Preplanned first-step analysis of LET-LOB neoadjuvant study: A double-blind randomized phase IIb trial of letrozole (L) plus lapatinib (Lp) or placebo (P) in postmenopausal HER2-ve, HR+ve operable breast cancer.

Background: In HR+ve BC, the simultaneous blockade of ER and HER-related pathways could prevent the hormone-resistance due to activation of EGFR-family signalling, as shows the high activity of the combination of letrozole and lapatinib in HR+ve/HER2+ve advanced BC. The LET-LOB trial evaluates the clinical and biological effects of the combined inhibitory strategy with letrozole + lapatinib in untreated ER+ve/HER2-ve BC patients suitable for hormonal neoadjuvant therapy. Methods: Postmenopausal women with stage II-IIIa, HR+ve/HER2-ve BC are randomized to L (2.5 mg/d) + Lp (1500 mg/d) or L + P, given continuously for 24 weeks before surgery. Primary end point is the clinical RR (with ultrasonography, US); secondary endpoints are the pathological RR, the safety, and HR/EGFR-related biomarker evaluation. According to the "two step Simon's design" of the study, at least 20 cORs (8 in L+P and 12 in L+Lp) must be observed in the first 43 patients; then, additional 48 patients will be recruited to demonstrate a 40% increase in cOR with L+Lp, assuming a cOR of 50% with L+P. Results: Since April 2007, 39/55 randomized patients completed the preoperative treatment. Median age was 68 yrs. At diagnosis, mean US tumor size was 3 cm. All patients were HER2-ve, and either ER+ve or PR+ve (both +ve: 76%). After 3 and 6 months of therapy, a 29% and 41% reduction from baseline mean US longest tumor diameter was observed. No change in mean LVEF has been reported at the 3- and 6-month evaluations. 5 episodes of G3 toxicity have occured (skin rash, 1; liver function parameters, 4). So far 31 women underwent surgery (conservative in 65 %). The efficacy results according to the first step Simon's analysis will be performed by the IDMC on march 2009, and will be presented at the meeting along with updated clinical and safety data. Conclusions: Preliminary blinded results suggest that the combination of L+Lp in ER+ve/HER2-ve operable BC is feasible, without early cardiac events or other severe toxicities, and associated with clear tumor downstaging. Biological correlative studies will clarify the relationship between the double inhibition strategy and the clinical response. Supported by GlaxoSmithKline.