Treatment process of ALK and ROS1 double-rearranged lung adenocarcinoma cell carcinoma: a case report

Introduction

The positivity of anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1 (ROS1) in non-small cell lung cancer (NSCLC) is 2.6% and 1.4% (1), and they are typically mutually exclusive (2). Lin et al. analyzed 62 NSCLC cases harboring ROS1 rearrangements and found no concurrent epidermal growth factor receptor (EGFR) mutations or ALK fusions, reinforcing that ROS1 fusions seldom co-occur with other oncogenic drivers in this setting (3). In a cohort of 732 lung adenocarcinoma (LUAD) cases, Song et al. identified 32 (4.4%) with ROS1 rearrangements, of whom only one exhibited simultaneous ALK/ROS1 fusions, highlighting the extreme rarity of this subtype (4). To date, ALK/ROS1 rearrangements have been reported in a few patients with a single tumor, and their therapeutic approaches and prognosis are largely unknown (5-10). The first case of ALK/ROS1 dual rearrangements was found in the circulating tumor DNA of an LUAD patient, but it was not confirmed in tumor tissue (11). Uguen et al. later described the first tissue-validated ALK/ROS1 double-positive NSCLC patient treated with crizotinib (7). Here, we present the first LUAD case with confirmed ALK/ROS1 dual rearrangements that achieved an exceptional 48-month progression-free survival (PFS) following first-line pemetrexed plus cisplatin chemotherapy. We present this case in accordance with the CARE reporting checklist (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-92/rc).

Case presentation

A 47-year-old non-smoking Chinese woman with hypertension presented to Guangzhou Chest Hospital on May 16, 2017, reporting a 2-week history of spontaneous, non-productive cough and progressive exertional dyspnea. Initial antitussive therapy provided only transient relief, and her symptoms soon recurred, prompting referral. Chest radiography revealed an infiltrative shadow in the right mid-lower lung field, initially suggestive of infection.

Bronchoscopy and guided biopsy on May 18, 2017 confirmed poorly differentiated LUAD (Figure 1A,1B), with strong immunohistochemical positivity for thyroid transcription factor-1 (TTF-1) and cytokeratin 7 (CK7) (Figure 1C,1D). The patient’s clinical course, summarized in Figure 2, began on May 18, 2017, with baseline staging chest computed tomography (CT) demonstrating a 3.5 cm × 2.5 cm central right-lung mass (cT2) with mediastinal invasion, right hilar lymphadenopathy (cN2), and ipsilateral pleural involvement (cM1a), consistent with stage IV (cT2N2M1a) LUAD (Figure 2A). Subsequent molecular profiling of formalin-fixed paraffin-embedded (FFPE) tumor tissue by reverse transcription quantitative polymerase chain reaction (RT-qPCR) using the ADx-ARMS-ALK + ROS1 Gene Fusions Detection Kits confirmed the presence of both ALK and ROS1 rearrangements, although the assay’s technical limitations preclude resolution of specific fusion partners (Figure 3). For personal reasons, the patient declined any anti-tumor therapy and was discharged. “When I first heard the word ‘cancer’, I was terrified—not just of the diagnosis, but of the cost and burden it would bring to my family”, she later recalled.

Figure 1 Histopathological and immunohistochemical analysis of bronchial mucosal biopsy from the right middle lobe. (A,B) Hematoxylin and eosin staining (×400) reveals focal epithelial regions with pleomorphic cells arranged in glandular (adenoid) structures and infiltrative growth within the stroma. (C,D) Immunohistochemistry (×400) demonstrates strong nuclear TTF-1 and cytoplasmic CK7 positivity, confirming poorly differentiated lung adenocarcinoma. CK7, cytokeratin 7; TTF-1, thyroid transcription factor-1.

