BACKGROUND : We investigated whether the increase in pathological complete
response (pCR) rates with neoadjuvant combination of lapatinib and
trastuzumab in addition to weekly paclitaxel would translate into improved
survival outcomes in HER2-positive early breast cancer (EBC) patients.
METHODS : This multicentre, randomised, open-label, phase III trial enrolled 455
women with HER2-positive EBC. Given treatments were: oral lapatinib,
intravenous trastuzumab, or their combination for 6 weeks (biological window),
followed by an additional 12 weeks of the assigned anti-HER2 therapy in
combination with weekly paclitaxel (80 mg/m²). Definitive surgery was performed
4 weeks after the last dose of paclitaxel. After surgery, women received 3 cycles
of intravenous 5-fluorouracil, epirubicin and cyclophosphamide (FEC) followed
by 34 weeks of the same assigned neoadjuvant anti-HER2 therapy. The primary
endpoint was pCR which was reported by Baselga et al (Lancet 2012).
Secondary endpoints included event-free (EFS) and overall survival (OS). EFS
and OS were reported in the intention-to-treat population. Associations between
pCR and EFS or OS were reported using landmark analysis. This trial is
registered with ClinicalTrials.gov, NCT00553358 and it is in follow-up phase. FINDINGS : 154 women received lapatinib, 149 trastuzumab and 152 the
combination of lapatinib and trastuzumab. At a median clinical follow-up of 3·77
years (95% CI 3·72-3·98), the3-year EFS was numerically higher for women
treated with lapatinib and trastuzumab compared with trastuzumab [84% (95%
CI 77%-89%) vs. 76% (95% CI 68%-82%); HR 0·78; 95% CI 0·47-1·28; p=0·33]
in the whole population. In the landmark analysis, we observed better EFS [HR 0·38; 95% CI 0·22-0·63; p=0·0003] and OS [HR 0·35; 95% CI 0·15-0·70;
p=0·005] for women with pCR compared to those without pCR. Women treated
with the combination of lapatinib plus trastuzumab had better EFS with pCR
than without pCR [HR 0·32; 95% CI 0·12-0·74; p=0·012]. Adverse events were
consistent with known safety profile of lapatinib and/or trastuzumab.
INTERPRETATION : The observed correlation between pCR and improved EFS with
dual HER2 blockade has implications for clinical care and reinforces the validity
of neoadjuvant HER2 therapies while setting the stage for studies aimed at
improving the outcome for patients that do not achieve a pCR.