Medline ® Abstracts for References 36,37
of 'Anaplastic lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer'
Alectinib in Crizotinib-Refractory ALK-Rearranged Non-Small-Cell Lung Cancer: A Phase II Global Study.
Ou SH, Ahn JS, De Petris L, Govindan R, Yang JC, Hughes B, Lena H, Moro-Sibilot D, Bearz A, Ramirez SV, Mekhail T, Spira A, Bordogna W, Balas B, Morcos PN, Monnet A, Zeaiter A, Kim DW
J Clin Oncol. 2016;34(7):661. Epub 2015 Nov 23.
PURPOSE: Crizotinib confers improved progression-free survival compared with chemotherapy in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), but progression invariably occurs. We investigated the efficacy and safety of alectinib, a potent and selective ALK inhibitor with excellent CNS penetration, in patients with crizotinib-refractory ALK-positive NSCLC.
PATIENTS AND METHODS: Alectinib 600 mg was administered orally twice daily. The primary end point was objective response rate (ORR) by central independent review committee (IRC).
RESULTS: Of the 138 patients treated, 84 patients (61%) had CNS metastases at baseline, and 122 were response evaluable (RE) by IRC. ORR by IRC was 50% (95% CI, 41% to 59%), and the median duration of response (DOR) was 11.2 months (95% CI, 9.6 months to not reached). In 96 patients (79%) previously treated with chemotherapy, the ORR was 45% (95% CI, 35% to 55%). Median IRC-assessed progression-free survival for all 138 patients was 8.9 months (95% CI, 5.6 to 11.3 months). CNS disease control rate was 83% (95% CI, 74% to 91%), and the median CNS DOR was 10.3 months (95% CI, 7.6 to 11.2 months). CNS ORR in 35 patients with baseline measurable CNS lesions was 57% (95% CI, 39% to 74%). Of the 23 patients with baseline CNS metastases (measurable or nonmeasurable) and no prior radiation, 10 (43%) had a complete CNS response. At 12 months, the cumulative CNS progression rate (24.8%) was lower than the cumulative non-CNS progression rate (33.2%) for all patients. Common adverse events were constipation (33%), fatigue (26%), and peripheral edema (25%); most were grade 1 to 2.
CONCLUSION: Alectinib is highly active and well tolerated in patients with advanced, crizotinib-refractory ALK-positive NSCLC, including those with CNS metastases.
Sai-Hong Ignatius Ou, University of California Irvine School of Medicine, Orange, CA; Jin Seok Ahn, Sungkyunkwan University School of Medicine; Luigi De Petris, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden; Ramaswamy Govindan, Washington University School of Medicine, St Louis, MO; James Chih-Hsin Yang, National Taiwan University, Taipei, Taiwan; Brett Hughes, The Prince Charles Hospital, Chermside, and University of Queensland, Queensland, Australia; HervéLena, Centre Hospitalier Universitaire de Rennes, Rennes; Denis Moro-Sibilot, Centre Hospitalier Universitaire de Grenoble, Institut National de la Santéet de la Recherche Médicale U823, Grenoble, France; Alessandra Bearz, National Cancer Institute, Aviano, Italy; Santiago Viteri Ramirez, Quiron-Dexeus University Hospital, Barcelona, Spain; Tarek Mekhail, Florida Hospital Cancer Institute, Orlando, FL; Alexander Spira, Virginia Cancer Specialists, Fairfax, VA; and Walter Bordogna, Bogdana Balas, Peter
Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial.
Shaw AT, Gandhi L, Gadgeel S, Riely GJ, Cetnar J, West H, Camidge DR, Socinski MA, Chiappori A, Mekhail T, Chao BH, Borghaei H, Gold KA, Zeaiter A, Bordogna W, Balas B, Puig O, Henschel V, Ou SH, study investigators
Lancet Oncol. 2016;17(2):234. Epub 2015 Dec 19.
BACKGROUND: Alectinib--a highly selective, CNS-active, ALK inhibitor-showed promising clinical activity in crizotinib-naive and crizotinib-resistant patients with ALK-rearranged (ALK-positive) non-small-cell lung cancer (NSCLC). We aimed to assess the safety and efficacy of alectinib in patients with ALK-positive NSCLC who progressed on previous crizotinib.
METHODS: We did a phase 2 study at 27 centres in the USA and Canada. We enrolled patients aged 18 years or older with stage IIIB-IV, ALK-positive NSCLC who had progressed after crizotinib. Patients were treated with oral alectinib 600 mg twice daily until progression, death, or withdrawal. The primary endpoint was the proportion of patients achieving an objective response by an independent review committee using Response Evaluation Criteria in Solid Tumors, version 1.1. Response endpoints were assessed in the response-evaluable population (ie, patients with measurable disease at baseline who received at least one dose of study drug), and efficacy and safety analyses were done in the intention-to-treat population(all enrolled patients). This study is registered with ClinicalTrials.gov, number NCT01871805. The study is ongoing and patients are still receiving treatment.
FINDINGS: Between Sept 4, 2013, and Aug 4, 2014, 87 patients were enrolled into the study (intention-to-treat population). At the time of the primary analysis (median follow-up 4·8 months [IQR 3·3-7·1]), 33 of 69 patients with measurable disease at baseline had a confirmed partial response; thus, the proportion of patients achieving an objective response by the independent review committee was 48% (95% CI 36-60). Adverse events were predominantly grade 1 or 2, most commonly constipation (31 [36%]), fatigue (29 [33%]), myalgia 21 [24%]), and peripheral oedema 20 [23%]). The most common grade 3 and 4 adverse events were changes in laboratory values, including increased blood creatine phosphokinase (seven [8%]), increased alanine aminotransferase (five [6%]), and increased aspartate aminotransferase (four [5%]). Two patients died: one had a haemorrhage (judged related to study treatment), and one had disease progression and a history of stroke (judged unrelated to treatment).
INTERPRETATION: Alectinib showed clinical activity and was well tolerated in patients with ALK-positive NSCLC who had progressed on crizotinib. Therefore, alectinib could be a suitable treatment for patients with ALK-positive disease who have progressed on crizotinib.
FUNDING: F Hoffmann-La Roche.
Massachusetts General Hospital, Boston, MA, USA. Electronic address: ASHAW1@mgh.harvard.edu.