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

Abstract

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/m 2 or docetaxel 75 mg/m 2 , 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 EML 4 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 .

Incidence of pneumonitis following the use of different anaplastic lymphoma kinase tyrosine kinase inhibitor regimens: An updated systematic review and meta‐analysis

“…Our literature search yielded a total of 1798 articles, of which 1680 were excluded after the initial screening of abstracts or titles (Figure 1). After screening and assessing eligibility, 26 studies, which included 31 cohorts, were selected 6,9,10,12,14–16,21–39 …”

Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT)

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Effective Systemic Treatment of Choroidal Metastases NSCLC With Surgery After Crizotinib: A Case Report

“…Targeted therapy is playing a significant role in the treatment of lung cancer, but drug resistance is inescapable which is more intractable and intensifies the psychological burden on patients ( 21 , 22 ). In crizotinib-resistant cases, patient switched to alectinib observed a 55% overall response rate ( 23 , 24 ). Two studies reported that patients who are resistant to crizotinib as the first-line treatment achieved significant PFS when they were switched to aletinib.…”