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• First-line crizotinib treatment is beneficial in Chinese patients with ROS1 -positive advanced NSCLC. • Involvement of more than two metastatic organs was an independent factor associated with shorter PFS. • G2032R mutation in the ROS1 kinase domain was the most common mechanism of resistance to crizotinib. ROS1 rearrangements are seen in 1–2 % of non-small cell lung cancer (NSCLC) patients. The aim of this study was to determine the effectiveness of crizotinib as first-line treatment in patients with ROS1 rearranged NSCLC. The data of 56 patients with ROS1 -rearranged advanced NSCLC who received first-line crizotinib treatment from 5 hospitals in China were retrospectively reviewed. The clinical characteristics, outcomes of first-line crizotinib therapy and prognostic factors were evaluated. In addition, mechanisms of resistance to crizotinib were analyzed in a cohort of crizotinib-resistant patients. The median age of the cohort was 53.0 years and most patients (91.1 %) had adenocarcinomas. The median progression free survival (mPFS) after first-line crizotinib therapy was 23.0 months, and the median overall survival (mOS) was 60.0 months. In the univariate analysis, mPFS was significantly shorter in female patients compared to males (12.0 months versus 24.0 months; p = 0.015) and in patients with >2 baseline metastatic organ involvement compared to those with ≤2 baseline metastatic organ involvement (4.0 months vs 24.0 months; p < 0.001).In addition, the mOS was significantly shorter in patients with >2 baseline metastatic organ involvement relative to that in patients with ≤2 baseline metastatic organ involvement (6.0 months vs 60.0 months; p < 0.001). Multivariable analysis further showed that >2 baseline metastatic organ involvement was the only independent prognostic factor of PFS (p = 0.008). Four out of 8 patients (50 %) with crizotinib resistance harbored a G2032R mutation in the ROS1 kinase domain. First-line crizotinib treatment is beneficial in Chinese patients with ROS1 -rearranged advanced NSCLC. Resistance to crizotinib correlated with the G2032R mutation in the ROS1 kinase domain. [ABSTRACT FROM AUTHOR]

• The efficacy of crizotinib in ALK positive NSCLC patients are heterogeneous. • The implications of co-occurring mutations in ALK + patients is very limited. • Concurrent deleterious mutations have prognostic implications in ALK+ patients. Despite the efficacy of crizotinib in non-small cell lung cancer (NSCLC) with genomic rearrangement between echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK), clinical outcomes are heterogeneous among these patients. In our study, we investigated concurrent molecular factors that could contribute to the heterogeneity of their clinical outcomes to crizotinib therapy. We retrospectively analyzed the clinical and targeted sequencing data from 32 crizotinib-treated patients with EML4-ALK -rearranged advanced NSCLC. Analysis of the mutation profile revealed the detection of concurrent deleterious mutations in 17 patients (53 %, 17/32). Of which, 5 patients had deleterious copy number variations and 12 patients had deleterious single nucleotide variations. Seven patients did not harbor any concurrent mutations from the genes included in the panel. The remaining 8 patients harbored concurrent mutations which were either non-deleterious or variants of uncertain significance. TP53 , detected from 34 % (11/32) of the patients and the most commonly co-occurring mutation in our cohort, was not significantly associated with survival outcomes. Interestingly, significantly shorter progression-free survival (P = 0.032) was observed in patients harboring concurrent deleterious mutations, particularly copy number amplifications (PFS, P = 0.0021; OS, P = 0.034), than those without concurrent deleterious mutations. Harboring more copy number variations, reflected by chromosomal fluctuation coefficient varscore, was associated with shorter progression-free survival (P = 0.02). Our study revealed that concurrent deleterious mutations, particularly copy number amplifications in oncogenic genes have prognostic implications in patients with EML4-ALK -rearranged NSCLC receiving crizotinib therapy. These observations advance the understanding of the heterogeneity of treatment responses among patients with EML4-ALK -rearranged tumors. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The goal of this study was to assess the safety and tolerability of icotinib hydrochloride (BPI-2009H), a new selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI), and to explore its pharmacokinetics (PK) and clinical activity in patients with advanced solid tumors, mainly those with non-small-cell lung cancer (NSCLC) after the failure of the prior platinum-based chemotherapy. Experimental design: Different doses of oral icotinib were administered once every 8h (Q8H) for a 28-continuous-day cycle until disease progression and or undue toxicity was observed. PK studies of subjects’ blood were performed during cycle one (day 1 through 28). Patients aged ≥18 and ≤70 years with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1 and adequate organ functions eligible for the study. Tumor responses were assessed by Response Evaluation Criteria in Solid Tumors (RECIST). K-ras and EGFR mutations in the extracted DNA of fourteen specimens were examined using PCR-based direct sequencing assay. Results: Thirty-six patients were enrolled in the study. PK analysis demonstrated that the mean elimination half-life of icotinib was 6h, and the T max was around 2h. The steady-state concentration of icotinib administered at a dose of 125mg once every 8h (Q8H) was significantly higher than that achieved by a dose of 100mg Q8H. The most frequent treatment-related adverse events (TRAEs) were an acne-like (folliculitis) rash (16/36, 44.4%), diarrhea (8/36, 22.2%) and a decrease in white blood cells (4/36, 11.1%). The maximum-tolerated dose (MTD) was not reached. Among 33 patients with NSCLC, 7 patients exhibited a partial response, 7 showed stable disease at the 24 weeks. Among 14 patients undergoing DNA sequence for K-ras and EGFR mutations, 3 with K-ras mutation presented 2 stable disease (SD) and 1 partial response (PR), 5 with EGFR exon 19 or 21 mutation 2 PR and 3 SD within 4 weeks. Conclusions: Oral icotinib was generally well tolerated, with manageable and reversible adverse events (AEs) and showed positive clinical anti-tumor activities in patients with advanced NSCLC. The recommended dose for phase II/III studies with icotinib is 125mg or 150mg Q8H. [Copyright &y& Elsevier]