D. Ross Camidge, MD, PhD
A new study has confirmed that low testosterone is a side effect in a large proportion of patients who received crizotinib for the treatment of ALK-positive non–small cell lung cancer (NSCLC). In the international, multicenter study, 84% of patients had low testosterone, which was associated with other side effects, including sexual dysfunction and depression. Additionally, the researchers found that hormone replacement therapy is an effective method of managing these side effects.
Crizotinib inhibits several tyrosine kinases associated with the development of NSCLC, including ALK. When the FDA approved crizotinib for the treatment of patients with locally advanced or metastatic NSCLC, a companion diagnostic was also approved to identify patients with an ALK
“With advances in targeted therapies and in the biomarkers we can use to select who to best give these new treatments to, we’re starting to see drugs being approved more quickly, and based on the results from far smaller numbers of patients than ever before,” said D. Ross Camidge, MD, PhD, investigator at the University of Colorado Cancer Center, director of the Thoracic Oncology Clinical Program at the University of Colorado Hospital, and lead author of the study, in a statement. “That’s great—it helps streamline the path of these drugs into clinics where they can benefit patients who desperately need them. However, it also puts the onus on clinicians who then start using these drugs in day-to-day practice to recognize either subtle or later onset side effects that may have been missed during the initial testing.”
In a previous study, researchers found that patients receiving crizotinib had a total testosterone that was below the lower limit of normal (LLN). In those patients, testosterone levels returned to normal after treatment with the drug was stopped. Researchers sought to determine the etiology of the effect of low testosterone, its symptomatic significance, and the effectiveness of testosterone replacement to manage these symptoms.
In this study, three groups of patients with metastatic NSCLC were analyzed: 32 crizotinib-treated patients assessed at the University of Colorado Cancer Center and other sites (crizotinib-treated group 1 [CTG1]), 19 patients from the previous study assessed at the University of Colorado Cancer Center, and 19 patients with metastatic NSCLC who had never received crizotinib to serve as a control population.
The researchers found that the mean total testosterone levels were -25% below the LLN in CTG1, with a total of 27 of 32 patients (84%) falling below LLN versus +29% above LLN in the control group (P
= .0012). Additionally, levels of albumin and sex hormone-binding globulin, two proteins that bind to testosterone and are able to store the hormone, rapidly declined when patients were treated with crizotinib, as did levels of follicle-stimulating hormone, luteinizing hormone, and free testosterone. The researchers said these findings suggest that crizotinib affects the body’s ability to both store and produce the hormone.
In 9 patients who were assessed for the benefits of testosterone replacement, 5 (55%) reported improvement in symptoms of hypogonadism between 2 and 3 months after beginning treatment with hormone replacement therapy. All 5 patients who had testosterone replacement and whose hormone levels were raised above LLN reported improved symptoms.
Camidge said that awareness of a link between crizotinib use and testosterone levels will allow doctors to have more open conversations with patients about these symptoms and discussions on how to manage them.“With each breakthrough we’re really trying to put people with advanced cancer back in control of their own lives,” said Camidge. “The more we can make these highly effective new treatments tolerable, the closer we are to achieving that goal.”
Weickhardt AJ, Doebele RC, Purcell WT, et al. Symptomatic reduction in free testosterone levels secondary to crizotinib use in male cancer patients [published online ahead of print April 12, 2013]. Cancer. doi:10.1002/cncr.28089.