Authors: Agampodi Danushi M Gunasekara 1,2 , Thunyarat Anothaisintawee1,3,4, Sitaporn Youngkong1,5, Nguyen T Ha1,6, Gareth J McKay7, John Attia8, Ammarin Thakkinstian1,4
1Mahidol University Health Technology Assessment Graduate Program (MUHTA), Mahidol University, Bangkok 10400, Thailand.
2Department of Paraclinical Sciences, Faculty of Medicine, General Sir John Kotelawala Defence University, Ratmalana, Colombo 10390, Sri Lanka.
3Department of Family Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
4Department of Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
5Social and Administrative Pharmacy Division, Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand.
6School of Medicine, Vietnam National University, Ho Chi Minh City 700000, Vietnam.
7Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University, Belfast BT12 6BA, UK.
8School of Medicine and Public Health, College of Health and Wellbeing, University of Newcastle, Newcastle, NSW 2308, Australia.
Objective: This systematic review aimed to identify neoadjuvant anti-human epidermal growth factor receptor 2 (HER2) therapies with the best balance between efficacy and safety.
Methods: A network meta-analysis was applied to estimate the risk ratios along with 95% confidence intervals (CIs) for pathological complete response (pCR) and serious adverse events (SAE). A mixed-effect parametric survival analysis was conducted to assess the disease-free survival (DFS) between treatments.
Results: Twenty-one RCTs with eleven regimens of neoadjuvant anti-HER2 therapy (i.e., trastuzumab + chemotherapy (TC), lapatinib + chemotherapy (LC), pertuzumab + chemotherapy (PC), pertuzumab + trastuzumab (PT), trastuzumab emtansine + pertuzumab (T-DM1P), pertuzumab + trastuzumab + chemotherapy (PTC), lapatinib + trastuzumab + chemotherapy (LTC), trastuzumab emtansine + lapatinib + chemotherapy (T-DM1LC), trastuzumab emtansine + pertuzumab + chemotherapy(T-DM1PC), PTC followed by T-DM1P (PTC_T-DM1P), and trastuzumab emtansine (T-DM1)) and chemotherapy alone were included. When compared to TC, only PTC had a significantly higher DFS with a hazard ratio (95% CI) of 0.54 (0.32-0.91). The surface under the cumulative ranking curve (SUCRA) suggested that T-DM1LC (91.9%) was ranked first in achieving pCR, followed by the PTC_T-DM1P (90.5%), PTC (74.8%), and T-DM1PC (73.5%) regimens. For SAEs, LTC, LC, and T-DM1LC presented with the highest risks (SUCRA = 10.7%, 16.8%, and 20.8%), while PT (99.2%), T-DM1P (88%), and T-DM1 (83.9%) were the safest regimens. The T-DM1PC (73.5% vs. 71.6%), T-DM1 (70.5% vs. 83.9%), and PTC_T-DM1P (90.5% vs. 47.3%) regimens offered the optimal balance between pCR and SAE.
Conclusions: The T-DM1PC, T-DM1, and PTC_T-DM1P regimens had the optimal balance between efficacy and safety, while DFS was highest for the PTC regimen. However, these results were based on a small number of studies, and additional RCTs assessing the efficacy of regimens with T-DM1 are still needed to confirm these findings.