Authors: Sunil Verma Date posted: December 22, 2008 First line Therapy with Lapatinib combined with Letrozole vs Letrozole alone in MBC EGF30008 Trial Presented by Dr. S. Johnston Authors: Sunil Verma Date posted: December 22, 2008

Background There is significant cross talk between the ER receptor and the EGFR family It is felt that targeting the two receptors may help overcome endocrine resistance Previous results from the TAnDEM trial (Anastrozole(A) alone vs. A + Trastuzumab) have shown a significant improvement in PFS

R ER+ and/or PR+ Postmenopausal Her 2 +/-/unknown Stage IIIb/IIIc/IV Letrozole 2.5 mg po daily + Placebo R Letrozole 2.5 mg daily + Lapatinib 1500 mg daily ER+ and/or PR+ Postmenopausal Her 2 +/-/unknown Stage IIIb/IIIc/IV No prior treatment of MBC

RESULTS Her 2 positive ( n=218) Treatment A B p-value Response Rate (%) Clinical Benefit Rate 15 % 29% 28% 48% p=0.021 p=0.003 PFS/TTP (median, mos) 3.0 m 8.2 m HR=0.71 p=0.019 OS (median, mos) 32.3 33.3 HR = 0.74 p=0.113

STUDY COMMENTARY The primary endpoint of the trial was to demonstrate an improvement in PFS for patients with HR+,HER2+ MBC the secondary endpoint was to show an improvement in PFS in the HR+ ITT population (which includes Her 2+, Her 2 –ve/Unknown) There was no significant improvement in PFS in the ITT population there was a suggested benefit in patients who were <6months since d/c of tamoxifen Median tam duration was 2.8 years with a median time since d/c 1 months PFS 3.1 m vs. 8.3 m HR0.78 p=0.117 CBR – 32% vs. 44% Overall the combination was well tolerated

BOTTOM LINE FOR CANADIAN MEDICAL ONCOLOGISTS There is the second key trial showing that the addition of an anti-Her 2 agent in combination with an Aromatase inhibitor improves PFS in HR+ve Her2 +ve MBC There is only a small proportion of patients who have ER+ve/Her2 +ve MBC where one would consider using endocrine therapy as the first line of treatment In such patients there is now evidence that if we do decide to use endocrine therapy then one can also use an anti-Her 2 therapy in combination While there is a suggestion that the addition of Lapatinib to Letrozole may have an increased efficacy in those patients who have ER+ve, Her 2 negative with recent (<6m) discontinuation of Tamoxifen, the results are too preliminary to have a clinical impact