Abstract
Background
Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have demonstrated substantial efficacy in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but evidence for their use in the neoadjuvant setting remains limited. This study aimed to evaluate and compare the efficacy and safety of neoadjuvant ALK-targeted therapy and chemotherapy-based neoadjuvant treatment in surgically treated patients with ALK-rearranged NSCLC.
Methods
We retrospectively analyzed the clinical data of 20 patients with ALK-rearranged NSCLC who received neoadjuvant therapy followed by curative-intent surgery at the Department of Thoracic Surgery, Hunan Cancer Hospital, between October 2018 and April 2025. Patients were retrospectively classified into an ALK-TKI group (n=13) and a chemotherapy-based group (n=7) according to the neoadjuvant regimen received. A comparative analysis assessed radiological response, pathological response, postoperative complications, adverse events, and survival outcomes between the 2 groups after neoadjuvant therapy.
Results
The baseline characteristics of the 2 groups were comparable without statistically significant differences. Among the 13 patients in the ALK-TKI group, 9 achieved partial response (PR) and 4 had stable disease (SD), resulting in an objective response rate (ORR) of 69.2%. Among the 7 patients in the chemotherapy-based group, 3 achieved PR and 4 had SD, resulting in an ORR of 42.9% (P=0.35). Six patients (46.2%) in the ALK-TKI group and one patient (14.3%) in the chemotherapy-based group achieved major pathological response (MPR) (P=0.32). Four patients (30.8%) in the ALK-TKI group and one patient (14.3%) in the chemotherapy-based group achieved pathological complete response (pCR) (P=0.61). The proportion of patients with ypN0 disease was significantly higher in the ALK-TKI group than in the chemotherapy-based group (11/13 vs. 3/7, P=0.043), and the extent of pathological nodal downstaging was also greater in the ALK-TKI group (P=0.008). There were no significant differences between the 2 groups in the incidence of adverse events, grade ≥3 adverse events, postoperative complications, surgical approach, operative time, blood loss, thoracic drainage duration, or postoperative hospital stay. Kaplan-Meier analyses showed nonsignificant numerical trends toward improved overall survival and recurrence-free survival in the ALK-TKI group. However, these findings were based on a small number of recurrence and death events and should be interpreted with caution.
Conclusions
Neoadjuvant ALK-TKI therapy showed numerically higher radiological and pathological response rates and a significantly higher ypN0 rate and greater pathological nodal downstaging relative to the baseline clinical nodal stage compared with chemotherapy-based neoadjuvant therapy. No statistically significant differences in the observed safety or perioperative outcomes were identified between the groups.
Keywords: Neoadjuvant therapy, anaplastic lymphoma kinase (ALK), pathological downstaging, non-small cell lung cancer (NSCLC)
Highlight box.
Key findings
• In this real-world retrospective study, neoadjuvant anaplastic lymphoma kinase tyrosine kinase inhibitor (ALK-TKI) therapy showed higher objective response rate (ORR), major pathological response (MPR), and pathological complete response (pCR) rates than chemotherapy-based neoadjuvant treatment, although these differences were not statistically significant. ALK-TKI therapy was associated with a significantly higher ypN0 rate and greater pathological nodal downstaging, with no statistically significant differences in the observed safety or perioperative outcomes.
What is known and what is new?
• ALK-TKIs have established efficacy in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but evidence for neoadjuvant ALK-targeted therapy in surgically treated patients remains limited because of the low incidence of ALK rearrangements and the small number of clinical studies.
• This study adds real-world comparative evidence suggesting that neoadjuvant ALK-TKI therapy may improve conversion to ypN0 and pathological downstaging without increasing treatment-related toxicity, surgical difficulty, or postoperative complications.
What is the implication, and what should change now?
• Neoadjuvant ALK-TKI therapy may be a feasible strategy for selected patients with ALK-rearranged NSCLC considered suitable for curative-intent surgery after multidisciplinary evaluation. Routine molecular testing before neoadjuvant treatment decision-making should be emphasized, and larger prospective multicenter trials are needed to confirm efficacy, optimize treatment duration, and clarify long-term survival benefits.
Introduction
Lung cancer remains a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases (1-3). Radical surgery remains the cornerstone of curative-intent treatment for resectable NSCLC. However, recurrence after surgery remains common, particularly in patients with locally advanced disease (4). This underscores the continued challenges in the treatment of the disease.
Neoadjuvant therapy aims to reduce tumor burden, eradicate micrometastatic disease, and improve the likelihood of complete surgical resection (5). Platinum-based chemotherapy has traditionally been used in the neoadjuvant setting (6). Compared with surgery alone, neoadjuvant platinum-based chemotherapy has demonstrated a significant survival benefit in patients with resectable NSCLC, as supported by randomized trials and meta-analyses. An individual participant data meta-analysis of 15 randomized trials involving 2,385 patients showed a 13% relative reduction in the risk of death and an absolute improvement of 5% in 5-year survival (7). A more recent meta-analysis of 12 randomized trials also showed significantly improved 1- and 3-year survival rates with neoadjuvant chemotherapy followed by surgery compared with surgery alone (8). This marginal increase in survival is comparable to the benefits conferred by postoperative adjuvant chemotherapy (9). Nevertheless, treatment-related toxicities remain an important consideration when selecting perioperative treatment strategies.
With advances in molecular profiling, targeted therapy, which selectively targets specific molecular features of cancer cells, has become an important strategy for oncogene-driven NSCLC (10,11). However, NSCLC harboring actionable driver alterations, particularly EGFR mutations or anaplastic lymphoma kinase (ALK) rearrangements, generally derives limited benefit from immune checkpoint inhibitor monotherapy (12,13). This limited efficacy may be related to a relatively low tumor mutational burden and a less inflamed tumor immune microenvironment, including limited co-occurrence of programmed death ligand 1 (PD-L1) expression and CD8-positive tumor-infiltrating lymphocytes, which may reduce neoantigen-driven antitumor immune responses and sensitivity to programmed cell death protein 1 (PD-1)/PD-L1 blockade (13-15). These biological and clinical observations have prompted interest in extending molecularly matched targeted therapy into the perioperative setting.