Figure 2 Timeline of diagnosis and treatment. Red marks (circle in A; arrows in C, D and F) highlight primary or metastatic lesions. On May 18, 2017, bronchoscopy revealed poorly differentiated lung adenocarcinoma and chest CT demonstrated a central right lung mass (3.5 cm × 2.5 cm) with right hilar, mediastinal lymph node, and pleural metastases (A). From Aug 18 to Nov 10, 2017, the patient received four cycles of pemetrexed plus cisplatin; orbital CT on Sep 20, 2017, identified a 1.5 cm × 0.9 cm metastatic lesion in the right eye (D), and chest CT on Sep 29, 2017, after two cycles, showed a PR (B). On Nov 28, 2017, chest CT demonstrated reduction of the hilar mass to 3.3 cm × 2.4 cm with overall SD (C), initiating a TFS period, and by Apr 26, 2018, no residual soft-tissue mass was visible in the right hilum (E). On Sep 4, 2021, progression was noted by chest CT (new right middle-lobe mass, 2.5 cm × 4.5 cm, and increased pulmonary metastases; and cranial MRI (multiple bilateral cerebral and right ocular lesions with subtemporal herniation) (PD) (F). Ensartinib was then initiated. CT, computed tomography; MRI, magnetic resonance imaging; PD, progressive disease; PR, partial response; PFS, progression-free survival; SD, stable disease; TFS, treatment-free survival.

Figure 3 RT-qPCR amplification plots showing ALK and ROS1 fusion transcripts in FFPE tumor tissue. The blue curve (Ct 16.08) suggests ROS1-exon-32 and SDC4 exon 2/4, CD74 exon 6, SLC34A2 fusion mutations, and the yellow curve (Ct 26.31) suggests ALK-exon-20 and EML4 exon-6/13/20 fusion mutations (Ct <30 defined as positive). The blue horizontal line indicates the threshold line used to calculate Ct values, while the orange horizontal line represents the baseline fluorescence level. Genomic DNA was extracted using the AmoyDx FFPE DNA Kit, and fusion detection was performed with the ADx-ARMS-ALK + ROS1 Gene Fusions Detection Kit. ALK, anaplastic lymphoma kinase; CD74, CD74 molecule; FFPE, formalin-fixed paraffin-embedded; ROS1, ROS proto-oncogene 1; RT-qPCR, reverse transcription quantitative polymerase chain reaction; SDC4, syndecan-4; SLC34A2, solute carrier family 34 member 2.

In August 2017, the patient was readmitted with worsening cough but declined targeted therapy owing to financial constraints (crizotinib cost approximately ¥50,000 per month and required full out-of-pocket payment). With no contraindications to cytotoxic treatment, she underwent four 21-day cycles of pemetrexed (820 mg on day 1) plus cisplatin (40 mg on days 1–3) from August 18 to November 10, 2017 (Cycle 1: August 18; Cycle 2: September 8; Cycle 3: September 29; Cycle 4: October 20). An orbital CT performed mid-treatment revealed a 1.5 cm × 0.9 cm right-eye metastasis, restaging her disease as cT2N2M1b, and after two cycles, chest CT demonstrated a partial response (PR) (Figure 2B). Upon completing chemotherapy on November 28, follow-up CT confirmed stable disease (SD) with lesion shrinkage to 3.3 cm × 2.4 cm, initiating a treatment-free survival (TFS) period (Figure 2C); by April 26, 2018, no residual soft-tissue mass was visible in the right hilum (Figure 2E). Due to the patient’s preference and concerns over the long-term financial burden, pemetrexed maintenance therapy was not administered, and she did not return for review during the subsequent year.

In August 2021, the patient developed dizziness, headache, and blurred vision. The overall thoracic and cranial imaging findings are summarized in Figures 4,5. On September 4, 2021, chest CT revealed a new 2.5 cm × 4.5 cm right middle-lobe mass (Figure 4, A1) accompanied by increased pulmonary metastases, right middle-lobe atelectasis, mediastinal lymphadenopathy, and augmented pleural effusion (Figure 4, A2), while cranial magnetic resonance imaging (MRI) demonstrated multiple contrast-enhancing lesions—in both cerebral hemispheres, the basal ganglia, and the right orbit—with the largest left frontal lobe lesion measuring 5.4 cm × 5.6 cm and evidence of subfalcine herniation (Figure 5A); these findings were consistent with progressive disease (PD). Despite clinical recommendations, the patient declined whole-brain radiotherapy (WBRT) for symptomatic brain metastases due to personal preference.

