Prolonged survival with alectinib in a patient with advanced lung adenocarcinoma: a case report and literature review
Case Report

Prolonged survival with alectinib in a patient with advanced lung adenocarcinoma: a case report and literature review

Man Sun#, Dan Zang#, Huan Zhou#, Jun Chen

Department of Oncology, The Second Hospital of Dalian Medical University, Dalian, China

Contributions: (I) Conception and design: M Sun, J Chen; (II) Administrative support: J Chen; (III) Provision of study materials or patients: D Zang, H Zhou; (IV) Collection and assembly of data: M Sun, D Zang; (V) Data analysis and interpretation: M Sun; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Jun Chen, MD. Department of Oncology, The Second Hospital of Dalian Medical University, No. 467 Zhongshan Road, Shahekou District, Dalian 116023, China. Email: chenjun_dmu@126.com.

Background: Alectinib is a second-generation tyrosine kinase inhibitor (TKI) that selectively targets anaplastic lymphoma kinase (ALK) rearrangements and is recommended as first-line therapy for patients with advanced ALK-positive non-small cell lung cancer (NSCLC). Pivotal clinical trials have demonstrated its superior efficacy and favorable safety profile compared with earlier ALK inhibitors and chemotherapy. However, long-term real-world outcomes remain insufficiently characterized, particularly in patients harboring concurrent ALK alterations and additional rare genetic variants, whose clinical relevance is often unclear.

Case Description: We report a case of a 41-year-old female diagnosed with stage IV lung adenocarcinoma (LUAD) following routine imaging. Comprehensive diagnostic evaluation, including positron emission tomography/computed tomography (PET-CT), cervical lymph node biopsy, and targeted next-generation sequencing, revealed an EML4-ALK fusion (variant 1) together with a concurrent RET p.R820H mutation. The patient initiated first-line treatment with alectinib at a daily dose of 1,200 mg. A partial response was achieved within two months of therapy, and disease control was sustained throughout long-term follow-up. Remarkably, after more than 62 months of continuous alectinib treatment, the patient remained progression-free, with no evidence of disease relapse, distant metastasis, or treatment-related adverse events. The identified RET p.R820H alteration is currently classified as a variant of uncertain significance, and its functional or clinical impact has not been established.

Conclusions: This case demonstrates an exceptionally durable response to first-line alectinib in an ALK-positive LUAD patient with a concurrent rare RET variant. It underscores the long-term efficacy and tolerability of alectinib and highlights the importance of comprehensive genomic profiling in guiding personalized targeted therapy for genetically complex NSCLC.

Keywords: Lung adenocarcinoma (LUAD); anaplastic lymphoma kinase (ALK); alectinib; case report

Submitted Dec 06, 2025. Accepted for publication Jan 21, 2026. Published online Jan 27, 2026.

doi: 10.21037/tcr-2025-1-2726

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Key findings

• Alectinib treatment led to over 62 months of progression-free survival (PFS) in a patient with advanced lung adenocarcinoma (LUAD) harboring both EML4-ALK fusion and a RET p.R820H mutation, with no treatment-related adverse events observed.

• This is the first reported case of such prolonged survival in an ALK-positive non-small cell lung cancer (NSCLC) patient with a co-occurring RET variant.

What is known and what is new?

• Alectinib is a second-generation ALK TKI approved for first-line treatment of ALK-positive NSCLC, with demonstrated superiority over chemotherapy in clinical trials.

• This case provides real-world evidence of durable alectinib efficacy and excellent safety in a genetically complex patient harboring both a known driver (EML4-ALK) and a rare variant of uncertain significance (RET p.R820H), highlighting the relevance of extended genomic profiling.

What is the implication, and what should change now?

• This case supports the use of alectinib as a frontline therapy even in the presence of co-mutations of unclear pathogenicity, suggesting that ALK-targeted therapy may remain effective despite genetic complexity.

• Clinicians should consider comprehensive genomic testing beyond known drivers to inform treatment selection and improve long-term outcomes. Further research is warranted to understand the functional impact of concurrent RET variants and optimize precision therapy strategies in ALK-positive NSCLC.