ALK rearrangement is an established oncogenic driver in NSCLC, occurring in approximately 5% of patients (16). ALK rearrangement involves breakage of the ALK gene followed by its fusion with a partner gene. This results in the production of an ALK fusion protein, whose conformational change after translation leads to dysregulated phosphorylation, driving tumorigenesis and establishing ALK as a key oncogenic driver (13). ALK-TKIs have substantially improved clinical outcomes in patients with advanced ALK-rearranged NSCLC compared with conventional chemotherapy (17-20). The efficacy of ALK inhibition has also been extended to the postoperative setting. In the phase III ALINA trial, 24 months of adjuvant alectinib significantly improved disease-free survival and central nervous system (CNS) disease-free survival compared with platinum-based chemotherapy in patients with completely resected ALK-positive NSCLC (21). These findings provide clinical proof of principle that sustained inhibition of the ALK oncogenic driver may control occult micrometastatic disease and reduce postoperative recurrence risk, thereby supporting further investigation of ALK-targeted therapy throughout the perioperative period.
Evidence from EGFR-mutated NSCLC further supports the feasibility of moving targeted therapy into the neoadjuvant setting. The EMERGING-CTONG 1103 trial demonstrated clinical activity of perioperative erlotinib in stage IIIA–N2 EGFR-mutated NSCLC (22), while the phase III NeoADAURA trial showed that neoadjuvant osimertinib significantly improved major pathological response (MPR) compared with chemotherapy alone (23). However, these findings cannot be directly extrapolated to ALK-rearranged NSCLC. Evidence for neoadjuvant ALK inhibition remains limited because of the low prevalence of ALK rearrangements and the small size and heterogeneity of published studies (24,25). Recent phase II results from ALNEO and NAUTIKA1 support the feasibility and pathological activity of neoadjuvant alectinib, but randomized comparative evidence and mature survival data remain unavailable (26,27).
Therefore, this retrospective cohort study aimed to compare the radiological and pathological responses, perioperative safety, and exploratory survival outcomes of neoadjuvant ALK-TKI therapy and chemotherapy-based treatment in surgically treated patients with ALK-rearranged NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1625/rc).
Methods
Clinical data
This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Hunan Cancer Hospital (No. KY2026032), and all enrolled patients provided written informed consent. We reviewed 20 patients with ALK-rearranged NSCLC who received neoadjuvant therapy followed by curative-intent surgery after multidisciplinary team (MDT) evaluation at Hunan Cancer Hospital between October 2018 and April 2025 (Figure 1).
Figure 1.
Flow diagram of patient screening and treatment classification. ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor; MPR, major pathological response; NSCLC, non-small cell lung cancer; pCR, pathological complete response; PR, partial response; SD, stable disease; TKI, tyrosine kinase inhibitor.
The inclusion criteria were as follows: (I) age 18–75 years; (II) pathologically confirmed NSCLC; (III) ALK rearrangement confirmed by next-generation sequencing (NGS); (IV) neoadjuvant therapy recommended by the MDT; (V) Eastern Cooperative Oncology Group performance status (ECOG PS score) of 0–1 and (VI) complete clinical and follow-up data.
The exclusion criteria were as follows: (I) concurrent ALK rearrangement and an EGFR mutation with receipt of neoadjuvant EGFR-TKI therapy; (II) previous local radiotherapy or systemic antitumor therapy before the current neoadjuvant treatment; (III) receipt of neoadjuvant ALK-targeted therapy combined with chemotherapy; (IV) insufficient documentation of the targeted therapy regimen, including the specific agent or administration details, precluding reliable treatment classification; (V) active concomitant malignancy; and (VI) severe cardiac, hepatic, or renal dysfunction. None of the 20 patients included in the present study harbored a concurrent EGFR mutation or received neoadjuvant EGFR-TKI therapy.
Patients were originally staged according to the tumor-node-metastasis (TNM) edition in use at the time of diagnosis, with the 8th edition applied before 2025 and the 9th edition applied in 2025. For this retrospective analysis, all pretreatment clinical and postoperative pathological stages were harmonized according to the 9th edition using available imaging and pathological records (28,29). Because nodal downstaging was evaluated using the conventional N0–N3 categories, which are retained in the 9th edition, reclassification did not alter the nodal outcomes. NGS was performed on pretreatment tumor specimens using a targeted NGS assay based on rhAmpSeq PCR and the Gene+seq-2000 platform, covering 35 cancer-related genes and 58 microsatellite loci for microsatellite instability assessment.
Baseline evaluation included contrast-enhanced chest computed tomography (CT), abdominal CT or ultrasonography, contrast-enhanced brain magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), or bone scintigraphy using single-photon emission CT (SPECT) bone scintigraphy, as clinically indicated. Tumor tissue samples for histopathological diagnosis and molecular testing were obtained by CT-guided percutaneous needle biopsy or endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA).
Pretreatment clinical nodal (cN) status was pathologically confirmed by EBUS-TBNA lymph-node sampling when available. In patients without pathological lymph-node confirmation, cN status was determined on the basis of PET-CT or contrast-enhanced chest CT. EBUS-TBNA performed without lymph-node sampling was not considered pathological confirmation of nodal status.
