Entry Detail
| General information | |
| Database: | DB00655 |
| Objective: | Brain metastases develop in one third of patients with advanced human epidermal growth factor receptor 2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/human epidermal growth factor receptor 2 inhibitor, was associated with regressions of CNS lesions in a smallphase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine. |
| Authors: | Lin NU, et al |
| Title: | Multicenterphase II study of lapatinib in patients with brain metastases from human epidermal growth factor receptor 2positive breast cancer. |
| Journal: | Clin Cancer Res. |
| Year: | 2009 |
| PMID: | 19228746 |
| Trial Design | |
| Clinical Trial Id: | NCT00263588 |
| Agent: | lapatinib |
| Target: | Epidermal growth factor receptor Receptor proteintyrosine kinase erbB2 |
| Cancer Type: | advanced cancer with brain metastasis |
| Cancer Subtype: | brain metastases from human epidermal growth factor receptor 2-positive breast cancerhuman epidermal growth factor receptor 2positive breast cancer |
| Therapy Type: | mono |
| Therapeutic Combination Type: | NA |
| Therapeutic Combination Content: | NA |
| Study Type: | Multicenterphase II Study |
| Key Patients Feature: | Patients were eligible if they had human epidermal growth factor receptor 2+ breast cancer (defined as 3+ immunohistochemistry or evidence of gene amplification by fluorescence in situ hybridization) and unequivocal evidence of new and/orprogressive brain metastases after completion of wholebrain radiotherapy or stereotactic radiosurgery. At least one brain lesion neededto be measurable (z10 mm on T1 weighted, gadoliniumenhancedmagnetic resonance imaging). Prior treatment with trastuzumab wasalso required. Additional inclusion criteria included age, z18 years, lifeexpectancy of z12 weeks, left ventricular ejection fraction within theinstitution¡¯s reference range, and adequate hematologic, renal, andhepatic function. |
| Biomarker: | human epidermal growth factor receptor 2positive |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | The starting dose of singleagent lapatinib was 750 mg twice daily (b.i.d.). Dose delays of up to 2 weeks and two dose reductions, first to 1, 500 mg once daily (q.d.) and second to 1, 250 mg q.d., were allowed for treatmentrelated toxicities. |
| Primary End Point: | CNS objective response. |
| Secondary End Point: | safety and tolerability, neurologic signs and symptoms (NSS), progression free survival (PFS), and overall survival. |
| Patients Number: | 242 |
| Trial Results | |
| DLT_MTD: | The most common adverse events werediarrhea (65%), rash (30%), nausea (26%), and vomiting(24%). The most common grade 3 adverse event was diarrhea(13%), and two patients (<1%) experienced grade 4 diarrhea. Atotal of 17 patients (7%) had serious or non-serious adverseevents that led to withdrawal from the study |
| Objective Response Rate: | CNS objective responsesto lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patientsexperienced a z20% volumetric reduction in their CNS lesions. |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 2.4 months in Lapatinib monotherapy. In Lapatinib plus capecitabine combination:3.65 months (95% CI, 2.434.37) |
| Median OS A vs. C: | 6.4 months. Cohort A had a longer median survival than cohort B (9.6 and 5.5 months, respectively) in laptinib monotherapy. In Lapatinib plus capecitabine combination: NR |
| Adverse Event(agent arm): | The most common adverse events were diarrhea (65%), rash (30%), nausea (26%), and vomiting (24%). The most common grade 3 adverse event was diarrhea (13%), and two patients (<1%) experienced grade 4 diarrhea. A total of 17 patients (7%) had serious or non-serious adverse events that led to withdrawal from the study. The most common adverse events reported with the combination of lapatinib plus capecitabine were palmarplantar erythrodysesthesia (45%), diarrhea (37%), and nausea (29%). Palmarplantar erythrodysesthesia (8%), nausea (8%), vomiting (6%), and diarrhea (4%) constituted the most common grade 3 adverse events. |
| Conclusions: | This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinibbased regimens for CNS metastases from human epidermal growth factor receptor 2+ breast cancer are warranted. |