PerspectiveIn the Journals

Radiation therapy controlled progression in crizotinib-treated ALK-positive NSCLC

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March 3, 2014

Radiotherapeutic local ablative therapy may help control the progression of lesions in patients with oligoprogressive anaplastic lymphoma kinase-positive non–small cell lung cancer who are treated with crizotinib, study results suggest.

“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,” researcher Gregory Gan, MD, a chief resident at the University of Colorado School of Medicine’s department of radiation oncology, said in a press release. “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? Using stereotactic body radiotherapy, we can ablate these limited sites of progressive disease so patients can continue on the drug they are on.”

Gan and colleagues evaluated 38 anaplastic lymphoma kinase (ALK)-positive patients with NSCLC on a regimen of crizotinib (Xalkori, Pfizer). Patients demonstrating four or fewer distinct sites of extra-central nervous system (CNS) progression were categorized as having oligoprogressive disease suitable for radiation therapy. In cases where further progression was categorized as oligoprogressive disease, additional courses of radiation therapy were assessed. The crizotinib regimen was maintained until extra-CNS progression exceeded oligoprogressive disease criteria or was otherwise not considered appropriate for additional radiation therapy.

Of the 38 patients, 33 progressed on the crizotinib regimen, and 14 had extra-CNS progression fulfilling oligoprogressive disease criteria for which radiotherapeutic radiation therapy was indicated.

Patients with extra-CNS oligoprogressive disease underwent one to three courses of radiation therapy. The radiation therapy achieved a 6-month actuarial local lesion control rate of 100% and a 12-month rate of 86%. Researchers observed a higher 12-month local lesion control rate among patients who received single-fraction equivalent doses of >25 Gy compared with those who received doses ≤25 Gy (100% vs. 60%; P=.01). No acute or late grade >2 radiation therapy-related toxicities occurred.

The median duration of crizotinib treatment among patients who underwent radiation therapy was 28 months, compared with 10.1 months for those who progressed but were not suitable for radiation therapy. Rates of 2-year OS were 72% for patients who took crizotinib for at least 12 months and 12% for those who took crizotinib for less than 12 months (P<.0001).

Disclosure: The researchers report no relevant financial disclosures.

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Targeted therapy for molecularly defined subtypes of non–small cell lung cancer has had a tremendous impact on the lives of many patients in the last few years. In NSCLC patients with tumors harboring rearrangements in the anaplastic lymphoma kinase (ALK) gene, drugs like crizotinib can control the cancer in a majority of patients and bring rapid relief of symptoms for many. Unfortunately, most ALK-positive patients eventually progress on crizotinib, with the cancer developing what is known as acquired resistance to the drug within an average of 8 to 9 months.

In a very interesting phenomenon that seems to be distinct to molecularly defined tumors treated with specific inhibitors, some patients will develop resistance in only one or a few metastatic sites, whereas the remainder of the cancer remains under control. This has been termed “oligoprogression” and is felt by groups like Gan and colleagues at the University of Colorado (UC) to represent an opportunity to treat the limited areas of progression while allowing the patient to continue taking crizotinib.

It is an elegant idea, and the UC group had published studies showing that the local control of oligoprogressing lesions treated with stereotactic radiation is excellent, and that these patients are able to continue on crizotinib for an average of 5 to 6 months after treatment. Although this is a very reasonable approach and — in fact — is commonly done at many centers outside of clinical trials, care must be taken when concluding that this significantly impacts patient survival. Oligoprogression occurs in less than half of all advanced ALK-positive patients, and it clearly represents a distinct and highly selected group with a better prognosis than those with more rapid and generalized progression. In an era in which we now have an FDA-approved second-line therapy for ALK-positive patients who fail crizotinib (ie, ceritinib [Zykadia, Novartis]), and when patients may not yet have received chemotherapy, it is not clear if squeezing in those extra months of crizotinib treatment will impact their survival. Prospective trials in this group of patients and others are underway and hopefully will answer the question of where this strategy fits in the management of acquired resistance.

Nathan Pennell, MD, PhD
Staff physician Department of hematology and medical oncology Cleveland Clinic

Disclosure: Pennell reports no relevant financial disclosures.