The study cohort was defined by the receipt of curative-intent surgical resection after neoadjuvant therapy rather than by conventional clinical-stage criteria alone. Two patients in the ALK-TKI group were clinically classified as cM1a and cN3, corresponding to overall stage IVA, because pretreatment imaging showed pleural thickening suspicious for pleural metastasis. Following MDT evaluation and neoadjuvant therapy, both patients were considered suitable candidates for curative-intent surgery and subsequently underwent radical resection. They were therefore included in this surgically treated cohort.
Treatment selection and perioperative treatment
Neoadjuvant treatment was not assigned according to a predefined protocol but was individualized through MDT evaluation based on clinical stage and tumor burden, technical resectability, expected efficacy and toxicity, patient condition and preference, and treatment availability. The final treatment regimen was determined jointly by the MDT and the patient after discussion of the available options.
Patients were divided into an ALK-TKI group (n=13) and a chemotherapy-based group (n=7) according to the neoadjuvant regimen. Patients in the ALK-TKI group received monotherapy with a first- or second-generation ALK-TKI. Specifically, 3 patients received crizotinib, 5 received alectinib, 2 received brigatinib, and 3 received iruplinalkib. The median duration of neoadjuvant ALK-TKI therapy was 3 months (range, 1–8 months). Most patients (11/13, 84.6%) received treatment for 1–4 months, whereas two patients received prolonged treatment for 6 and 8 months, respectively. The duration of neoadjuvant ALK-TKI therapy was not prespecified or standardized but was individualized in routine clinical practice. Treatment duration was determined through MDT assessment based on serial radiological response, treatment tolerability, technical resectability, patient-related factors, and the planned timing of surgery. Surgery was performed when the MDT considered the tumor technically resectable and the patient medically suitable for surgery.
In the chemotherapy-based group, 5 patients received platinum-based doublet chemotherapy alone and 2 received platinum-based chemotherapy plus an immune checkpoint inhibitor. The detailed regimens and individual outcomes are provided in Table S1. Because only two patients received chemoimmunotherapy, subgroup comparisons according to treatment type were not performed.
After surgery, continuation of ALK-TKI therapy was determined according to the postoperative pathological findings, treatment tolerance, and MDT assessment. The duration of postoperative ALK-TKI therapy was calculated from the initiation of postoperative ALK-TKI treatment to the earliest occurrence of completion of the planned treatment period (24 or 36 months, as applicable), disease recurrence or progression, treatment discontinuation, death, or the last follow-up. ALK-TKI treatment administered or restarted after disease recurrence was considered post-recurrence systemic therapy and was not included in the calculation of the initial postoperative adjuvant treatment duration.
Response assessment
Radiological and pathological response endpoints were assessed before the initiation of any postoperative systemic treatment and were therefore used to evaluate the effects observed during the neoadjuvant treatment period.
Radiological responses were assessed before neoadjuvant therapy and before surgery. Pre-treatment chest CT scans were compared with preoperative scans obtained after neoadjuvant therapy, and all responses were evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (30). Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). The objective response rate (ORR) was defined as the proportion of patients with CR or PR.
Pathological response was used as an oncological endpoint to evaluate the efficacy of neoadjuvant therapy (31). Pathological response was assessed according to the proportion of residual viable tumor cells in resected specimens. MPR was defined as ≤10% residual viable tumor cells in the resected specimen. Pathological complete response (pCR) was defined as no residual viable tumor cells. Postoperative pathological stage was compared to evaluate treatment response. Specifically, postoperative pathological tumor stage (ypT), postoperative pathological nodal stage (ypN), and postoperative pathological tumor-node-metastasis stage (ypTNM) were analyzed to assess primary tumor regression, postoperative nodal status, and overall pathological downstaging after different neoadjuvant regimens. The extent of pathological nodal downstaging was calculated as cN minus ypN.
Adverse events (AEs) and surgery-related outcomes
AEs occurring during neoadjuvant therapy were graded from 1 to 5 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (32). Surgery-related outcomes were analyzed by comparing surgical approach, operative time, intraoperative blood loss, postoperative thoracic drainage volume, time to chest tube removal and postoperative hospital stay between the 2 groups. Postoperative complications, including pulmonary infection, arrhythmia, pleural effusion, bronchopleural fistula, and other complications, were recorded within 30 days after surgery. The severity of postoperative complications was classified according to the Clavien-Dindo classification system (33,34).
Survival outcomes
Kaplan-Meier curves were used to estimate survival outcomes in each group, including recurrence-free survival (RFS) and overall survival (OS) (35). RFS was defined as the time from initiation of neoadjuvant therapy to tumor recurrence or death from any cause, whichever occurred first, whereas OS was defined as the time from initiation of neoadjuvant therapy to death from any cause; patients without the corresponding event were censored at the last follow-up.
Statistical analysis
Statistical analyses were performed using SPSS version 26.0. Normally distributed continuous variables were expressed as the mean ± standard deviation and compared between groups using the independent-samples t-test. Non-normally distributed variables were expressed as the median with interquartile range (IQR) and compared using the Mann-Whitney U test. Categorical variables were summarized as frequencies and percentages and compared using the χ2 test or Fisher’s exact test, as appropriate. Survival outcomes between the 2 groups were compared using the log-rank test. A two-sided P<0.05 was considered statistically significant.
Because of the small sample size, limited number of outcome events, and close association between treatment modality and treatment duration, multivariable adjustment or reliable subgroup analyses according to neoadjuvant treatment duration were not performed.
Results
Patient characteristics
A total of 20 patients with ALK-rearranged NSCLC who received neoadjuvant therapy were included, comprising 13 patients in the neoadjuvant ALK-TKI group (ALK-TKI group) and 7 patients in the neoadjuvant chemotherapy-based group. The median duration of ALK-TKI therapy was 3 months (IQR, 2–4 months; range, 1–8 months), with 11 of 13 patients receiving treatment for 1–4 months. The median number of neoadjuvant treatment cycles in the chemotherapy-based group was 2 cycles (IQR, 2–3 cycles), corresponding to a median treatment duration of 1.5 months (IQR, 1.5–2.25 months), with no significant difference between groups (P=0.10; Table 1).
