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Introduction: B-cell lymphoma 2-like 11 (BCL-2-like 11, BCL2L11, also known as BIM) deletion polymorphism (BIM-del) has been associated with resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), and is a poor prognostic factor for EGFR-mutant non-small-cell lung cancer (NSCLC) patients. Nevertheless, the impact of BIM-del in advanced NSCLC patients treated with the third-generation EGFR-TKI osimertinib remains undetermined. This study aims to evaluate the relationship between BIM-del and therapeutic efficacy of osimertinib in pretreated NSCLC patients., Methods: Patients subjected to EGFR T790 M detection and prior osimertinib treatment between December 2015 and December 2019 in our hospital were enrolled in this study. Peripheral blood samples from these patients were collected to detect BIM-del by polymerase chain reaction. Cox proportional hazards models were used to analyze the clinical outcomes of patients with and without BIM-del., Results: In total, 152 Chinese Han NSCLC patients-including 143 T790M-positive and nine T790M-negative patients-were enrolled. BIM-del was detected in only 17.5 % of T790M-positive patients (25/143). The majority of patients were aged <65 years (81.8 %, 117/143), were female (58.7 %, 84/143), were non-smokers (82.5 %, 118/143), had Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1 (88.8 %, 129/143), and exhibited metastases in the central nervous system (CNS) (54.5 %, 78/143). There were no associations between the BIM-del and clinical characteristics (including age, sex, histology, smoking status, stage, ECOG PS score, and CNS metastases). Patients with BIM-del had a poorer objective response rate than those without (28.0 % versus 52.5 %, p = 0.026). Besides, BIM-del was associated with a significantly shorter progression-free survival (PFS) and a moderately shorter overall survival (OS) (8.3 versus 10.5 months, p = 0.031 and 15.9 versus 25.2 months, p = 0.1, respectively). Multivariate analysis indicated that BIM-del was an independent prognostic factor for PFS but not for OS in EGFR T790 M NSCLC patients., Conclusions: BIM-del is associated with poor clinical responses and outcomes, and might be a negative predictive and prognostic biomarker in EGFR T790 M NSCLC patients with osimertinib treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.) more...

Purpose: Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer with BIM deletion polymorphism may have a limited response to EGFR tyrosine kinase inhibitors (EGFR-TKIs). However, some results of previous reports are discordant. It is necessary to evaluate the relationship between BIM polymorphism and the efficacy of EGFR-TKIs., Methods: We retrospectively analyzed patients treated with EGFR-TKIs. We collected serum samples from patients before EGFR-TKI administration. We analyzed BIM deletion polymorphism and BIM single nucleotide polymorphism in exon 5 c465C > T by the Invader ® assay., Results: BIM deletion polymorphism was identified in 27 of 194 patients (13.9%). BIM single nucleotide polymorphism was identified in 29 of 194 patients (14.9%). The overall response ratio was 81.5% in patients with BIM deletion polymorphism, 89.7% with BIM single nucleotide polymorphism, and 83.6% with BIM wild type. Median progression-free survival was 10.3 months with BIM deletion polymorphism, 8.5 months with BIM single nucleotide polymorphism, and 10.4 months with BIM wild type. Overall survival was 38.4 months with BIM deletion polymorphism, 29.1 months with BIM single nucleotide polymorphism, and 31.6 months with BIM wild type. There were no significant differences between the groups in overall response ratio, progression-free survival, and overall survival., Conclusions: BIM polymorphism does not affect EGFR-TKI efficacy. more...

Patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) harboring BIM deletion polymorphism (BIM deletion) have poor responses to EGFR TKI. Mechanistically, the BIM deletion induces preferential splicing of the non-functional exon 3-containing isoform over the functional exon 4-containing isoform, impairing TKI-induced, BIM-dependent apoptosis. Histone deacetylase inhibitor, vorinostat, resensitizes BIM deletion-containing NSCLC cells to EGFR-TKI. In the present study, we determined the safety of vorinostat-gefitinib combination and evaluated pharmacodynamic biomarkers of vorinostat activity. Patients with EGFR-mutated NSCLC with the BIM deletion, pretreated with EGFR-TKI and chemotherapy, were recruited. Vorinostat (200, 300, 400 mg) was given daily on days 1-7, and gefitinib 250 mg was given daily on days 1-14. Vorinostat doses were escalated based on a conventional 3 + 3 design. Pharmacodynamic markers were measured using PBMC collected at baseline and 4 hours after vorinostat dose on day 2 in cycle 1. No dose-limiting toxicities (DLT) were observed in 12 patients. We determined 400 mg vorinostat as the recommended phase II dose (RP2D). Median progression-free survival was 5.2 months (95% CI: 1.4-15.7). Disease control rate at 6 weeks was 83.3% (10/12). Vorinostat preferentially induced BIM mRNA-containing exon 4 over mRNA-containing exon 3, acetylated histone H3 protein, and proapoptotic BIM EL protein in 11/11, 10/11, and 5/11 patients, respectively. These data indicate that RP2D was 400 mg vorinostat combined with gefitinib in BIM deletion/EGFR mutation double-positive NSCLC. BIM mRNA exon 3/exon 4 ratio in PBMC may be a useful pharmacodynamic marker for treatment., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.) more...

Background: Non-small-cell lung cancer (NSCLC) patients with both epidermal growth factor receptor (EGFR) positive mutation and B-cell chronic lymphocytic leukemia/lymphoma-like 11 (BIM) deletion polymorphism had a poor clinical response to EGFR-tyrosine kinase inhibitors (TKIs). The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus chemotherapy versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletion polymorphism., Methods: A retrospective, non-randomized analysis was conducted. BIM deletion polymorphism was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from peripheral blood cells. Clinical characteristics, overall survival (OS), progress-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared between EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy group., Results: 65 patients were enrolled. 36 of them received EGFR-TKIs and 29 received EGFR-TKIs plus chemotherapy. EGFR-TKIs plus chemotherapy had significantly higher ORR than TKIs alone (65.5% vs. 38.9%, P = 0.046). Median PFS was significantly longer in EGFR-TKIs plus chemotherapy group than in TKIs group (7.2 vs 4.7 m; P = 0.008). Median OS was numerically longer in EGFR-TKIs plus chemotherapy group than in TKIs alone (18.5 vs 14.2 m; P = 0.107). EGFR-TKIs plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKIs alone., Conclusion: EGFR-TKIs plus chemotherapy conferred a significantly higher ORR, prolonged PFS and numerically longer OS in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism. Further prospective studies are needed to validate these findings., (Copyright © 2018 Elsevier B.V. All rights reserved.) more...