Complete and durable response of pulmonary large‐cell neuroendocrine carcinoma to pembrolizumab

Abstract Background Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare and aggressive tumor with a poor prognosis and standard therapy has not yet been established. Case A 65‐year‐old male with a cough for 2 months presented to our hospital. He was clinically diagnosed with non small cell lung cancer cT3N1M0 stage IIIA and underwent right pneumonectomy. The final diagnosis was pulmonary LCNEC pT3N1M0 stage IIIA. Multiple subcutaneous masses were detected 4 months after surgery, and biopsy revealed postoperative recurrence and metastasis. Chemotherapy with carboplatin plus etoposide was initiated. Subcutaneous masses increased and multiple new brain metastases developed after two cycles. Additional tests revealed that epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 (PD‐L1) expression rate in tumor cells was 40% (22C3 clones). The primary cells infiltrating the tumor were CD3‐positive T cells and CD138‐positive plasma cells. Second‐line treatment with pembrolizumab was started. The shrinkage of subcutaneous masses was observed after one cycle, and the tumor had completely disappeared after six cycles. Treatment was continued for approximately 2 years. This response has been maintained for 4 years and is still ongoing. Conclusion Pembrolizumab may be used as a treatment option for pulmonary LCNEC.

ealed postoperative recurrence and metastasis. Chemotherapy with carboplatin plus etoposide was initiated. Subcutaneous masses increased and multiple new brain metastases developed after two cycles. Additional tests revealed that epidermal growth factor receptor and anaplastic lymphoma kinase were negative, and the programmed death ligand 1 (PD-L1) expression rate in tumor cells was 40% (22C3 clones). The primary cells infiltrating the tumor were CD3-positive T cells and CD138-positive plasma cells.
Second-line treatment with pembrolizumab was started. The shrinkage of subcutaneous masses was observed after one cycle, and the tumor had completely disappeared after six cycles. Treatment was continued for approximately 2 years. This response has been maintained for 4 years and is still ongoing.
Conclusion: Pembrolizumab may be used as a treatment option for pulmonary LCNEC. Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) with antitumor activity for advanced NSCLC. 2,3 However, limited information is currently available on the effectiveness of pembrolizumab for pulmonary LCNEC. 4 We herein report a rare case of the complete response (CR) of pulmonary LCNEC to pembrolizumab.

| CASE
A 65-year-old male presented to our hospital with a cough for 2 months. Chest X-ray revealed a tumor shadow in the right middle lung field. He had smoked two packets of cigarettes a day for 47 years and was diagnosed with prostatic cancer at 56 years. The Eastern Cooperative Oncology Group Performance Status was 1. Blood tests F I G U R E 1 (A) Chest X-ray and (B, C) contrast-enhanced CT at the first admission. Chest X-ray and contrast-enhanced CT showed a tumor in the right upper lobe

| DISCUSSION
We encountered a rare case showing the CR of pulmonary LCNEC to pembrolizumab monotherapy. This response has been maintained for 4 years and is still ongoing. To the best of our knowledge, the CR of pulmonary LCNEC to immune checkpoint inhibitors (ICI) is extremely rare, with only three case reports in the literature. [5][6][7] LCNEC is classified as pulmonary neuroendocrine carcinoma by the 2015 World Health Organization classification. The prognosis of pulmonary LCNEC is poor and standard therapy has not yet been established.
However, ICI were effective in several cases of pulmonary LCNEC. 4,[8][9][10] Our case and previous case reports are summarized in Table 1. The mean age of patients was 55 years, and only two cases were women. Many cases were heavy smokers and PD-L1 expression levels were not high.
Two cases were treated with pembrolizumab, six with nivolumab, and one with nivolumab plus ipilimumab. The effects of ICI were CR in four patients, a partial response (PR) in three, and stable disease (SD) in two. In a retrospective cohort of 11 patients with LCNEC treated with ICI, the response rate was 9.1% (one patient) and median progression-free survival was 2.7 months. 11 PD-L1 was previously reported to be expressed in approximately 10%-20% of pulmonary LCNEC cases. 12,13 However, no correlation has been reported between PD-L1 expression levels and OS with ICI. On the other hand, although it was not measured in the present study, pulmonary LCNEC harbors a high mutation burden. 13 Immune cell infiltration is more frequent in pulmonary LCNEC versus SCLC (58% vs. 23%), as is the expression of PD-L1 on immune cells (46% vs. 23%). 13 In the present case, the primary cells infiltrating the tumor were CD138-positive plasma cells.
A similar case report was published for lung cancer. 14  cancer. 15,16 However, this is merely suggestive. In various cancer types, the presence of tertiary lymphoid structures has been associated with longer disease-free and overall survival in patients treated with ICI. 17 In contrast, the suppression of antitumor effects by plasma cell subgroups has been demonstrated. 18 Further studies are needed to identify predictive biomarkers of ICI for LCNEC.
Immunotherapy is expected to improve the prognosis of patients with pulmonary LCNEC. 19 According to the findings of several phase II studies, ICI are a promising therapeutic option for pulmonary LCNEC. 20 Therefore, ICI may be used to treat patients with pulmonary LCNEC.

| CONCLUSION
We encountered a rare case showing the CR of pulmonary LCNEC to pembrolizumab monotherapy. ICI are a promising treatment option for pulmonary LCNEC.

CONFLICT OF INTEREST
The authors have stated explicitly that there are no conflicts of interest in connection with this article.

AUTHOR CONTRIBUTIONS
All authors had full access to the data in the study and take responsi-

DATA AVAILABILITY STATEMENT
The data that support the results of this study are available from the corresponding author upon reasonable request.

ETHICS STATEMENT
Informed consent was obtained to publish this report.