Treatment of Resistant TPM3::ALK + Fusion Protein Metastatic Inflammatory Myofibroblastic Tumor with ALK Targeting and Immune Checkpoint Inhibitor Combined Therapy

Abstract

Background and Clinical Significance: Inflammatory myofibroblastic tumors (IMTs) are rare neoplasms with low metastatic potential but a high recurrence rate. Approximately 60–80% of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, making ALK inhibitors (ALKis) a key therapeutic option. However, resistance to ALKis remains a significant clinical challenge, necessitating alternative treatment strategies. Case Presentation: We report the case of a 23-year-old woman diagnosed with a metastatic TPM3::ALK fusion-positive IMT, initially managed with crizotinib and ceritinib. Disease progression prompted a switch to alectinib, followed by lorlatinib in combination with immune checkpoint inhibitors (nivolumab + ipilimumab). The patient tolerated this regimen well, with manageable side effects, and has remained progression-free for over three years, demonstrating the potential efficacy of ALK-ICI combination therapy. Conclusions: This case highlights the rapid development of resistance to first- and second-generation ALKis and the emerging role of immune checkpoint inhibitors (ICIs) in IMT treatment. PD-L1 expression in ALK-positive IMTs suggests an immune escape mechanism, supporting combination ALK-ICI therapy as a viable approach. The successful long-term disease control achieved in this case underscores the importance of molecular profiling in guiding personalized treatment strategies for IMT. This report contributes to the growing body of evidence supporting precision medicine and immunotherapy in rare sarcomas.

1. Introduction

Inflammatory myofibroblastic tumors (IMTs) are ultra-rare mesenchymal neoplasms, with a 0.04–0.07% worldwide prevalence that can be locally aggressive. They are defined by the World Health Organization as rarely metastasizing fibroblastic/myofibroblastic neoplasms containing a prominent inflammatory infiltrate, chiefly lymphocytes and plasma cells [1]. IMTs mainly occur in the abdominal cavity, but can also originate in the lungs, genitourinary system, CNS, and head/neck region; most cases are diagnosed in children and young adults [2,3]. The pathogenesis of IMTs may be linked to multiple factors, including Epstein–Barr virus (EBV) exposure, infection, surgery, and trauma [4].

The first-line treatment for localized disease is a complete surgical excision, but for rare examples of advanced or non-resectable tumors, chemotherapy and targeted therapy are the preferred option [2]. Approximately 60–80% of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, some of which have been shown to drive a more aggressive oncogenic pattern, to have increased resistance to therapy, and to have higher metastatic potential [5,6,7]. On the other hand, other studies suggest that ALK-negative IMTs are associated with more aggressive behavior and metastatic potential, and the prognostic significance of ALK expression remains controversial, with conflicting data across the literature [8]. At the same time, these mutations have also allowed for the usage of targeted therapy [5,6,7]. ALK targeted therapy has transformed the treatment of ALK + IMTs; however, resistance to them is a major challenge, requiring the use of next-generation therapies and combination treatment regimens [6,7].

Here, we present a case of a patient with early metastatic IMT who developed resistance to multiple ALKis and underwent multiple changes to her therapy.

2. Case Report

The patient is a 23-year-old woman from Jamaica who, at age 17, began experiencing flu-like symptoms, including nasal congestion and cough. Her primary care provider (PCP) initially prescribed a course of antibiotics; however, her symptoms persisted. Subsequent chest imaging revealed a mixed-density mass in the right upper lung lobe.

Two months later, she experienced an episode of copious hematemesis, leading to an emergency upper and middle right lobectomy in Jamaica. A final pathologic review diagnosed an inflammatory myofibroblastic tumor (IMT) with a TPM3::ALK fusion, confirmed by genetic analysis.

