metastatic breast cancer.MethodsThis double-blinded, 1:1 randomized, parallel-group, active-controlled, phase III equivalence trial recruited women aged 18-75 years with histologically/cytologically confirmed HER2- positive, locally recurrent or metastatic breast cancer with systemic metastasis, from 59 sites in India. Patients were randomly allocated 1:1 stratified by estrogen receptor/progesterone receptor status to receive BP02/RT (8-mg/kg loading dose on day 1-cycle 1, 6 mg/kg on day 1-cycles 2-8, of each 3-week cycle) combined with docetaxel (75 mg/m2 on day 1-cycles 1-8) [induction phase]. Participants with complete or partial response, or stable disease at the end of the induction phase continued the study drug until disease progression/treatment discontinuation [maintenance phase]. The primary efficacy endpoint was the objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.ResultsBetween 23 September, 2020 and 16 September, 2022, 690 patients were recruited (n = 345 each to BP02/RT). At the end of the induction phase (intent-to-treat population), a similar proportion of patients achieved an objective response rate with BP02 (n = 231 [67.0%], 95% confidence interval [CI] 62.0, 71.9) and RT (n = 238 [69.0%], 95% CI 64.1, 73.9). The 95% CI of risk difference (-2.03, 95% CI -9.15, 5.09) and 90% CI of risk ratio (0.97, 90% CI 0.89, 1.06) were within equivalence margins of ± 13% and (0.80, 1.25), respectively. Treatment-emergent adverse events leading to treatment withdrawal were reported in 2.9% and 3.2% patients with BP02 and RT, respectively.ConclusionsBP02 showed an equivalent efficacy and similar safety profile to RT at the end of 24 weeks.Clinical trial registrationCTRI Number: CTRI/2020/04/024456.

Project description:PurposePF-05280014 is a biosimilar to trastuzumab (Herceptin®). Following demonstration of pharmacokinetic (PK) similarity in healthy volunteers, a comparative clinical study in patients with HER2-positive metastatic breast cancer (mBC) compared the efficacy, safety and immunogenicity of PF-05280014 and trastuzumab sourced from the EU (trastuzumab-EU), both with paclitaxel.MethodsPopulation PK of PF-05280014 and trastuzumab-EU was evaluated.ResultsOverall, 702 patients were treated: PF-05280014 (n = 349) and trastuzumab-EU (n = 353). Peak-and-trough serum drug concentration samples were collected (selected doses) following repeated intravenous administration of PF-05280014 or trastuzumab-EU. Population PK analysis was performed with drug concentration-time data to cycle 17 for each compound, using nonlinear mixed effect modeling. Potential baseline covariates (circulating HER2 concentrations, body weight, Japanese race, Eastern Cooperative Oncology Group status, number of metastatic sites and antidrug antibody status) were evaluated. Concentration-time data of PF-05280014 and trastuzumab-EU were adequately described by a two-compartment model with first-order elimination, with inter-individual variability (IIV) on clearance (CL), volumes of distribution in central compartment (V1) and peripheral compartments, and intercompartment clearance. Similar estimated PK parameters and IIV were obtained for both treatments. For PF-05280014 and trastuzumab-EU, baseline body weight was an influential covariate on CL and V1; the magnitude was comparable between treatments. PK was consistent between the limited number of Japanese and non-Japanese patients for both compounds.ConclusionsPF-05280014 and trastuzumab-EU had similar PK parameters and influential PK covariates in patients with HER2-positive mBC. These results provided further evidence in patients for PK similarity between PF-05280014 and trastuzumab-EU.Clinical trial registrationClinicalTrials.gov, NCT01989676.

Project description:IntroductionMyocardial strain imaging and blood biomarkers have been proposed as adjuncts to left ventricular ejection fraction (LVEF) monitoring for the early detection of cardiotoxicity during cancer therapy. We report the results of a preplanned cardiac safety analysis of global longitudinal strain (GLS), and troponin-I (TnI) and brain natriuretic peptide (BNP) levels in the phase II study of paclitaxel, trastuzumab, and pertuzumab (THP) for metastatic HER2-positive breast cancer.Patients and methodsPatients with 0-1 lines of prior therapy were treated with weekly paclitaxel (80 mg/m(2)) plus trastuzumab (8 mg/kg loading dose followed by 6 mg/kg) and pertuzumab (840 mg loading dose followed by 420 mg) every 3 weeks. Exploratory endpoints were GLS measured with speckle-tracking echocardiography every 3 months and TnI and BNP levels measured every 6 weeks (immediately pre- and postchemotherapy infusion) at 6 time points.ResultsSixty-seven of 69 enrolled patients were treated with THP: 19 (28%) had hypertension, 8 (12%) had diabetes, 11 (16%) had hyperlipidemia, and 26 (38%) had smoking history. After a median follow-up of 21 months (range: 3-38 months), no patients developed symptomatic heart failure. Two patients (3.0%) experienced asymptomatic LVEF decline (grade 2). The mean GLS (±SD) was 19% ± 2% (baseline), 19% ± 2% (month 6), and 19% ± 3% (month 12). Detectable TnI (>0.06 ng/mL) and elevated BNP (>100 pg/mL) levels were observed in 3 (4.3%) and 2 (3.0%) patients, respectively, but were not associated with LVEF decline.ConclusionThe absence of any significant changes in GLS and cardiac biomarkers (TnI and BNP) further support the cardiac safety of THP in patients with metastatic HER2-positive breast cancer.Implications for practiceDual anti-HER2 therapy with trastuzumab and pertuzumab in combination with taxane-based chemotherapy improves overall survival in patients with metastatic HER2-positive breast cancer. There is a critical need to investigate the potential cardiotoxicity of dual anti-HER2 blockade, given the importance of HER2 signaling in cardiac homeostasis and stress response. Global longitudinal strain and cardiac biomarkers have been proposed as adjuncts to left ventricular ejection fraction for the early detection of cardiotoxicity. In this phase II study of combination trastuzumab and pertuzumab with paclitaxel, no clinically significant change was observed in global longitudinal strain or cardiac biomarkers. These results further support the cardiac safety of dual anti-HER2 blockade previously reported in the CLEOPATRA study. The findings in the current study also call into question the role of intensive cardiac monitoring among patients treated with anti-HER2 therapy in the absence of anthracyclines. Less frequent cardiac assessments could lead to a reduction in unnecessary treatment interruption and is an important consideration given the rise in medical expenditures, but this requires further investigation.

Dataset Information

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

Background

Patients and methods

Results

Conclusions

Publications

Phase II study of a trastuzumab biosimilar in combination with paclitaxel for HER2-positive recurrent or metastatic urothelial carcinoma: KCSG GU18-18.

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