Lung adenocarcinoma with ALK deletion of exons 6–20 with response to sequential ALK inhibitors: a case report

Introduction

Anaplastic lymphoma kinase (ALK) plays a pivotal role in the initiation and progression of several malignancies, including lymphoma, neuroblastoma, and non-small cell lung cancer (NSCLC) (1). ALK gene rearrangements occur in approximately 5% of NSCLC cases and most commonly involve translocations with echinoderm microtubule-associated protein-like 4 (EML4) as the predominant fusion partner (2). The advent of ALK inhibitors has significantly improved clinical outcomes in patients with ALK-rearranged advanced NSCLC (3). Crizotinib was the first ALK inhibitor approved by the Food and Drug Administration for frontline treatment (4). Subsequently, second- and third-generation ALK inhibitors have demonstrated superior disease control and intracranial activity, replacing crizotinib in clinical practice (5-7).

ALK internal deletions occur in 0.01% of lung cancer cases of ALK genomic aberrations (8). Due to this rarity, the therapeutic efficacy of ALK inhibitors in cases harboring ALK internal deletions remains unclear. Herein, we report a case of lung adenocarcinoma harboring ALK deletions of exons 6–20 that demonstrated a partial response to sequential alectinib and lorlatinib. We present this case in accordance with the CARE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-120/rc).

Case presentation

A 42-year-old woman without a history of smoking presented with cough and dyspnea. The patient had no remarkable medical or family history. The patient’s Eastern Cooperative Oncology Group performance status score was 1. Chest computed tomography (CT) and positron emission tomography (PET) revealed a primary lesion in the left upper lobe, bilateral carcinomatous lymphangitis, and pleural effusions, pericardial effusions, subcutaneous metastasis above the sternum, and multiple bone metastases (Figure 1A-1E). The patient’s clinical stage was IVB (according to the 8th edition of the American Joint Committee on Cancer, cT4N3M1c). The histopathological diagnosis of lung adenocarcinoma was confirmed via biopsy of the subcutaneous metastasis (Figures 1B,1D,2A). No genetic mutations were detected by multiplex reverse transcription-polymerase chain reaction (mRT-PCR)-based assays (Amoy Dx Pan Lung Cancer PCR Panel; Amoy Diagnostics Co. Ltd., Xiamen, China). The programmed death ligand 1 (PD-L1) (22C3, Dako/Agilent, Tokyo, Japan) tumor proportion score was 95%. Baseline laboratory test results revealed white blood cell count, 10,100/µL; lymphocyte count, 1,100/µL; platelet count, 413,000/µL; and carcinoembryonic antigen (CEA) level, 40.9 ng/mL. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were 10.1 and 375.0, respectively.

Figure 1 Baseline CT and PET-CT findings. (A) CT revealed a primary lesion in the left upper lobe, bilateral carcinomatous lymphangitis, and pleural effusions, (B) pericardial effusions and a subcutaneous metastasis above the sternum (arrow). (C) PET-CT showed increased uptake in the primary lesion, (D) the subcutaneous metastasis, and (E) the lymphatic and bone metastases. CT, computed tomography; PET, positron emission tomography.

Figure 2 Histopathological and immunohistochemical findings of the subcutaneous metastasis. (A) Hematoxylin-eosin staining confirmed adenocarcinoma morphology (scale bar: 100 µm). (B) ALK immunohistochemistry demonstrated ALK protein positive expression using the intercalated antibody-enhanced polymer method (scale bar: 100 µm). ALK, anaplastic lymphoma kinase.