Upon evaluation in Miami, initial imaging revealed multiple osseous enhancing lesions in both acetabula, with extension to the superior pubic ramus on the right and the left iliac wings, which is concerning for metastatic disease (Figure 1A). She was initiated on crizotinib, a first-generation ALKi which at the time was not FDA-approved for the treatment of IMTs, along with denosumab for bone metastasis management. Nine months into treatment, a 7.2 × 5.5 cm mass was detected in the right pelvic musculature and proximal thigh on surveillance CT, which had not been present three months prior (Figure 1B). Worsening osseous metastases prompted a switch from crizotinib to ceritinib, a second-generation ALKi, which, at the time, was also not yet approved for IMT treatment. The patient responded well to the therapy change, and molecular profiling performed by NGS confirmed the presence of an ALK pathogenic variant (Exon 22, p.I1171S), often detected following progression on crizotinib or alectinib, supporting resistance to crizotinib while demonstrating potential sensitivity to alectinib and ceritinib. Because these ALKis were not FDA-approved, we attempted to obtain them for free from the manufacturing companies. Therefore, which ALKi the patient was switched to depended on the fastest available access.

The patient subsequently underwent palliative stereotactic body radiation therapy (SBRT) to the right pelvic mass and left scapular wing (40 Gy in five fractions to both sites). Follow-up imaging showed a reduction in both the pelvic (Figure 1D) and scapular lesions, along with new cavitated opacities in both lungs.

Three months later, she was hospitalized for left arm weakness. During this admission, a right temporal lobe mass was identified, and a surgical resection was performed; however, the procedure was complicated by an intraoperative seizure. Pathologic evaluation confirmed metastatic disease to the brain (Figure 2). Due to disease progression, the treatment was switched after ten months from ceritinib to alectinib. Repeat NGS sequencing showed sensitivity to alectinib and it was the only one we could obtain within a reasonable timeframe.

Initially, the patient tolerated alectinib well; however, two months later, she developed a cough, shortness of breath (SOB), and persistent fevers. Consequently, she was switched from alectinib to lorlatinib, with the addition of immune checkpoint inhibitors (nivolumab + ipilimumab). The rationale for adding ICIs was that, despite NGS sequencing revealing that the tumor was PD-L1 negative, the presence of TILs in the brain biopsy supported an inflammatory component, which we hypothesized might benefit from immunotherapy.

The patient has tolerated the combination of ALKi and checkpoint inhibitor therapy well. She developed common side effects associated with lorlatinib, including lower extremity hyperpigmentation, which is managed with hydrocortisone cream, and an elevated lipid profile, controlled with rosuvastatin. She also experiences peripheral neuropathy, managed with supplemental vitamin B6 and gabapentin, as well as constipation, controlled with docusate and polyethylene glycol.

She has gained weight, and laboratory analysis revealed hypothyroidism. An MRI showed a small pituitary gland, although it remains unclear whether this is a consequence of immunotherapy. She was initiated on levothyroxine for hypothyroidism management. Additionally, the patient developed strabismus, requiring ophthalmologic management and partial correction via surgical intervention.

Currently, the patient is 3 years and 5 months into lorlatinib plus nivolumab/ipilimumab therapy and continues to tolerate treatment well. She has experienced no disease progression, and all lesions remain stable or have decreased in size (Figure 1E,F). The patient undergoes PET/CT scans every 4 months, and at the most recent follow-up, her thigh mass showed stable uptake compared to previous studies. The treatment plan remains unchanged, with ongoing side effect management and close monitoring.

3. Discussion

This case illustrates the complexities of managing metastatic ALK-rearranged inflammatory myofibroblastic tumors (IMTs), particularly in the context of sequential resistance to targeted therapies.

