Lung Cancer 139 (2020) 146–150

Contents lists available at ScienceDirect

Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan

PLEKHM2-ALK: A novel fusion in small-cell lung cancer and durable T

response to ALK inhibitors
Tao Lia,1, Fan Zhanga,1, Zhaozhen Wua,b, Longgang Cuic, Xiaochen Zhaoc, Jinliang Wanga,
Yi Hua,*
a
Department of Oncology, PLA General Hospital, PLA School of Medicine, No.28 Fuxing Road, Haidian District, Beijing, 100853, China
b
School of Medicine, Nankai University, China
c
The Medical Department, 3D Medicines Inc., Shanghai, China

ARTICLE INFO ABSTRACT

Keywords: Objectives: In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) rearrangement identifies a
Small-cell lung cancer subgroup of patients who are sensitive to ALK tyrosine kinase inhibitors (TKIs). ALK fusion is extremely rare in
Novel ALK fusion small-cell lung cancer (SCLC). To the best of our knowledge, only two cases of SCLC harboring ALK fusion
Durable clinical benefit mutation has been reported previously, both of whom carrying EML4-ALK fusion. There are no standard
NGS
treatment options for SCLC patients with ALK fusion mutations. Herein, we described a rare case of ALK-rear-
ranged SCLC responding to ALK inhibitors.
Materials and methods: Immunohistochemistry (IHC) assay and next-generation sequencing (NGS) were per-
formed on the biopsied tumor tissue.
Results: NGS detected a novel pleckstrin homology and RUN domain containing M2 (PLEKHM2)-ALK fusion,
while the IHC analysis revealed an ALK-positive tumor. For extensive SCLC patients, median OS was about 8–13
months. The patient in this case had durable clinical benefit upon the treatment with ALK inhibitors, achieving
an overall survival (OS) of more than 27 months.
Conclusion: This case provides a meaningful reference for the treatment of SCLC patients with ALK fusion
mutations. This case also provides valuable information on the response to ALK inhibitors of patients with
PLEKHM2-ALK fusion and better understanding of ALK-TKI applications in the future. NGS may be used as a
routine test to explore more treatment opportunities for tumor SCLC patients.

1. Introduction
In non-small cell lung cancer (NSCLC), anaplastic lymphoma kinase
(ALK) rearrangement identifies a subgroup of patients who are sensitive
to ALK tyrosine kinase inhibitors (TKIs) [1–3]. Over the past years, a
growing number of ALK rearrangement alterations has been identified in
non-small cell lung cancer (NSCLC) predicting response to ALK TKIs
treatment [4]. However, ALK fusion is extremely rare in small-cell lung
cancer (SCLC). To the best of our knowledge, only two cases of SCLC
harboring ALK fusion mutation has been reported previously, both of
whom carrying EML4-ALK fusion [5,6]. There are no standard treatment
options for SCLC patients with ALK fusion mutations. Herein, we de-
scribed a rare case of ALK-rearranged SCLC responding to ALK inhibitors.
For extensive SCLC patients, median OS was about 8–13 months. Patient
of this case achieved an overall survival (OS) of more than 27 months.
2. Case report
A 63-year-old non-smoking female visited our hospital for worsened
pain of the right chest and persistent cough. Chest computed tomo-
graphy (CT) revealed two lobulated masses in the right middle and
lower lobes with parts of atelectasis on June 16, 2017. Pathological
examination with CT guided biopsy demonstrated SCLC.
Immunohistochemical staining indicated the sample being positive for
TTF-1, CD56, Synaptophysin (Syn) and Ki-67 (about 70 % positive),
and negative for NapsinA and p40 on (Fig. 1).

⁎
Corresponding author.
E-mail address: huyi0401@aliyun.com (Y. Hu).
1
Tao Li and Fan Zhang contributed equally to this work.

https://doi.org/10.1016/j.lungcan.2019.11.002
Received 30 September 2019; Received in revised form 28 October 2019; Accepted 5 November 2019
0169-5002/ © 2019 Published by Elsevier B.V.
T. Li, et al.
Fig. 1. Multi-biomarker immunohistochemistry confirms pathological typing of small-cell lung cancer. (A) H&E, (B) TTF-1, (C) CD56, (D) Syn and (E) Ki-67.
With further fludeoxyglucose F18 positron emission tomography
computed tomography (PET-CT) result, the patient was diagnosed as
SCLC (extensive-stage, pT4N3M1c, stage IV), with bilateral pulmonary
metastasis, bone metastases (thoracic 10 vertebral body, right third
anterior rib), multiple lymph node metastasis (including hilum of right
lung, mediastinum, retroperitoneal, bilateral neck and supraclavicular
fossa). Chemotherapy with etoposide and carboplatin was applied from
July 18, 2017. After 2 cycles of chemotherapy, PET-CT scan showed a
147
Lung Cancer 139 (2020) 146–150
slight reduction in tumor size, achieving a stable disease according to
the Response Evaluation Criteria in Solid Tumors, version 1.1. Next-
generation sequencing (NGS) was then applied to detect potential
mutations on the tumor biopsy specimen. The sequencing results
identified a novel ALK rearrangement (PLEKHM2-ALK) (Fig. 2A, B).
Immunohistochemical staining (Ventana Medical Systems, Tucson, AZ)
showed an increased signal of ALK expression (Fig. 2C). Crizotinib
(250 mg BID) was administered accompanying with another 2 cycles of
T. Li, et al.
Fig. 2. (A) Next-generation sequencing analysis of ALK fusion mutation in the patient’s biopsy sample. (B) Illustration of PLEKHM2-ALK rearrangement. (C)
Immunohistochemical staining of ALK expression.
chemotherapy from September 12, 2017. CT scan on December 18,
2017 supported a partial response with a reduction from 41*29 mm to
27*22 mm for the middle lobe lesion and a reduction from 40*26 mm to
27*18 mm for the lower lobe lesion. Crizotinib was used as main-
tenance thereafter. The patient maintained stable disease until June
2018, achieving 12-month progress-free survival (PFS). In June 2018,
multiple brain metastases was detected by Magnetic resonance imaging
(MRI), without any symptoms. Brigatinib was recommended to replace
crizotinib from June 2018 due to its superior evidence on the man-
agement of brain metastasis [1]. A stable disease was reached and
maintained for 7 months with brigatinib monotherapy. In January
2019, her brain lesions slowly progressed and two cycles of whole brain
radiotherapy were administered between March and May 2019 with the
concurrent treatment of brigatinib. PFS achieving more than 12 months
in the second line treatment with brigatinib plus brain radiotherapy.
The patient’s disease maintained stable for both lung lesions and the
148
Lung Cancer 139 (2020) 146–150
brain metastases till the report date of this case (Fig. 3), achieving an
OS of more than 27 months.
3. Discussion
This is the first report of PLEKHM2-ALK rearrangement, a novel
fusion identified using NGS. This is also the first reported SCLC patient
with ALK fusion who exhibited long-term benefit from the treatment of
ALK inhibitors. Commonly, ALK fusions result in the activation of ALK
kinase domain through the autophosphorylation involving dimeriza-
tion. In this case, IHC showed the increased activity of ALK. Whether
retained domain in PLEKHM2 may contribute to dimerization or acti-
vation of PLEKHM2-ALK is still unknown, as PLEKHM2-ALK is a novel
fusion pattern. Further functional investigation is needed. This case has
provided valuable insights into the future cancer treatment in clinic.
Firstly, NGS may be used as a routine test to explore more treatment
T. Li, et al. Lung Cancer 139 (2020) 146–150

