Neoadjuvant ALK tyrosine kinase inhibitor in patients with resectable locally advanced non-small cell lung cancer harboring rearrangement.

Introduction
Non-small cell lung cancer (NSCLC) constitutes over 80% of all lung cancer cases and remains the leading cause of cancer-related mortality worldwide (1). Despite therapeutic advances, the prognosis for patients with locally advanced NSCLC remains poor due to its high heterogeneity (2). Anaplastic lymphoma kinase (ALK) gene rearrangements are found in approximately 4–5% of NSCLC patients (3). These patients are often younger, non-smokers, and typically present with a more aggressive disease course (4). Furthermore, up to 60% of ALK-positive patients develop brain metastases, further complicating disease control and worsening prognosis (5).
Recent studies have established ALK tyrosine kinase inhibitors (TKIs) as the standard first-line treatment for advanced ALK-positive NSCLC due to their superior efficacy over chemotherapy (6,7). Their benefit is also well-established in the adjuvant setting (3). However, in neoadjuvant setting, platinum-based chemotherapy remains the current standard therapy, as the use of ALK-TKIs is not yet supported by substantial evidence. The potential role of ALK-TKIs as neoadjuvant therapy in locally advanced ALK-positive NSCLC thus represents a significant unmet need and a key area for further research.
Notably, in resectable epidermal growth factor receptor (EGFR) mutant NSCLC, neoadjuvant EGFR-TKIs have shown considerable clinical efficacy. Neoadjuvant erlotinib resulted in a higher objective response rate (ORR) and improved overall survival (OS) compared to chemotherapy (8). Similarly, treatment with neoadjuvant osimertinib led to an ORR of 71.1% and a radical resection (R0) rate of 93.8% (9), and another study reported a major pathological response (MPR) rate of 26% with chemotherapy combination and 25% with TKI monotherapy (10). In contrast, evidence regarding neoadjuvant ALK-TKIs in locally advanced ALK-positive NSCLC is scarce and primarily derived from small scale exploratory studies. For example, one study documented an MPR rate of 55.6% and a pathological complete response (pCR) rate of 33.3%, with no recurrence, metastasis, or death during follow-up (11). Other clinical observations have also suggested potential therapeutic benefits, though larger prospective studies are needed to validate these findings.
Given the paucity of data and growing clinical interest, we herein present our initial experience with neoadjuvant ALK-TKI monotherapy in patients with locally advanced ALK-positive NSCLC. We present this article in accordance with the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-1-1333/rc).

Methods
This retrospective cohort study was conducted at West China Hospital, Sichuan University. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of West China Hospital, Sichuan University (approval No. 2024-1356), and written informed consent was waived due to its retrospective design. We included patients with pathologically confirmed ALK-positive, locally advanced NSCLC who received neoadjuvant ALK-TKI monotherapy between June 2019 and June 2024. All patients were assessed by a multidisciplinary team and considered potentially resectable before therapy. The primary outcomes were ORR, R0 resection rate, and pathological response. Secondary outcomes included disease-free survival (DFS) and OS, while also identifying the optimal duration of neoadjuvant therapy based on the pathological responses and adverse events (AEs). ORR was assessed according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria, and AEs were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Data collection encompassed patient demographics, tumor characteristics, ALK rearrangement status, treatment details, radiologic and pathological responses, and AEs. Quantitative variables were summarized using median and range. The optimal duration of neoadjuvant therapy was estimated via locally estimated scatterplot smoothing (LOESS) analysis. Survival outcomes were analyzed using the Kaplan-Meier method, with median follow-up estimated by the reverse Kaplan-Meier method. All analyses were performed using R software (version 4.3.2).

