Efficacy and safety of lorlatinib in first-line and subsequent-line treatments for patients with ALK-positive non-small cell lung cancer: a single-center real-world study in China

Introduction

Anaplastic lymphoma kinase (ALK) fusion is widely recognized as a critical therapeutic target in patients with non-small cell lung cancer (NSCLC) (1). Previous generations of ALK tyrosine kinase inhibitors (ALK-TKIs), such as crizotinib and alectinib, have demonstrated notable clinical benefits in this patient population (2). However, the introduction of the third-generation ALK-TKI lorlatinib has provided unprecedented advantages in first-line treatment. According to the latest findings from the CROWN study presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, lorlatinib, as a first-line therapy for patients with locally advanced or metastatic ALK-positive (ALK⁺) NSCLC, achieved a median progression-free survival (PFS) of over 64.3 months (3). Moreover, it also exhibited superior efficacy in preventing brain metastases (4). Predictive analyses using both the conditional PFS rate method and the Weibull distribution model estimated that the PFS duration for first-line lorlatinib treatment may extend to approximately 120 months (5,6). These outcomes represent a significant milestone in the ongoing effort to achieve long-term disease control and potential curative strategies for advanced malignancies.

Compared with randomized controlled trials (RCTs), real-world clinical scenarios present greater complexity and are influenced by a range of unpredictable confounding factors. In current clinical practice, lorlatinib is primarily prescribed to three distinct patient populations: first, patients with locally advanced or metastatic ALK⁺ NSCLC receiving first-line therapy; second, patients who have received no more than one prior ALK-TKI; and third, patients who have been exposed to two or more previous ALK-TKIs. While lorlatinib demonstrates well-documented efficacy in the first-line treatment setting, its role as a sequential therapy remains insufficiently explored in clinical research. Moreover, the mechanisms underlying lorlatinib resistance are not yet fully elucidated, and it is unclear whether resistant tumors develop actionable therapeutic targets that can be exploited for further intervention. In addition to its therapeutic profile, lorlatinib is associated with a distinct spectrum of adverse events that are not commonly encountered with other ALK-TKIs. Effectively managing these treatment-related toxicities represents a critical aspect of optimizing patient care and enhancing the quality of life for individuals with advanced malignancies. Previous real-world studies conducted in Japan (7), India (8), and China (9) have provided preliminary evidence of the efficacy of lorlatinib in later-line treatment settings; however, these studies were constrained by short follow-up durations or small sample sizes, leading to imprecise outcome estimates and limited generalizability. Another cohort study from China compared the efficacy of lorlatinib in later-line treatment; however, it did not adequately address the adverse events and resistance mechanisms associated with lorlatinib (10). Additionally, an analysis of the Clinformatics Data Mart Database revealed that survival among patients receiving first-line lorlatinib was significantly poorer compared to those treated with second-generation ALK-TKIs, a finding that contradicts evidence from other clinical studies (11). Overall, real-world evidence on lorlatinib remains limited.

Based on the above questions, we followed the footsteps of the CROWN study (4) and simultaneously initiated a long-term real-world research project. This study evaluated the safety and efficacy of lorlatinib in a real-world clinical setting. A series of interim analysis results will be released at prespecified time intervals to inform clinical practice and support academic research. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1148/rc).

Methods

Study design

This study is a single-center cohort study that integrates both retrospective and prospective design components. Patients with locally advanced or metastatic ALK⁺ NSCLC who initiated lorlatinib treatment at National Cancer Center from December 1, 2020 onward were enrolled. The data cut-off date for this study was set as July 18, 2025, with the final analysis based on the latest available follow-up data. Enrolled patients were categorized into two cohorts: the first-line lorlatinib treatment cohort and the subsequent-line lorlatinib treatment cohort. Within the sequential treatment cohort, patients were further stratified into two subgroups according to the number of prior ALK-TKIs received before lorlatinib initiation: those who had received ≤1 prior ALK-TKI and those who had received ≥2 prior ALK-TKIs.

Key exclusion criteria were as follows: presence of a second primary malignancy; co-existing EGFR mutations or ROS1 fusion variants in the tumor; and histological evidence of small cell lung cancer components. A standardized imaging assessment schedule [including computed tomography (CT) and magnetic resonance imaging (MRI) scans] was required for all eligible participants. This schedule mandated imaging assessments prior to lorlatinib initiation, one month after treatment initiation, and every three months thereafter.

The sample size was determined by including all patients who visited our hospital during the study period (from December 1, 2020 to July 18, 2025) and satisfied the predefined inclusion and exclusion criteria.