Fig. 3. Computed tomography scan of mediastinum and thorax; Magnetic resonance imaging scan of the brain, with time line.

opportunities for tumor SCLC patients. Secondly, ALK TKI alone or
combined with chemotherapy may be recommended for SCLC patients
with ALK rearrangement.
Declaration of Competing Interest
Longgang Cui and Xiaochen Zhao are employees of 3D Medicines
Inc. The others declare no conflict of interest.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (81672996,81770204); Research Support Fund of
PLA General Hospital (2018XXFC-3, 2018XXFC-11); National Key R&D
Program of China, Stem Cell and Translation Research
(2017YFA0106200).

149
T. Li, et al.
References
[1] D.R. Camidge, D.W. Kim, M. Tiseo, C.J. Langer, M.J. Ahn, A.T. Shaw, R.M. Huber,
M.J. Hochmair, D.H. Lee, L.A. Bazhenova, K.A. Gold, S.I. Ou, H.L. West,
W. Reichmann, J. Haney, T. Clackson, D. Kerstein, S.N. Gettinger, Exploratory ana-
lysis of brigatinib activity in patients with anaplastic lymphoma kinase-positive non-
small-cell lung Cancer and brain metastases in two clinical trials, J. Clin. Oncol. 36
(26) (2018) 2693–2701.
[2] S.N. Gettinger, L.A. Bazhenova, C.J. Langer, R. Salgia, K.A. Gold, R. Rosell,
A.T. Shaw, G.J. Weiss, M. Tugnait, N.I. Narasimhan, D.J. Dorer, D. Kerstein,
V.M. Rivera, T. Clackson, F.G. Haluska, D.R. Camidge, Activity and safety of briga-
tinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-
arm, open-label, phase 1/2 trial, Lancet Oncol. 17 (12) (2016) 1683–1696.
[3] E.L. Kwak, Y.J. Bang, D.R. Camidge, A.T. Shaw, B. Solomon, R.G. Maki, S.H. Ou,
B.J. Dezube, P.A. Janne, D.B. Costa, M. Varella-Garcia, W.H. Kim, T.J. Lynch,
P. Fidias, H. Stubbs, J.A. Engelman, L.V. Sequist, W. Tan, L. Gandhi, M. Mino-
150
Lung Cancer 139 (2020) 146–150
Kenudson, G.C. Wei, S.M. Shreeve, M.J. Ratain, J. Settleman, J.G. Christensen,
D.A. Haber, K. Wilner, R. Salgia, G.I. Shapiro, J.W. Clark, A.J. Iafrate, Anaplastic
lymphoma kinase inhibition in non-small-cell lung cancer, N. Engl. J. Med. 363 (18)
(2010) 1693-703.
[4] T. Feng, Z. Chen, J. Gu, Y. Wang, J. Zhang, L. Min, The clinical responses of TNIP2-
ALK fusion variants to crizotinib in ALK-rearranged lung adenocarcinoma, Lung
Cancer 137 (2019) 19–22.
[5] G. Toyokawa, K. Taguchi, T. Ohba, Y. Morodomi, T. Takenaka, F. Hirai,
M. Yamaguchi, T. Seto, M. Takenoyama, K. Sugio, Y. Ichinose, First case of combined
small-cell lung cancer with adenocarcinoma harboring EML4-ALK fusion and an exon
19 EGFR mutation in each histological component, J. Thorac. Oncol. 7 (12) (2012)
e39–e41.
[6] G. Toyokawa, M. Takenoyama, K. Taguchi, R. Toyozawa, E. Inamasu, M. Kojo,
Y. Shiraishi, Y. Morodomi, T. Takenaka, F. Hirai, M. Yamaguchi, T. Seto,
M. Shimokawa, Y. Ichinose, An extremely rare case of small-cell lung cancer har-
boring variant 2 of the EML4-ALK fusion gene, Lung Cancer 81 (3) (2013) 487–490.