Case Report

Lung Adenocarcinoma Harboring Concomitant EGFR Mutation and EML4-ALK Fusion That Benefits From Three Kinds of Tyrosine Kinase Inhibitors: A Case Report and Literature Review Ning Zhao,1 Shu-yi Zheng,1,2 Jin-ji Yang,1 Xu-chao Zhang,1 Zhi Xie,1 Bin Xie,3 Jian Su,1 Zhi-hong Chen,1 Shi-liang Chen,1 Na Zhang,1 Na-na Lou,1 Song Dong,1 Yi-long Wu1 Clinical Practice Points  The

concomitant presence of echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) and epidermal growth factor receptor (EGFR) is extremely rare.  Previous studies have shown that EGFR mutation and EML4-ALK fusion are mutually exclusive and that the coexistence of these 2 genes are associated with

resistance to EGFR tyrosine kinase inhibitors (TKIs) and ALK inhibitors.  We report a case of lung adenocarcinoma harboring a concomitant EGFR mutation and EML4-ALK fusion that benefited for a short period from 3 TKIs.  Additional study is warranted to clarify the therapeutic strategies in such patients with a concomitant EGFR mutation and EML4-ALK fusion.

Clinical Lung Cancer, Vol. 16, No. 2, e5-9 ª 2015 Elsevier Inc. All rights reserved. Keywords: Concomitant, Echinoderm microtubule-associated protein-like 4, Epidermal growth factor receptor, NSCLC, Tyrosine kinase inhibitor

Introduction During the past decade, the emerging effect of targeted therapies has led to a therapeutic paradigm shift in lung cancer. A driver gene alteration has been detected in 64% of lung adenocarcinoma cases. The epidermal growth factor receptor (EGFR) and echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) are important driver genes that have been found in 17% and 8% of patients, respectively.1 Previous studies have shown that an EGFR mutation and EML4-ALK fusion are mutually exclusive and that the coexistence of these 2 genes is associated with N.Z. and S.-Y.Z. contributed equally to this work. 1 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Science, Guangzhou, China 2 Shantou University Medical College, Shantou, China 3 Nanchang University Medical College, Nanchang, China

Submitted: Oct 15, 2014; Accepted: Nov 11, 2014; Epub: Nov 18, 2014 Address for correspondence: Yi-long Wu, MD, Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Science, 106 Zhongshan 2nd Road, Guangzhou 510080 People’s Republic of China E-mail contact: [email protected]

1525-7304/$ - see frontmatter ª 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cllc.2014.11.001

resistance to both EGFR tyrosine kinase inhibitors (TKIs) and ALK inhibitors.2-4 The concomitant presence of EML4-ALK and EGFR has been extremely rare and was found in only 13 of 977 cases (1.3%) of nonesmall-cell lung cancer (NSCLC). Also, the EGFR-ALK coexistence rate was 3.9% (13 of 336) and 18.6% (13 of 70) in patients with EGFR-mutant and ALK-rearranged patients, respectively.5 Although the incidence was rare, the question of how to treat this small subgroup of patients still warrants additional investigations. We report a case of lung cancer harboring concomitant EGFR mutation and EML4-ALK fusion that benefited for a short period from 3 TKIs.

Case Report A 48-year-old Asian woman who had never smoked was diagnosed in December 2012 with clinical stage IA (cT1aN0M0, TNM, version 7.0) disease before surgery. However, pleural invasion and involvement of 9 mediastinal lymph nodes were found intraoperatively. Next, the patient underwent wedge resection and mediastinal lymph node and pleural nodule sampling. The pathologic diagnosis was mixed subtype lung adenocarcinoma

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Lung Adenocarcinoma With EGFR Mutation and EML4-ALK Fusion (acinar growth pattern [90%] combined with bronchioloalveolar carcinoma [10%]; Figure 1A), stage IV (pleural involvement, pT1aN2M1a). Cold-polymerase chain reaction and pyrosequencing was performed to detect EGFR mutation, which showed the exon 21 (L861Q) mutation (Figure 1C). The patient received erlotinib as

first-line treatment, and disease stability was achieved for 5.3 months (Figure 2A,B). The carcinoembryonic antigen (CEA) level in the serum increased gradually from 15.9 to 275.0 ng/mL. At disease progression according to the Response Evaluation Criteria in Solid Tumors, the patient received nedaplatin plus

Figure 1 (A) Hematoxylin-Eosin Staining of the Primary Tumor Revealed Adenocarcinoma (December 2012). (B) Fluorescent In Situ Hybridization Assay (FISH) Revealed Echinoderm Microtubule-Associated Protein-Like 4 Anaplastic Lymphoma Kinase (EML4-ALK) Fusion (December 2012). (C). Pyrosequencing Showed Epidermal Growth Factor Receptor (EGFR) Exon 21 (L861Q) Mutation (December 2012). (D) Immunohistochemistry (IHC) Showed Low Expression of p-EGFR (December 2012). (E) IHC Showed High Expression of p-ALK (December 2012). (F). Gene Analysis of Our Patient at Different Times

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Abbreviations: DS ¼ DNA sequencing; ND ¼ not done.

