ALK Inhibition in a Patient with Inflammatory Myofibroblastic Tumor Harboring CARS1-ALK Fusion

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J Korean Cancer Assoc. 2024;.crt.2024.1184

Publication date (electronic) : 2024 December 18

doi : https://doi.org/10.4143/crt.2024.1184

Songji Choi¹, Miso Kim^,2, Sheehyun Kim¹, Taekeun Park², Yoonjin Kwak³, Jeong Mo Bae³, Hongseok Yun¹, Jee Hyun Kim⁴

¹Department of Genomic Medicine, Seoul National University Hospital, Seoul, Korea

²Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea

³Department of Pathology, Seoul National University Hospital, Seoul, Korea

⁴Department of Internal Medicine, Department of Genomic Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea

Correspondence: Miso Kim, Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea Tel: 82-2-2072-4035 E-mail: misokim@snu.ac.kr

Received 2024 December 10; Accepted 2024 December 14.

Abstract

Introduction

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor predominantly occurring in the abdomen, pelvis, mesentery, or lung, but can present anywhere in the body, and is most frequently observed in pediatric, adolescent, and young adult populations [1]. Histologically, IMTs are characterized by differentiated myofibroblastic spindle cells accompanied by numerous plasma cells and/or lymphocyte infiltrates [2]. Complete surgical resection remains the standard of care for localized IMT; however, there is no consensus on the most optimal treatment regimen for advanced cases [1]. Recently, targeted therapies have dramatically changed the treatment landscape for IMT, especially for patients with anaplastic lymphoma kinase (ALK) rearrangements [3].

Approximately half of the IMT cases involve ALK fusions, thus rendering them amenable to ALK inhibition [4]. Prescription of drugs out of approved indications is, however, strictly regulated in many countries, posing significant challenges for the treatment of ALK-positive advanced IMT. In this respect, the KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study was designed to promote nationwide, prospective study in Korea to overcome these limitations by providing molecularly-guided therapies for patients with refractory metastatic solid tumors through a central molecular tumor board [5].

In this case report, we describe a 40-year-old female patient diagnosed with widely metastatic IMT harboring CARS1-ALK fusion, identified through next-generation sequencing (NGS). The patient demonstrated a favorable response to an ALK inhibitor provided through the KOSMOS-II trial, underscoring the potential of precision medicine in managing rare and challenging cases like advanced IMT in countries with restricted use of targeted agents outside of its approved indications.

Case Report

A 40-year-old female was initially diagnosed in May 2019 from another institution with IMT, with extensive metastases to the soft tissues, lungs, and bones. As surgical resection was not feasible, she received six cycles of ifosfamide, carboplatin, and etoposide from June to October 2019, achieving a response of stable disease, followed by progression in October 2021. Pazopanib was then initiated but halted after one month due to infection. By August 2022, disease progression led to a large thigh mass accompanied by severe pain and an intractable infection that needed a hindquarter amputation. Despite this, growing neck mass with increasing pain led to her referral to our institution. She presented as wheelchair-bound with significant functional deterioration. Imaging studies including magnetic resonance imaging, contrast-enhanced computed tomography (CT), and positron emission tomography/computed tomography (PET/CT) scans revealed multiple metastatic lesions involving the neck, pelvis, thigh muscles, and lungs, showing significant progression compared to previous imaging. In particular, the anterior right neck mass measured more than 30 cm, with extensive tumor infiltration around the right thigh and pelvis (Fig. 1).

Fig. 1.

Magnetic resonance imaging (MRI) before alectinib treatment. (A) MRI with T2 fat suppression-weighted cross-section of the neck revealed the irregular enhancing mass lesions involving the right anterior, lateral, and posterior neck muscles. The arrow indicates the area of muscle infiltration. (B) MRI with T2 fat suppression-weighed cross-section of the right thigh revealed irregular skin thickening and infiltration in the right thigh muscles. Arrows indicate sites of subcutaneous and intramuscular infiltration.

