Response to selpercatinib in a patient with RET fusion-positive pulmonary large-cell neuroendocrine carcinoma: A case report

Large-cell neuroendocrine carcinoma (LCNEC) is a rare subtype of non-small-cell lung cancer associated with a poor prognosis. LCNEC is genetically heterogeneous, and studies have revealed distinct molecular subtypes of LCNEC, which may have therapeutic implications. Herein, we present a case of a patient with stage IV LCNEC harboring a KIF5B–RET fusion whose disease responded to the selective RET inhibitor selpercatinib both extra- and intra-cranially, highlighting the importance of comprehensive molecular testing in LCNEC for selection of optimal treatment.


Introduction
RET fusions are oncogenic drivers found in 1%-2% of non-small cell lung cancer (NSCLC) (1). Patients with RET fusion-positive NSCLC are characterized by younger age and never-smoker status and frequently have adenocarcinoma histology (1). Several fusion partners have been identified, including KIF5B, CCDC6, and NCOA4 (2). RET fusions promote carcinogenesis by activating various downstream signaling pathways such as RAS/ MAPK/ERK, PI3K/AKT, and JAK/STAT (2). There are two potent and selective RET tyrosine kinase inhibitors (TKIs) approved by the U.S. Food and Drug Administration: selpercatinib and pralsetinib. Several strategies and new target drugs are currently under investigation (3).
According to the 2021 World Health Organization (WHO) classification of lung tumors, neuroendocrine neoplasms encompass typical carcinoid and atypical carcinoid, as well as high-grade neuroendocrine carcinomas (NECs), including large cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (4). LCNEC is a rare subtype of non-small cell lung cancer (NSCLC), accounting for about 3% of all lung malignancies. LCNEC is associated with poor prognosis, with median overall survival less than a year in patients with stage IV disease (5, 6). Although not common, targetable genomic alterations such as alterations to EGFR, BRAF, and ALK are also seen (7,8).
Here, we describe a patient with stage IV pulmonary LCNEC harboring a KIF5B-RET fusion whose disease responded to selpercatinib, highlighting the importance of characterizing the molecular profile of pulmonary LCNEC for optimal treatment selection.

Case presentation
A 52-year-old never-smoking Asian female with no significant past medical history presented with back pain and increasing abdominal girth with firmness in the right upper quadrant. A computed tomography (CT) chest showed a spiculated mass in the right upper lobe measuring 2.1 cm, a left lower lobe nodule measuring 5 mm, extensive mediastinal and hilar adenopathy, diffuse hepatic metastases, and numerous osseous lesions in the thoracic and lumbar spine and in the left iliac bone. A brain magnetic resonance imaging (MRI) scan showed numerous subcentimeter brain lesions.
The patient received cisplatin (75 mg/m 2 on day 1) and etoposide (100 mg/m 2 on days 1-3), which was complicated by grade 4 neutropenia. Subsequently, molecular testing including whole exome sequencing and whole transcriptome sequencing (Caris Life Sciences, Phoenix, AZ) revealed KIF5B-RET fusion and NFE2L2 E82D without other genomic alterations such as mutations in TP53 and Rb1, and selpercatinib 160 mg twice a day (BID) was initiated on cycle 1, day 21. Ten days after initiation of selpercatinib, she received cycle 2, day 1 carboplatin (AUC 5 on day 1) and etoposide (100 mg/m 2 on days 1-3). The decision to combine selpercatinib and chemotherapy was based on the limited knowledge about the efficacy of RET inhibitor therapy in LCNEC and the effectiveness of platinum-etoposide for LCNEC, as well as the encouraging initial results from clinical trials testing the combination of platinum doublet chemotherapy and targeted therapy for driver mutation-positive NSCLC, such as EGFRmutant NSCLC. Cycle 2, day 1 chemotherapy was complicated by reactions including chest tightness and elevated blood pressure during etoposide administration. Chemotherapy was discontinued, and the patient continued selpercatinib at a lower dose of 120 mg BID. A month after initiation of selpercatinib, she developed grade 2 alanine aminotransferase (ALT; 227 units/L) elevation and grade 1 aspartate aminotransferase (AST; 83 units/L) elevation, leading to dose interruption for 10 days. After improvement in liver function tests, selpercatinib was restarted at 80 mg BID, which led to another dose interruption for 10 days due to elevations in grade 2 ALT (239 units/L) and grade 1 AST (95 units/L). Selpercatinib was resumed at 40 mg BID, which was titrated up over 6 months to 120 mg BID without episodes of transaminitis. Due to hypertension, an anti-hypertensive, amlodipine, was started about 5 months after the initiation of selpercatinib. The patient achieved a partial response with shrinkage of the right upper lobe nodule (Figures 2A-D) and liver lesions ( Figures 2E-H). Her brain lesions also responded to selpercatinib (Figures 2I-L, arrows), except for the development of tiny new brain lesions when the patient was on a low dose of selpercatinib 40 mg BID ( Figure 2K, arrowhead), which have improved ( Figure 2L, arrowhead) or remained stable with subsequent increases in dose of selpercatinib. At the time of this report, the patient is 1 year into treatment with selpercatinib and continues to derive clinical benefit from selpercatinib.