Table 1. Patient characteristics.
| Characteristic | Total | ALK-TKI | Chemotherapy-based | P value |
|---|---|---|---|---|
| Sex | 13 | 7 | >0.99 | |
| Male | 6 | 4 | 2 | |
| Female | 14 | 9 | 5 | |
| Age (years) | 51.2±11.3 | 57.86±6.54 | 0.17 | |
| Height (cm) | 159.31±8.32 | 160.00±6.58 | 0.84 | |
| Weight (kg) | 59.31±10.02 | 60.36±12.11 | 0.83 | |
| BSA (m2) | 1.60±0.17 | 1.62±0.17 | 0.82 | |
| ECOG PS scores | 0.35 | |||
| 0 | 12 | 9 | 3 | |
| 1 | 8 | 4 | 4 | |
| Smoking status | 0.53 | |||
| Ever | 3 | 1 | 2 | |
| Never | 17 | 12 | 5 | |
| Pathological type | >0.99 | |||
| LUAD | 18 | 12 | 6 | |
| SCC | 2 | 1 | 1 | |
| cT | 0.64 | |||
| 1 | 7 | 5 | 2 | |
| 2 | 5 | 2 | 3 | |
| 3 | 4 | 3 | 1 | |
| 4 | 4 | 3 | 1 | |
| Pretreatment nodal-staging method | – | |||
| Pathological confirmation by EBUS-TBNA | 4 | 4 | 0 | |
| PET-CT | 7 | 4 | 3 | |
| Contrast-enhanced chest CT | 9 | 5 | 4 | |
| cN | 0.16 | |||
| 0 | 0 | 0 | 0 | |
| 1 | 9 | 4 | 5 | |
| 2 | 7 | 5 | 2 | |
| 3 | 4 | 4 | 0 | |
| cTNM | 0.14 | |||
| IA | 0 | 0 | 0 | |
| IB | 0 | 0 | 0 | |
| IIA | 1 | 1 | 0 | |
| IIB | 3 | 0 | 3 | |
| IIIA | 11 | 7 | 4 | |
| IIIB | 2 | 2 | 0 | |
| IIIC | 1 | 1 | 0 | |
| IVA | 2 | 2 | 0 | |
| Dosing time, months | 3 [2–4] | 1.5 [1.5–2.25] | 0.10 | |
Data are presented as number, mean ± standard deviation, or median [interquartile range]. 1 chemotherapy cycle =0.75 month (21 days); Patients diagnosed before 2025 were originally staged according to the 8th edition of the TNM classification, whereas those diagnosed in 2025 were staged according to the 9th edition. All stages presented in this table were retrospectively harmonized according to the 9th edition. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; BSA, body surface area; cN, baseline clinical nodal stage; cT, baseline clinical tumor stage; CT, computed tomography; cTNM, baseline clinical tumor-node-metastasis stage; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; ECOG PS, Eastern Cooperative Oncology Group performance status; LUAD, lung adenocarcinoma; PET, positron emission tomography; SCC, squamous cell carcinoma; TNM, tumor-node-metastasis.
Pretreatment cN status was pathologically confirmed by EBUS-TBNA lymph-node sampling in 4 of the 20 patients, all in the ALK-TKI group. In the remaining patients, cN status was determined by PET-CT or contrast-enhanced chest CT. One patient in the chemotherapy-based group underwent EBUS-TBNA of the primary tumor without lymph-node sampling and was therefore not considered to have pathological nodal confirmation.
Radiological response assessment
Radiological responses after neoadjuvant therapy in the 2 groups are summarized in Table 2. Regarding post-treatment clinical T stage, ycT1 accounted for the largest proportion in both the ALK-TKI and chemotherapy-based groups, with no significant between-group difference in ycT-stage distribution (P>0.99). In the ALK-TKI group, 9 patients achieved a PR, 4 had SD, and none developed PD (Figure 2A). The ORR was 69.2% (9/13). In the chemotherapy-based group, 3 patients achieved a PR, 4 had SD, and none developed PD (Figure 2B). The ORR was 42.9% (3/7; Figure 2C). The ORR was numerically higher in the ALK-TKI group than in the chemotherapy-based group (69.2% vs. 42.9%), although the difference was not statistically significant (P=0.35).
Table 2. Radiologic response assessment of neoadjuvant therapy.
| Characteristic | Total | ALK-TKI (n=13) | Chemotherapy-based (n=7) | P value |
|---|---|---|---|---|
| ycT | >0.99 | |||
| 1 | 15 | 10 | 5 | |
| 2 | 2 | 1 | 1 | |
| 3 | 2 | 1 | 1 | |
| 4 | 1 | 1 | 0 | |
| PR | 0.35 | |||
| Yes | 12 | 9 | 3 | |
| No | 8 | 4 | 4 | |
| SD | 0.35 | |||
| Yes | 8 | 4 | 4 | |
| No | 12 | 9 | 3 | |
| PD | – | |||
| Yes | 0 | 0 | 0 | |
| No | 20 | 13 | 7 | |
| ORR | 0.35 | |||
| Yes | 12 | 9 | 3 | |
| No | 8 | 4 | 4 | |
| ORR, % | – | 69.2 | 42.9 |
Data are presented as number unless otherwise specified. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; ycT, post-neoadjuvant clinical tumor stage; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.
Figure 2.
