Letrozole in Combination with Trastuzumab Is Superior to Letrozole Monotherapy as First Line Treatment in Patients with Hormone-Receptor-Positive, HER2- Positive Metastatic Breast Cancer (MBC) – Results of the eLEcTRA Trial.

Abstract

Background: Letrozole (LET) and trastuzumab (TRA) are established agents for the treatment of hormone-receptor (HR) positive metastatic breast cancer (MBC) patients and HER2 positive disease, respectively. The “eLEcTRA” trial was designed to compare the efficacy and safety of LET combined with TRA to LET alone in patients that are both HER2 and HR positive. Furthermore, LET alone was compared in patients with HER2 and HR positive disease vs. those with HER2 negative, HR positive tumors.Methods: In this multicenter trial, 92 pts from 32 sites in 7 countries were enrolled from 2003 to 2007. Initially, enrollment of 370 pts was planned, however, due to slow recruitment the trial was prematurely closed in 2007. Patients with HER2 and HR positive MBC were randomized to either LET alone (Arm A, n=31) or LET + TRA (Arm B, n=26) as first-line treatment. In addition, 35 patients with HER2 negative and HR positive tumors were assigned to receive LET alone as first-line treatment (Arm C). Tumor response assessments were based on RECIST. Primary endpoint was time to progression (TTP), secondary endpoints were overall response rate (ORR) and clinical benefit rate (CBR).Results: Median age in the three arms was 61 (arm A), 61,5 (arm B), and 70 years (arm C), respectively. Median TTP in the LET alone arm (A) was 3.3 months compared to 14.1 months in the LET + TRA combination arm (B) (hazard ratio=0.67; p=0.23) and 15.2 months in arm C (hazard ratio=0.71; p=0.03). CBR was 39% for arm A compared to 65% in arm B (odds ratio 3.15, CI 1.07-9.26) and 77% in arm C (odds ratio 5.34, CI 1.83-15.58), respectively. ORRs were 13% for arm A, 27% for arm B, and 11% for arm C.LVEF as cardiac safety parameter showed no change from baseline to the minimum value during the treatment for arms A and C and a slight decrease by 5% for arm B.The incidence of other cardiac adverse events was comparable in all arms (10%, 8%, and 9%). Gastrointestinal disorders or musculoskeletal and connective tissue disorders were slightly more frequent for patients receiving LET and TRA (arm B).Conclusion: The results of the eLEcTRA trial show that the combination of letrozole and trastuzumab can be safely administered and is superior to letrozole alone as first-line therapy in patients with HER2 and HR positive MBC. Our results also confirm earlier evidence that aromatase-inhibitor therapy alone is only associated with a rather short TTP in HER2 and HR positive MBC. In contrast, outcome in letrozole-treated patients with HER2 negative HR positive tumors is significantly better compared to that associated with tumors with both HR and HER2 expression.(Trial was sponsored by Novartis Pharmaceuticals) Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4094.

Combination of trastuzumab and letrozole after resistance to sequential trastuzumab and aromatase inhibitor monotherapies in patients with estrogen receptor-positive, HER-2-positive advanced breast cancer: a proof-of-concept trial (SAKK 23/03)

“…However, the goal of the trial -proof-of-concept for clinical relevant activity of combination AI plus trastuzumab in patients with resistant disease to single-agent exposure -was achieved with less patients accrued than initially planned due to the surprisingly high CBR in the first 11 patients included. This observation is in concordance with the CBR of 65%, observed in 26 patients with ERC/HERC breast cancers receiving first-line treatment with letrozole and trastuzumab within a randomized trial (Huober et al 2009). Furthermore, this finding is in line with results of the anastrozole plus trastuzumab arm (CBR 43%) of the randomized TAnDEM trial (Kaufman et al 2009) and of another phase II trial using letrozole and trastuzumab (CBR 52%) as first-or second-line therapy (Marcom et al 2007).…”

“…These trials when interpreted together suggest that single-agent endocrine therapy in HER-2C disease has low efficacy and is clearly inferior to combination therapy (Huober et al 2009, Johnston et al 2009, Kaufman et al 2009). Upfront combination on targeted therapy, especially in elderly patients, patients declining chemotherapy, or without extensive, life-threatening visceral involvement, might become a reasonable treatment option in the near future in light of these trials.…”

“…The primary goal to improve disease control over a prolonged time and delay endocrine resistance was achieved in most of these trials with combined treatment, compared with single-agent endocrine treatment (Johnston et al 2009, Kaufman et al 2009, Normanno et al 2009, Huober et al 2009.…”

Lapatinib and trastuzumab in combination with an aromatase inhibitor for the first-line treatment of metastatic hormone receptor-positive breast cancer which over-expresses human epidermal growth factor 2 (HER2): a systematic review and economic analysis

“…[41][42][43][44][45][46][47][48][49][50][51] Four of these citations 48-51 reporting on two trials [the efficacy and safety of lapatinib combined with letrozole (EGF30008) 49 trial and the efficacy and safety of trastuzumab combined with anastrozole (TAnDEM) 50 trial] met the inclusion criteria and a further trial [efficacy and safety of letrozole combined with trastuzumab (eLEcTRA) 52 trial], reported only as a conference abstract, was also suitable for inclusion following information passed on to the AG by Roche at the NICE consultation meeting in February 2010. Thus, three trials were included in the systematic review.…”

“…All three trials (the EGF30008, 49 the TAnDEM 50 and the eLEcTRA 52 ) were multicentre and multinational trials (between 7 and 29 countries) enrolling post-menopausal patients receiving first-line treatment for mBC; all three trials included patients who had HR+/HER2+ mBC, although the EGF30008 49 and the eLEcTRA 52 also included patients who were HR+/ human epidermal growth factor receptor 2 negative (HER2-). The trials were designed to evaluate the efficacy and safety of the addition of LAP + LET to LET (EGF30008 49 ), TRA + ANA to ANA (TAnDEM 50 ) and TRA + LET to LET (eLeCTRA 52 ).…”