Safety of First-Line Letrozole Compared with Lapatinib Plus Letrozole in Patients with Postmenopausal Hormone Receptor Positive Metastatic Breast Cancer: EGF30008 Study.

Abstract

Background: EGF30008 was a double-blind, placebo-controlled phase III study which evaluated the benefit of adding lapatinib (L) to letrozole (Let) alone in patient (pts) with hormone receptor positive (HR+), metastatic breast cancer. Median progression-free survival (PFS) in pts with HER2+ tumors was significantly increased from 3 to 8.2 mos with dual therapy (HR [95% CI] =0.71 [0.53, 0.96], P=.019). Safety data presented at the 2008 San Antonio Breast Cancer Symposium demonstrated that the combination of L+Let was manageable and predictable, with no unexpected toxicity.Methods: 1286 pts were randomized 1:1 to treatment with Let versus L+Let. Safety data were collected from start of study drug until 30 days after discontinuation. The safety population was based on the actual treatment received (Let n=623; L+Let n=655). Updated adverse events (AEs) associated with L were evaluated at both pt and event level as a function of time on study. AEs were categorized into 4 groups: diarrhea, rash, cardiac, and hepatobiliary events. Multiple AE terms were classified within these groups.Results: Safety data through 03Feb09 are reported (additional 8 mos data beyond trial reporting). Let group: median exposure of Let=37.57 weeks (range 0.9-251.1). L+Let group: median exposure of Let= 40.43 (range 0.1-248.6) and median exposure of L=40.14 weeks (range 0.3-248.6). Overall, there were 537 AE events (86%) in the Let alone group, and 629 (96%) in the L+Let group. Incidence, counts, and time to first occurrence of AEs associated with HER1 and HER2 inhibition are summarized below. Let (n=623)L+Let (n=655)Rash Pts with AE, n95 (15%)328 (50%)- Max Grade 30.012 (4%)- Max Grade 40.00.0AEs (n events)123638- Leading to study withdrawal1 (<1%)11 (2%)Median time to 1st onset, days7720Diarrhea Pts with AE, n127 (20%)419 (64%)- Max Grade 36 (5%)59 (14%)- Max Grade 40.02 (<1%)AEs (n events)1721026- Leading to study withdrawal2 (1%)22 (2%)Median time to 1st onset, days6114Hepatobiliary Pts with AE, n50 (8%)102 (16%)- Max Grade 39 (18%)33 (32%)- Max Grade 43 (6%)4 (4%)AEs (n events)103405- Leading to study drug withdrawal3 (3%)13 (3%)Median time to 1st onset12463LVEF decreases Pts with AE, n18 (3%)34 (5%)- Grade 32 (11%)8 (18%)- Grade 40.01 (3%)AEs (n events)1941- Leading to study drug withdrawal4 (21%)8 (20%)Median time to 1st onset, days323165 Graphs of AEs as a function of time as well as details on pts with multiple events will also be provided.Conclusion: Relatively few AEs were grade 3/4 or led to study drug discontinuation. Incidence, severity, and recovery of each toxicity as a function of time will be presented. The safety profile of L+Let remains consistent with the 8 additional months of data since initial reporting of study results. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5094.

Systemic treatment of HER2‐positive metastatic breast cancer: A systematic review

“…These studies established trastuzumab as the first‐line treatment for HER2‐positive metastatic breast cancer. Similarly, for hormone receptor positive, HER2‐positive metastatic breast cancer, trastuzumab and an aromatase inhibitor are superior to an aromatase inhibitor alone, both in the first‐line and second‐line settings. Only one small study of an aromatase inhibitor with or without trastuzumab had confidence intervals that crossed unity (HR 0.67, CI 0.35–1.29) (Fig.…”

Clinical utility of the combination of lapatinib and letrozole in the management of hormone receptor-positive and HER2-positive advanced breast cancer

“…Serious adverse events related to the study drugs were reported in 8% of patients on combination therapy compared to 4% on letrozole/placebo, but of 16 fatalities reported as serious adverse events, only three -one patient on combination therapy and two patients on letrozole/placebo -were attributed to the study drugs. 35,36,41,42 Quality of life was assessed using the Functional Assessment of Cancer Therapy (FACT)-Breast and FACTGeneral survey tools. In the HER2+ subpopulation, quality of life scores were equivalent in the letrozole plus lapatinib and the letrozole plus placebo arms, demonstrating that improvement in PFS with combination therapy did not come at the expense of a significant decrement in quality …”