Results

Patient characteristics and treatment
A total of 25 patients with ALK-positive lung adenocarcinoma were included. Baseline characteristics, neoadjuvant therapy and perioperative outcomes are detailed in Table 1. The median age was 49 years (range: 23–69 years), and median tumor size at diagnosis was 3.8 cm (range: 1.5–6.2 cm).
Lesions were distributed as follows: 6 (24.0%) in the right upper lobe, 6 (24.0%) in the right lower lobe, 8 (32.0%) in the left upper lobe, and 5 (20.0%) in the left lower lobe. At baseline, 13 patients (52.0%) had stage IIB disease, 7 (28.0%) had stage IIIA disease, and 5 (20%) had stage IIIB disease. A total of 21 (84.0%) patients harbored EML4-ALK rearrangements and the remaining cases included 2 (8.0%) with KIF5B-ALK, 1 (4.0%) with HIP-ALK, and 1 (4.0%) with KLHL29-ALK rearrangement. Among these patients, 16 (64.0%) received neoadjuvant alectinib, 4 (16.0%) received neoadjuvant ensartinib, 3 (12.0%) received neoadjuvant crizotinib, and 2 (8.0%) received neoadjuvant lorlatinib. The median duration of neoadjuvant ALK-TKI therapy was 5 months (range: 2–10 months). All patients continued the same targeted therapy postoperatively. The detailed treatment patterns of the patients are shown in Figure 1A.
During neoadjuvant ALK-TKI treatment, all patients experienced at least one treatment-related AE, mostly grades 1–2 (Table 2). The most common AEs were edema (36.0%), nausea (28.0%) and constipation (24.0%). Grade 3 AEs occurred in 6 patients (24.0%) and only 1 patient required temporary treatment interruption for drug-induced liver injury.

Efficacy and surgical outcomes
The ORR per RECIST 1.1 was 92.0%, comprising 22 (88.0%) partial responses (PR), 1 (4.0%) complete response (CR). All patients underwent R0 resection. Among them, 11 (44.0%) underwent video-assisted thoracoscopic surgery (VATS), 13 (52.0%) underwent open thoracotomy, and 1 (4.0%) was converted from VATS to open thoracotomy due to extensive pleural adhesions. Additionally, 20 patients (80.0%) received lobectomy, while 5 (20.0%) underwent segmentectomy. The median operative time was 134 minutes (range: 45–340 minutes), median intraoperative blood loss was 134 mL (range: 5–300 mL), and the median number of lymph nodes resected was 9 (range: 4–30). Postoperative complications occurred in 3 patients (12.0%), all of which resolved with appropriate intervention. No perioperative mortality was observed within 90 days after surgery.

Pathological response and survival outcomes
Pathological assessment demonstrated 8 patients (32.0%) achieved pCR, 9 (36.0%) achieved MPR, and 8 achieved PR, resulting in a combined pCR/MPR rate of 68.0%. Specifically, in alectinib group, 3 (18.8%) achieved pCR and 8 (50.0%) achieved MPR. In ensartinib group, 2 (50.0%) attained pCR. In crizotinib group, 2 (66.7%) reached pCR. In lorlatinib group, 1 (50.0%) achieved pCR and 1 (50.0%) attained MPR. An optimal efficacy-safety balance was observed with a neoadjuvant treatment duration of 4–6 months, achieving a pCR/MPR rate of approximately 80% while maintaining grade ≥3 AEs below 30% (Figure 1B).
The median postoperative follow-up was 23 months (range: 11–57 months). By August 2025, 5 patients had experienced disease recurrence, all of which involved central nervous system (CNS) metastases. Their ALK variants included 3 with EML4-ALK, 1 with KLHL29-ALK, and 1 with KIF5B-ALK, and the pathological responses varied (1 pCR, 1 MPR, and 3 PR). Regarding neoadjuvant ALK-TKI exposure, CNS recurrences occurred in patients treated with alectinib (n=2), ensartinib (n=1), lorlatinib (n=1), and crizotinib (n=1). The 3-year OS rate was 95.8%, and the 3-year DFS rate was 76.2%, with the longest DFS lasting 57 months (Figure 1C). One patient died due to intracranial hemorrhage secondary to CNS disease progression.