The oncogenic driver of this patient’s tumor, an ALK gene rearrangement resulting in a TPM3::ALK fusion, is one of the most common alterations in IMTs and underpins many targeted treatment strategies. ALK, a receptor tyrosine kinase located on chromosome 2p23, plays a key role in tumor progression when pathologically activated [6,9,10]. Although initially identified in hematologic and pulmonary malignancies, ALK fusions are now well established in IMT pathogenesis [6,11]. In this case, the TPM3::ALK fusion likely contributed to the patient’s aggressive disease course and early metastasis, and its identification allowed for the rational use of sequential ALK inhibitors throughout her treatment.

Experimental in vivo lung models of TPM3::ALK expression demonstrated cytoskeletal remodeling, disruption of actin stress fibers, and increased cell motility—findings that may explain the aggressive metastatic phenotype associated with this fusion [12]. Although TPM3::ALK rearrangements have been previously documented, this case represents the first report of an IMT harboring this specific fusion protein with a multi-drug-resistant pathogenic variant (Exon 22, p.I1171S) and presenting with early metastasis, successfully treated with a combination of lorlatinib and nivolumab/ipilimumab.

The I1171S mutation in the ALK kinase domain substitutes a hydrophobic isoleucine with a polar serine within the αC-helix, a region essential for maintaining the hydrophobic integrity of the ATP-binding pocket. This change disrupts the local structure, stabilizes the active conformation of ALK, and reduces the binding affinity of second-generation inhibitors like alectinib, ultimately leading to therapeutic resistance [13]. However, lorlatinib, a third-generation ALKi, is structurally designed to overcome such resistance. Its compact macrocyclic structure and conformational flexibility allow it to accommodate mutations like I1171S by effectively binding even when the kinase adopts an active conformation [14]. Additionally, lorlatinib exhibits high potency across a range of ALK resistance mutations and retains activity where earlier inhibitors fail [15].

ALKis have transformed IMT management, but rapid resistance development necessitates frequent therapy adjustments, often requiring combination or experimental regimens [7]. As observed in our patient, resistance to first- and second-generation ALKis (crizotinib and ceritinib, respectively) typically develops within 10–12 months of initiation. Resistance mechanisms include secondary mutations in the ALK kinase domain, ALK gene amplification, bypass signaling activation, and epithelial-to-mesenchymal transition (EMT) [5,11]. Although these mechanisms do not apply to our patient, it is important to understand the landscape of resistance to ALKis.

Given the high incidence of resistance, research has expanded to identify additional therapeutic targets in IMTs. Although ALK-negative IMTs demonstrate higher PD-L1 expression, ALK-positive IMTs also frequently express PD-L1. Tumors with PD-L1 expression exhibit an increased likelihood of recurrence and metastasis, and a potential role for immune checkpoint inhibitors (ICIs) in IMT treatment [16]. Moreover, PD-L1 expression correlates with larger tumor size and an increased level of CD8+ tumor-infiltrating lymphocytes (TILs), supporting the tumor immune escape hypothesis [16,17,18,19]. While clinical trials are ongoing, there are currently no established guidelines recommending ICIs for IMTs [20]. However, several case reports describe successful treatment of ALK-positive tumors, including NSCLC and IMTs, using immunotherapy [17,19,21]. Case reports suggest that some ALK-positive lung cancers, including those resistant to ALK inhibitors or transformed to small cell histology, may achieve durable partial or complete responses when treated with a combination of ALK inhibitors and immunotherapy [22,23,24]. Emerging strategies in sarcoma research increasingly aim to target both oncogenic signaling and the tumor microenvironment, underscoring the importance of biomarker testing; in particular, the presence of tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs), and tertiary lymphoid structures (TLSs) is gaining recognition as a potential predictor of immunotherapy response [25]. To our knowledge, this is the first case of an ALK + IMT successfully treated with a combination of ALKis and ICIs.

4. Conclusions

This case report highlights the successful application of precision medicine in treating an IMT harboring the TPM3::ALK fusion, using a combination of an ALKi and immune checkpoint inhibitors. Our findings underscore the importance of molecular and genetic testing, combined with histological findings in guiding personalized treatment strategies for rare cancers.