Dual HER2 Blockade versus a Single Agent in Trastuzumab-Containing Regimens for HER2-Positive Early Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Purpose. Although trastuzumab is the standard of care for patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), drug resistance and disease relapse occur. erefore, we performed a meta-analysis to assess the efficacy and safety of trastuzumab-containing dual anti-HER2 therapy compared to trastuzumab alone. Methods. A systematic search was performed to identify eligible randomized controlled trials (RCTs). Main outcomes including event-free survival/invasive disease-free survival (EFS/iDFS), overall survival (OS), and safety were considered. Results. Ten 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). Subgroup analysis revealed that 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, resp.). 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). Besides, patients receiving dual therapy, especially with the lapatinib-containing regimen, experienced more toxicity, but no increase in cardiotoxicity. Conclusions. Despite being 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. e correlation between survival and LN status needs further verification. Trastuzumab plus pertuzumab or plus neratinib is the preferred regimen with substantial efficacy and lower toxicity.

Efficacy and safety of neoadjuvant therapy for HER2-positive early breast cancer: a network meta-analysis

“…Similar to other studies, our study also demonstrated that dual-target therapy-based regimens are superior to single-target therapy-based regimens. 16 , 57 – 60 However, the question still remains that which is the best choice among all the dual-target therapies. According to our results, we suggest that the dual anti-HER2 blockade that combines trastuzumab and pertuzumab is better than the combination of trastuzumab and TKIs.…”

Signaling Pathways in Cancer: Therapeutic Targets, Combinatorial Treatments, and New Developments

“…However, due to the redundancy in signal transduction mediated by the many members of the HER family, incomplete inhibition of the signal can lead to resistance to targeted therapies. To overcome this, a combination of dual TKI lapatinib, or pan-TKI neratinib, plus mAbs has been shown to comprehensively block the known compensatory HER2 signaling network [ 69 , 70 ]. Recently, tucatinib, a highly selective HER2 TKI, has been shown to inhibit HER2/HER3-mediated MAPK and PI3K/AKT signaling [ 71 ].…”

A GLOBAL CONGRESS DIGEST ON SOLID TUMORS. Report from the ESMO Virtual Congress, 16th – 21st September 2021

“…Cetuximab is indicated for the first-line treatment of patients with EGFRexpressing, RAS wild-type (wt) mCRC in combination with FOLFOX; it is administered once a week with an initial dose of 400 mg/m 2 , followed by subsequent doses of 250 mg/m 2 [26]. Previous studies showed the noninferiority of the off-label schedule of cetuximab (500 mg/m 2 , Q2W) compared with the approved schedule [27][28][29].…”

“…Pucotenlimab (HX008) is a novel highly selective humanized anti-PD-1 antibody with a S228P hinge mutation and an engineered Fc domain. Pucotenlimab exhibits a decreased antibody-dependent cellular cytotoxicity (ADCC) and a complement-dependent cyto toxicity preventing depletion of PD-1-expressing lymphocytes, while retaining their antitumor activity [26,27].…”