Lapatinib combined with letrozole vs. letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): first results from the EGF30008 Trial.
Authors: S Johnston, M Pegram, M Press, J Pippen, X Pivot, H Gomez, A Florance, L O'Rourke, J Maltzman
Journal: Cancer Research (2009)

Abstract Abstract #46 Background: Cross-talk between growth factor and steroid receptor pathways has been implicated in endocrine resistance in breast cancer. Combining EGFR/HER2-targeted therapy with aromatase inhibitors for HR+ postmenopausal breast cancer may enhance endocrine responsiveness and delay the onset of resistance. EGF30008 is a double-blind, placebo-controlled, first-line phase III trial to explore the benefit of letrozole with/without lapatinib, an oral dual tyrosine-kinase inhibitor of HER2 and EGFR, in patients (pts) with HR+ postmenopausal MBC.&amp;#x2028; Methods: 1286 postmenopausal women with HR+ untreated MBC from 212 international centers were randomized to once daily treatment with letrozole 2.5 mg and lapatinib 1500 mg or letrozole and placebo. Pts were stratified according to presence of visceral vs bone only disease and time since completion of prior adjuvant endocrine tamoxifen therapy (&amp;lt;6 mo or ≥6 mo/never received). 219 pts were HER2+ (IHC 3+ and/or FISH amplified). The primary endpoint of the study was investigator assessed progression free survival (PFS) in the HR+ HER2+ population, and secondarily in the overall ITT population in closed hierarchical testing procedure. Additional secondary endpoints included overall survival, overall response rate, clinical benefit rate, time to and duration of response, and safety of letrozole with/without lapatinib.&amp;#x2028; Results: Median PFS in the HER2+ population was significantly increased from 3.0 months (mos) in the letrozole group to 8.2 mos in the lapatinib\letrozole group [Hazard Ratio (95% CI)=0.71(0.53,0.96), stratified log rank p=0.019]. Median PFS in the ITT population increased from 10.9 mos to 11.9 mos, respectively [Hazard Ratio (95% CI)=0.86 (0.76,0.98), stratified log rank p=0.026]. In a pre-planned Cox regression analysis exploring stratification and well known baseline prognostic factors in the HER2+ population, a significant benefit was confirmed [Hazard Ratio (95% CI)=0.65 (0.47-0.89), p=0.008]. In the ITT population, 952 tumor samples were centrally confirmed as HER2 negative. In this group, the Cox regression model after retaining treatment group identified ECOG status, prior adjuvant tamoxifen therapy stratification, number of metastatic sites, and baseline serum HER2 ECD as having a significant impact on PFS [Hazard Ratio (95% CI)=0.77(0.64,0.94), p=0.010].&amp;#x2028; Overall response rate (ORR) in the HER2+ population was significantly increased from 14.8% to 37.9% in the combination group [Odds Ratio = 0.4 (0.2, 0.9), p=0.021], with a clinical benefit rate (CBR) improvement from 28.7% to 48.7% [Odds Ratio = 0.4 (0.2,0.8), p=0.003]. There was no difference in ORR or CBR in the HER2 negative population. With 41% of pts still being followed, an overall survival trend was noted in the HER2+ group [Hazard ratio (95% CI) = 0.77 (0.52, 1.14), p=0.185]. The combination of letrozole and lapatinib was well tolerated and no new safety issues were identified.&amp;#x2028; Conclusion: This is the largest clinical trial to test whether combined endocrine and targeted EGFR/HER2 inhibition enhances endocrine responsiveness in HR+ MBC. Lapatinib significantly improved the clinical efficacy of an aromatase inhibitor in pts with known HR+ HER2+ MBC, and identified a subset of HR+ HER2-negative that may also benefit. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 46.