Radiologic response assessment after neoadjuvant therapy. (A) Waterfall plot showing the percentage change in tumor size from baseline in patients receiving neoadjuvant ALK-targeted therapy (ALK-TKI group). (B) Waterfall plot showing the percentage change in tumor size from baseline in patients receiving platinum-based chemotherapy with or without immunotherapy (chemotherapy-based group). (C) Comparison of the ORR between the ALK-TKI and chemotherapy-based groups. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; ORR, objective response rate; PR, partial response; SD, stable disease.
Pathological response assessment
Pathological responses are summarized in Table 3 and Figure 3. The distribution of postoperative ypT stage did not differ significantly between the two groups (P=0.66).
Table 3. Pathological response assessment of neoadjuvant therapy.
| Characteristic | Total | ALK-TKI (n=13) | Chemotherapy-based (n=7) | P value |
|---|---|---|---|---|
| ypT | 0.66 | |||
| 0 | 5 | 4 | 1 | |
| 1 | 10 | 6 | 4 | |
| 2 | 3 | 1 | 2 | |
| 3 | 1 | 1 | 0 | |
| 4 | 1 | 1 | 0 | |
| ypN | 0.043 | |||
| 0 | 14 | 11 | 3 | |
| 1 | 1 | 1 | 0 | |
| 2 | 5 | 1 | 4 | |
| 3 | 0 | 0 | 0 | |
| ypTNM | 0.25 | |||
| 0 | 5 | 4 | 1 | |
| IA | 5 | 4 | 1 | |
| IB | 0 | 0 | 0 | |
| IIA | 1 | 0 | 1 | |
| IIB | 2 | 2 | 0 | |
| IIIA | 6 | 2 | 4 | |
| IIIB | 0 | 0 | 0 | |
| IIIC | 0 | 0 | 0 | |
| IVA | 1 | 1 | 0 | |
| pN downstage (cN > ypN) | 0.12 | |||
| Yes | 14 | 11 | 3 | |
| No | 6 | 2 | 4 | |
| Unchanged nodal stage | 0.58 | |||
| Yes | 4 | 2 | 2 | |
| No | 16 | 11 | 5 | |
| Nodal upstaging | 0.11 | |||
| Yes | 2 | 0 | 2 | |
| No | 18 | 13 | 5 | |
| Nodal stage change score (cN − ypN) | – | |||
| −1 | 2 | 0 | 2 | |
| 0 | 4 | 2 | 2 | |
| 1 | 6 | 3 | 3 | |
| 2 | 4 | 4 | 0 | |
| 3 | 4 | 4 | 0 | |
| Median [IQR] | 2 [1–3] | 0 [−1 to 1] | 0.008 | |
| pTNM downstage | 0.12 | |||
| Yes | 14 | 11 | 3 | |
| No | 6 | 2 | 4 | |
| MPR | 0.32 | |||
| Yes | 7 | 6 | 1 | |
| No | 13 | 7 | 6 | |
| MPR, % | 46.2 | 14.3 | ||
| pCR | 0.61 | |||
| Yes | 5 | 4 | 1 | |
| No | 15 | 9 | 6 | |
Data are presented as number unless otherwise specified. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; cN, baseline clinical nodal stage; IQR, interquartile range; MPR, major pathological response; pCR, pathological complete response; pN, pathological nodal stage; pTNM, pathological tumor-node-metastasis stage; ypN, postoperative pathological nodal stage; ypT, postoperative pathological tumor stage; ypTNM, postoperative pathological tumor-node-metastasis stage.
Figure 3.
Pathologic response assessment after neoadjuvant therapy. (A) Distribution of ypN. In the ALK-TKI group, 11 of 13 patients (84.6%) had ypN0 disease, 1 (7.7%) had ypN1 disease, and 1 (7.7%) had ypN2 disease. In the chemotherapy-based group, 3 of 7 patients (42.9%) had ypN0 disease and 4 (57.1%) had ypN2 disease (P=0.043). (B) Individual nodal stage change scores, calculated as cN minus ypN. Each symbol represents one patient. Positive values indicate nodal downstaging relative to the baseline clinical nodal stage, 0 indicates no change, and negative values indicate nodal upstaging. Thick horizontal bars indicate the medians, and vertical whiskers indicate the IQRs. The median score was 2 (IQR, 1–3) in the ALK-TKI group and 0 (IQR, −1 to 1) in the chemotherapy-based group (P=0.008). (C) Comparison of the MPR rate between the groups. MPR was achieved in 6 of 13 patients (46.2%) in the ALK-TKI group and 1 of 7 patients (14.3%) in the chemotherapy-based group (P=0.32). *, P<0.05; **, P<0.01. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; cN, baseline clinical nodal stage; IQR, interquartile range; MPR, major pathological response; ypN, postoperative pathological nodal stage.
The postoperative ypN-stage distribution differed significantly between the groups (P=0.043; Figure 3A). In the ALK-TKI group, 11 of 13 patients (84.6%) had ypN0 disease, 1 (7.7%) had ypN1 disease, and 1 (7.7%) had ypN2 disease. In the chemotherapy-based group, 3 of 7 patients (42.9%) had ypN0 disease and 4 (57.1%) had ypN2 disease.
Nodal downstaging relative to the baseline clinical nodal stage, defined as a positive cN − ypN score, occurred in 11 of 13 patients (84.6%) in the ALK-TKI group and 3 of 7 patients (42.9%) in the chemotherapy-based group (P=0.12). The nodal stage remained unchanged in 2 patients in each group, whereas nodal upstaging occurred in 2 patients in the chemotherapy-based group and in none of the patients in the ALK-TKI group. The median nodal stage change score was significantly higher in the ALK-TKI group than in the chemotherapy-based group [2 (IQR, 1–3) vs. 0 (IQR, −1 to 1); P=0.008; Figure 3B].
