In NEJM this week, two researchers from the Memorial Sloan-Kettering Cancer Center discuss the clinical relevance of a model that elucidates the reasons behind resistance to BRAF inhibition in melanoma. About half of all melanomas contain a mutation in the gene that encodes the RAF family member BRAF, the authors write, and the mutation — which usually substitutes glutamic acid for valine at position 600 of the protein — activates and deregulates the kinase activity of BRAF. Selective RAF inhibitors do a good job helping patients with the V600E mutation, but the response is "often profound but temporary," the researchers say. Two recent studies shed light on the reasons why and validate a clinical model of how these inhibitors work, showing that the inhibitors' strength is also a weakness as a new mutation often develops in response to the drug, making the patient resistant to it. The studies suggest new treatment strategies, the authors conclude, but more work is needed to determine the relative prevalence of each event that could lead to drug resistance.
Also in NEJM this week, two teams of researchers respond to a study that was published in the journal last October, which concluded that the inhibition of anaplastic lymphoma kinase in patients with non-small cell lung cancer through treatment with crizotinib results in tumor shrinkage or disease stabilization in most patients. A team of clinicians from Italy writes that while ALK-positive lymphomas respond to cytotoxic drugs, "relapses occur and require salvage therapy." The team says they treated two such relapsed patients with crizotinib and found that their symptoms and lesions subsided with treatment. So while the crizotinib worked to treat relapsed patients, the two cases indicate that ALK inhibition in advanced ALK-positive lymphomas leads to relapse of the disease at first, rather than stabilization.
Another team of researchers from Japan also writes to respond to the crizotinib article. The researchers suggest that a "substantial" number of patients in the original study who were identified as having ALK rearrangements by means of FISH analysis were actually false positives, and that the diagnostic method should include other techniques like immunohistochemical staining for further studies of ALK inhibitors. In response, the authors of the original study, Kwak et al., say that the success of the crizotinib trial clearly shows that FISH is clinically valid for diagnosis and that the causes of different response rates between patients are "under investigation."