Hematoxylin and eosin staining of surgical specimens revealed a high cellularity lesion with a broad fibrous and myxoid background (Fig. 2A). A spindle cell proliferation, admixed with an inflammatory infiltrate of lymphoplasmatic cells, demonstrated minimal cytological atypia. No necrosis was observed, and the mitotic activity was 4 per 10 high-power fields (Fig. 2B). Immunohistochemistry staining showed strong positivity for ALK using 5A4 monoclonal antibody (Novocastra, Leica Biosystems) and positivity for smooth muscle actin. Other markers, including CD34, desmin, S-100, and MDM2, were negative (Fig. 2C).

Fig. 2.

Histological sections from surgical samples. (A) Sections showing high cellularity lesion with broad fibrous and myxoid background (H&E, ×4). (B) High-power view showing areas with a spindle cell proliferation admixed with an inflammatory infiltrate of lymphoplasmacytic cells (H&E, ×200). The arrow indicates lymphoplasmacytic cells within the inflammatory infiltrate. (C) Lesional cells demonstrating diffuse and strong anaplastic lymphoma kinase reactivity (ALK, ×200).

Targeted NGS was performed on tumor tissue obtained during surgery using customized SNUH FiRST Cancer Panel ver. 4.0, which contains 425 cancer-related genes. The average sequencing depth was 331-fold. The results revealed a CARS1-ALK fusion, along with MCL1 amplification (copy number [CN] 7), CCND1 amplification (CN 11), and FGF19 amplification (CN 7). The ALK rearrangement was confirmed through both DNA and RNA sequencing analyses, identifying the fusion between 5′-CARS1 (exon 1-18, NM_001014437) and ALK (exon 20-29, NM_004304) (Fig. 3). Although the ALK fusion was identified, administration of any ALK inhibitor was not possible; these had not been approved in adult patients with advanced IMT in Korea. The only ALK inhibitor allowed by the Health Insurance Review & Assessment Service in Korea was crizotinib and only for those under 12. Her case was submitted to the central molecular tumor board (cMTB) for consideration of enrollment in a KOSMOS-II trial aimed at providing access to targeted therapies approved through the Ministry of Food and Drug Safety–regulated pathway “Therapeutic Use of Investigational Drugs.”

Fig. 3.

Identification of anaplastic lymphoma kinase (ALK) fusion by next-generation sequencing. The schematic structure of the genomic DNA sequences shows fusion points for the CARS1-ALK fusion. Exons 20-29 of the ALK gene, which contain the tyrosine kinase domain, are fused with exons 1-18 of the CARS1 gene. ALK gene is located on chromosome 2p23.2, and CARS1 gene is located on chromosome 11p15.4.

While awaiting trial approval, she presented poor oral intake, generalized weakness, and altered consciousness. The patient was immediately hospitalized; her laboratory tests showed hypercalcemia (calcium 15.9 mg/dL; normal range, 8.8 to 10.5 mg/dL), and impaired renal function (creatinine 1.60 mg/dL; normal range, 0.70 to 1.40 mg/dL)—compatible with paraneoplastic hypercalcemia. Given the accelerated approval of the KOSMOS-II trial by the cMTB, the patient initiated alectinib 600 mg twice daily on February 9, 2023. The patient rapidly improved in general condition and paraneoplastic syndrome. However, alectinib was temporarily discontinued due to adverse events consisting of exfoliative dermatitis, fever, and eosinophilia. Alectinib was then resumed upon clinical recovery with a reduced dose of 450mg once daily.

Two months after initiating alectinib, a restaging PET/CT scan demonstrated pronounced improvement, with reductions in the size and fluorodeoxyglucose avidity of multiple hypermetabolic masses throughout the body (Fig. 4). Contrast-enhanced CT scans revealed complete resolution of the right buttock metastasis, while the left lower lobe lung lesion has reduced from 40 mm to 14 mm, representing a 77.4% reduction in the total sum of target lesions (Fig. 5). Non-target lesions, including axillary lymph nodes and soft tissue metastases—particularly in the right neck and right thigh—also demonstrated significant regression (Fig. 5). Thus, a partial response was achieved per Response Evaluation Criteria in Solid Tumor (RECIST) 1.1 criteria [6], which has been maintained for over 19 months to date, with good treatment tolerance and no notable treatment-related toxicities.