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (approval No. 24/395-4675). All participants provided written informed consent prior to enrollment.

Data extraction

The demographic and clinical characteristics were systematically extracted from Electronic Medical Records (EMR). The patients’ imaging data were obtained through direct measurement using the electronic imaging system or via manual measurement of physical films. Survival outcomes and adverse event profiles were collected through scheduled outpatient visits, telephone interviews, or WeChat follow-ups. Next-generation sequencing (NGS) results obtained before and after lorlatinib treatment were comprehensively documented. The use of a dedicated WeChat group ensured complete follow-up for all participants and the availability of all critical data.

Evaluation criteria and study endpoints

Three independent clinical researchers assessed the patients’ imaging data in accordance with the Response Evaluation Criteria in Solid Tumours 1.1 (RECIST 1.1) to evaluate therapeutic response. The severity of treatment-related adverse events (TRAEs) was graded according to the Common Terminology Criteria for Adverse Events 5.0 (CTCAE 5.0). The primary endpoints of the study were PFS, objective response rate (ORR), and TRAEs in patients treated with lorlatinib. The secondary endpoints included disease control rate (DCR), duration of response (DOR), and depth of tumor response (DpR) in the same patient population. The exploratory endpoint of the study was the identification of novel therapeutic targets associated with lorlatinib resistance through NGS analysis.

Statistical analysis

Statistical analysis and graphical visualization were conducted using R 4.5.0 (https://www.r-project.org/). Descriptive statistical methods were employed to summarize the distribution patterns of categorical variables. Survival curves were estimated using the Kaplan-Meier method, and differences between groups were analyzed using the log-rank test. Continuous variables were compared using Student’s t-tests. Statistical significance was defined as a two-sided P value <0.05.

The flowchart illustrating the research process of this study is presented in Figure 1.

Figure 1 Flowchart depicting the study design process. ALK-TKI, anaplastic lymphoma kinase tyrosine kinase inhibitor; BOR, best overall response; DCR, disease control rate; DOR, duration of response; NGS, next-generation sequencing; ORR, objective response rate; PD, progressive disease; PFS, progression-free survival; TRAE, treatment-related adverse event.

Results

Baseline characteristics

As of July 18, 2025, a total of 36 patients were enrolled in the lorlatinib first-line treatment cohort, and 43 patients were enrolled in the lorlatinib subsequent-line treatment cohort for analysis. The baseline clinical characteristics of both groups prior to lorlatinib treatment are summarized in Table 1. In the first-line cohort, 19.4% (7/36) of patients had brain metastases at baseline, compared with 51.2% (22/43) in the subsequent-line cohort.

It should be emphasized that all patients were included in the TRAE analysis. However, one patient from each cohort was excluded from the efficacy analysis due to adverse reactions resulting in a treatment duration of less than one month as of the data cut-off date. Moreover, within the subsequent-line cohort, only 16 patients underwent repeat NGS testing before initiating lorlatinib treatment following resistance to other ALK-TKIs. Additionally, among the 42 patients in the subsequent-line cohort who underwent efficacy assessment, 21 had previously received at most one ALK-TKI, while the remaining 21 had been exposed to two or more ALK-TKIs.

Additionally, in the first-line treatment cohort, all patients received genetic testing based on tissue from the primary lung lesion at initial diagnosis. In the subsequent-line treatment cohort, 41 patients were tested using primary lung lesion tissue, one using pleural effusion, and one using blood samples.

Efficacy analysis of lorlatinib as first-line treatment in patients with ALK⁺ NSCLC

In the lorlatinib first-line treatment cohort, 16.7% (6/36) of patients had their ALK gene status determined at baseline using fluorescence in situ hybridization (FISH) or Ventana-IHC testing, while the remaining patients underwent NGS of tumor tissues. Additionally, one patient was identified with an ALK gene deletion mutation (Figure 2A).

Figure 2 Efficacy of lorlatinib as a first-line treatment in patients with ALK⁺ NSCLC. (A) The ALK mutation status of patients in the first-line treatment cohort (N=36). (B) Kaplan-Meier curve for PFS (N=35). (C) The DpR in the first-line treatment cohort (N=35). (D) The DOR in the first-line treatment cohort (N=29). ALK, anaplastic lymphoma kinase; ALK⁺, ALK-positive; CI, confidence interval; CR, complete response; DOR, duration of response; DpR, depth of tumor response; mDOR, median DOR; mPFS, median PFS; NA, not available; NSCLC, non-small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, not available; SD, stable disease.

