How dacomitinib works
Dacomitinib is part of a class of drugs called tyrosine-kinase inhibitors (TKIs). Tyrosine kinases are proteins involved in sending signals that controlling certain biological processes, such as triggering a cell to divide. Cancer cells often have abnormal activity in these pathways, resulting in increased cell growth and proliferation.
Dacomitinib irreversibly blocks the HER-1 (or EGFR), HER-2, and HER-4 tyrosine kinases that are frequently over-activated in tumor cells. Many NSCLC tumors have a mutation in HER-1 that result in increased activity (EGFR-positive tumors). Other TKIs currently approved to treat NSCLC, Tarceva (erlotinib) and Iressa (geftinib), only target and inhibit HER-1. However, it is possible for the other tyrosine kinases (HER-2 and HER-4) to take on the role of HER-1, leading to a resistance to these drugs. As dacomitinib is a TKI that blocks all HERs, it could be used when other treatments fail.
Dacomitinib in clinical trials
Dacomitinib is currently under clinical study to assess if the treatment has any benefit over similar, currently marketed treatments for NSCLC, with mixed results.
Clinical trials comparing dacomitinib to Tarceva are completed, and the results have been published in the scientific journal Annals of Oncology. The article was based on a Phase 2 (NCT00769067) and a Phase 3 study (ARCHER 1009, NCT01360554), and concluded that there was no significant difference in the efficacy of dacomitinib compared to Tarceva in EGFR-positive NSCLC patients, finding the two treatments comparable in their effectiveness.
Pfizer recently announced positive results from an ongoing Phase 3 open-label study, ARCHER-1050 (NCT01774721), where a total of 452 newly diagnosed EGFR-positive, advanced NSCLC patients across Asia and Europe are randomly assigned to either dacomitinib or Iressa as a first-line treatment. The study’s primary aim is to assess if a significant difference in progression-free survival is seen in these two treated groups of patients. The current results were presented at the 2017 American Society of Clinical Oncology (ASCO) annual meeting and suggest that dacomitinib could be a more effective first-line treatment compared to Iressa. Progression-free survival was 14.7 months in dacomitinib-treated patients compared to 9.2 months in those given Iressa. Dacomitinib also reduced the risk of cancer progression or death by 41 percent compared to Iressa. The trial is still ongoing, so further results (including overall survival after 30 months) are yet to be released.
Dacomitinib is an orally administered tablet that is taken daily. The most common side effects of dacomitinib seen in clinical trials are acne, diarrhea, and mucositis, a painful inflammation of the mucous membranes lining the digestive tract.
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