MPR was achieved in 6 of 13 patients (46.2%) in the ALK-TKI group and 1 of 7 patients (14.3%) in the chemotherapy-based group (P=0.32; Figure 3C). pCR was achieved in 4 of 13 patients (30.8%) in the ALK-TKI group and 1 of 7 patients (14.3%) in the chemotherapy-based group, with no statistically significant between-group difference (P=0.61).
AEs during neoadjuvant therapy
AEs during neoadjuvant therapy are summarized in Table 4. Any-grade AEs occurred in 3 patients in the ALK-TKI group and 3 patients in the chemotherapy-based group. The incidence of any-grade AEs did not differ significantly between the 2 groups (P=0.61). Grade ≥3 AEs occurred in 1 patient in each group (P>0.99). In the ALK-TKI group, one patient developed a marked increase in alanine aminotransferase (ALT) level to 574.6 U/L, corresponding to >5–20× the upper limit of normal. The only grade ≥3 AE in the chemotherapy-based group was immune-related myocarditis, which occurred in a patient who received chemotherapy combined with an immune checkpoint inhibitor. Therefore, this event should not be attributed to platinum-based chemotherapy alone. In addition, no statistically significant between-group differences were observed in AE-related treatment interruption or surgical delay.
Table 4. Adverse events during neoadjuvant therapy.
| Characteristic | Total | ALK-TKI (n=13) | Chemotherapy-based (n=7) | P value |
|---|---|---|---|---|
| AE of any level | 0.61 | |||
| Yes | 6 | 3 | 3 | |
| No | 14 | 10 | 4 | |
| AE of grade ≥3 | >0.99 | |||
| Yes | 2 | 1 | 1 | |
| No | 18 | 12 | 6 | |
| Dose reduction due to AE | >0.99 | |||
| Yes | 1 | 1 | 0 | |
| No | 19 | 12 | 7 | |
| Discontinued medication due to AE | 0.35 | |||
| Yes | 1 | 0 | 1 | |
| No | 19 | 13 | 6 | |
| Hematological AE | 0.35 | |||
| Yes | 1 | 0 | 1 | |
| No | 19 | 13 | 6 | |
| Non hematological AE | 0.61 | |||
| Yes | 6 | 3 | 3 | |
| No | 14 | 10 | 4 | |
| Surgical delay due to AE | 0.35 | |||
| Yes | 1 | 0 | 1 | |
| No | 19 | 13 | 6 | |
Data are presented as number. AE, adverse event; ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor.
Surgery-related outcomes
Surgery-related outcomes in the 2 groups are summarized in Table 5. Video-assisted thoracoscopic surgery (VATS) was performed in 12 patients in the ALK-TKI group and 5 in the chemotherapy-based group; thoracotomy was performed in 1 and 2 patients, respectively. The distribution of surgical approaches did not differ significantly between the 2 groups (P=0.27). The median operative time was 120 (IQR, 104–143) min in the ALK-TKI group and 160 (IQR, 116.5–177) min in the chemotherapy-based group (P=0.38). Median intraoperative blood loss was 200 mL in both groups (P=0.33). Thoracic drainage volume was also comparable between the ALK-TKI and chemotherapy-based groups [870 (IQR, 710–1,320) vs. 1,130 (IQR, 890–1,490) mL, P=0.60]. Chest drainage duration and postoperative hospital stay were also comparable between the ALK-TKI and chemotherapy-based groups (4.46±1.13 vs. 5.14±1.57 days, P=0.34; 5.85±1.34 vs. 6.14±1.57 days, P=0.68, respectively). Postoperative complications occurred in 2 patients in each group, all of which were classified as Clavien-Dindo grade I (P=0.58). Overall, perioperative outcomes were comparable between groups.
Table 5. Surgery-related information.
| Characteristic | Total | ALK-TKI (n=13) | Chemotherapy-based (n=7) | P value |
|---|---|---|---|---|
| Surgery approach | 0.27 | |||
| VATS | 17 | 12 | 5 | |
| Thoracotomy | 3 | 1 | 2 | |
| Operation duration (min) | – | 120 [104–143] | 160 [116.5–177] | 0.38 |
| Blood loss (mL) | – | 200 [100–250] | 200 [100–200] | 0.33 |
| Thoracic drainage volume (mL) | – | 870 [710–1,320] | 1,130 [890–1,490] | 0.60 |
| Thoracic drainage duration (days) | – | 4.46±1.13 | 5.14±1.57 | 0.34 |
| Postoperative hospital stay (days) | – | 5.85±1.34 | 6.14±1.57 | 0.68 |
| Complication | 0.58 | |||
| Yes | 4 | 2 | 2 | |
| No | 16 | 11 | 5 |
Data are presented as number, mean ± standard deviation, or median [interquartile range]. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; VATS, video-assisted thoracoscopic surgery.
Survival outcomes
Among the 13 patients in the ALK-TKI group, 12 continued the same ALK-TKI after surgery. The median duration of the initial postoperative ALK-TKI treatment was 24 months (IQR, 15.8–24.3 months; range 6–36 months). One patient with cT4N2M0 disease who received 4 months of neoadjuvant alectinib achieved SD and was subsequently staged as ypT4N0M0 after surgery. Pathological examination showed a non-MPR. Because of financial constraints, this patient declined postoperative systemic therapy and remained recurrence-free at the last follow-up.
In the chemotherapy-based group, 4 patients received postoperative platinum-based doublet chemotherapy for 3–4 cycles, 2 received postoperative ALK-TKI therapy with crizotinib and ensartinib, respectively. One patient declined further adjuvant treatment despite residual ypN2 disease (ypT2N2M0, with metastatic involvement of lymph node stations 7 and 8) and remained recurrence-free at the data cutoff.