As of July 18, 2025, the median follow-up duration for this cohort was 12.7 months. The median PFS for patients receiving lorlatinib as first-line treatment for ALK⁺ NSCLC has not yet been reached (Figure 2B), which aligns with the findings of the CROWN study. Moreover, the Kaplan-Meier method estimated that the PFS rate for lorlatinib as first-line treatment was 100% at 6 months and 89.2% at 12 months. Among the 35 patients included in the efficacy evaluation, the ORR reached 82.9% (29/35), and the DCR was 100% [1 patient experienced slow progression but was classified as stable disease (SD) with a duration exceeding 4 weeks, thus included in the DCR]. Regarding the DpR, 8.6% (3/35) of patients achieved complete response (CR), 74.3% (26/35) achieved partial response (PR), and 14.3% (5/35) achieved SD during the follow-up period (Figure 2C). The median DOR among the 29 patients who achieved objective response has not yet been reached (Figure 2D). These findings indicate that lorlatinib demonstrates robust and durable efficacy in the first-line treatment of ALK⁺ NSCLC patients.

Among the 7 patients with baseline brain metastases, 6 were evaluable for intracranial tumor response. During the treatment follow-up period, 2 patients achieved a CR, 3 achieved a PR, and 1 demonstrated SD with tumor shrinkage in the intracranial metastases.

Efficacy analysis of lorlatinib as subsequent-line treatment in patients with ALK⁺ NSCLC

In the lorlatinib subsequent-line treatment cohort, 37.2% (16/43) of patients had their ALK gene status determined at baseline using FISH or Ventana-IHC testing, while 62.8% (27/43) underwent NGS analysis of tumor tissue (25/27), pleural fluid (1/27), or blood (1/27) (Figure 3A). And 16 patients underwent repeat NGS testing before initiating lorlatinib treatment following resistance to other ALK-TKIs.

Figure 3 Efficacy of lorlatinib as a subsequent-line treatment in patients with ALK⁺ NSCLC. (A) The ALK mutation status of patients in the subsequent-line treatment cohort (N=43). (B) Kaplan-Meier curve for PFS (N=42). (C) The DpR in the subsequent-line treatment cohort (N=42). (D) The DOR in the subsequent-line treatment cohort (N=17). ALK, anaplastic lymphoma kinase; ALK⁺, ALK-positive; CI, confidence interval; CR, complete response; DOR, duration of response; DpR, depth of tumor response; IHC, immunohistochemistry; mDOR, median DOR; mPFS, median PFS; NA, not available; NSCLC, non-small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.

As of July 18, 2025, the median follow-up duration for this cohort was 19.9 months. The median PFS for ALK⁺ NSCLC patients receiving lorlatinib as subsequent-line treatment was 16.8 months [95% confidence interval (CI): 9.0–24.6] (Figure 3B). Among the 42 patients included in the efficacy evaluation, the ORR reached 40.5% (17/42), and the DCR was 92.9% (39/42). Regarding the DpR, 4.8% (2/42) of patients achieved CR, 35.7% (15/42) achieved PR, and 38.1% (16/42) achieved SD during the follow-up period (Figure 3C). Additionally, 3 patients exhibited progressive disease (PD) at their first efficacy assessment following treatment initiation, while 6 patients initially presented with increased SD, which subsequently progressed to PD. The median DOR among the 17 patients who achieved an objective response was 14.0 months (95% CI: 6.2–21.8) (Figure 3D). Overall, lorlatinib has demonstrated promising efficacy as a sequential treatment option for patients with ALK⁺ NSCLC.

Among the 22 patients with baseline brain metastases, 14 were evaluable for intracranial tumor response. The best intracranial response during the treatment period was as follows: 14.3% (2/14) achieved a CR, 42.9% (6/14) achieved a PR, 28.6% (4/14) had SD with tumor shrinkage, 7.1% (1/14) had SD with tumor progression, and 7.1% (1/14) experienced PD.

Next, we examined whether the number of prior ALK-TKI treatments influenced the efficacy of lorlatinib in subsequent-line therapy for patients with ALK⁺ NSCLC. Patients in the subsequent-line cohort were stratified into two groups: those who had received no more than one ALK-TKI (n=21) and those who had received two or more ALK-TKIs (n=21). The median PFS was 23.2 versus 16.8 months, with a hazard ratio (HR) of 1.48 (95% CI: 0.59–3.72), and the difference was not statistically significant (Figure 4A). Further analysis of tumor response dynamics revealed a trend toward greater DpR in patients who had received fewer prior ALK-TKI exposures; however, this difference was also not statistically significant (P=0.08) (Figure 4B).