Clinical Lung Cancer March 2015

Ning Zhao et al Figure 2 Computed Tomography (CT) Scans of Our Patient. (A) Chest CT Scan Before Erlotinib Treatment. (B) Chest CT Scan After 1 Month of Erlotinib Treatment. (C) Chest CT Scan Before Crizotinib Treatment. (D) Chest CT Scan After 2 Months of Crizotinib Treatment. (E) Chest CT Scan Before AP26113 Treatment. (F) Chest CT Scan After 1 Month of AP26113 Treatment

pemetrexed chemotherapy for 3 cycles and then experienced progressive disease (PD) with greater omentum, pleural effusion, and mediastinal lymph nodes metastases. The patient underwent repeat biopsy in August 2013 to detect ALK rearrangement using fluorescent in situ hybridization assay. She received crizotinib because she harbored the EML4-ALK fusion gene (53% rearrangement) (Figure 1B), and stable disease (SD) was achieved for 3.5 months (Figure 2C,D). During this setting, the patient experienced high fever and progressive dysphagia, and her performance status (PS) changed to 3. Her disease progressed to distant organs, including liver, retroperitoneal lymph nodes, contralateral lung, and mediastinal lymph nodes. From December 2013, the patient began taking AP26113 by herself at a dose of 150 mg/d. The symptoms improved quickly, and the CEA decreased to 51.1 ng/mL. A partial remission (PR) was obtained after 1 month (Figure 2E,F), the mediastinal lymph nodes shrunk significantly, and the ascites were controlled well. However, the patient’s symptoms deteriorated in February, and the chest computed tomography scan showed disease progression, with a progression-free survival (PFS) of only 2 months. The pleural

effusion after failure with AP26113 in March 2014 was sampled and cancer cells could be found (the tumor content was low). However, EGFR mutation analysis (by amplification refractory mutation system and sequencing) revealed both were wild type (Figure 1F). Her therapy was changed to axitinib at a dose of 5 mg twice daily. However, no clinical benefit was observed, and the patient died in April 2014.

Discussion To our knowledge, this is the first case of NSCLC harboring a concomitant EGFR mutation and EML4-ALK fusion gene that benefitted from 3 TKIs. Previously,  29 cases with coexistence of EGFR and ALK-altered genes were reported.4,6-13,17 The patient characteristics and treatment outcomes are listed in Table 1. From the data presented in Table 1, we noted that 22 patients had received an EGFR-TKI, 1 had achieved complete remission (CR), 13 PR, 4 SD, and 4 PD. The response rate (RR) was 63.6% (14 of 22), and the disease control rate (DCR) was 81.8% (18 of 22). In addition, 9 patients received crizotinib, of whom 1 achieved CR, 4 PR, 3 SD, and 1 PD. The RR was 55.6% (5 of 9), and the DCR

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Investigator

Patients (n)

Age (years)

Sex

Race

1

67

F

White

Never

AC

Miyanaga et al12

1

55

F

Asian

Never

AC

Chen et al11 Tanaka et al9 Tiseo et al8 Papat et al7 Kuo et al6 Santelmo et al17 Lee et al10 Sasaki et al4 Yang et al5

1 1 1 1 1 1 4 3 13

56 39 48 65 72 52 73 NR Median age, 59

M M M F F F M NR F, 8; M, 5

Asian Asian White White Asian White Asian White Asian

Heavy Light Never Never Never Heavy Former NR Never, 12; light, 1

AC AC SC/AC AC AC AC AC NR AC

Present patient Total

1 29

48 e

F e

Asian e

Never e

AC e

Chiari et al

13

Smoking Status Histologic Type

EGFR-TKI

Response

ALK-TKI

Response

Gefitinib Erlotinib/afatinib Gefitinib Erlotinib Erlotinib Erlotinib Erlotinib Erlotinib Gefitinib Gefitinib Gefitinib Erlotinib, 2 Gefitinib, 3 Erlotinib, 5 Afatinib, 2 Erlotinib 22

