Abstract PD05-01: CALGB 40302: Fulvestrant with or without Lapatinib as Therapy for Hormone Receptor Positive Advanced Breast Cancer: A Double-Blinded, Placebo-Controlled, Randomized Phase III Study
Authors: Burstein HJ , Barry WT , Cirrincione C , Chew HK , Tolaney S , Lake D , Pluard T , Blackwell K , Winer EP , Hudis CA. 
Published: April 2011

Abstract
Background: Preclinical data suggest that inhibition of the EGFR and HER2 growth factor signaling pathways might potentiate the efficacy of endocrine treatment for ER positive breast cancer. CALGB 40302 was designed to determine whether the addition of the dual-kinase inhibitor, lapatinib, would improve progression-free survival (PFS) among women with hormone receptor positive metastatic breast cancer treated with the anti-estrogen, fulvestrant.
Patients and Methods: This study was activated on 9/15/2006 for women with advanced (stage IV or stage III, not curable) breast cancer with measurable or evaluable (bone-only) disease, ECOG PS 0-2, adequate end-organ function, ER and/or PR positive tumors, and prior therapy with an aromatase inhibitor. Prior tamoxifen and up to 1 line of prior chemotherapy for advanced breast cancer were permitted. Patients were eligible regardless of HER2 status. All patients received fulvestrant 500 mg IM day 1, followed by 250 mg day 15 and day 28, and every 4 weeks thereafter. Patients were randomized 1:1 to lapatinib 1500 mg daily or placebo. Patients were restaged every 2 months, and continued on treatment until disease progression or prohibitive toxicity. The study was designed to accrue 324 patients and powered to show a 50% improvement in PFS with addition of lapatinib from 5 to 7.5 months. Results: At the 3rd planned interim analysis, 173 events were observed and the futility boundary was crossed, such that the predictive probability of concluding superiority of lapatinib over placebo if the study went to completion was 0.5%. At the recommendation of the Data Safety and Monitoring Board, the study was closed and treatment unblinded on 7/14/2010, having accrued 267 patients. The log-rank test showed no difference in PFS (hazard ratio [HR] = 0.982, 95% CI: 0.73 to 1.33; p = 0.94); median PFS was 5.2 months for fulvestrant + lapatininb vs 4.0 months for fulvestrant + placebo. There was no difference in median overall survival (22.3 vs 21.9 months for fulvestrant ± lapatinib; p= 0.64). Outcomes among HER2 normal (78%) and HER2 positive (22%) cohorts were not significantly different under an interaction model (p = 0.23). No differences in median PFS were seen in patients with HER2 normal tumors (4.1 vs 4.0 months for fulvestrant ± lapatinib, p=0.53). In patients with HER2+ tumors, a trend favored improved median PFS with addition of lapatinib (5.9 vs 2.8 months for fulvestrant ± lapatinib, p = 0.29). Treatment was generally well tolerated. The most frequent toxicities were grade 3 diarrhea (9%), fatigue (4%), and rash (4%) associated with lapatinib therapy.
Conclusions: Among women with hormone receptor positive breast cancer previously treated with an AI, adding lapatinib to fulvestrant does not improve PFS or OS. Updated efficacy, response, and toxicity data will additionally be presented.
Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD05-01.