ALK/ROS1-Rearranged NSCLC: Approaching Therapy

Justin Gainor, MD:The global ALEX study was a randomized phase III study for patients with newly diagnosedALK-positive lung cancer, and patients were randomized to receive either crizotinib, the standard ALK inhibitor, prior to the ALEX study, or alectinib, a second-generation ALK inhibitor. And in the ALEX study, alectinib produced significant improvements in progression-free survival compared with crizotinib. Indeed, the median progression-free survival with first-line alectinib was extremely impressive. With the latest ASCO [American Society of Clinical Oncology] update, the median progression-free survival was nearly 3 years, which is quite impressive for newly diagnosed patients withALK-positive lung cancer.

Importantly, compared with crizotinib, alectinib also resulted in superior control of CNS [central nervous system] metastases, with far fewer cumulative incidence of CNS metastases, compared with patients treated with crizotinib. And so, based upon the results of the ALEX study—which I should also mention confirmed the results of a parallel Japanese study called the J-ALEX study, which had a very comparable design—together, those 2 phase III studies have really confirmed that alectinib should be the first-line standard of care for patients with newly diagnosedALK-rearranged lung cancer.

Alexander Drilon, MD:Fortunately, many of the tyrosine kinase inhibitors [TKIs] that are available forALK-rearranged lung cancers have good CNS coverage. And I’m speaking specifically about alectinib, ceritinib, and brigatinib, which are next-generation agents, compared with crizotinib, which was the former standard of care and is a first-generation ALK TKI. Now, similar to theEGFRspace, where the FLAURA trial was positive for osimertinib in terms of progression-free survival over earlier generation TKIs, there’s the ALEX trial that randomized patients to alectinib versus crizotinib. Those are patients withALK-rearranged disease. And no surprise, because alectinib targets potential mechanisms of resistance to earlier generation therapy with crizotinib and has better CNS penetration, alectinib won in terms of progression-free survival and is now the new standard of care forALK-rearranged lung cancers.

ROS1-rearranged lung cancers also have a proclivity for metastases to the brain, although there are reports of theROS1-rearranged population potentially having a lower level of brain metastases. Crizotinib is FDA approved for this population, and it can have activity in the CNS. However, there are other drugs that are currently being developed that may have better CNS penetration. An example of 1 drug that’s currently in clinic trials is entrectinib, which has been looked at inROS1-rearranged lung cancer patients, and that drug is known to effectively cross the blood-brain barrier and address CNS disease.

Transcript edited for clarity.

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