Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double‐positive lung cancer

Takeuchi, Shinji; Hase, Takashi; Shimizu, Shinobu; Ando, Masahiko; Hata, Akito; Murakami, Haruyasu; Kawakami, Takahiro; Nagase, Kazuhiko; Yoshimura, Kenichi; Fujiwara, T.; Tanimoto, Azusa; Nishiyama, Akihiro; Arai, Sachiko; Fukuda, Koji; Katakami, Nobuyuki; Takahashi, Toshiaki; Hasegawa, Yoshinori; Ko, Tun Kiat; Ong, S. Tiong; Yano, Seiji

doi:10.1111/cas.14260

Cited by 30 publications

(28 citation statements)

References 34 publications

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“…A preclinical study by Nakagawa et al found that combining EGFR-TKIs with histone deacetylase (HDAC) inhibition could circumvent the resistance induced by BIM-del [14]. Furthermore, a recent phase I study of patients with BIM-del and EGFR-mutant double-positive lung cancer who were treated with an HDAC inhibitor (vorinostat) and gefitinib in combination obtained satisfying results with regard to safety and ascertained 400 mg of vorinostat as the recommended dose for a phase II study [15]. Additionally, EGFR-TKIs plus chemotherapy also showed a significant clinical benefit compared to EGFR-TKI monotherapy in advanced NSCLC patients with EGFR mutation and BIM-del [10].…”

Section: Discussionmentioning

confidence: 99%

Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy

Zhang

et al. 2021

Lung Cancer

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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.

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Section: Discussionmentioning

confidence: 99%

Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy

Zhang

et al. 2021

Lung Cancer

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“…Vorinostat was insufficient to reverse EGFR-TKI acquired resistance in EGFR mutant condition [ 364 ]. Similarly, vorinostat failed to improve PFS in combination with gefitinib in other clinical trials including patients with EGFR-mutant NSCLC [ 365 , 366 ]. ICI and particularly pembrolizumab combined with vorinostat (400 mg/day) was explored in a phase 1 study, including 33 patients with advanced NSCLC.…”

Section: Hypoxia-related Treatments and Research Developmentmentioning

confidence: 99%

Hypoxia in Lung Cancer Management: A Translational Approach

Ancel

Perotin

Dewolf

et al. 2021

Cancers

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Lung cancer represents the first cause of death by cancer worldwide and remains a challenging public health issue. Hypoxia, as a relevant biomarker, has raised high expectations for clinical practice. Here, we review clinical and pathological features related to hypoxic lung tumours. Secondly, we expound on the main current techniques to evaluate hypoxic status in NSCLC focusing on positive emission tomography. We present existing alternative experimental approaches such as the examination of circulating markers and highlight the interest in non-invasive markers. Finally, we evaluate the relevance of investigating hypoxia in lung cancer management as a companion biomarker at various lung cancer stages. Hypoxia could support the identification of patients with higher risks of NSCLC. Moreover, the presence of hypoxia in treated tumours could help clinicians predict a worse prognosis for patients with resected NSCLC and may help identify patients who would benefit potentially from adjuvant therapies. Globally, the large quantity of translational data incites experimental and clinical studies to implement the characterisation of hypoxia in clinical NSCLC management.

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“…EGFR-TKI combination therapy with histone deacetylase (HDAC) inhibitors may be one approach to overcome the inferior outcomes conferred by the BIM deletion. A recent phase I study with 12 patients treated with the combination of gefitinib and vorinostat (a small-molecule HDAC inhibitor) revealed a DCR of 83.3% (10/12) at six weeks, with a median PFS of 5.2 months (95% CI, 1.4–15.7) ( 43 ). In addition, retrospective analysis revealed that EGFR-TKIs plus chemotherapy conferred a significantly higher ORR (65.5 vs. 38.9%, p = 0.046), prolonged PFS (7.2 vs. 4.7 months; p = 0.008) and a longer OS (18.5 vs. 14.2 months; p = 0.107) compared to TKIs alone in advanced NSCLC patients with EGFR mutations and BIM deletion polymorphism ( 176 ).…”

Section: Other Biomarkersmentioning

confidence: 99%

Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

et al. 2020

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Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

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Phase I study of vorinostat with gefitinib in BIM deletion polymorphism/epidermal growth factor receptor mutation double‐positive lung cancer

Cited by 30 publications

References 34 publications

Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy

Clinical implications of germline BCL2L11 deletion polymorphism in pretreated advanced NSCLC patients with osimertinib therapy

Hypoxia in Lung Cancer Management: A Translational Approach

Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

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