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ESMO Open
2022 Feb 01;71:100333. doi: 10.1016/j.esmoop.2021.100333.
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Final efficacy and safety data, and exploratory molecular profiling from the phase III ALUR study of alectinib versus chemotherapy in crizotinib-pretreated ALK-positive non-small-cell lung cancer.
Wolf J
,
Helland Å
,
Oh IJ
,
Migliorino MR
,
Dziadziuszko R
,
Wrona A
,
de Castro J
,
Mazieres J
,
Griesinger F
,
Chlistalla M
,
Cardona A
,
Ruf T
,
Trunzer K
,
Smoljanovic V
,
Novello S
.
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BACKGROUND: At the primary data cut-off, the ALUR study demonstrated significantly improved progression-free survival (PFS) and central nervous system (CNS) objective response rate (ORR) with alectinib versus chemotherapy in pretreated, advanced anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer. We report final efficacy and safety data, and exploratory molecular profiling.
PATIENTS AND METHODS: Patients who received prior platinum-doublet chemotherapy and crizotinib were randomized 2 : 1 to receive alectinib 600 mg twice daily (n = 79) or chemotherapy (pemetrexed 500 mg/m2 or docetaxel 75 mg/m2, every 3 weeks; n = 40) until progressive disease, death or withdrawal. The primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, CNS ORR and safety. Plasma samples were collected at baseline, then every 6 weeks until progressive disease; molecular factors detected by next-generation sequencing were correlated with outcomes.
RESULTS: Investigator-assessed PFS was significantly longer with alectinib than chemotherapy (median 10.9 versus 1.4 months; hazard ratio 0.20, 95% confidence interval 0.12-0.33; P < 0.001). ORR was 50.6% with alectinib versus 2.5% with chemotherapy (P < 0.001). In patients with measurable CNS metastases at baseline, CNS ORR was 66.7% with alectinib versus 0% with chemotherapy (P < 0.001). No new safety signals were seen. ALK rearrangement was identified in 69.5% (n = 41/59) of baseline plasma samples. Confirmed partial responses were observed with alectinib in 6/11 patients with a secondary ALK mutation and 4/6 patients with a non-EML4-ALK (where EML4 is echinoderm microtubule-associated protein-like 4) fusion. Detection of mutant TP53 in baseline plasma resulted in numerically shorter PFS with alectinib (hazard ratio 1.88, 95% confidence interval 0.9-3.93).
CONCLUSIONS: Final efficacy data from ALUR confirmed the superior PFS, ORR and CNS ORR of alectinib versus chemotherapy in pretreated, advanced ALK-positive non-small-cell lung cancer. Alectinib prolonged PFS versus chemotherapy in patients with wild-type or mutant TP53; however, alectinib activity was considerably decreased in patients with mutant TP53.
Figure 1. Kaplan–Meier curves of (A) final investigator-assessed PFS and (B) OS in the ITT population.CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; OS, overall survival; PFS, progression-free survival.
Figure 2. Maximum change in tumor size from baseline and confirmed response observed in alectinib-treated patients with (A) a non-EML4-ALK fusion detected and (B) a secondary ALK mutation detected in baseline plasma.Figures show best change in tumor size from baseline and tables show confirmed response category at last tumor assessment (as assessed by RECIST v1.1). The response of one patient with a non-EML4-ALK fusion was NE and was therefore excluded from the waterfall plot.ALK, anaplastic lymphoma kinase; CR, complete response; EML4, echinoderm microtubule-associated protein-like 4; NE, not evaluable; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
Figure 3. Kaplan–Meier curve of investigator-assessed PFS by baseline TP53 status (WT or mutant) in each treatment arm.PFS, progression-free survival; WT, wild-type.
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