Sequential Therapy with Crizotinib and Alectinib in ALK-Rearranged Non-Small Cell Lung Cancer-A Multicenter Retrospective Study.

Alectinib and crizotinib have been approved for the therapy of NSCLC caused by anaplastic lymphoma kinase gene (ALK) rearrangement. The effect of alectinib or crizotinib on overall survival (OS) in patients with ALK-rearranged NSCLC remains unknown. A multicenter retrospective study was conducted to compare OS between patients receiving alectinib and crizotinib and between patients treated with alectinib and those treated sequentially with crizotinib and then alectinib after crizotinib failure. The time to treatment failure (TTF), progression-free survival (PFS), and OS were compared. Sixty-one patients with ALK-rearranged NSCLC were enrolled. Forty-six patients were treated with anaplastic lymphoma kinase (ALK) inhibitors (31 with crizotinib, 28 with alectinib, and 13 with both ALK inhibitors). The response rate was 66.7% for the crizotinib-treated group and 80.8% for the alectinib-treated group. Among all patients, TTF and PFS were significantly prolonged in the alectinib-treated group compared with in the crizotinib-treated group. Subgroup analyses revealed significantly prolonged TTF for alectinib compared with crizotinib therapy in the ALK inhibitor-naive population. OS was significantly longer in the alectinib-treated group than in the crizotinib-treated group. The TTF and OS of patients treated sequentially with crizotinib and then with alectinib after crizotinib failure tended to be longer than those of patients treated with alectinib alone. Therapy with alectinib alone was significantly superior to therapy with crizotinib alone in terms of TTF, PFS, and OS, and sequential therapy with crizotinib and alectinib after crizotinib failure tended to provide a better OS benefit than did therapy with alectinib alone in patients with ALK-positive NSCLC. However, large-scale prospective studies are needed to confirm these observations.

Ito K ，Hataji O ，Kobayashi H ，Fujiwara A ，Yoshida M ，D'Alessandro-Gabazza CN ，Itani H ，Tanigawa M ，Ikeda T ，Fujiwara K ，Fujimoto H ，Kobayashi T ，Gabazza EC ，Taguchi O ，Yamamoto N ... -  《-》

Progression-Free and Overall Survival of Patients With ALK Rearrangement-Positive Non-Small Cell Lung Cancer Treated Sequentially With Crizotinib and Alectinib.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show marked therapeutic efficacy in patients with non-small cell lung cancer (NSCLC) harboring the echinoderm microtubule-associated protein-like 4-ALK fusion gene. The effect on overall survival (OS) of sequential treatment with the first- and second-generation ALK-TKIs crizotinib and alectinib, respectively, has remained unknown. We have examined the clinical outcome of such sequential treatment in a retrospective analysis of patients with ALK-rearranged NSCLC. Eleven patients with ALK-rearranged NSCLC treated with crizotinib followed by alectinib were identified. The progression-free survival (PFS) and OS for these patients were determined from a retrospective review of their medical records. The median PFS on crizotinib or alectinib was 6.1 months (range, 1.0-15.4 months) and 15.2 months (range, 1.0-28.3 months), respectively. The median combined PFS for both crizotinib and alectinib was 18.2 months (range, 10.4-43.7 months). Crizotinib was continued beyond radiographic evidence of progressive disease in 6 of the 11 patients, with a median duration of postprogression crizotinib treatment of 9.4 months (range, 0-20.5 months). The OS period from the diagnosis of metastatic disease or the initiation of crizotinib treatment was 51.1 months (range, 20.9-69.5 months) and 48.6 months (range, 19.8-50.1 months), respectively. Our retrospective study has revealed durable survival for alectinib treatment after crizotinib failure in patients with ALK-rearranged NSCLC.

Watanabe S ，Hayashi H ，Okamoto K ，Fujiwara K ，Hasegawa Y ，Kaneda H ，Tanaka K ，Takeda M ，Nakagawa K ... -  《-》

Sequential Use of Anaplastic Lymphoma Kinase Inhibitors in Japanese Patients With ALK-Rearranged Non-Small-Cell Lung Cancer: A Retrospective Analysis.

Second-generation anaplastic lymphoma kinase (ALK) inhibitors, such as alectinib and ceritinib, have recently been approved for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC). An optimal strategy for using 2 or more ALK inhibitors has not been established. We sought to investigate the clinical impact of sequential use of ALK inhibitors on these tumors in clinical practice. Patients with ALK-rearranged NSCLC treated from May 2010 to January 2016 at the National Cancer Center Hospital were identified, and their outcomes were evaluated retrospectively. Fifty-nine patients with ALK-rearranged NSCLC had been treated and 37 cases were assessable. Twenty-six received crizotinib, 21 received alectinib, and 13 (35.1%) received crizotinib followed by alectinib. Response rates and median progression-free survival (PFS) on crizotinib and alectinib (after crizotinib failure) were 53.8% (95% confidence interval [CI], 26.7%-80.9%) and 38.4% (95% CI, 12.0%-64.9%), and 10.7 (95% CI, 5.3-14.7) months and 16.6 (95% CI, 2.9-not calculable), respectively. The median PFS of patients on sequential therapy was 35.2 months (95% CI, 12.7 months-not calculable). The 5-year survival rate of ALK-rearranged patients who received 2 sequential ALK inhibitors from diagnosis was 77.8% (95% CI, 36.5%-94.0%). The combined PFS and 5-year survival rates in patients who received sequential ALK inhibitors were encouraging. Making full use of multiple ALK inhibitors might be important to prolonging survival in patients with ALK-rearranged NSCLC.

Asao T ，Fujiwara Y ，Itahashi K ，Kitahara S ，Goto Y ，Horinouchi H ，Kanda S ，Nokihara H ，Yamamoto N ，Takahashi K ，Ohe Y ... -  《-》

Sequential therapy of crizotinib followed by alectinib for non-small cell lung cancer harbouring anaplastic lymphoma kinase rearrangement (WJOG9516L): A multicenter retrospective cohort study.

The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the 'TTF of CRZ' plus the 'TTF of ALEC' if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P < 0.0001). The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

Ito K ，Yamanaka T ，Hayashi H ，Hattori Y ，Nishino K ，Kobayashi H ，Oya Y ，Yokoyama T ，Seto T ，Azuma K ，Fukui T ，Kozuki T ，Nakamura A ，Tanaka K ，Hirano K ，Yokoi T ，Daga H ，Sakata S ，Fujimoto D ，Mori M ，Maeno K ，Aoki T ，Tamura A ，Miura S ，Watanabe S ，Akamatsu H ，Hataji O ，Suzuki K ，Hontsu S ，Azuma K ，Bessho A ，Kubo A ，Okuno M ，Nakagawa K ，Yamamoto N ... -  《-》

Overall survival with crizotinib and next-generation ALK inhibitors in ALK-positive non-small-cell lung cancer (IFCT-1302 CLINALK): a French nationwide cohort retrospective study.

Duruisseaux M ，Besse B ，Cadranel J ，Pérol M ，Mennecier B ，Bigay-Game L ，Descourt R ，Dansin E ，Audigier-Valette C ，Moreau L ，Hureaux J ，Veillon R ，Otto J ，Madroszyk-Flandin A ，Cortot A ，Guichard F ，Boudou-Rouquette P ，Langlais A ，Missy P ，Morin F ，Moro-Sibilot D ... -  《Oncotarget》