Fig. 4.

Positron emission tomography/computed tomography (PET/CT) demonstrating the burden of disease. (A) At the initial presentation, PET/CT demonstrated multiple hypermetabolic muscle and soft tissue masses along the whole body (maximum standardized uptake value [SUV_max], 27.5). (B) Two months after alectinib therapy initiation, PET/CT demonstrated a marked decrease in metabolic activity and the extent of multiple hypermetabolic soft tissue lesions involving the whole body (SUV_max 5.4).

Fig. 5.

Enhanced computed tomography (CT) scan before and after treatment with alectinib. (A) Chest CT of left lower lobe metastasis. (B) Abdomen/pelvis CT of right buttock metastasis. (C) Chest CT of right neck metastasis. (D) Abdomen/pelvis CT of right thigh metastasis. (E-H) CT scan after 2 months of alectinib treatment, showing partial response. Arrows in panels A-D indicate metastatic lesions.

Discussion

We present the improved outcomes under ALK inhibitor treatment, in treating a 40-year-old female patient with metastatic IMT harboring CARS1-ALK fusion after experiencing two lines of systemic chemotherapy failures. The patient received treatment through the KOSMOS-II trial, providing a pathway for accessing alectinib outside of its approved indication. In this case, the timely intervention with alectinib led to significant tumor shrinkage, improved symptoms, and durable response, illustrating the potential of personalized medicine to improve patient outcomes in otherwise challenging cases, particularly in regions with stringent drug regulations, such as Korea.

Approximately 50% of IMTs harbor an ALK gene rearrangement that appears to play a major role in the pathogenesis of these tumors [7]. The CARS1-ALK fusion presented herein was initially described in a report by Debelenko et al. [4], which provided valuable insights into the molecular characteristics of IMT. This rearrangement comprises a genetic fusion between the CARS gene and ALK, resulting in an in-frame chimeric protein that retains the ALK catalytic domain at the C-terminus [4]. Moreover, it demonstrated that this fusion also occurred in both primary and metastatic tumors—a finding that pointed to clonality and thus supported the metastatic potential of IMT [4].

The first therapeutic efficacy of ALK inhibitors in ALK-positive IMT was first demonstrated with crizotinib, showing remarkable clinical benefit with a partial response rate of 50% and a median duration of response of 8.3 months [8]. Based on this, crizotinib obtained accelerated approval from the U.S. Food and Drug Administration for the treatment of unresectable ALK-positive IMTs in 2020 [9]. However, resistance to crizotinib often arises and further demands options for alternative therapeutic approaches [10]. Second-generation ALK inhibitors, such as alectinib, developed to overcome such resistance mechanisms and further improve efficacy, were much more potent with better central nervous system penetration [11]. In our case, treatment with alectinib resulted in a dramatic reduction of tumor burden and significant symptom relief, including pain and clinical decline, greatly improving her quality of life. These findings are consistent with those from previous reports on the efficacy of alectinib in the treatment of ALK-positive IMT and other ALK-rearranged tumors [12,13].

In Korea, regulatory barriers restrict the use of drugs outside of their approved indications; treatment for rare cancers such as IMT poses significant challenges. To overcome such challenges, many drug re-purposing trials, such as Targeted Agent and Profiling Utilization Registry (TAPUR) and Drug Rediscovery protocol (DRUP), are ongoing, testing the feasibility and effectiveness of molecular profiling guided therapy outside of its approved indications, using already approved drugs [14,15]. KOSMOS-II is one of those pragmatic trials addressing these unmet needs, and our patient could achieve rapid improvement through the use of molecular profiling–guided treatment with alectinib [5].

In conclusion, this case emphasizes the value of prompt access to clinical trials and cMTB evaluations, which offer potentially life-saving molecular-guided therapy that might not otherwise be available. A framework for providing individualized therapy options that can optimize patient outcomes is created by combining molecular profiling, clinical trials, and cMTBs. Expanding access to molecular profiling and clinical trials is essential for ensuring that patients with rare cancers receive effective treatments.

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