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Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1
Accepted Manuscript Title: Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1 Authors: Yuki Ikematsu, Yasuto Yoneshima, Kayo Ijichi, Kentaro Tanaka, Taishi Harada PII: DOI: Reference:
S0169-5002(17)30399-9 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.020 LUNG 5417
To appear in:
Lung Cancer
Author: Yoshinao Oda PII: DOI: Reference:
S0169-5002(17)30399-9 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.020 LUNG 5417
To appear in:
Lung Cancer
Authors: Yoichi Nakanishi, Isamu Okamoto PII: DOI: Reference:
S0169-5002(17)30399-9 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.020 LUNG 5417
To appear in:
Lung Cancer
Received date:
9-7-2017
Please cite this article as: {http://dx.doi.org/ This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Letter to Editor
Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1 Yuki Ikematsu, MD,1, Yasuto Yoneshima, MD, PhD1, Kayo Ijichi, MD1, Kentaro Tanaka, MD, PhD1, Taishi Harada, MD, PhD1, Yoshinao Oda, MD, PhD2, Yoichi Nakanishi, MD, PhD1, Isamu Okamoto, MD,PhD1,*
1
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan 2
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan *To whom correspondence should be addressed at: Research Institute for Diseases of the Chest,
Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel.: +81-92-642-5378. Fax: +81-92-642-5390. E-mail: [email protected]
The KEYNOTE-024 trial demonstrated the superiority of pembrolizumab, a monoclonal antibody to programmed cell death–1 (PD-1), over platinum-based combination chemotherapy as a first-line treatment for advanced non–small cell lung cancer (NSCLC) that expresses programmed cell death–ligand 1 (PD-L1) on at least 50% of tumor cells and which is negative for epidermal growth factor receptor gene (EGFR) mutation and anaplastic lymphoma kinase gene (ALK) rearrangement [1]. However, little is known of
1
the efficacy of anti–PD-1 therapy for pulmonary pleomorphic carcinoma (PPC), a rare form of NSCLC with a poor prognosis. We here describe a patient with PPC highly positive for PD-L1 who showed a marked response to pembrolizumab. A 71-year-old man developed severe left chest pain in February 2017. He had smoked cigarettes for 51 years. Computed tomography (CT) revealed a large mass in the left chest wall with fifth and sixth rib fractures (Fig. 1A). [18F]Fluoro-deoxyglucose positron emission tomography (FDG-PET) showed a high level of tracer uptake in a right iliac bone lesion (Fig. 1B). Blood analysis revealed an abnormally high white blood cell (WBC) count (53,160/mm3) and an elevated serum concentration of granulocyte colonystimulating factor (G-CSF) at 316 pg/ml (normal, <39 pg/ml). Ultrasound-guided percutaneous biopsy of the chest wall mass was performed for diagnosis, and histological examination showed that the isolated tissue contained ≥10% spindle cells (Fig. 2A). The tissue was positive for AE1/AE3 and CAM5.2 by immunohistochemistry (Fig. 2B), indicative of epithelial differentiation. Staining for TTF-1, P40, and S-100 was negative. The patient was diagnosed with PPC on the basis of the morphological findings of admixed sarcomatoid and epithelioid cells. The tumor tested negative for EGFR mutation and ALK rearrangement. Immunohistochemistry also detected PD-L1 expression on 80% of tumor cells (Fig. 2C). Pembrolizumab was administered at a dose of 200 mg every 3 weeks. After three cycles of pembrolizumab treatment, CT revealed marked shrinkage of the left chest wall mass (Fig. 1C) and FDG-PET (80 days after the first treatment) showed a pronounced decrease in tracer uptake in the right iliac bone metastasis (Fig. 1D). The WBC count and serum G-CSF level had decreased to 10,210/mm3 and 42 pg/ml,
2
respectively. Pembrolizumab therapy has been ongoing for five cycles without serious adverse events or tumor progression. Patients with PPC show an aggressive clinical course and poor survival, and standard therapy for such tumors has not been established [2]. Furthermore, patients with tumorrelated leukocytosis and lung cancer producing G-CSF have manifested rapid tumor growth and poor responses to chemotherapy and radiotherapy [3]. Patients with PPC producing G-CSF have rarely been reported, although one previous study also described more aggressive clinical characteristics and rapid tumor growth compared with other nonsmall cell lung cancer [4]. PD-L1 was recently shown to be highly expressed in PPC, suggestive of potential efficacy for anti-PD-1 therapy [5,6]. The present case had a PDL1 tumor proportion score of 80% and showed a pronounced response to pembrolizumab. Leukocytosis and the high serum level of G-CSF were resolved after three cycles of treatment. As far as we are aware, this is the first report of a marked response to pembrolizumab in a patient with PPC highly positive for PD-L1. This result reinforces the importance of measuring PD-L1 expression on tumor cells in order to provide the opportunity for anti-PD-1 therapy in patients with PPC. Further studies will be required to confirm the efficacy of anti–PD-1 therapy for PPC. A single-arm study of nivolumab in patients with advanced sarcomatoid carcinoma including PPC is currently ongoing (UMIN000023433).