Figure 4 Efficacy of lorlatinib in second-line and later-line treatment among patients with ALK⁺ NSCLC. (A) PFS in patients treated with ≤1 ALK-TKI (n=21) and ≥2 ALK-TKIs (n=21). (B) The DpR in patients treated with ≤1 ALK-TKI (n=21) and ≥2 ALK-TKIs (n=21). ALK, anaplastic lymphoma kinase; ALK⁺, ALK-positive; ALK-TKI, ALK tyrosine kinase inhibitor; CI, confidence interval; DpR, depth of tumor response; HR, hazard ratio; mPFS, median PFS; NSCLC, non-small cell lung cancer; PD, progressive disease; PFS, progression-free survival; PR, partial response.

The safety profile of lorlatinib in first-line and subsequent-line treatment

Among all patient groups included in this study (n=79), the adverse events associated with lorlatinib treatment predominantly comprised hypercholesterolemia (any grade: 100%; grade ≥3: 16.5%), hypertriglyceridemia (any grade: 93.7%; grade ≥3: 22.8%), edema (any grade: 57.0%; grade ≥3: 1.3%), cognitive impairment/mood disorders (any grade: 44.3%; grade ≥3: 2.5%), elevated transaminases (any grade: 31.6%; grade ≥3: 1.3%), weight gain (any grade: 24.1%), and peripheral neuropathy (any grade: 20.3%). Additional adverse events included hypertension (any grade: 19.0%), arthralgia (any grade: 16.5%), fatigue (any grade: 13.9%), hyperglycemia (any grade: 8.9%), and pneumonitis (any grade: 6.3%). Notably, no cases of interstitial lung disease were observed during the study.

The incidence rates of adverse events associated with lorlatinib treatment in the first-line treatment cohort and the subsequent-line treatment cohort are summarized in Table 2. In the first-line treatment cohort, two patients developed grade 3 mood disorders, primarily characterized by irritability, with one patient discontinuing treatment before completing 28 days. In the subsequent-line treatment cohort, one patient had lorlatinib therapy interrupted due to grade 3 elevated transaminase levels and received intravenous hepatoprotective therapy, and the patient subsequently resumed lorlatinib treatment at a reduced dose.

Our observation revealed that the cognitive impairment caused by lorlatinib mainly manifested as blurred short-term memory and delayed responses to external stimuli, while the mood disorders caused by lorlatinib were mainly characterized by irritability. Most patients who experienced cognitive impairment or mood disorders that do not interfere with daily functioning, do not require specific intervention, and may spontaneously resolve or improve within several months. In a minority of patients with significant irritability, dose reduction of lorlatinib or psychiatric consultation may be necessary. Edema associated with lorlatinib treatment primarily presents as swelling of the fingers and facial areas, frequently accompanied by localized skin tightness and numbness. Almost all patients who received lorlatinib developed hypercholesterolemia, and the vast majority of patients also had hypertriglyceridemia. Additionally, 10.1% (8/79) of patients experienced concomitant grade ≥3 hypercholesterolemia and hypertriglyceridemia. For patients with elevated blood lipids, we usually provide monotherapy or combination therapy with rosuvastatin, ezetimibe, fenofibrate, and evolocumab; all treated patients achieved a reduction in the CTCAE grade of hypercholesterolemia and hypertriglyceridemia.

Investigation of the mechanism underlying lorlatinib resistance

As of July 18, 2025, a total of 6 patients underwent NGS testing both prior to initiation of lorlatinib treatment and following the development of lorlatinib resistance. Among the 2 patients who developed resistance to first-line lorlatinib treatment, 1 acquired MET gene amplification and the other developed an STK11 mutation. Among the 4 patients who developed resistance to subsequent-line lorlatinib treatment, 1 patient exhibited a novel ALK fusion variant (ALK-MIR100HG), 1 patient developed a new C1156Y mutation (G1202R/C1156Y), 1 patient acquired an E1132K/G1269A compound mutation (G1202R/E1132K/G1269A), and 1 showed no new genetic alterations. Notably, 5 of 6 patients with acquired resistance harbored concurrent TP53 mutations when resistance developed.

Discussion

The remarkably prolonged PFS associated with lorlatinib has likely transformed the treatment paradigm for patients with locally advanced or metastatic ALK⁺ NSCLC. Inspired by the methodology and objectives of the CROWN trial, we designed and conducted this real-world cohort study.