Discussion
ALK-TKI therapy has shown significant clinical benefits in advanced NSCLC patients with ALK rearrangements (3). However, whether these therapeutic advantages observed in advanced NSCLC extend to improving R0 rates and OS in locally advanced NSCLC patients undergoing neoadjuvant ALK-TKI therapy remains to be fully elucidated. In our study, we conducted a retrospective analysis to evaluate the efficacy of neoadjuvant ALK-TKI monotherapy in patients with locally advanced ALK-positive NSCLC. The results demonstrated a remarkable ORR (92.0%), surpassing that of neoadjuvant EGFR-TKIs in locally advanced NSCLC patients. Specifically, the ORR of neoadjuvant ALK-TKI therapy was higher than that reported for neoadjuvant osimertinib (71.1%) (9), gefitinib (54.5%) (12), erlotinib (54.1%) (13), highlighting its potential as an effective treatment strategy in this patient population. Another study similarly reported that neoadjuvant crizotinib therapy achieved an ORR of 90.9% in patients with locally advanced ALK-positive NSCLC (14). Collectively, these findings are encouraging and suggest potential clinical activity of neoadjuvant ALK-TKI therapy in this setting, laying the groundwork for its formal evaluation as a neoadjuvant strategy.
The safety profile of neoadjuvant ALK-TKI therapy closely aligns with findings from previous studies on advanced NSCLC (6,15,16). The most frequently reported AEs in our cohort were edema, nausea, and constipation, which were generally mild to moderate and manageable with supportive care. While nausea and elevated aspartate/alanine aminotransferase levels were commonly observed, the relatively higher incidence of other AEs in our analysis may reflect differences in patient population or TKI dosing regimens. Moreover, no new safety concerns were identified and no perioperative deaths occurred. Only one patient required temporary treatment interruption due to liver toxicity. These findings further support the acceptable safety profile of neoadjuvant ALK-TKI therapy and suggest that its toxicity in the neoadjuvant setting does not exceed that observed in the adjuvant setting.
Neoadjuvant therapy is a promising strategy for reducing tumor size and increasing the likelihood of radical excision. Its efficacy is typically assessed through pathological responses and R0 resection. In our study, the R0 resection rate was 100%, which is higher than that reported in neoadjuvant therapy studies involving EGFR-TKIs (68.4–87.9%) (13,17-19), as well as chemotherapy or chemoradiotherapy (50–93.8%) (9,20). It is worth noting that Zhang et al. reported an R0 resection rate of 91% in a study investigating neoadjuvant crizotinib in patients with locally advanced ALK-positive NSCLC (14), which is also higher than other treatment modalities. These finding suggest that ALK-TKI therapy may provide superior tumor downstaging in locally advanced ALK-positive NSCLC, potentially improving surgical outcomes.
Pathological responses provide further insight into treatment efficacy. A favorable pathological response is associated with longer survival. In patients with NSCLC, the reported MPR rate following neoadjuvant EGFR-TKIs therapy ranges from 9.7% to 67% (19,21), while neoadjuvant crizotinib in resectable ALK-positive NSCLC has achieved a pCR rate of 18.2% (14). In our study, 8 (32.0%) achieved pCR and another 9 (36.0%) achieved MPR, resulting in a combined pCR/MPR rate of 68.0%. This rate appears favorable when compared to historical reports with other TKI classes, suggesting a potentially enhanced pathological response with neoadjuvant ALK-TKI therapy. Consistently, emerging evidence supports a biological distinction between ALK- and EGFR-driven NSCLC in the neoadjuvant setting. In a recent case series, residual viable tumor was observed in all EGFR-mutant tumors after neoadjuvant TKI therapy, whereas an ALK-rearranged tumor achieved pCR (22). This contrast underscores a potentially meaningful biological difference between these driver mutations in the perioperative setting and provides external validation for the high pathological response rates observed in our ALK-positive cohort. It further strengthens the rationale for investigating ALK-TKIs in neoadjuvant protocols, as they may offer the potential for deeper tumor eradication. Notably, as this was a retrospective study, the choice of neoadjuvant targeted therapy was actually guided by shared decision-making between oncologists and patients, resulting in heterogeneity in drug choice and treatment duration. Given the limited sample size, robust statistical comparisons of efficacy between different agents were not feasible. Nevertheless, the overall pathological response rates were encouraging, with both pCR and MPR achieved at considerable levels across the study population. Overall, these findings highlight the potential of neoadjuvant ALK-TKI therapy to achieve high pathological response rates in resectable ALK-positive NSCLC. The observed outcomes warrant confirmation in prospective, larger-scale studies with extended follow-up to determine whether these pathological responses translate into durable survival benefits.