Introduction

Lung cancer, accounting for 11.4% of global cancer cases and ranking second in incidence, is a major cause of cancer mortality, with non-small cell lung cancer (NSCLC) comprising 80–85% and lung adenocarcinoma (LUAD) being the most common subtype (1). The advent of precision medicine has enabled the identification of key tumor driver genes in NSCLC, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), rearranged during transfection (RET), mesenchymal-epithelial transition factor (MET), and c-ros oncogene 1 (ROS1) mutations (2). Driver mutations in NSCLC are typically mutually exclusive.

ALK gene rearrangements, including the common EML4-ALK fusion, occur in 3–7% of NSCLC cases and are associated with younger, never-smoker or light-smoker LUAD patients (3,4). EML4-ALK, a key target for ALK-TKIs, demonstrates significant efficacy. EML4-ALK fusions are well-characterized oncogenic drivers in LUAD and are distinct from ALK point mutations that often arise as resistance mechanisms (5). The Food and Drug Authority (FDA) has approved several first-line ALK-TKIs for advanced ALK-positive NSCLC, with alectinib, the standard second-generation ALK-TKI, showing superior efficacy and safety (6,7). The PROFILE 1014 trial showed better progression-free survival (PFS) with ALK-TKIs compared to chemotherapy, and the ALEX study reported a median PFS of 34.8 months with alectinib (8,9). This case details a patient with EML4-ALK and RET p.R820H mutations who responded well to first-line alectinib, highlighting the potential for genotype-driven treatment strategies. We present this article in accordance with the CARE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2726/rc).

Case presentation

Fundamental symptoms and diagnosis

A 41-year-old female, asymptomatic except for a 3 cm consolidative lesion in the left lower lobe (LLL) detected during a routine health check in December 2019, was found to have increased metabolic activity in the LLL and metastatic lesions in the mediastinal and right supraclavicular lymph nodes, as well as the T12 vertebra, on positron emission tomography-computed tomography (PET-CT) (Figure 1). Brain magnetic resonance imaging (MRI) was performed at diagnosis and showed no evidence of intracranial metastases. A cervical lymph node biopsy performed on 27 December 2019 confirmed pulmonary adenocarcinoma, with immunohistochemical positivity for CK7, TTF-1, and Ki67 (20%), and negativity for other markers. Genetic testing was performed using a targeted 425-gene next-generation sequencing (NGS) panel (Geneseeq Technology Inc., Nanjing, China), conducted on the Illumina HiSeq/MiSeqDx platform (Illumina, San Diego, CA, USA). The EML4-ALK fusion identified was variant 1 (EML4 exon 13–ALK exon 20), with a variant allele frequency (VAF) of 5.5%. The patient also tested positive for programmed cell death ligand-1 (PD-L1) with a tumor proportion score (TPS) of 1–49% (Figure 2). Following a multidisciplinary team (MDT) discussion, she was staged as stage IVA, with no indication for surgery. The patient denied a history of smoking, alcohol use, or any hereditary or psychiatric disorders in her family.

Figure 1 PET-CT scan lesions at the time of diagnosis. (A) Lesion in the left lower lobe of the lung; (B) right supraclavicular lymph node; (C) mediastinal lymph node; (D) T12 vertebra. PET-CT, positron emission tomography-computed tomography.
Figure 2 PD-L1 immunohistochemical testing results. The tumor shows positive PD-L1 staining with a TPS of 1–49%. Images were acquired at ×100 (left and middle) and ×400 (right) magnification. HE, hematoxylin-eosin; IHC, immunohistochemistry; PD-L1, programmed cell death ligand-1; TPS, tumor proportion score.

Alectinib treatment

In January 2020, the patient began first-line treatment with alectinib (1,200 mg daily) and zoledronic acid. After two cycles, chest CT revealed significant tumor reduction in the left lower hilum (13 mm × 10 mm) with mild enhancement, and a slightly enlarged mediastinal lymph node (13 mm × 10 mm) also showed mild enhancement. No enlargement of cervical lymph nodes was noted. Lymph node metastases in the neck achieved complete remission (CR), and the overall response was classified as partial response (PR) according to the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1). Alectinib was continued at the same dosage.

