Inconclusive Outcome for Lapatinib vs Trastuzumab Plus Capecitabine in Preventing CNS Metastases as First Relapse Site in HER2-Positive Breast Cancer
In the phase III CEREBEL study reported in the Journal of Clinical Oncology, Pivot et al compared lapatinib (Tykerb)-capecitabine vs trastuzumab (Herceptin)-capecitabine in the prevention of central nervous system (CNS) metastases as first relapse site in patients with metastatic HER2-positive breast cancer. The study was terminated early on the basis of low rates of the primary endpoint, with no difference between treatments being observed.
Study Details
In the open-label trial, 540 patients without baseline CNS metastases were randomly assigned to receive lapatinib at 1,250 mg plus capecitabine at 2,000 mg/m2 on days 1 to 14 every 21 days (n = 271) or trastuzumab at a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks plus capecitabine at 2,500 mg/m2 on days 1 to 14 every 21 days (n = 269). The first patient was enrolled in April 2009 and the study was terminated in June 2012 after interim analysis of data from 475 patients.
The presence of asymptomatic CNS metastases accounted for 20% of screening failures for the study. The modified intent-to-treat population consisted of 501 patients, with 39 not included due to presence of abnormal baseline brain scans. Overall, 38% of patients in the lapatinib group and 41% of the trastuzumab group had received no prior trastuzumab, and 43% and 45% had received no prior treatment for metastatic disease.
CNS Relapse
CNS metastases occurred as first site of relapse in 8 (3%) of 251 patients in the lapatinib group and 12 (5%) of 250 in the trastuzumab group (P = .360). The incidence of CNS progression at any time was 7% vs 6% (P = .8646).
The investigators noted that the rates of CNS as first site of relapse were well below expected rates. The study was underpowered for the primary endpoint due to the overestimation of the incidence of CNS recurrence, which was contributed to by the exclusion of patients with asymptomatic metastases during screening. The lower than expected rates may also have been related to the high proportion of patients who were receiving study treatment as first-line treatment for metastatic disease.
Other Outcomes
In intent-to-treat analyses, median progression-free survival was 6.6 months in the lapatinib group vs 8.1 months in the trastuzumab group (hazard ratio [HR] = 1.30, 95% confidence interval [CI] = 1.04–1.64), and median overall survival was 22.7 vs 27.3 months (HR = 1.34, 95% CI = 0.95–1.64).
Progression-free survival appeared to be better in the trastuzumab group in analyses among patients with no prior trastuzumab exposure (HR = 1.7, 95% CI = 1.15–2.50) and among patients with no prior treatment for metastatic disease (HR = 1.61, 95% CI = 1.13–2.29), with no differences being observed between treatments among patients with previous trastuzumab treatment or previous treatment of metastatic disease.
Adverse Events
The most common adverse events of any grade were palmar-plantar dysesthesia (49%), diarrhea (45%), and nausea (29%) in the lapatinib group and palmar-plantar dysesthesia (58%) and diarrhea (39%) in the trastuzumab group. The most common grade 3 or 4 adverse events were palmar-plantar dysesthesia (9% vs 15%) and diarrhea (6% vs 8%). Adverse events led to treatment discontinuation in 11% vs 13%. Serious adverse events occurred in 13% vs 17%. Grade 3 or 4 neutropenia occurred in < 7% of both groups and serious cardiac dysfunction occurred in 0% and < 1%.
The investigators concluded: “CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinib[-capecitabine] and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.”
Xavier Pivot, MD, PhD, of Centre Hospitalier Universitaire-Hôpital Jean Minjoz, Besançon, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by GlaxoSmithKline. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
