Small Molecules in Oncology

Minna Voigtlaender, Tanja Schneider-Merck, Martin Trepel, Voigtlaender, Minna, Schneider-Merck, Tanja, Trepel, Martin

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinases plays an important role in the biology of many cancers. In breast and gastrointestinal cancer, and at lower rates also in additional tumor types, HER2 and its homo- or heterodimerization with HER1 or HER3 are essential for cancer cell growth and survival. Breast cancer patients overexpressing HER2 have a more aggressive course of their disease. The poor prognosis associated with HER2 overexpression can be substantially improved by adding HER2-targeted therapy to standard of care using the monoclonal antibody trastuzumab. Lapatinib, an oral dual tyrosine kinase inhibitor, blocks HER1 and HER2 tyrosine kinase activity by binding to the ATP-binding site of the receptor's intracellular domain, resulting in inhibition of tumor cell growth. Lapatinib is generally well tolerated with diarrhea being the most common adverse effect. However, although being mainly of mild to moderate severity, interruption or discontinuation of treatment has been reported in a substantial proportion of patients in clinical trials. In 2007, lapatinib has been approved in combination with capecitabine in patients with advanced HER2-positive breast cancer upon progressive disease following standard therapy with anthracyclines, taxanes, and trastuzumab. In 2013, the approval was extended to a chemotherapy-free combination with trastuzumab for patients with metastatic HER2-positive, hormone receptor-negative breast cancer progressing on prior trastuzumab and chemotherapy. Since 2010, lapatinib is approved in combination with letrozole in the treatment of postmenopausal women with advanced HER2- and hormone receptor-positive breast cancer. In contrast, in first-line cytotoxic-based therapy of both early and advanced HER2-positive breast cancer, data from clinical trials did not provide evidence of additional benefit of lapatinib compared to trastuzumab. Moreover, over the past few years, novel HER2-targeted drugs, either alone or as a combined anti-HER2 approach, have been extensively evaluated, demonstrating a more favorable outcome. Also, neither in first- nor second-line treatment of advanced gastric cancer, lapatinib has been proven to be superior compared to trastuzumab as hitherto standard of care HER2 blockade. Therefore, lapatinib has become somewhat less important in patients with HER2-positive breast cancer during the past 10 years since its first introduction. Nevertheless, consideration of treatment with lapatinib appears to be reasonable in selected patients not only in the approved applications but also beyond, and further indications such as HER2-positive refractory metastatic colorectal cancer may arise in future. Also, lapatinib may have distinct advantages over antibodies in targeting truncated HER2 and crossing the blood-brain barrier. Finally, the favorable cardiac toxicity profile of lapatinib makes it an attractive alternative to trastuzumab-based regimens in patients at risk for cardiac events.