The optimal duration of postoperative adjuvant targeted therapy is well-established based on current consensus. In contrast, the optimal duration for neoadjuvant targeted therapy remains poorly defined and represents an emerging area of investigation. This uncertainty stems in part from constraints imposed by the surgical timing and challenges in assessing treatment response during the neoadjuvant period. In our cohort, a 4–6 months treatment window appeared to offer an optimal efficacy-toxicity balance, yielding a combined pCR/MPR rate of 68%. Notably, the ongoing phase II studies, ALNEO (23) and NAUTIKA1 (24) trials, using shorter 8-week courses of neoadjuvant ALK-TKI therapy reported lower MPR rates of 46.0% and 60.7%, respectively. This comparison indicates that longer treatment exposure may be necessary to achieve deeper pathological responses, likely because an extended therapeutic window enables more complete tumor eradication at the biological level and permits response-guided clinical management. This principle aligns with real-world practices where therapy is often continued until no further tumor regression is observed. However, prolonging treatment invariably elevates the cumulative risk of AEs. Therefore, the key is to balance the pursuit of maximal pathological response against the management of treatment-related toxicity and the potential risks of delaying surgery. Our preliminary findings suggest that response kinetics may better guide treatment timing than a fixed duration, offering a potential framework for this balance. It suggests that therapy might be optimized within a defined efficacy-safety window rather than extended indefinitely. Further research is needed to more thoroughly investigate this question and validate its clinical applicability for optimizing individualized therapeutic strategies.
For patients with resectable NSCLC receiving adjuvant therapy, DFS is a well-established surrogate of treatment efficacy and an important predictor of long-term outcomes. In our study, the improvement in DFS observed following neoadjuvant ALK-TKI therapy suggests a favorable prognosis, analogous to the DFS benefit seen with adjuvant osimertinib in EGFR-mutant NSCLC, which ultimately translated into prolonged OS (25). However, interpretation of this DFS benefit requires careful consideration of both selection bias and patterns of disease failure. Notably, all postoperative recurrences in our cohort manifested as CNS metastases, including in patients who achieved pCR or MPR. These events occurred across patients treated with different generations of ALK-TKIs, consistent with prior studies showing variable CNS penetration among first- and next-generation TKIs (e.g., ALEX, ALTA-1L, CROWN) (26-28), indicating that CNS relapse occurred regardless of TKI generation and highlighting the CNS as a critical sanctuary site. This CNS-dominant relapse pattern suggests that DFS improvement driven by excellent locoregional control may not fully capture residual intracranial disease risk. The phase III ALINA trial showed that adjuvant alectinib markedly reduced CNS recurrence versus chemotherapy, supporting a class-wide rationale for early ALK inhibition to control micrometastatic disease (3). These findings indicate that ALK-driven tumors are highly sensitive to ALK blockade even at minimal residual disease, supporting TKIs as suitable neoadjuvant agents despite differences in CNS penetration.
Moreover, our analysis included only patients who successfully underwent surgical resection, inherently excluding those with primary resistance, early progression, or intolerance to neoadjuvant therapy, thereby introducing a selection bias that may have contributed to the observed favorable DFS and OS. In addition, the relatively short follow-up duration limits assessment of long-term survival outcomes. Nonetheless, 80.0% of patients remained disease-free during the follow-up period, providing preliminary evidence of durable disease control in a highly selected population. Together, these findings suggest that while neoadjuvant ALK-TKI therapy can achieve meaningful DFS improvement through deep primary tumor control, sustained perioperative strategies, particularly those addressing CNS relapse risk, may be required to translate early DFS gains into durable long-term benefit. Future studies with standardized CNS surveillance, longer follow-up, and intention-to-treat designs are warranted to validate these observations and to clarify the role of ALK-TKIs across different perioperative strategies.
Our study has several important limitations that must be considered when interpreting the findings. First, the retrospective nature, small sample size, heterogeneous ALK-TKI regimens, and absence of a control group limit the generalizability of the conclusions and precludes any definitive comparisons between specific ALK-TKIs. Second, the proposed optimal duration for neoadjuvant therapy remains an exploratory finding, and its definitive role requires prospective validation. Third, longer follow-up is required to fully evaluate long-term outcomes. Despite these limitations, our preliminary experience and outcomes still offer valuable insights and a meaningful reference for the application of neoadjuvant ALK-TKIs in this setting. To further validate our findings and optimize treatment strategies, prospective clinical trials are warranted to provide more robust evidence and benefit a broader patient population.

Conclusions
In summary, our findings provide preliminary evidence that neoadjuvant ALK-TKI therapy is effective and well-tolerated in patients with locally advanced ALK-positive NSCLC. These observations support the rationale for and warrant further prospective investigation of neoadjuvant ALK-TKIs to confirm their potential benefits and define optimal treatment paradigms.

Supplementary
The article’s supplementary files as