In April 2021, due to the inconvenience of zoledronic acid infusions and the associated risk of jaw necrosis, the patient switched to denosumab for bone metastasis treatment (8,9). Regular follow-ups during this period showed no signs of tumor progression, with sustained PR. By October 2021, after 21 months of alectinib therapy, CT scans revealed complete resolution of the small nodule in the left lower lobe hilum and the mediastinal lymph nodes, maintaining sustained PR (Figure 3). Throughout the follow-up, regular imaging assessments were conducted every 3 months. During follow-up, no neurological symptoms suggestive of central nervous system involvement were observed, and brain imaging was performed when clinically indicated. Over 62 months of alectinib treatment, no progression or metastasis was detected, and the patient experienced no treatment-related adverse events. The patient’s quality of life remained high, with ongoing monitoring through regular follow-up imaging. During treatment, adverse events were monitored through regular outpatient visits every three months, including clinical symptom assessment, physical examination, and routine laboratory tests (hematology and liver function). No clinically significant abnormalities or treatment-related adverse events were observed throughout follow-up. The key diagnostic, therapeutic, and follow-up milestones are summarized in Table 1. 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 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.

Figure 3 Changes observed in the patient before and after alectinib treatment. (A) Chest CT at 2 months after treatment initiation (2020.03.20) showing marked reduction of the primary lung lesion, consistent with partial response; (B) Chest CT at 18 months (2021.07.26) demonstrating sustained partial response; (C) Chest CT at 21 months (2021.10.29) showing complete resolution of the left lower lobe hilar lesion and mediastinal lymph nodes; (D) Chest CT at 25 months (2022.02.09) demonstrating continued disease control with no evidence of progression; (E) Chest CT at 51 months (2024.03.21) showing ongoing partial response with no radiological evidence of disease progression. Baseline imaging prior to treatment initiation was not available in our institution. The images shown represent the earliest available follow-up after treatment initiation. PR, partial response.

Table 1

Timeline of diagnosis, treatment, and clinical course

Time point Clinical events
December 10, 2019 A left lower lobe lung lesion was detected during routine health examination. PET-CT revealed hypermetabolic primary lesion with mediastinal, right supraclavicular lymph node, and T12 vertebral metastases. Brain MRI at diagnosis showed no evidence of intracranial metastases
December 27, 2019 Cervical lymph node biopsy confirmed lung adenocarcinoma. Immunohistochemistry was positive for CK7 and TTF-1, with Ki67 index of 20%
December 28, 2019 Targeted 425-gene next-generation sequencing identified EML4-ALK fusion (variant 1; EML4 exon 13–ALK exon 20; VAF 5.5%) and a concurrent RET p.R820H variant of uncertain significance. PD-L1 tumor proportion score was 1–49%
January 2020 First-line treatment with alectinib (1,200 mg/day) was initiated in combination with zoledronic acid for bone metastasis
March 2020 Radiological evaluation after two treatment cycles demonstrated partial response according to RECIST 1.1; cervical lymph node metastases achieved complete remission
April 2021 Bone-modifying therapy was switched from zoledronic acid to denosumab due to treatment convenience and safety considerations
October 2021 After 21 months of alectinib therapy, CT scans showed complete resolution of the primary lung lesion and mediastinal lymph nodes, with sustained partial response
At last follow-up (>62 months) Continuous alectinib treatment was maintained with no evidence of disease progression, new metastases, or treatment-related adverse events. No neurological symptoms were observed, and brain imaging was performed when clinically indicated

ALK, anaplastic lymphoma kinase; CT, computed tomography; MRI, magnetic resonance imaging; PD-L1, programmed cell death ligand-1; PET, positron emission tomography; RECIST 1.1, Response Evaluation Criteria in Solid Tumors 1.1; RET, rearranged during transfection; VAF, variant allele frequency.

Discussion

Some 2–8% of LUAD patients harbor ALK gene fusions, with EML4-ALK being the most common, typically showing high sensitivity to ALK-TKIs (10). EML4-ALK fusion LUAD patients tend to be younger, nonsmokers, with larger lymph nodes, higher clinical stages, and more aggressive pathology, often affecting females aged under 40 years (11,12). They also have an increased risk of brain metastases compared to other NSCLC subtypes, warranting close neurological monitoring and regular brain imaging (13).

