Lapatinib

Lapatinib (Tykerb) TKI EGFR, ErbB2/Her-2, ErbB4 Inhibition of kinase activity - ATP-competitive Breast cancer... 

Note that application in the particular indications is usually restricted either to patients expressing the target (e.g. trastuzumab, cetuximab, lapatinib, imatinib) and/or after failure of prior therapies (e.g. cetuximab, erlotinib, lapatinib, sutinib, dasatinib). Furthermore, for cancer treatment most tyrosine kinase inhibitors are applied in combination with conventional chemotherapeutic drugs, such as fluorouracil, taxanes, platin-based regimens, anthracylines and irinotecan or radiotherapy. 

Lapatinib, a tyrosine kinase inhibitor that targets both HER2 and the epidermal growth factor receptor, improved response rates and time to progression in combination with capecitabine, as compared to capecitabine alone, in patients previously treated with an anthracycline, taxane, and trastuzumab. The most common adverse events were rash and diarrhea. 

Sources (1) Jarvis LM. Battling breast cancer, Chemical Engineering News 84 21-27 (2007). (2) FDA News, March 2007. http //www.fda.gov/bbs/topics/NEWS/2007/NEW01586.html, http //www.fda.gOv/cder/foi/label/2007/0220591bl.pdf [accessed September 20, 2007]. (3) Moy B, et al. Lapatinib, Nature Reviews Drug Discovery 6 431-432 (2007). 

Lapatinib Breast EGFR/erbB2 kinase inhibitor 2... 

Fig. 3 Comparison of erlotinib (thin lines) with lapatinib (thick lines). Tbe C-helix is portrayed as a backbone ribbon, and tbe side chain of Met742 is explicitly shown...

Table 1 Cell growth inhibition by lapatinib, gefitinib, and erlotinib [69] ...

Cell line EGFR ErbB2 Lapatinib ICso ( xM) Gefitinib ICso (irM) Erlotinib ICso (flM)... 

Lapatinib is currently undergoing clinical evaluation for several cancer indications. In a phase II study, doses of lapatinib escalating from 1250 to 1500mg/day resulted in ca. 10% objective response in trastuzumab-refractory metastatic breast cancers [71]. More recently, approximately 30% objective response was observed when lapatinib was administered at 1500 mg/qd or 500 mg/bid in first-line ErbB2-positive (as determined by the FISH technique) breast cancer [72]. 

ErbB inhibitors in development differ in several aspects, including potency, selectivity, and mechanism of inhibition. Fortunately, there are data that compare erlotinib, gefitinib, lapatinib, canertinib, HKI-272, and BIBW 2992 directly in enzymatic and cellular studies, as shown in Tables 2 and 3 [89,95]. 

Imatinib (Gleevec) Irinotecan (Camptosar) Lapatinib (Tykerb) Letrozole (Femara) Leucovorin (Wellcovorin) Mitoxantrone (Novantrone) Paclitaxel (Taxol, Abraxane)... 

Lapatinib, another 4-aminoquinazoline, is a dual ebB l/erbB2 kinase inhibitor. It is currently undergoing Phase III clinical trials for several cancers. 

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