Discussion
In this case report, we describe a patient with stage IV pulmonary LCNEC harboring a KIF5B-RET fusion whose disease responded to selpercatinib both extra-and intra-cranially, highlighting the importance of comprehensive molecular testing in LCNEC for selection of optimal treatment. To the best of our knowledge, this is one of the first reports demonstrating the presence of RET fusions and the activity of RET inhibitor therapy in pulmonary LCNEC.
LCNEC is associated with a high mutation burden and alterations in various molecular pathways such as cell cycle signaling, RAS/MAPK, and PI3K/AKT/mTOR pathways (9). Studies investigating the molecular characteristics of pulmonary LCNEC have revealed two major subtypes (10,11): small-cell lung cancer (SCLC)-like LCNEC characterized by co-alterations in TP53 and RB1, and NSCLC-like LCNEC characterized by harboring NSCLC-type mutations. Targetable genomic alterations such as EGFR mutations, KRAS G12C mutations, BRAF V600E mutations, and ALK fusions have been identified in LCNEC (8)(9)(10)(11)(12), though at lower rates compared with lung adenocarcinoma. Response to matching targeted therapy has been reported for EGFR mutations (13,14), BRAF V600E mutation (15), and ALK fusions (16,17), suggesting the role of targeted therapy in driver mutationpositive LCNEC. These findings emphasize the importance of performing comprehensive molecular profiling for patients with LCNEC in order to select the most effective treatment options, in accordance with evidence-based guidelines such as the CAP/ IASLC/AMP molecular testing guideline for lung cancer (18).
RET fusions have not been well described in pulmonary LCNEC, likely because of the rarity of the genomic alteration and the fact that only a handful of studies utilized genomic technologies involving RNA analysis. In a study of 52 pulmonary LCNECs where reverse transcription-polymerase chain reaction (RT-PCR) was used for analysis, only one patient was found to have a RET fusion (12). The patient received first-line treatment with  carboplatin and pemetrexed, with progression-free survival (PFS) of 3.3 months and overall survival (OS) of 34 months. No further details about the treatment course are available in the report. There are two case reports describing the activity of selpercatinib against RET-fusion-driven high-grade neuroendocrine carcinoma of thoracic origin (19) and atypical lung carcinoid (20), suggesting that, across the spectrum of pulmonary neuroendocrine neoplasms, RET fusions are actionable alterations and RET-targeting therapy is a therapeutic option. Of note, it was observed that the patient developed small new brain lesions when the dose of selpercatinib was decreased due to toxicities. With increased doses of selpercatinib, stabilization and improvement in the lesions were observed. An important clinical question is whether increasing the dose of targeted therapy in cases of central nervous system (CNS) progression is effective. This has been studied in certain driver mutation-positive NSCLCs. For example, in patients with EGFR-mutant NSCLC who were experiencing CNS progression while taking osimertinib at 80 mg per day, increasing the dose to 160 mg resulted in modest improvement with CNS control lasting about 3 to 6 months (21). Further studies are necessary to determine the possible advantages of increasing the dose of RET inhibitor therapy for patients with RET-fusion-driven NSCLC who are experiencing progression in the CNS.

Conclusion
Identification of actionable genomic alterations via molecular profiling can play an important role in the care of patients with pulmonary LCNEC. RET-TKI therapy is a viable therapeutic option for RET fusion-driven pulmonary LCNEC.

Data availability statement
The datasets presented in this article are not readily available because of ethical/privacy restrictions. Requests to access the datasets should be directed to the corresponding author.

Ethics statement
Written informed consent was obtained from the individual for the publication of any potentially identifiable images or data included in this article.

Author contributions
AA: data curation, formal analysis, investigation, visualization, writing-original draft, and writing-review and editing. JZ: data curation and writing-review and editing. MO: data curation, visualization, and writing-review and editing. CK: conceptualization, data curation, investigation, supervision, visualization, writing-original draft, and writing-review and editing.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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