Lapatinib With Trastuzumab For Her2-Positive Early Breast Cancer (Neoaltto) : Survival Outcomes Of A Randomised, Open-Label, Multicentre, Phase 3 Trial And Their Association With Pathological Complete Response
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.