Figure 4 Serial mediastinal [1] and lung [2] window CT images demonstrating tumor response to second-line ensartinib. Red arrows denote new metastatic lesions. (A) Baseline scan on Sep 4, 2021, showing a new 2.5 cm × 4.5 cm right middle-lobe mass (A1), increased pulmonary metastases, and enlarged mediastinal and right hilar lymph nodes (A2). (B) After one month of ensartinib (Oct 14, 2021), the right middle-lobe mass and pulmonary lesions had markedly regressed (B1), with reduction in mediastinal lymphadenopathy (B2). (C) At 3 months (Dec 30, 2021), further shrinkage of both the primary tumor and mediastinal nodes was evident. (D) At 16 months (Jan 12, 2023), the middle-lobe mass showed slight enlargement while mediastinal nodes remained reduced. (E) At 26 months (Nov 14, 2023), the primary lung lesion was stable without significant change. CT, computed tomography.

Figure 5 Evolution of brain metastases on MRI following ensartinib therapy. Red arrows indicate metastatic lesions. (A) Baseline MRI on Sep 4, 2021, demonstrating multiple contrast-enhancing lesions in both cerebral hemispheres, the basal ganglia, and the right orbit, accompanied by subfalcine herniation; the largest lesion in the left frontal lobe measured 5.4 cm × 5.6 cm. (B) Follow-up MRI after 26 months of ensartinib (Oct 14, 2021) showing marked regression of all intracranial lesions, with the left frontal lobe mass reduced to about 3.3 cm × 2.2 cm and resolution of the subfalcine herniation. MRI, magnetic resonance imaging.

During her hospitalization, cerebrospinal fluid analysis, bronchoscopic biopsy, and next-generation sequencing (NGS; 120-gene DNA panel) of blood, cerebrospinal fluid, and fresh formalin-fixed tissue were performed. NGS of the tissue confirmed an echinoderm microtubule-associated protein-like 4 (EML4) exon 13-ALK exon 20 fusion with a variant frequency of 10.33%, and no other co-mutations were detected. Given the presence of an ALK rearrangement and concurrent brain metastasis, we initiated second-line targeted therapy with ensartinib, which had been added to China’s national insurance formulary in 2021 (approximately ¥5,000 per month, with 80% reimbursement). The patient commenced ensartinib 225 mg once daily under insurance coverage on September 7, 2021.

Follow-up chest CT at one month showed marked regression of the right middle-lobe mass and pulmonary metastases (Figure 4, B1) with reduced mediastinal lymphadenopathy (Figure 4, B2), and a concurrent cranial MRI demonstrated significant intracranial response, with the left frontal lesion shrinking to 3.3 cm × 2.2 cm and resolution of herniation (Figure 5B). Further imaging at 3 months confirmed continued tumor and nodal shrinkage (Figure 4C), at 16 months revealed slight enlargement of the middle-lobe mass with persistent nodal reduction (Figure 4D), and at 26 months showed SD, without appreciable change in the primary lesion (Figure 4E). Treatment remains ongoing. “Since starting ensartinib, I finally feel like I can breathe again, my headaches have eased, and I’m grateful for every day it gives me”, she shared.

