Efficacy And Safety Of Dual HER2 Blockade Versus A Single-Agent In Trastuzumab-Containing Regimens For HER2-Positive Early Breast Cancer:A Meta-analysis

ObjectiveAlthough trastuzumab has undergone extensive advances and become the standard of care for patients with HER2-positive early breast cancer,incidents of drug resistance remain.Studies have indicated that a dual HER2 blockade might overcome trastuzumab resistance and be more effective than single-agent targeting.Therefore,we performed a meta-analysis to evaluate the efficacy and safety of trastuzumab-containing dual anti-HER2 therapy compared to trastuzumab alone therapy in patients with HER2-positive early breast cancer,aiming to determine the potential benefit of a dual HER2 blockade.MethodsWe searched Pubmed(MEDLINE),Cochrane,EMBASE,and Clinical Trials.gov,as well as other sources for eligible RCTs up to December 2018.Outcomes including event-free survival/invasive disease-free survival(EFS/iDFS),overall survival(OS),overall response rate(ORR),pathological complete response(pCR)and safety were considered.The the risk of bias tool of The Cochrane Collaboration was applied to assess the quality of each trial.The RevMan software was used for pool analysis.The reporting bias was assessed using funnel plots and Begg’s test.ResultsTen RCTs were included(15,284 patients).Significant improvements were observed in both EFS/iDFS(HR 0.86,p=0.0003)and OS(HR 0.86,p=0.02)with trastuzumab-based dual anti-HER2 therapy,especially in adjuvant treatment.While in the neoadjuvant setting,dual-targeted therapy also achieved a substantial pathological complete response(pCR)benefit(HR 1.34,p=0.0002),and it was higher in hormone receptor-negative patients.Subgroup analysis revealed the EFS/iDFS benefit was slightly higher with trastuzumab plus pertuzumab or plus neratinib than trastuzumab plus lapatinib,while OS benefit was significant with trastuzumab plus lapatinib,but there were no subgroup differences(interaction test,p=0.80 and 0.24,respectively).In addition,EFS/iDFS benefit was unrelated to hormone receptor status but pronounced in the lymph node-positive(LN+)subgroup,which should be interpreted cautiously for lacking interaction(p=0.18).As for safety,patients receiving a dual block,especially with the lapatinib-containing regimen,had a significantly higher risk of grade 3/4diarrhea,hepatic toxicity,skin disorder,nausea and vomiting,but no increase in cardiotoxicity.ConclusionsAlthough associated with more toxicity,trastuzumab-containing dual anti-HER2 therapy is superior to trastuzumab single-agent for HER2-positive EBC independent of hormone receptor status.The correlation between survival and LN status needs further verification for lacking interaction.Trastuzumab plus pertuzumab or plus neratinib is the preferred regimen with substantial efficacy and lower toxicity when compared to trastuzumab plus lapatinib.