The patient received two courses of pembrolizumab and four cycles of carboplatin plus nanoparticle albumin-bound paclitaxel. The best responses were progressive disease and stable disease. Prior to second-line therapy, skin biopsy specimens were subjected to comprehensive genomic profiling (CGP) (FoundationOne CDx, Foundation Medicine, Cambridge, MA, USA). Although no typical ALK fusion mutations were found, ALK deletions of exons 6–20 were detected. Microsatellite instability was absent; the tumor mutational burden was low (1 muts/Mb). Highly sensitive ALK-immunohistochemistry (IHC) using the intercalated antibody-enhanced polymer (iAEP) method showed ALK positivity (Figure 2B). The CGP also revealed mutS homolog 6 R1076C mutation (with preserved mismatch repair protein expression confirmed by IHC) and several variants of unknown significance, including fanconi anemia complementation group G A153G, inositol polyphosphate-4-phosphatase B E735K, signal transducer and activator of transcription 3 E616V, and mitogen-activated protein kinase kinase kinase 1 T949 duplication.

Alectinib treatment (300 mg twice daily; approved dosage in Japan) was initiated based on ALK IHC positivity. The patient’s dyspnea promptly improved; a partial response was confirmed radiographically at 2 weeks (Figure 3A-3D), with disease control maintained for nine months. Subsequent disease progression was indicated by increased CEA levels (from 29.7 to 112.8 ng/mL) and new brain metastases on contrast-enhanced magnetic resonance imaging. Lorlatinib (100 mg, once daily) was administered as a second-line ALK inhibitor. This led to a rapid decrease in CEA levels (42.2 ng/mL, the following month) and regression of the brain metastases. No disease progression was observed after three months of lorlatinib therapy. Figure 4 illustrates the timeline of chemotherapy administration in this case.

Figure 3 Radiological findings before and after alectinib initiation. (A) Chest X-ray and (B) CT before alectinib treatment showed extensive disease burden, including the primary lung tumor, bilateral carcinomatous lymphangitis, pleural, and pericardial effusions. (C) Two weeks after alectinib treatment, chest X-ray and (D) CT showed significant regression of the primary lesion (arrow), resolution of carcinomatous lymphangitis, and improvement in pleural and pericardial effusions. CT, computed tomography.

Figure 4 Timeline of chemotherapy administration in this case. Nab-paclitaxel, nanoparticle albumin-bound paclitaxel.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

This case highlights the potential therapeutic efficacy of ALK inhibitors in lung adenocarcinomas harboring ALK internal deletions, particularly involving exons 6–20. To date, only two similar cases have been reported. One patient with an ALK exon 13–19 deletion demonstrated a partial response to crizotinib, with a progression-free survival (PFS) of 16 months (8). In another case, a patient harboring ALK deletions of exons 2–19 demonstrated a complete response to alectinib, with PFS exceeding 23 months (9). Similar to the findings in this case, CGP did not detect any ALK rearrangements in the previous cases. Instead, internal deletions have been identified. Collectively, these findings support the hypothesis that ALK internal deletions might serve as oncogenic driver alterations and actionable targets for ALK inhibition. Although functional assays and molecular modeling regarding ALK deletions have not been established in patients with NSCLC, ALK deletions of exons 2–17 and exons 2–3 in anaplastic large cell lymphoma and neuroblastoma cases, respectively, have been reported to enhance tyrosine kinase activity in vitro (10,11). Aberrant forms of ALK and ALK expression are generally caused by at least one of three primary mechanisms: ALK fusion mutations, ALK gain-of-function mutations, or ALK amplification. Although ALK inhibitors are generally effective against various ALK fusion variants, their efficacy in amplification cases is inconsistent. Certain point mutations, such as G1202R, are well-known resistance drivers to first- and second-generation ALK inhibitors (12).

A notable distinction in our case was the involvement of exon 20, which encodes part of the ALK tyrosine kinase domain (13). Regarding ALK translocations, 96.7% of the breakpoints occur in intron 19, preserving exons 20–29 that are essential for kinase activity (14). Previously reported ALK internal deletions retained exons 20–29, whereas the present case involved a partial deletion of exon 20. Nevertheless, the patient responded to ALK inhibitors, suggesting that even partially disrupted kinase domains retain oncogenic activity and therapeutic sensitivity.