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

Discussion

Dual rearrangements of the ALK and ROS1 genes in LUAD are exceptionally rare, with only a few such cases documented in the literature (5,7,9,10). Owing to the scarcity of reported cases, there is no established consensus on the optimal first‑line therapy for ALK/ROS1 co‑altered tumors. Most published cases of concurrent ALK/ROS1positive NSCLC were managed with targeted tyrosinekinase inhibitors (TKIs)—typically crizotinib, which inhibits both ALK and ROS1 kinases, yielding variable outcomes (5-7). In our case, the patient received upfront platinum‑doublet chemotherapy (pemetrexed plus cisplatin) and achieved an exceptional response: after four cycles, the primary lung lesion had regressed and the best overall response was SD, with an ongoing PFS of 48 months on chemotherapy alone. This prolonged chemo‑induced PFS substantially exceeds the typical outcomes seen with first‑line TKIs in driverpositive NSCLC [crizotinib’s median PFS is roughly 16.4 months in ALKrearranged NSCLC (12)]. Although one case cannot overturn current standards of care, the observation invites a closer look at the biological factors that might confer such protracted chemotherapy sensitivity.

Beyond the remarkable chemotherapy sensitivity, the pattern of metastatic spread in our patient also warrants closer attention. Ocular metastases are exceptionally rare in NSCLC—in a cohort of 2,872 cases, only three developed ocular involvement (13). Doebele et al. have proposed that oncogene-addicted NSCLC follow distinctive metastatic patterns (14). In our case, the emergence of an ocular metastasis during chemotherapy (Figure 2D) represents an unprecedented pattern in ALK/ROS1 co-rearranged LUAD. Given the absence of guidelines for routine orbital imaging in asymptomatic patients (15) and the low incidence of ocular spread, it is plausible that the eye lesion was present at baseline but went undetected. This observation underscores the importance of maintaining vigilance for atypical metastatic sites in patients with oncogene‑driven NSCLC, especially those who experience prolonged survival.

After nearly four years of remission on chemotherapy, our patient’s disease progressed with recurrence that was ALK‑positive (and ROS1negative by NGS) and involved new metastases to the brain. At that juncture, we initiated targeted therapy with ensartinib, a secondgeneration ALK TKI known for its potency and central nervous system (CNS) activity (16,17). Ensartinib has demonstrated excellent intracranial efficacy in ALKrearranged NSCLC, with intracranial objective response rates of approximately 64–70% in patients with brain metastases (16,17). Consistent with this, our patient responded well to ensartinib, with significant regression of both thoracic tumors and brain lesions (Figures 4,5). Although primarily developed as an ALK inhibitor, ensartinib also exhibits inhibitory activity against ROS1 fusions in clinical study (18). This broader target profile was relevant given the tumor’s initial dual‑positive status, and may have provided additional tumor control. The successful outcome with ensartinib in second line emphasizes the importance of employing TKIs to control driver‑positive disease.

An intriguing aspect of this case is the mechanistic basis for the patient’s unusually prolonged response to chemotherapy. Mounting translational evidence indicates that tumors harbouring ALK or ROS1 fusions are intrinsically sensitive to pemetrexed. Both oncogenic drivers are associated with markedly low expression of thymidylate synthase (TS) (19,20), the principal target of pemetrexed, thereby enhancing susceptibility to antifolate cytotoxicity (21). In addition, ALK- and ROS1-positive adenocarcinomas frequently arise from the terminal respiratory unit (TRU) lineage, characterised by high expression of TTF-1 and folate-receptor-α (FRα). TTF-1 positivity correlates with lower TS levels, while FRα facilitates pemetrexed uptake—both factors that predict superior response to pemetrexed-based regimens (22).

Within this shared molecular backdrop, clone-specific chemotherapy sensitivity still shapes outcome. Although ALK and ROS1 rearrangements are usually mutually exclusive, their coexistence here likely reflects genetically distinct subclones (4,23). A plausible scenario is that a ROS1-driven clone—intrinsically more chemotherapy sensitive because of low TS—dominated the tumor bulk at diagnosis and was effectively eradicated by pemetrexed plus cisplatin, thereby producing the long PFS. Clinical series confirm that ROS1-rearranged NSCLC is indeed more responsive to platinum/pemetrexed than other molecular subtypes (24); this superiority parallels the significantly lower TS levels seen in ROS1-positive tumors compared with ROS1-negative cases (20). Once the vulnerable subclone was eliminated, competitive constraints lifted (“competitive release”) (25), allowing an ALK-dominant lineage—more tolerant of chemotherapy—to expand and become the sole fusion detected at progression. Such chemotherapy-induced clonal selection fits established models of tumor evolution and helps explain why the disease eventually relapsed yet remained highly responsive to ALK-targeted therapy.

