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Sequencing Switches, Intriguing Combos Being Debated in ALK+ NSCLC

Gina Columbus @ginacolumbusonc
Published: Tuesday, Aug 08, 2017

Dr. Joel Neal
Joel Neal, MD
Recent regulatory approvals of second-generation ALK inhibitors for the frontline treatment of patients with ALK-positive non–small cell lung cancer (NSCLC) have helped advance the field; however, it is leading to more sequencing questions from researchers on what to now administer in the second-line setting. In May 2017, the FDA approved ceritinib (Zykadia) as a first-line treatment of patients with ALK-positive, metastatic NSCLC—a follow-up to its April 2014 approval of second-line treatment for patients who progressed on crizotinib (Xalkori), the frontline standard of care.

Most recently, alectinib (Alecensa) was granted a priority review by the FDA for frontline ALK-positive NSCLC, based in part on findings from the phase III ALEX trial presented at the 2017 ASCO Annual Meeting. Results showed that alectinib reduced the risk of disease progression or death by 53% versus crizotinib (HR, 0.47; 95% CI, 0.34-0.65; P <.0001).

“There are now 4 ALK inhibitors that are FDA approved and the second-generation ALK inhibitors are moving toward the frontline setting; so, what do we do with the first-line choice, second-line choice, and the third-line choice?” asked Joel Neal, MD, in an interview during the 2017 OncLive® State of the Science SummitTM on Advanced Non–Small Cell Lung Cancer. “This is a field in flux. The old system was crizotinib (first), one of the second-generation inhibitors FDA approved in the second-line setting, maybe now distinguished by side effect profile. But, it’s going to become that the second-generation inhibitors will be first and we'll have to see what to do in the second-line setting.” 

Neal an assistant professor of medicine and oncology at Stanford Medicine, discussed the latest therapeutic changes to the ALK-positive NSCLC armamentarium. He also explored current sequencing questions as second-line inhibitors are poised to move to the upfront setting, and also some early combination studies that could flip the field around yet again.

OncLive: It’s been a busy year for the field of ALK-positive NSCLC. What did you reflect on?

Neal: ALK-positive lung cancer is about 4% of NSCLCs. We have, historically, identified ALK-positive lung cancer by a variety of testing methods: fluorescence in situ hybridization, immunohistochemistry, and next-generation sequencing is sometimes used. Once the ALK-positive tumors are identified, then we ask, what drug can we use? There are 4 FDA-approved targeted therapies for ALK-positive NSCLC. 

The 2 approved in the frontline setting are crizotinib, which has been around for a while, and ceritinib that just got approval in the first-line setting for ALK-positive lung cancer. But, 1 of the new developments that we saw at the 2017 ASCO Annual Meeting was about alectinib. Alectinib was [explored] in a head-to-head clinical trial versus crizotinib, the old standard of care, first-line drug in ALK-positive NSCLC. We saw that, while crizotinib performed as expected with a median PFS of 10 to 11 months, alectinib gave a PFS of 25.7 months, which was more than double what crizotinib did. In the first-line setting, that is 1 of the most exciting developments and some pretty compelling data to say that alectinib is moving forward. 

Is it safe to say that alectinib will become the frontline standard of care?

Its [current] approval is technically for patients who are refractory to crizotinib or intolerant of crizotinib, although I have heard stories about people saying that, after 1 week, they were intolerant to crizotinib and moving along and moving to alectinib. My personal preference is the data are compelling with alectinib, but whether its ceritinib or alectinib in the second-line setting versus after crizotinib, or using ceritinib or alectinib in the first-line setting, I hope that the PFS are additive. I don’t think there is something about starting with alectinib or ceritinib that is going to outperform the sequential treatment. 

However, 1 of the big differences is that that the second-generation drugs seem to penetrate the brain a lot better. Patients with ALK-positive NSCLC get a lot of brain metastases. We saw in the ALEX trial that more than half on ceritinib within 2 years developed brain metastases, and only about 10% on alectinib developed brain metastases. Being on a stable dose of a tolerated therapy without developing new brain metastases that need to be managed is a good thing for patients. They don’t have to worry for an average of 2 years. 

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TitleExpiration DateCME Credits
Online Medical Crossfire®: 5th Annual Miami Lung Cancer ConferenceMay 30, 20196.5
Community Practice Connections™: Working Group for Changing Standards in EGFR-Mutated Lung Cancers: Real-World Applications of the Evidence for NursesJun 29, 20191.5
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