Dataset Information

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

ABSTRACT:

Introduction

Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.

Methods

This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluated the safety, efficacy, and pharmacokinetics of the combination at the MTD in patients with HER2-positive breast cancer.

Results

Eight patients were included in the dose-escalation study; no dose-limiting toxicities were observed, and an MTD of oral neratinib 240 mg once daily plus intravenous paclitaxel 80 mg m(-2) on days 1, 8, and 15 of each 28-day cycle was determined. A total of 102 patients with HER2-positive breast cancer were enrolled in part 2. The overall median treatment duration was 47.9 weeks (range: 0.1-147.3 weeks). Common treatment-emergent adverse events (all grades/grade ?3) included diarrhoea (92%/29%; none grade 4), peripheral sensory neuropathy (51%/3%), neutropenia (50%/20%), alopecia (46%/0%), leukopenia (41%/18%), anaemia (37%/8%), and nausea (34%/1%). Three (3%) patients discontinued treatment due to an adverse event (mouth ulceration, left ventricular ejection fraction reduction, and acute renal failure). Among the 99 evaluable patients in part 2 of the study, the overall response rate (ORR) was 73% (95% confidence interval (CI): 62.9-81.2%), including 7 (7%) patients who achieved a complete response; an additional 9 (9%) patients achieved stable disease for at least 24 weeks. ORR was 71% among patients with 0/1 prior chemotherapy regimen for metastatic disease and no prior lapatinib, and 77% among those with 2/3 prior chemotherapy regimens for metastatic disease with prior lapatinib permitted. Kaplan-Meier median progression-free survival was 57.0 weeks (95% CI: 47.7-81.6 weeks). Pharmacokinetic analyses indicated no interaction between neratinib and paclitaxel.

Conclusion

The combination of neratinib and paclitaxel was associated with higher toxicity than that of neratinib as a single agent, but was manageable with antidiarrhoeal agents and dose reductions in general. The combination therapy also demonstrated a high rate of response in patients with HER2-positive breast cancer. A phase III trial is ongoing to assess the benefit and risk of this combination in the first-line setting.

SUBMITTER: Chow LW

PROVIDER: S-EPMC3670493 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Publications

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

Chow L W-C LW Xu B B Gupta S S Freyman A A Zhao Y Y Abbas R R Vo Van M-L ML Bondarenko I I

British journal of cancer 20130430 10

<h4>Introduction</h4>Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor that has demonstrated antitumour activity and an acceptable safety profile in patients with human epidermal growth factor receptor (HER)-2-positive breast cancer and other solid tumours.<h4>Methods</h4>This was a phase I/II, open-label, two-part study. Part 1 was a dose-escalation study to determine the maximum tolerated dose (MTD) of neratinib plus paclitaxel in patients with solid tumours. Part 2 evaluat ...[more]

PMID: 23632474

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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.

Project description:BackgroundCyclin-dependent kinases (CDK) 4 and 6 regulate G1 to S cell cycle progression and are often altered in cancers. Abemaciclib is a selective inhibitor of CDK4 and CDK6 approved for administration on a continuous dosing schedule as monotherapy or as combination therapy with an aromatase inhibitor or fulvestrant in patients with advanced or metastatic breast cancer. This Phase 1b study evaluated the safety and tolerability, pharmacokinetics, and antitumor activity of abemaciclib in combination with endocrine therapy for metastatic breast cancer (MBC), including aromatase inhibitors (letrozole, anastrozole, or exemestane) or tamoxifen.Patients and methodsWomen ≥18 years old with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) MBC were eligible for enrollment. Eligibility included measurable disease or non-measurable but evaluable bone disease by Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, Eastern Cooperative Oncology Group performance status 0-1, and no prior chemotherapy for metastatic disease. Adverse events were graded by the National Cancer Institute Common Terminology Criteria for Adverse Events v4.0 and tumor response were assessed by RECIST v1.1.ResultsSixty-seven patients were enrolled and received abemaciclib 200 mg every 12 hours in combination with letrozole (Part A, n=20), anastrozole (Part B, n=16), tamoxifen (Part C, n=16), or exemestane (Part D, n=15). The most common treatment-emergent adverse events (TEAE) were diarrhea, fatigue, nausea, and abdominal pain. Grade 4 TEAEs were reported in five patients (one each with hyperglycemia, hypertension, neutropenia, procedural hemorrhage, and sepsis). There was no effect of abemaciclib or endocrine therapy on the pharmacokinetics of any combination study drug. Across all treated patients, the median progression-free survival was 25.4 months (95% confidence interval: 18.0, 35.8). The objective response rate was 38.9% in 36 patients with measurable disease.ConclusionsAbemaciclib in combination with multiple endocrine therapy options exhibited manageable safety and promising antitumor activity in patients with HR+, HER2- MBC.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT02057133.

Dataset Information

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

Introduction

Methods

Results

Conclusion

Publications

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer.

Similar Datasets

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