Worse Outcomes With Lapatinib vs Trastuzumab Plus Taxane in Advanced HER2-Positive Breast Cancer
In the phase III National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.31 trial, first-line treatment with lapatinib (Tykerb) vs trastuzumab (Herceptin) combined with a taxane was associated with poorer progression-free survival and greater toxicity in patients with advanced HER2-positive breast cancer. The final results of the trial were reported in the Journal of Clinical Oncology by Gelmon et al.
Study Details
In this open-label trial, 652 patients with locally or centrally confirmed HER2-positive metastatic disease from 21 countries were randomly assigned between July 2008 and December 2011 to receive first-line lapatinib (n = 326) or trastuzumab (n = 326) plus a taxane for 24 weeks followed by the same anti-HER2 monotherapy until progression. Of these, a total of 537 (270 in lapatinib group, 267 in trastuzumab group) had centrally confirmed HER2-positive tumors.
Lapatinib was given orally at 1,250 mg/d when combined with taxane and at 1,500 mg/d as monotherapy. Taxane treatment consisted of intravenous paclitaxel at 80 mg/m2 once weekly on days 1, 8, and 15 of a 28-day schedule or docetaxel at 75 mg/m2 once every 3 weeks. Trastuzumab was given intravenously either once weekly for 24 weeks (4 mg/kg bolus followed by 2 mg/kg maintenance) with once-weekly paclitaxel or once every 3 weeks (8 mg/kg bolus followed by 6 mg/kg maintenance) with docetaxel once every 3 weeks. Trastuzumab was given at 6 mg/kg once every 3 weeks as monotherapy. The primary endpoint was progression-free survival in the intention-to-treat population.
Excess incidence of febrile neutropenia and diarrhea in the lapatinib group led to the requirement of granulocyte colony-stimulating factor (Neupogen) treatment in patients receiving lapatinib and docetaxel and institution of rigorous diarrhea management guidelines in February 2010.
Overall, 45% of patients in both groups had planned weekly paclitaxel treatment and 55% had planned every-3-week docetaxel treatment.
Progression-Free Survival
Median follow-up was 21.5 months. Median progression-free survival was 9.0 months in the lapatinib group vs 11.3 months in the trastuzumab group (stratified hazard ratio [HR] = 1.37, P < .001) among all patients and 9.1 vs 13.6 months (HR = 1.48, P < .001) in those with centrally confirmed HER2-positive tumors.
Median overall survival was not reached in either group. More deaths were observed in the lapatinib group overall (102 vs82; HR = 1.28, P = .11) and among patients with centrally confirmed HER2-positive tumors (84 vs56, HR = 1.47, P = .03).
Toxicity
During combination therapy, the lapatinib group had a higher frequency of grade 3 or 4 diarrhea (19% vs 1%) and rash (8% vs 0%; both P < .001). Prior to the institution of granulocyte colony-stimulating factor treatment, febrile neutropenia occurred in 17.3% of patients receiving lapatinib/docetaxel vs 2.0% of those receiving trastuzumab/docetaxel.
The investigators concluded: “As first-line therapy for HER2-positive metastatic [breast cancer], lapatinib combined with taxane was associated with shorter [progression-free survival] and more toxicity compared with trastuzumab combined with taxane.”
Karen A. Gelmon, MD, FRCPC, of the British Columbia Cancer Agency-Vancouver Centre, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by grants from the Canadian Cancer Society Research Institute and 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®.