PR PD SD SD SD PD PD CR PR PR PD 2 PR 3 PR 4 PR, 1 PD 1 PR, 1 SD; SD 1 CR, 13 PR, 4 SD, 4 PD

Crizotinib

PR

Crizotinib

SD

Crizotinib ND ND ND ND ND Crizotinib ND Crizotinib, 4

CR e e e e e PR e 2 PR, 1 PD, 1 SD

Crizotinib 9

SD 1 CR, 4 PR, 3 SD, 1 PD

Abbreviations: AC ¼ adenocarcinoma; ALK ¼ anaplastic lymphoma kinase; CR ¼ complete remission; EGFR ¼ epidermal growth factor receptor; F ¼ female; M ¼ male; ND ¼ not done; NR ¼ not reported; PD ¼ progressive disease; PR ¼ partial response; SC ¼ squamous carcinoma; SD ¼ stable disease; TKI ¼ tyrosine kinase inhibitor.

Lung Adenocarcinoma With EGFR Mutation and EML4-ALK Fusion

Clinical Lung Cancer March 2015 Table 1 Patient Characteristics and Treatment Outcomes of NSLLC With Concomitant EGFR Mutation and ALK Fusion Previously Reported

Ning Zhao et al was 88.9% (8 of 9). Of the 8 patients who received both EGFRTKI and crizotinib, only 1 patient13 had a response to both agents, and none resist to these 2 drugs. This suggests that patients harboring the EGFR/ALK co-alteration might not be associated with resistance to both EGFR-TKIs and ALK inhibitors but could obtain different responses with one of these agents. If the tumor is driven by 2 driver genes, which agent becomes more effective might depend on the levels of the relevant gene alterations. Yang et al5 found that differential phosphorylation of EGFR or ALK might contribute to different sensitivities to EGFR-TKIs or crizotinib. Accordingly, EGFR-TKIs or ALK-TKIs should be chosen according to relative phospho-EGFR and phospho-ALK levels in patients with an EGFR/ALK coalteration. The present patient had a moderate response to erlotinib and crizotinib. The phospho-EGFR expression was low but the phospho-ALK expression was high (Figure 1D,E); thus, the ALK, and not the EGFR, was the dominant pathway. Therefore, using erlotinib as the first-line therapy might not have been the wisest choice. In addition, crizotinib was used as third-line treatment, and could be the reason she had SD for only 3.5 months. In contrast, our patient achieved a dramatic response to the secondgeneration dual EGFR/ALK inhibitor—AP26113, which exhibited promising antitumor activities in mutation-based resistance of EGFR and ALK both in vivo and in vitro,14-16 although it resulted in PFS of only 2 months. It might be that after the cancer had developed resistance to erlotinib and crizotinib, the dual altered genes within this patient drove equal numbers of tumor cells. Tumor growth could not be limited unless pathways were both inhibited. We regret that we could not perform a repeat biopsy after failure of AP26113 owing to the patient’s poor PS. Also, the tumor content of the pleural effusion was so low we could not detect any biomarkers. It is important to obtain repeat biopsy tissue samples to detect the gene profile when disease progression has occurred. Currently, phase I and II clinical trials of AP26113 are ongoing, with potential activity to inhibit ALK and EGFR shown. The coexistence of dual or multiple oncogenes should been considered by oncologists to determine the optimal therapeutic strategies such as combination or sequential treatment modes. Additional study is warranted to clarify the therapeutic strategies in such patients with a concomitant EGFR mutation and EML4-ALK fusion.

Conclusion We have reported a case of lung adenocarcinoma harboring a concomitant EGFR mutation and EML4-ALK fusion that benefitted for a short time from 3 TKIs. Additional studies are

warranted to clarify the therapeutic strategies for patients with EGFR/ALK coalterations.

Acknowledgments This work was supported by Key Technologies R&D Program of Guangzhou (grant 2011Y2-00014) and the Key Laboratory Program of Guangdong (grant 2012A061400006), Guangdong Department of Science & Technology Translational Medicine Center (grant 2011A080300002) (to Y. L. Wu).

Disclosure The authors have stated that they have no conflicts of interest.

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Lung adenocarcinoma harboring concomitant EGFR mutation and EML4-ALK fusion that benefits from three kinds of tyrosine kinase inhibitors: a case report and literature review.

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