Relevance of Detection of Mechanisms of Resistance to ALK Inhibitors in ALK-Rearranged NSCLC in Routine Practice.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have shown efficacy in the treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), but the disease eventually progresses in all patients. In many cases, resistance to ALK TKIs arises through ALK mutations. Although clinical and biological data suggest variations in TKI efficacy according to the mechanism of resistance, ALK mutations are still rarely investigated in routine practice. We performed a retrospective multicentric study with an aim to determine the frequency and clinical relevance of ALK alterations detected using targeted next-generation sequencing in patients with advanced ALK-rearranged NSCLC after progression during an ALK TKI treatment. Data on clinical, pathological, and molecular characteristics and patient outcomes were collected. We identified 23 patients with advanced ALK-rearranged NSCLC who, between January 2012 and May 2017, had undergone at least 1 repeat biopsy at progression during an ALK TKI treatment. A resistance mechanism was identified in 9 of the 23 patients (39%). The anomalies involved included 9 ALK mutations in 8 patients and one ALK amplification. The ALK mutation rate was 15% after failure of a first ALK TKI and 33% after failure of 2 ALK TKI treatments. Five of 7 patients who received a different ALK TKI after detection of an ALK mutation achieved an objective response. All of the patients who received a TKI presumed to act on the detected ALK mutant achieved disease control. Targeted next-generation sequencing is suitable for detecting ALK resistance mutations in ALK-rearranged NSCLC patients in routine practice. It might help select the best treatment at the time of disease progression during treatment with an ALK TKI.

Jamme P ，Descarpentries C ，Gervais R ，Dansin E ，Wislez M ，Grégoire V ，Richard N ，Baldacci S ，Rabbe N ，Kyheng M ，Kherrouche Z ，Escande F ，Copin MC ，Cortot AB ... -  《-》

Management of Central Nervous System Metastases in Patients With Advanced Anaplastic Lymphoma Kinase-Rearranged Non-Small-Cell Lung Cancer During Crizotinib Treatment.

Central nervous system (CNS) progression is a common manifestation of acquired resistance to crizotinib in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, an optimal tailored treatment approach has not been established in patients with CNS failure during crizotinib treatment. Patients with ALK-rearranged NSCLC with CNS progression during crizotinib treatment between January 2013 and December 2016 were included for analysis. Clinical data for different treatments after CNS failure during crizotinib treatment were retrospectively collected. Among the 44 patients who had CNS progression during crizotinib treatment, 19, 15, 8, and 2 patients received crizotinib treatment beyond progressive disease (CBPD), a second ALK tyrosine kinase inhibitor (TKI), chemotherapy, and best supportive care, respectively. Post progression survival offered by treatment with a second ALK TKI was significantly more favorable than that of chemotherapy (P < .001) or CBPD (P = .045). In addition, patients who received sequential treatment with a second ALK TKI had significantly longer intracranial time to progression (IC-TTP) compared with those treated with chemotherapy (P < .01) or CBPD after radiotherapy (P = .003). In the 7 patients who received brigatinib, the median IC-TTP was 21.8 months (95% confidence interval, 11.7-32.0). The additional use of CNS radiotherapy in patients treated with a second ALK TKI showed no significance in terms of IC-TTP (P = .54). Although CBPD is an option in patients with isolated CNS progression during crizotinib treatment, sequential treatment with a second ALK TKI, particularly brigatinib, might be preferable. The newly approved TKI, brigatinib, showed promise in the control of brain metastases, even without radiotherapy.

Zhao Y ，Zhang B ，Wang S ，Qiao R ，Xu J ，Zhang L ，Zhang Y ，Han B ... -  《-》

Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear. This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed. Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%. The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.

Lin YT ，Chiang CL ，Hung JY ，Lee MH ，Su WC ，Wu SY ，Wei YF ，Lee KY ，Tseng YH ，Su J ，Chung HP ，Lin CB ，Ku WH ，Chiang TS ，Chiu CH ，Shih JY ... -  《-》

Concomitant resistance mechanisms to multiple tyrosine kinase inhibitors in ALK-positive non-small cell lung cancer.

ALK tyrosine kinase inhibitors (TKIs), including crizotinib and several next generation TKIs, have demonstrated beneficial clinical outcomes in ALK-positive non-small cell lung cancer (NSCLC). However, resistance mechanisms following multiple TKI treatments in ALK-positive NSCLC are not fully elucidated. Mutation profiles of 422 cancer-relevant genes in 52 patients with post-TKI biopsy samples were analyzed using next-generation sequencing (NGS), and compared between patients receiving crizotinib alone (n = 35) and multi-TKIs (n = 17). EML4-ALK variant 3 is the most frequent ALK variants in this cohort, followed by EML4-ALK variant 1. Half of the patients harbored ALK activating mutations upon progression on crizotinib treatment. After multi-TKIs treatment, 59% of the cases developed resistant ALK mutations, and concomitant ALK activating mutations were more commonly observed in this cohort (P = 0.031). Specifically, ALK G1269 A, L1196 M, and C1156Y substitutions were more common in crizotinib-alone samples, while ALK G1202R was significantly more enriched post-multi-TKIs (P = 0.009). Activated bypass signaling tended to be more prevalent in patients post-multi-TKIs. Furthermore, dual activation of ALK and bypass signaling was more frequently found in the multi-TKIs group (5/17, 29%) in contrast to crizotinib-alone (2/35, 6%) (P = 0.031). Additionally, concurrent TP53 mutation demonstrated significantly shorter progression-free survival (PFS) compared with TP53 wildtype in crizotinib-alone group (median PFS: 8 vs 13 months, Hazard Ratio = 1.494, P = 0.019). Concurrent ALK activating mutations and/or upregulated bypass signaling are more enriched in patients undergoing multiple ALK TKI treatments compared to crizotinib alone. Concomitant TP53 mutation correlated to unfavorable survival when receiving a single TKI crizotinib.

Yu Y ，Ou Q ，Wu X ，Bao H ，Ding Y ，Shao YW ，Lu S ... -  《-》

Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression.

Chen RL ，Zhao J ，Zhang XC ，Lou NN ，Chen HJ ，Yang X ，Su J ，Xie Z ，Zhou Q ，Tu HY ，Zhong WZ ，Yan HH ，Guo WB ，Wu YL ，Yang JJ ... -  《BMC CANCER》