Elsevier

Lung Cancer

Volume 120, June 2018, Pages 82-87
Lung Cancer

EGFR-TKIs plus chemotherapy demonstrated superior efficacy than EGFR-TKIs alone as first-line setting in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism

https://doi.org/10.1016/j.lungcan.2018.04.004Get rights and content

Highlights

  • BIM deletion polymorphism was a prognostic factor to the therapy of EGFR-TKIs.

  • EGFR-TKIs plus chemotherapy could improve BIM deletion polymorphism mediated intrinsic resistance to TKIs.

  • EGFR-TKIs plus chemotherapy showed better outcome in NSCLC patients with BIM deletion polymorphism.

Abstract

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.

Introduction

The epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib, erlotinib and osimertinib, are recommended as the first-line therapy in advanced EGFR mutation-positive NSCLC patients [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]]. However, approximately 20%–30% of NSCLC patients with activated EGFR mutation show primary resistance to EGFR-TKIs [13]. One intrinsic resistance mechanism was B-cell chronic lymphocytic leukemia/lymphoma-like 11 (BIM) deletion polymorphism [14].

BIM, also called BCL2L11, is a proapoptotic protein and a member of the B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) families of proteins, binding to the pro-survival Bcl-2 family members with high affinity and directly activating proapoptotic BAX and BAK to promote cell death [[15], [16], [17]]. Several previous studies have demonstrated that BIM was a key modulator of apoptosis triggered by EGFR-TKIs [[18], [19]]. BIM deletion polymorphism, a germline alteration, was reported about 12.8% in NSCLC and was thought to be associated with intrinsic resistance to EGFR-TKIs [[20], [21], [22]]. In a study that screened 2597 healthy individuals, BIM deletion polymorphism was present in 12.3% of East Asians but absent in Africans and Europeans [14]. EGFR-mutant NSCLC cells with the BIM deletion polymorphism showed impaired generation of BIM with the proapoptotic BH3 domain, as well as resistance to EGFR-TKIs induced apoptosis [[14], [15], [23]]. JY Ma et al. reported that BIM deletion polymorphism was significantly associated with a poor response to EGFR-TKIs therapy in EGFR mutation positive NSCLC patients [24]. Another study also demonstrated that decreased BIM expression level inhibited the apoptotic response and tumor shrinkage induced by EGFR-TKIs therapy [22].

Our previous study found the correlation between BIM deletion polymorphism and poor response to EGFR-TKIs in patients with activating EGFR mutations [20]. Therefore, to find out a better clinical treatment strategy, we retrospectively compared EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy as the first-line treatment for NSCLC patients harboring both activating EGFR mutations and BIM deletion polymorphism.

Section snippets

Patients

This retrospective, non-randomized analysis had screened all NSCLC patients treated in Shanghai Pulmonary Hospital from June 2014 to September 2016, and only those harboring both mutated EGFR and BIM deletion polymorphism and their therapies were either oral EGFR-TKIs alone or oral EGFR-TKIs plus intravenous chemotherapy with cisplatin or carboplatin plus pemetrexed, docetaxel, paclitaxel or gemcitabine were enrolled. All involved patients met the following inclusion criteria: they were aged

Patient characteristics

In this retrospective study, 547 NSCLC patients were screened and 69 (12.7%) harbored both EGFR mutations and BIM deletion polymorphism. Among this filtered population, one abandoned therapy, two lost connections and the other one accepted EGFR-TKI combined with bevacizumab. 65 patients were finally enrolled into this study, 36 of them received EGFR-TKIs (20 of them received gefitinib and 16 received erlotinib), among those patients, 26(72.2%) received second-line chemotherapy after disease

Discussion

The current study, to the best of our knowledge, was the first one to compare the clinical efficiency of EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy in the treatment of NSCLC patients with EGFR mutation and BIM deletion polymorphism. As we all know, EGFR-TKIs has undisputedly been recommended as the standard first-line therapy for NSCLC patients with activated EGFR mutation. However, several studies found that EGFR activated-mutation patients with BIM deletion polymorphism showed a poor

Conclusions

In conclusion, combination of EGFR-TKIs with chemotherapy showed a better efficacy and acceptable side effects comparing with EGFR-TKIs alone in advanced NSCLCs with activating EGFR mutation and BIM deletion polymorphism. Besides on these results, we have initiated a single arm phase II clinical trial (NCT02930954) to evaluate the effectiveness and safety of EGFR-TKIs alone versus combination of EGFR-TKIs with doublet chemotherapy or antiangiogenic drug in advanced NSCLC patients with EGFR

Funding

This study was supported in part by a grant from Shanghai Pujiang Program (17PJD036). Major disease clinical skills enhancement program of three-year action plan for promoting clinical skills and clinical innovation in municipal hospitals, Shanghai Shen Kang Hospital Development Center ‘Clinical Research Plan of SHDC’ (16CR1001A). The fundamental research funds for the central universities.

Conflict of interest

None.

Acknowledgements

Sangtian Liu, Yayi He, Chao Zhao, Shengxiang Ren, Xuefei Li, Jiang Tao, Jie Zhang, Chunxia Su, Xiaoxia Chen, Weijing Cai, Guanghui Gao, Wei Li, Fengying Wu, Jiayu Li, Jing Zhao, Fei Zhou, Qiong Hu, Mingchuan Zhao collected the relevant data; Sangtian Liu, Yayi He drafted the manuscript text; Caicun Zhou and Fred R Hirsch give critical comments and revised the paper; all authors approved the final version of the manuscript.

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      The pro-apoptotic role of BIM relies on the pro-apoptotic domain, namely, BCL-2 homology domain 3 (BH3) [8]. However, BIM deletion polymorphism (BIM-del) specifically occurring in 12–18 % of East Asians could result in the absence of BH3, thereby blocking apoptosis [8–10]. Previous studies have reported that BIM-del is associated with resistance to first-generation EGFR-TKIs and ALK/ROS1-TKIs, and is a poor prognostic factor for NSCLC patients with EGFR/ALK/ROS1 mutations [8,9,11].

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      Unfortunately, acquired resistance to EGFR-TKIs has been shown in patients with NSCLC after receiving EGFR-TKIs for one year, and this resistance is mainly due to a secondary mutation in exon 20 causing methionine to replace threonine at position 790 in the kinase domain, critically attenuating the therapeutic effect of EGFR-TKIs for NSCLC [6–8]. Previous studies manifested that a combination of EGFR-TKIs and chemotherapeutic agents, especially in a time-staggered administration manner, could achieve a synergistic effect on cell proliferation in vitro [9–12]. For example, Lee et al. reported that pretreatment of lung cancer cells withEGFR-TKI Er markedly synergized the apoptotic response of lung cancer cells to the DNA-damaging agent DOX [9].

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    Sangtian Liu and Yayi He contributed equally to the article.

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