Efficacy and safety of lapatinib and trastuzumab for HER2-positive breast cancer: a systematic review and meta-analysis of randomised controlled trials

Abstract

ObjectivesThe anti-HER2 monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib have complementary mechanisms of action and synergistic antitumour actively in models of HER2-positive breast cancer. However, the efficacy of trastuzumab in combination with lapatinib remains controversial. Therefore, we conducted this meta-analysis to compare combination treatment with lapatinib and trastuzumab to trastuzumab or lapatinib alone in the treatment of HER2-positive breast cancer.MethodsRandomised controlled trials (RCTs), published in PubMed, Embase and Web of Science, were systematically reviewed to assess the survival benefits and toxicity profile of HER2-positive patients with breast cancer who were treated with lapatinib and trastuzumab. Outcomes included pathological complete response (pCR), event-free survival (EFS), overall survival (OS) and toxicities. Results were expressed as the risk ratio (RR) or HR with 95% CIs. Pooled estimates were calculated by using a fixed-effects model or a randomised-effects model.ResultsA total of 7 RCTs involving 2084 patients met the inclusion criteria and were included in this meta-analysis. The combination of lapatinib and trastuzumab significantly improved pCR (RR=1.43, 95% CI 1.23 to 1.67; p<0.001), EFS (HR=0.75, 95% CI 0.60 to 0.93; p=0.009) and OS (HR=0.72, 95% CI 0.56 to 0.93; p=0.011) in the treatment of HER2-positive breast cancer compared with trastuzumab or lapatinib alone. The combination treatment also increased the pCR irrespective of hormone receptor status and tumour size. More frequent grade 3 or 4 adverse events, including diarrhoea, rash or erythema, neutropenia and hepatic adverse events, were found in the combination group than in the trastuzumab or lapatinib group.ConclusionsOn the basis of the current evidence, our results reveal that the addition of lapatinib to trastuzumab can significantly improve pCR, EFS and OS with a tolerated toxicity in patients with HER2-positive breast cancer. Further well-conducted, large-scale trials are needed to validate these findings.

Identification of potentially druggable molecular alterations in skin adnexal malignancies

“…Given this background, the activity of small molecules tyrosine kinase inhibitor, lapatinib, could be also studied in this molecularly selected group of diseases. 26 Targeted next-generation sequencing confirmed mutations in TP53, PIK3CA, CDKN2A, RB, ATM, HRAS and HER2 genes, previously described in two smaller series of SAC. 25,27,28 In addition, the use of a more extensive NGS panel, targeting 50 cancer-related genes, allowed us to reveal mutations in further genes such as NRAS, KRAS, MET, FBXW7 and FGFR3 in porocarcinoma, AKT1 in hidradenocarcinoma and APC or FLT3 in PDSAC.…”

“…Unfortunately, in our series we could not verify if in the HER2‐positive cases the score 2+ was sustained by gene amplification, which is mandatory for eligibility to anti‐HER2 monoclonal antibody. Given this background, the activity of small molecules tyrosine kinase inhibitor, lapatinib, could be also studied in this molecularly selected group of diseases …”

Preclinical Activity of HER2-Selective Tyrosine Kinase Inhibitor Tucatinib as a Single Agent or in Combination with Trastuzumab or Docetaxel in Solid Tumor Models

“…The increased activity of dual targeting of HER2, either through combinations of two different HER2-targeted antibodies or by use of a HER2-targeted antibody and TKI, has been shown to improve outcomes in preclinical studies and in patients with HER2 þ cancers (10,38). In this study, the combinatorial activity of tucatinib þ trastuzumab also produced improved antitumor activity in vivo in HER2 þ CDX and PDX xenograft models of breast, gastric, colorectal, and esophageal cancers.…”

Trastuzumab Resistance: What Are We Offering to Breast Cancer Patients?

“…A recent meta-analysis which included seven clinical trials concluded that the combination of trastuzumab and lapatinib can improve pCR, PFS and OS without added toxicity in patients with HER2-positive BC. This might indicate that large-scale trials and statistical power are needed to fully evaluate the efficacy of dual blockade regimens [24].…”