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Reported by IASLC News

Changing treatment paradigm for ALK-Positive lung cancer:

Rearrangements in the anaplastic lymphoma kinase (ALK) gene occur in approximately 2% to 7% of patients with advanced non-small cell lung cancer (NSCLC).

For patients with advanced ALK-positive NSCLC, the current firstline standard of care is crizotinib. It has been shown to yield very high response rates (exceeding 60%) and to improve progression-free survival (PFS) compared with standard chemotherapy when used in patients with advanced ALK-positive NSCLC whose disease has progressed on previous chemotherapy, including those with brain metastases.

Nevertheless, most patients with ALK-positive NSCLC treated with firstline crizotinib will eventually relapse, either due to the development of ALK resistance mutations or inadequate CNS drug penetration.

Ceritinib, alectinib, and brigatinib are next-generation ALK TKIs that have emerged as standard therapy for patients with advanced ALK-positive NSCLC who experience disease progression while on crizotinib. These agents have been shown to be more potent with more brain penetrance than crizotinib. Additionally, ceritinib and alectinib both demonstrate activity against common crizotinib-resistance mutations, such as the gatekeeper ALK L1196M mutation.

Emerging data suggest that these agents also may have a role in the first-line setting. The global, randomized phase III ASCEND-4 trial compared ceritinib with platinum/pemetrexed chemotherapy in newly diagnosed patients with advanced ALK-positive NSCLC. Ceritinib reduced the risk of disease progression or death by 45% compared with standard chemotherapy. Patients who received ceritinib had significantly longer median PFS, 16.6 months versus 8.1 months in the chemotherapy arm.

Based on these positive results, ceritinib (Zykadia) was approved by the FDA on May 26, 2017, for first-line treatment of patients with ALK-positive, advanced NSCLC. Following closely behind is alectinib, which in the phase III global ALEX trial showed superior efficacy compared with crizotinib as first-line therapy for treatment-naive patients with advanced ALK-positive NSCLC. Compared with crizotinib, alectinib prolonged PFS, as well as the time to CNS progression, in treatment-naive patients with ALKpositive NSCLC. Results of the ALEX trial were presented in June at the 2017 annual meeting of the American Society of Clinical Oncology during the thoracic oncology plenary session.

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