Alectinib shows superior overall survival and fewer Grade 3 adverse events than platinum-based chemotherapy in advanced ALK-positive NSCLC (14,15). However, alectinib has been associated with hemolytic anemia and diffuse alveolar hemorrhage in some patients; both conditions generally improved after dose reduction or discontinuation along with supportive treatment. Regular hematologic monitoring is recommended for early detection of such reactions (16).

In this case, a RET p.R820H missense mutation was identified with a VAF of 2.7%. According to established databases such as OncoKB and ClinVar, this alteration is classified as a variant of uncertain significance (VUS), with no functional validation or evidence supporting its oncogenic role in NSCLC (17). To date, no studies have confirmed RET p.R820H as a bona fide driver mutation, and its clinical relevance remains undetermined. Consequently, the rationale for targeted therapy against this site should be approached with caution. Although preclinical data have demonstrated that alectinib possesses anti-tumor activity against specific RET fusion-positive models, such as NCOA4-RET in NSCLC cell lines, this effect has not been corroborated in clinical settings (18,19). Moreover, alectinib is not recognized as a selective RET inhibitor, and its therapeutic utility in RET-mutant or fusion-driven tumors remains investigational. Importantly, no causal association between the RET p.R820H variant and the favorable clinical response observed in this case can be inferred.

Although the ALEX study reported a median PFS of up to 34.8 months with alectinib in treatment-naïve ALK-positive NSCLC patients, real-world evidence suggests that a substantial subset of patients may develop resistance within 1–2 years due to heterogeneity in tumor burden, co-mutations, brain metastasis, and treatment adherence (20,21). Against this background, the present case provides an opportunity to examine the durability of ALK inhibition at the individual level in a clinically and genomically non-canonical setting. This study reports an LUAD patient with both EML4-ALK and RET p.R820H mutations, who achieved sustained disease control exceeding 62 months under uninterrupted first-line alectinib despite a genomically non-canonical background, providing insight into the potential persistence of ALK dependency beyond population-level expectations.

Strengths and limitations

This case represents the longest documented PFS with first-line alectinib in ALK-positive NSCLC, uniquely complicated by a co-occurring RET p.R820H mutation—an uncharacterized variant of uncertain significance. Its strength lies not only in the exceptional clinical course exceeding 62 months without adverse events, but also in its illumination of how rare co-mutations may not preclude, and potentially coexist with, sustained TKI benefit. By integrating longitudinal clinical, imaging, and genomic data, this report underscores the need to revisit assumptions about mutual exclusivity and resistance pathways in oncogene-driven lung cancer. However, as an isolated observation, mechanistic generalizability remains limited. The lack of functional interrogation of the RET variant constrains biological inference, and no serial molecular profiling was conducted to monitor clonal evolution under treatment pressure. Nonetheless, this case prompts deeper inquiry into the therapeutic permissiveness of ALK inhibition in genomically composite tumors and supports the inclusion of rare variants in prospective biomarker frameworks.

Conclusions

This case highlights the durable efficacy and excellent tolerability of alectinib in ALK-positive LUAD, even in the presence of a co-occurring RET variant of uncertain significance. It underscores the value of comprehensive genomic profiling and raises important questions about the therapeutic impact of compound oncogenic alterations. Further studies are needed to elucidate the clinical and biological relevance of rare co-mutations in targeted therapy landscapes.

Acknowledgments

All data used in this study are available in the public repository. The authors thank all investigators for sharing these data.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2726/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2726/prf

Funding: This work was supported by the National Natural Science Foundation of China (No. 82203056).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2726/coif). All authors report that this work was supported by the National Natural Science Foundation of China (No. 82203056). The authors have no other 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 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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(English Language Editor: J. Jones)

Cite this article as: Sun M, Zang D, Zhou H, Chen J. Prolonged survival with alectinib in a patient with advanced lung adenocarcinoma: a case report and literature review. Transl Cancer Res 2026;15(1):70. doi: 10.21037/tcr-2025-1-2726

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