Our research findings demonstrate that the therapeutic efficacy of lorlatinib as a first-line treatment for patients with ALK⁺ NSCLC is broadly consistent with the outcomes observed in the CROWN study. During the treatment period, the majority of patients exhibited substantial tumor regression, achieving a PR, while a minority of patients achieved a CR. Adverse events associated with lorlatinib administration are generally manageable through concomitant medical interventions. Notably, severe adverse events tend to occur predominantly within the initial month of treatment. Therefore, it is recommended that patients receiving lorlatinib undergo close monitoring and timely management of adverse events during the first month to enhance treatment tolerance. Furthermore, cases involving severe cognitive impairment or mood disorders necessitate comprehensive evaluation and targeted intervention by specialists, including psychiatrists and neurologists. Overall, real-world evidence demonstrates that lorlatinib, as a first-line treatment for patients with ALK⁺ NSCLC, exhibits robust efficacy and a manageable safety profile. In addition, a case report has documented a patient being switched to lorlatinib due to intolerance to adverse events associated with other ALK-TKIs, offering valuable guidance for clinical decision-making (12).

Our study further demonstrates that lorlatinib, as a sequential therapeutic strategy for patients who have developed resistance to prior ALK-TKIs, exhibits significant clinical efficacy. In the subsequent-line cohort, over half of the patients achieved disease control, with an overall median PFS of 16.8 months. Among patients who had received no more than one prior ALK-TKI, sequential lorlatinib treatment was associated with a median PFS of 23.2 months. From the perspective of DCR, patients with limited prior ALK-TKI exposure may achieve a numerically higher DCR compared to those with extensive prior ALK-TKI treatment, although the difference was not statistically significant. These findings support the consideration of lorlatinib as a preferred sequential treatment option following resistance to other ALK-TKI therapies. It should be noted that real-world data from another center in China showed that patients who had received one prior ALK-TKI had a median PFS of 49.73 months for lorlatinib, while those who had received two or more prior ALK-TKIs had a median PFS of 12.17 months (10). This is somewhat different from our results.

Mechanistically, lorlatinib demonstrates superior efficacy in the subsequent-line cohort due to its continued effectiveness against common resistance mutations associated with first- and second-generation ALK-TKIs, such as the single ALK mutations G1202R and I1171N/S/T (13,14). Nevertheless, like all targeted therapies, lorlatinib inevitably develops resistance. Previous analyses of NGS data from repeat biopsies of lorlatinib-resistant patients revealed that 35% developed ALK compound mutations following the onset of resistance (15), which may represent a key mechanism underlying lorlatinib resistance. In the subsequent-line cohort of our study, we identified one case with a G1202R/E1132K/G1269A compound mutation and another with a G1202R/C1156Y compound mutation, yielding a compound mutation frequency of 33.3% (2/6), which aligns with previously reported findings (15). Furthermore, in vitro cell experiments have indicated that epithelial-mesenchymal transition may also serve as a potential mechanism contributing to lorlatinib resistance (16). Regarding the potential mechanisms underlying resistance to first-line lorlatinib treatment, we report the identification of an acquired MET amplification in one patient and an STK11 mutation in another.

A meticulous examination of the evolutionary journey of ALK-TKIs unveils a compelling truth: distinct ALK mutations demonstrate diverse sensitivities to various ALK-TKIs. Hence, an in-depth and systematic exploration of the intricate physicochemical characteristics and pharmacogenomic landscapes of both individual and combined ALK mutations becomes not merely beneficial, but indispensable for propelling the relentless advancement and refinement of ALK-TKI therapeutics.

Finally, this study has several limitations that warrant consideration. First, the current sample size remains relatively small, and we plan to expand both cohorts substantially in the coming years. Our research is a single-center observational study, and the results still need to be further verified in RCTs or multicenter studies. Second, although the study encourages, but does not require, patients to undergo re-biopsy and NGS testing following the development of lorlatinib resistance, the number of patients available for mutation analysis remains limited. Third, due to the small number of patients with brain metastases, we were unable to compare the efficacy of lorlatinib in controlling or preventing intracranial disease in both first- and subsequent-line settings. We intend to report updated findings at an appropriate time as more data become available.

Conclusions

Lorlatinib has demonstrated promising efficacy in both first-line and subsequent-line treatment settings for patients with locally advanced or metastatic ALK⁺ NSCLC. The effective management of lorlatinib-related adverse events, achieved through close monitoring and timely intervention, is crucial for improving patient tolerance and treatment adherence. Lorlatinib resistance mechanisms differ between first-line and sequential-line treatments; therefore, treatment plans should be individualized based on NGS results from second biopsies. Our study addresses the gap in real-world evidence regarding lorlatinib; however, further validation through multicenter studies or RCTs remains necessary.

Acknowledgments

We thank all the patients and family members for participating in the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1148/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1148/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1148/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-aw-1148/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. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College (approval No. 24/395-4675). All participants provided written informed consent prior to enrollment.

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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