Disclosure The authors report that they have no relevant relationships to disclose.
Conflicts of Interest and Source of Funding: None declared. 3
References
1.
Reck M, Rodríguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375(19):1823-1833.
2. Fishback NF, TravisWD, Moran CA et al. Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases. Cancer 1994;73:2936– 2945. 3.
Ikuma K, Shigeru M, Hiroshi K et al. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer 2001;92:2399–2405.
4.
Matsumoto M, Nakayama T, Inoue D et al. A pleomorphic carcinoma of the lung producing multiple cytokines and forming a rapidly progressive mass-like opacity. BMC Cancer. 2014;14:588.
5.
Kim S, Kim MY, Koh J et al. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Eur J Cancer 2015;51:2698–2707.
6.
Ito K, Hataji O, Katsuta K et al. “Pseudoprogression” of pulmonary pleomorphic carcinoma during nivolumab therapy. J Thorac Oncol 2016;10:117–119.
4
Figure Legends Figure 1. Before treatment, CT revealed a large mass in the left chest wall (A) and FDGPET showed a high level of tracer uptake in a right iliac lesion (B). After three cycles of pembrolizumab treatment, CT showed marked shrinkage of the tumor (C) and FDG-PET (80 days after the first treatment) revealed a pronounced decrease in tracer uptake in the right iliac lesion (D)．
Figure 2. Histological examination of a tumor biopsy specimen by hematoxylin-eosin staining (A) revealed pleomorphic carcinoma with spindle cells. Immunohistochemical staining for CAM5.2 was positive (B). A 22C3 IHC pharmDx assay detected PD-L1 expression on 80% of tumor cells (C).
5
Fig. 1
Fig. 2
6
S0169-5002(17)30399-9 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.020 LUNG 5417
To appear in:
Lung Cancer
Author: Yoshinao Oda PII: DOI: Reference:
S0169-5002(17)30399-9 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.020 LUNG 5417
To appear in:
Lung Cancer
Authors: Yoichi Nakanishi, Isamu Okamoto PII: DOI: Reference:
S0169-5002(17)30399-9 http://dx.doi.org/doi:10.1016/j.lungcan.2017.07.020 LUNG 5417
To appear in:
Lung Cancer
Received date:
9-7-2017
Please cite this article as: {http://dx.doi.org/ This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Letter to Editor
Marked response to pembrolizumab in a patient with pulmonary pleomorphic carcinoma highly positive for PD-L1 Yuki Ikematsu, MD,1, Yasuto Yoneshima, MD, PhD1, Kayo Ijichi, MD1, Kentaro Tanaka, MD, PhD1, Taishi Harada, MD, PhD1, Yoshinao Oda, MD, PhD2, Yoichi Nakanishi, MD, PhD1, Isamu Okamoto, MD,PhD1,*
1
Research Institute for Diseases of the Chest, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan 2
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu
University, Fukuoka, Japan *To whom correspondence should be addressed at: Research Institute for Diseases of the Chest,
Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Tel.: +81-92-642-5378. Fax: +81-92-642-5390. E-mail: [email protected]
The KEYNOTE-024 trial demonstrated the superiority of pembrolizumab, a monoclonal antibody to programmed cell death–1 (PD-1), over platinum-based combination chemotherapy as a first-line treatment for advanced non–small cell lung cancer (NSCLC) that expresses programmed cell death–ligand 1 (PD-L1) on at least 50% of tumor cells and which is negative for epidermal growth factor receptor gene (EGFR) mutation and anaplastic lymphoma kinase gene (ALK) rearrangement [1]. However, little is known of
1
the efficacy of anti–PD-1 therapy for pulmonary pleomorphic carcinoma (PPC), a rare form of NSCLC with a poor prognosis. We here describe a patient with PPC highly positive for PD-L1 who showed a marked response to pembrolizumab. A 71-year-old man developed severe left chest pain in February 2017. He had smoked cigarettes for 51 years. Computed tomography (CT) revealed a large mass in the left chest wall with fifth and sixth rib fractures (Fig. 1A). [18F]Fluoro-deoxyglucose positron emission tomography (FDG-PET) showed a high level of tracer uptake in a right iliac bone lesion (Fig. 1B). Blood analysis revealed an abnormally high white blood cell (WBC) count (53,160/mm3) and an elevated serum concentration of granulocyte colonystimulating factor (G-CSF) at 316 pg/ml (normal, <39 pg/ml). Ultrasound-guided percutaneous biopsy of the chest wall mass was performed