At the last follow-up on March 31, 2026, tumor recurrence occurred in 3 of 13 patients in the ALK-TKI group. Among these patients with recurrence, 1 subsequently died after disease progression. Among patients who completed their planned postoperative ALK-TKI treatment, one patient who completed 24 months of brigatinib developed pleural metastasis 7 months after treatment completion and subsequently resumed brigatinib. Another patient who completed 36 months of crizotinib developed brain metastasis 2 months after treatment completion and was subsequently switched to alectinib. In addition, one patient developed brain metastasis after 6 months of postoperative crizotinib therapy. Crizotinib was discontinued, and the patient was subsequently treated with alectinib for 23 months before death.
In the chemotherapy-based group, the recurrence sites included bone metastasis in two patients and brain metastasis in one patient. One patient with bone metastasis initiated brigatinib after recurrence and remained on treatment at the data cutoff. The patient with brain metastasis subsequently received alectinib and died in June 2025. The other patient with bone metastasis switched from crizotinib to iruplinalkib and died in January 2023. Overall, two of the three patients with recurrence in the chemotherapy-based group subsequently died (Table 6). Kaplan-Meier analysis showed numerically better OS in the ALK-TKI group. However, the difference was not significant (log-rank P=0.42; Figure 4A). RFS analysis showed a similar trend without statistical significance (log-rank P=0.21; Figure 4B). Given the small cohort and limited number of recurrence and death events, the Kaplan-Meier estimates were imprecise and the survival comparisons were considered exploratory.
Table 6. Postoperative tumor recurrence and survival status of patients.
| Characteristic | Total | ALK-TKI (n=13) | Chemotherapy-based (n=7) | Survival analysis |
|---|---|---|---|---|
| Survival status | OS log-rank P=0.42 | |||
| Survival | 17 | 12 | 5 | |
| Death | 3 | 1 | 2 | |
| Tumor recurrence | RFS log-rank P=0.21 | |||
| Yes | 6 | 3 | 3 | |
| No | 14 | 10 | 4 | |
Data are presented as number. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; OS, overall survival; RFS, recurrence-free survival.
Figure 4.
Kaplan-Meier survival analysis from the day of starting neoadjuvant therapy. (A) OS in ALK-rearranged patients receiving neoadjuvant ALK-TKI therapy and chemotherapy-based neoadjuvant therapy. (B) RFS in patients receiving neoadjuvant ALK-TKI therapy and chemotherapy-based neoadjuvant therapy. The number of patients at risk is shown below each plot. Survival outcomes were compared using the log-rank test. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; OS, overall survival; RFS, recurrence-free survival.
Discussion
This retrospective study compared neoadjuvant ALK-TKI monotherapy with chemotherapy-based neoadjuvant therapy in surgically treated patients with ALK-rearranged NSCLC who underwent curative-intent resection after multidisciplinary evaluation. The ALK-TKI group showed numerically higher ORR, MPR, and pCR rates, although these differences were not statistically significant. Notably, the proportion of patients achieving ypN0 disease and the extent of pathological nodal downstaging were significantly greater after ALK-TKI neoadjuvant therapy. These findings suggest that ALK inhibition therapy may be particularly effective in controlling regional nodal disease; however, the nonsignificant differences in radiological and overall pathological responses should be interpreted with caution given the limited sample size.
The optimal neoadjuvant strategy for oncogene-driven NSCLC remains uncertain. Given the established efficacy of ALK-TKIs in advanced disease (17-20) and the relatively limited benefit of immune checkpoint inhibitors in ALK-rearranged NSCLC (12-14), extending ALK inhibition into the neoadjuvant setting is biologically and clinically relevant.
An important consideration is that this cohort was defined by receipt of curative-intent surgery after neoadjuvant therapy rather than by conventional clinical-stage criteria alone. Two patients in the ALK-TKI group had radiologically defined cM1a/cN3 disease (stage IVA) and underwent surgery after individualized MDT evaluation. These highly selected cases should not be interpreted as supporting routine surgery or neoadjuvant ALK-TKI therapy for stage IVA or cN3 disease. Because cM1a status was based on radiological suspicion of pleural involvement, potential over-staging or misclassification cannot be excluded, and their inclusion may have contributed to baseline stage imbalance.
The most notable finding of our study was the improvement in nodal outcomes following neoadjuvant ALK-TKI therapy. Compared with the chemotherapy-based group, the ALK-TKI group showed a higher ypN0 rate and more pronounced pathological nodal downstaging. Given that nodal involvement is an important determinant of recurrence risk and long-term prognosis, effective conversion to ypN0 may represent a key potential advantage of neoadjuvant ALK inhibition. Nevertheless, the association between nodal downstaging and long-term survival in this specific population requires confirmation in prospective studies.
Although the ALINA trial established the efficacy of adjuvant ALK inhibition, it did not evaluate patients previously treated with neoadjuvant ALK-TKIs (21). Similarly, findings from neoadjuvant EGFR-TKI trials cannot be directly extrapolated to ALK-rearranged NSCLC. Prospective evidence for neoadjuvant ALK inhibition has recently emerged from the phase II ALNEO and NAUTIKA1 trials. In ALNEO, 8 weeks of neoadjuvant alectinib produced ORR, MPR, and pCR rates of 67%, 46%, and 12%, respectively (26). In the updated ALK-positive cohort of NAUTIKA1, the corresponding rates were 63.3%, 60.7%, and 25.0%, with nodal downstaging observed in 26.7% of patients (27). In our cohort, the ORR, MPR, and pCR rates were 69.2%, 46.2%, and 30.8%, respectively, broadly consistent with the antitumor activity reported in these prospective studies. However, direct comparisons are limited by differences in study design, patient selection, staging methods, ALK-TKI agents, treatment duration, and postoperative management. Thus, our findings provide complementary real-world evidence but do not define the optimal perioperative ALK-TKI strategy.