At relapse, however, the absence of ROS1 fusion on DNA-based NGS should be interpreted cautiously, given that DNA-NGS can occasionally yield false-negative results for ROS1 fusions when breakpoints occur in intronic regions rich in repetitive elements that are not fully covered by capture probes. In a head-to-head comparison of 23 ROS1-positive NSCLC cases, Davies et al. reported that DNA-NGS missed 4/18 fusions, whereas an anchored-multiplex RNA-NGS assay detected all fusions in samples that met RNA-quality thresholds, highlighting the superior sensitivity of RNA-NGS when tissue quality permits (26). Accordingly, whenever sufficient, well-preserved material is available, incorporating RNA-NGS alongside—or in place of—DNA-NGS can mitigate the risk of overlooking clinically actionable ROS1 rearrangements.

Despite this exceptional chemotherapy-responsiveness, one must recognise that TKIs remain the standard of care for driver-positive NSCLC. For any advanced NSCLC harboring actionable fusions like ALK or ROS1, TKIs have demonstrated markedly improved efficacy and survival benefits compared with cytotoxic chemotherapy (27,28). Patients with dual ALK/ROS1 positivity should therefore be considered for targeted therapy as part of their management. A TKI capable of inhibiting both fusion drivers (such as crizotinib or newer‑generation inhibitors) is a logical firstline option, and indeed most previously reported dualpositive cases utilized TKIs (5,7). The dramatic, durable responses achievable with modern ALK/ROS1 inhibitors have transformed the prognosis of oncogene‑driven NSCLC. For instance, the third‑generation ALK inhibitor lorlatinib recently achieved a 5year PFS rate of approximately 60% (versus only 8% with crizotinib) in the firstline CROWN trial (12)—an unprecedented outcome in ALK‑positive disease. Such data underscore why targeted therapy is the preferred modality in driver‑positive lung cancer. In our patient’s course, TKI therapy was introduced in the second line, which reinforces an important point: even if chemotherapy is used initially, integrating targeted therapy is crucial to control residual disease. Ultimately, without further evidence, we cannot assume that chemotherapy offers comparable benefit to TKIs in dual‑positive cases. Our case suggests an interesting sequential approach that chemotherapy followed by TKI can yield prolonged disease, but it remains an open question whether this strategy is optimal or generalizable.

Conclusions

We describe a rare case of LUAD with concomitant ALK and ROS1 rearrangements that responded remarkably well to first‑line pemetrexed + cisplatin chemotherapy and subsequently to second‑line ensartinib. This case illustrates that prolonged disease control is possible with chemotherapy in dual‑driver tumors, and also highlights the need for timely, high-precision molecular profiling and integration of targeted therapy. Given the breadth of evidence supporting TKIs, they remain the cornerstone of treatment for advanced ALK‑ or ROS1‑positive NSCLC. The optimal first‑line strategy for patients harboring dual ALK/ROS1 fusions is still undefined; an individualized approach—potentially involving chemotherapy followed by targeted therapy—may be warranted until there are studies with large cohorts clarifying the best practice. Ultimately, more clinical experience and collaborative data are required to establish evidence‑based guidelines for this exceedingly rare molecular subset.

Acknowledgments

We would like to thank the patient and her family. We are equally grateful to the staff of Guangzhou Chest Hospital and Guangzhou Medical University.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-92/rc

Peer Review File: Available at https://acr.amegroups.com/article/view/10.21037/acr-2025-92/prf

Funding: This study was supported by the National Natural Science Foundation of China Grant (Nos. 82173609 and 82373678).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://acr.amegroups.com/article/view/10.21037/acr-2025-92/coif). The 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) and with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from the patient for the publication of the 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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