for diagnosis, and histological examination showed that the isolated tissue contained ≥10% spindle cells (Fig. 2A). The tissue was positive for AE1/AE3 and CAM5.2 by immunohistochemistry (Fig. 2B), indicative of epithelial differentiation. Staining for TTF-1, P40, and S-100 was negative. The patient was diagnosed with PPC on the basis of the morphological findings of admixed sarcomatoid and epithelioid cells. The tumor tested negative for EGFR mutation and ALK rearrangement. Immunohistochemistry also detected PD-L1 expression on 80% of tumor cells (Fig. 2C). Pembrolizumab was administered at a dose of 200 mg every 3 weeks. After three cycles of pembrolizumab treatment, CT revealed marked shrinkage of the left chest wall mass (Fig. 1C) and FDG-PET (80 days after the first treatment) showed a pronounced decrease in tracer uptake in the right iliac bone metastasis (Fig. 1D). The WBC count and serum G-CSF level had decreased to 10,210/mm3 and 42 pg/ml,
2
respectively. Pembrolizumab therapy has been ongoing for five cycles without serious adverse events or tumor progression. Patients with PPC show an aggressive clinical course and poor survival, and standard therapy for such tumors has not been established [2]. Furthermore, patients with tumorrelated leukocytosis and lung cancer producing G-CSF have manifested rapid tumor growth and poor responses to chemotherapy and radiotherapy [3]. Patients with PPC producing G-CSF have rarely been reported, although one previous study also described more aggressive clinical characteristics and rapid tumor growth compared with other nonsmall cell lung cancer [4]. PD-L1 was recently shown to be highly expressed in PPC, suggestive of potential efficacy for anti-PD-1 therapy [5,6]. The present case had a PDL1 tumor proportion score of 80% and showed a pronounced response to pembrolizumab. Leukocytosis and the high serum level of G-CSF were resolved after three cycles of treatment. As far as we are aware, this is the first report of a marked response to pembrolizumab in a patient with PPC highly positive for PD-L1. This result reinforces the importance of measuring PD-L1 expression on tumor cells in order to provide the opportunity for anti-PD-1 therapy in patients with PPC. Further studies will be required to confirm the efficacy of anti–PD-1 therapy for PPC. A single-arm study of nivolumab in patients with advanced sarcomatoid carcinoma including PPC is currently ongoing (UMIN000023433).
Disclosure The authors report that they have no relevant relationships to disclose.
Conflicts of Interest and Source of Funding: None declared. 3
References
1.
Reck M, Rodríguez-Abreu D, Robinson AG et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016; 375(19):1823-1833.
2. Fishback NF, TravisWD, Moran CA et al. Pleomorphic (spindle/giant cell) carcinoma of the lung. A clinicopathologic correlation of 78 cases. Cancer 1994;73:2936– 2945. 3.
Ikuma K, Shigeru M, Hiroshi K et al. Tumor-related leukocytosis is linked with poor prognosis in patients with lung carcinoma. Cancer 2001;92:2399–2405.
4.
Matsumoto M, Nakayama T, Inoue D et al. A pleomorphic carcinoma of the lung producing multiple cytokines and forming a rapidly progressive mass-like opacity. BMC Cancer. 2014;14:588.
5.
Kim S, Kim MY, Koh J et al. Programmed death-1 ligand 1 and 2 are highly expressed in pleomorphic carcinomas of the lung: comparison of sarcomatous and carcinomatous areas. Eur J Cancer 2015;51:2698–2707.
6.
Ito K, Hataji O, Katsuta K et al. “Pseudoprogression” of pulmonary pleomorphic carcinoma during nivolumab therapy. J Thorac Oncol 2016;10:117–119.
4
Figure Legends Figure 1. Before treatment, CT revealed a large mass in the left chest wall (A) and FDGPET showed a high level of tracer uptake in a right iliac lesion (B). After three cycles of pembrolizumab treatment, CT showed marked shrinkage of the tumor (C) and FDG-PET (80 days after the first treatment) revealed a pronounced decrease in tracer uptake in the right iliac lesion (D)．
Figure 2. Histological examination of a tumor biopsy specimen by hematoxylin-eosin staining (A) revealed pleomorphic carcinoma with spindle cells. Immunohistochemical staining for CAM5.2 was positive (B). A 22C3 IHC pharmDx assay detected PD-L1 expression on 80% of tumor cells (C).
5
Fig. 1
Fig. 2
6