Neoadjuvant ALK-TKI therapy also appeared feasible from a perioperative perspective. Previous studies of neoadjuvant targeted therapy have reported predominantly manageable toxicities without a marked increase in surgical complexity or postoperative complications (36,37). Consistent with these observations, no patient in the ALK-TKI group discontinued treatment or experienced surgical delay because of AEs, and surgical approach, operative time, blood loss, drainage duration, hospital stay, and postoperative complications were comparable between groups.
Although OS and RFS numerically favored the ALK-TKI group, neither difference was statistically significant. These analyses should be considered exploratory because of the small sample size, limited number of recurrence and death events, and heterogeneous follow-up duration. Importantly, the radiological and pathological response endpoints were assessed before postoperative therapy and therefore reflect outcomes observed during the neoadjuvant treatment period. In contrast, OS and RFS were influenced by the entire perioperative treatment course. Postoperative treatment differed substantially between groups, including subsequent ALK-TKI use in the chemotherapy-based group; therefore, the observed survival trends cannot be attributed solely to the neoadjuvant regimen.
In our cohort, recurrence was observed both after completion of the planned postoperative ALK-TKI treatment and during ongoing postoperative ALK-TKI therapy, highlighting the need to clarify the optimal postoperative treatment strategy. The optimal postoperative strategy following neoadjuvant ALK-TKI and surgery remains undefined. Aoki et al. reported favorable long-term disease control in an ALK-rearranged patient who achieved pCR and continued ALK-TKI after surgery (38). In contrast, Ohta et al. reported a patient who achieved a pCR after preoperative alectinib and salvage surgery but developed brain and pulmonary metastases 20 months after postoperative discontinuation of alectinib; reintroduction of alectinib subsequently restored disease control (39). Furthermore, the phase III ALINA trial demonstrated that 24 months of adjuvant alectinib significantly improved disease-free survival and CNS disease-free survival compared with platinum-based chemotherapy in patients with completely resected ALK-positive NSCLC (21). Notably, in our cohort, one patient who achieved MPR developed recurrence 7 months after completing postoperative brigatinib. Nevertheless, the reports by Aoki et al. and Ohta et al. provide only case-based evidence, and the ALINA trial did not evaluate patients who had previously received neoadjuvant ALK-TKI therapy. Therefore, the optimal postoperative ALK-TKI agent, treatment duration, and discontinuation criteria following neoadjuvant ALK-targeted therapy remain to be established.
This study has several limitations. First, the single-center retrospective design, individualized nonrandomized treatment allocation, small sample size, and limited number of recurrence and death events introduced potential selection bias, confounding by indication, and limited statistical power. Treatment selection was influenced by clinical characteristics, multidisciplinary judgment, patient preference, and treatment availability rather than by a predefined institutional protocol. Consequently, multivariable adjustment, reliable subgroup analyses, and sensitivity analyses were not feasible, and the observed between-group differences should not be interpreted as establishing causal superiority of neoadjuvant ALK-TKI therapy. The survival findings should therefore be considered exploratory. Second, pretreatment nodal status was pathologically confirmed by EBUS-TBNA in only 4 of 20 patients and was otherwise based mainly on PET-CT or contrast-enhanced CT. Thus, the observed cN-to-ypN changes may have been influenced by baseline nodal misclassification and should be interpreted cautiously. Third, treatment heterogeneity may have affected the between-group comparisons. The ALK-TKI group included several different agents with varying systemic potency, CNS activity, and levels of perioperative evidence supporting their use (40). In addition, the duration of neoadjuvant ALK-TKI therapy ranged from 1 to 8 months and was less standardized than that of chemotherapy-based treatment. The chemotherapy-based group was also heterogeneous, including both chemotherapy alone and chemoimmunotherapy. Notably, the only grade ≥3 AE in this group was immune-related myocarditis in a patient who received chemoimmunotherapy. Therefore, the independent contributions of chemotherapy and immunotherapy could not be separated, and comparisons of efficacy and safety with ALK-TKI monotherapy should be interpreted cautiously. These sources of treatment heterogeneity also precluded reliable agent- or regimen-specific analyses. Finally, postoperative treatment strategies differed substantially between groups, including postoperative ALK-TKI use and treatment crossover, which may have confounded OS and RFS and prevented attribution of the observed survival trends solely to the neoadjuvant regimen. Therefore, the present findings should be interpreted as exploratory and require confirmation in larger prospective studies with standardized perioperative treatment strategies.
In summary, neoadjuvant ALK-TKI therapy was associated with favorable nodal pathological outcomes and acceptable perioperative safety in this highly selected cohort. Larger prospective studies with standardized perioperative treatment are needed to confirm these findings and determine their long-term clinical significance.
Conclusions
Neoadjuvant ALK-TKI therapy showed promising efficacy and acceptable safety in surgically treated patients with ALK-rearranged NSCLC. Compared with chemotherapy-based neoadjuvant therapy, neoadjuvant ALK-TKI therapy was associated with better pathological conversion to ypN0 and did not increase perioperative risks. Larger prospective multicenter studies with longer follow-up and an adequate number of recurrence and death events are required to determine whether neoadjuvant ALK-TKI therapy provides any long-term survival benefit.
Supplementary
The article’s supplementary files as
Acknowledgments
None.
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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Institutional Review Board of Hunan Cancer Hospital (No. KY2026032), and all enrolled patients provided written informed consent.
Footnotes
Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1625/rc
Funding: This work was supported by the Natural Science Foundation Program of Hunan Province (No. 2026JJ82175), the High-level Talent Program of Hunan Health Commission (No. 20230227-1001), the Provincial Health and Wellness Project of the Finance Department of Hunan Province (No. 20241220-1001), and the 2025 Health Research Project of the Hunan Provincial Health Commission (No. 20257611).
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1625/coif). The authors have no conflicts of interest to declare.
Data Sharing Statement
Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2026-1625/dss
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