Although the initial response to alectinib was encouraging in our case, the observed PFS at nine months was shorter than that reported in previous cases or clinical trials. In the ALEX study, the median PFS was 34.8 months using alectinib (5). However, 11% and 32% of patients exhibited progressive disease as their best response and experienced progression within the first year, respectively. The relatively shorter PFS in this case might reflect a high baseline tumor burden characterized by extensive lymphatic and bone metastases. Tumor volume has been associated with elevated circulating tumor DNA levels, which correlate with poor prognosis in ALK-positive NSCLC cases (15,16). Additionally, an elevated NLR of 10.1 and PLR of 375.0 might have contributed to the shorter PFS. Elevated NLR has been linked to inferior PFS in EGFR-positive NSCLC cases (17). Moreover, in patients with ALK-positive NSCLC, both NLR (≥3) and PLR (≥120) have been associated with reduced overall survival (18).

Molecular factors associated with poor prognosis in ALK-positive NSCLC include unfavorable EML4-ALK fusion variants, tumor suppressor mutations such as Tumor Protein P53, and bypass pathway alterations (19). In the present case, the CGP did not show any such co-alterations. Although EML4-ALK variants differ in their EML4 breakpoints, they all retain the complete ALK tyrosine kinase domain (20). The significance of exon 20 deletion remains unclear and warrants further investigation in larger prospective cohort studies.

Acquired resistance to ALK inhibitors is often caused by secondary mutations. An in vitro study has shown that the G1202R mutation and G1202 deletion confer resistance to first- and second-generation inhibitors, while retaining sensitivity to lorlatinib (21). Although post-alectinib molecular profiling was not conducted in this case, the observed clinical response suggests that lorlatinib remains effective despite prior resistance.

Diagnostic challenges were also apparent. mRT-PCR did not detect ALK alterations, whereas CGP and ALK-IHC were positive. mRT-PCR might miss non-EML4-ALK fusions owing to limited target coverage (22). Additionally, CGP, although broader, might fail to identify entirely novel rearrangements (23). Furthermore, under the current Japanese national health insurance system, CGP is only reimbursed after completion or planned completion of standard therapy, limiting its use at initial diagnosis. In contrast, IHC is low-cost and provides a protein-level assessment independent of fusion partners. Therefore, IHC remains a critical adjunctive diagnostic modality. ALK-IHC has been reported to achieve a sensitivity of 100% and specificity of 98%, demonstrating its high reliability as a screening method for ALK rearrangements (24). The iAEP method demonstrated high concordance with fluorescence in situ hybridization (99.4%) (25).

Clinically, ALK-positive NSCLC typically affects younger, never-smoking patients who often present with advanced disease (26). These tumors tend to be less responsive to immune checkpoint inhibitors than do other molecular subtypes (27). Our patient shared many of these characteristics and had high PD-L1 expression yet responded poorly to pembrolizumab, which is consistent with the existing evidence. Although signet ring cells, often observed in ALK-positive NSCLC, were not observed, the clinical and immunohistochemical profiles supported ALK involvement (28). ALK-IHC remains a valuable diagnostic tool in such scenarios and should be used when conventional molecular testing yields inconclusive results.

This case has limitations. First, although ALK-IHC was instrumental in guiding treatment, it reflects protein expression and does not confirm kinase activation or oncogenic function. Thus, although the observed clinical response supported the relevance of the ALK exon 6–20 deletion, causality could not be established. Second, functional validation—such as in vitro assays or structural modeling—was not performed. Moreover, the biological impact of this rare alteration remains speculative. Future studies are needed to clarify its mechanistic significance.

Conclusions

This case suggested that ALK deletions, even those involving exon 20, demonstrated oncogenic potential and sensitivity to ALK inhibitors. Although the deletions were identified by CGP, ALK-IHC confirmed protein expression and provided key support for initiating ALK-targeted therapy. In clinical practice, ALK-IHC should be considered as a complementary diagnostic tool, particularly in cases of high clinical suspicion wherein initial molecular testing reveals negative or inconclusive findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-120/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-120/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-120/coif). TI received lecture fees from Chugai and Takeda Pharmaceuticals. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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