'Weeding the garden' technique extends effectiveness of crizotinib for NSCLC

Patients taking crizotinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) may safely and durably use up to three courses of targeted radiation therapy to eradicate pockets of drug-resistant disease. Eliminating these pockets of resistant disease allows patients to continue treating the overall condition with crizotinib, leading to improved 2-year survival rates compared with patients forced to discontinue the drug sooner, according to a new study.

ALK-positive lung cancers are caused by the aberrant reactivation of the ALK gene, and comprise about 3% to 5% of all cases of NSCLC. In these cases, clinical studies showed the drug crizotinib to be highly effective and therefore, it received rapid approval by the FDA in 2011. Unfortunately, at around 8 to 10 months after the initiation of treatment, the cancer tends to acquire resistance to crizotinib. Earlier work showed that resistance occurs through a change in the biology of the cancer. At this point, patients are generally switched to another drug.

However, it may not be the entire cancer that develops resistance to the drug. Instead, as the change in biology is an evolutionary event, only pockets of the cancer may become immune. Previous work has described the use of a single course of radiotherapeutic local ablative therapy to eliminate these isolated pockets of resistant disease.

“The traditional paradigm for cancer patients has been to switch your systemic therapy to another agent if you progress, even though a majority of your cancer may still be controlled by the original drug. But what if we could use targeted radiation therapy to eliminate those sites of errant disease so a person could stay on a specific drug longer?” hypothesized first author Gregory Gan, MD, PhD, of the University of Colorado Cancer Center in Aurora. “Using stereotactic body radiotherapy, we can ablate these limited sites of progressive disease so patients can continue on the drug they are on—a technique we refer to as weeding the garden.”

The current study reports median 2-year follow-up results of up to three courses of local ablative therapy to control resistant, progressive disease in ALK-positive lung cancer patients. The study was published in the International Journal of Radiation Oncology Biology and Physics (2014; doi:10.1016/j.ijrobp.2013.11.010).

Specifically, the group followed the experience of 38 ALK-positive NSCLC patients. Of these 38 patients, 33 progressed during the study, meaning the disease gained resistance to crizotinib. Fourteen of those patients progressed in a way that allowed for local ablative therapy. These eligible patients received 1 to 3 rounds of radiotherapeutic local ablative therapy to weed out resistant pockets of disease. Examples of sites that were treated included metastases to the lung, liver, abdominal lymph nodes, and adrenal glands.

Among the 38 ALK-positive patients, the overall survival at 2 years was 57%; but among those who stayed on crizotinib for more than 1 year, it was 72% compared with 12% in those who discontinued crizotinib earlier.

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