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Clinical Trial
. 2018 Nov 1;29(11):2214-2222.
doi: 10.1093/annonc/mdy405.

Alectinib Versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive (ALK+) Non-Small-Cell Lung Cancer: CNS Efficacy Results From the ALEX Study

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Free PMC article
Clinical Trial

Alectinib Versus Crizotinib in Treatment-Naive Anaplastic Lymphoma Kinase-Positive (ALK+) Non-Small-Cell Lung Cancer: CNS Efficacy Results From the ALEX Study

S Gadgeel et al. Ann Oncol. .
Free PMC article

Abstract

Background: The phase III ALEX study in patients with treatment-naive advanced anaplastic lymphoma kinase mutation-positive (ALK+) non-small-cell lung cancer (NSCLC) met its primary end point of improved progression-free survival (PFS) with alectinib versus crizotinib. Here, we present detailed central nervous system (CNS) efficacy data from ALEX.

Patients and methods: Overall, 303 patients aged ≥18 years underwent 1:1 randomization to receive twice-daily doses of alectinib 600 mg or crizotinib 250 mg. Brain imaging was conducted in all patients at baseline and every subsequent 8 weeks. End points (analyzed by subgroup: patients with/without baseline CNS metastases; patients with/without prior radiotherapy) included PFS, CNS objective response rate (ORR), and time to CNS progression.

Results: In total, 122 patients had Independent Review Committee-assessed baseline CNS metastases (alectinib, n = 64; crizotinib, n = 58), 43 had measurable lesions (alectinib, n = 21; crizotinib, n = 22), and 46 had received prior radiotherapy (alectinib, n = 25; crizotinib, n = 21). Investigator-assessed PFS with alectinib was consistent between patients with baseline CNS metastases [hazard ratio (HR) 0.40, 95% confidence interval (CI): 0.25-0.64] and those without (HR 0.51, 95% CI: 0.33-0.80, P interaction = 0.36). Similar results were seen in patients regardless of prior radiotherapy. Time to CNS progression was significantly longer with alectinib versus crizotinib and comparable between patients with and without baseline CNS metastases (P < 0.0001). CNS ORR was 85.7% with alectinib versus 71.4% with crizotinib in patients who received prior radiotherapy and 78.6% versus 40.0%, respectively, in those who had not.

Conclusion: Alectinib demonstrated superior CNS activity and significantly delayed CNS progression versus crizotinib in patients with previously untreated, advanced ALK+ NSCLC, irrespective of prior CNS disease or radiotherapy.

Clinical trial registration: ClinicalTrials.gov NCT02075840.

Figures

Figure 1.
Figure 1.
Study population overview. *One patient in the alectinib arm received both radiosurgery and whole-brain radiotherapy (WBRT). CNS, central nervous system; IRC, independent review committee; ITT, intent-to-treat.
Figure 2.
Figure 2.
Progression-free survival according to central nervous system (CNS) metastatic status at baseline and history of radiotherapy: (A) patients with CNS metastases at baseline, (B) patients without CNS metastases at baseline, (C) patients with CNS metastases at baseline who had received prior radiotherapy, and (D) patients with CNS metastases at baseline who had not received prior radiotherapy. CI, confidence interval; HR, hazard ratio; NR, not reached.
Figure 3.
Figure 3.
Cumulative incidence rate (CIR) of central nervous system (CNS) progression. For each patient, the first event of CNS or non-CNS progression or death was counted: (A) patients with CNS metastases at baseline, (B) patients without CNS metastases at baseline, (C) patients with CNS metastases at baseline who had received prior radiotherapy, and (D) patients with CNS metastases at baseline who had not received prior radiotherapy. CI, confidence interval.
Figure 4.
Figure 4.
Central nervous system (CNS) response: (A) patients with measurable CNS disease at baseline who had received prior radiotherapy, (B) patients with measurable CNS disease at baseline who had not received prior radiotherapy, (C) patients with measurable or non-measurable CNS disease at baseline who had received prior radiotherapy, and (D) patients with measurable or non-measurable CNS disease at baseline who had not received prior radiotherapy. CI, confidence interval; CR, complete response; DoR, duration of response; NR, not reached; RT, radiotherapy.

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