End-of-life management and causes of death in ALK-positive non-small cell lung cancer in France: a multicentric analysis

Introduction

Anaplastic lymphoma kinase (ALK) positive non-small cell lung cancers (NSCLC) account for 3–5% of all NSCLC. They affect a younger population (median age at diagnosis: 55 years), with a higher proportion of females, fewer smokers, and fewer comorbidities compared to unselected NSCLC patients (1). The common metastatic sites are the lymph nodes, the central nervous system (CNS) and the serous membranes (2). The development of ALK-specific tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of these patients. Alectinib and lorlatinib were respectively authorized in 2017 and 2022 as first-line treatments in Europe. In the updated 5-year results published in 2024 of the CROWN phase III trial comparing lorlatinib to crizotinib as first-line treatment in ALK-positive NSCLC, median progression-free survival (PFS) was not reached with lorlatinib, and 60% of patients remained progression-free at 5 years (3). These results have modified our practice with a broader first line administration of lorlatinib.

Despite the substantial and durable responses achieved with ALK-targeted therapies (4,5), advanced ALK-positive NSCLC remains incurable, and most patients ultimately experience disease progression. CNS metastases represent a major unmet need. Although second- and third-generation TKIs have improved systemic and intracranial response rates, CNS involvement continues to be associated with poorer outcomes. Leptomeningeal metastases are particularly challenging, as they are underrepresented in clinical trials, difficult to assess radiologically, and associated with significant morbidity and shortened survival (6,7). These specific characteristics, including younger age at diagnosis, distinct patterns of metastatic spread (particularly CNS and leptomeningeal involvement), and the availability of multiple sequential TKI therapies—raise important questions about disease progression trajectories and end-of-life (EOL) care in this patient population.

Two retrospective studies published in 2017 and 2022 using the SEER database examining cause of death in unselected metastatic NSCLC populations found that 80–87% of patients died from lung cancer-related causes (8,9). The main non-cancer causes of death were suicide during the first year after diagnosis, followed by cardiovascular disease and other comorbidities such as chronic obstructive pulmonary disease (COPD) and cerebrovascular disease in subsequent years (9). A California state database study of long-term NSCLC survivors demonstrated similar patterns, apart from suicide (10).

In advanced NSCLC, early integration of palliative care has been shown to improve patient outcomes, including quality of life, symptom control, and nutritional status (11,12), and reduce both in-hospital deaths and the use of systemic anti-cancer treatments in the final weeks of life (13,14). Despite these benefits, data suggest suboptimal EOL care patterns: in approximately half of cases, death occurs during an acute hospitalization (13,15), and 40% of patients receive systemic anti-cancer treatment within the last 2 weeks of life (15). Second- and third-generation TKIs are costly. A recent real-world study in Greece reported annual per-patient costs of ALK TKIs increasing from €39,220 to €44,609 between 2020 and 2022 (16). These findings underscore the need to better characterize EOL care in ALK-positive NSCLC to ensure the sustainable and equitable integration of novel therapies.

To date, no study has specifically examined EOL trajectories in ALK-positive NSCLC. Therefore, the aim of our study was to describe disease evolution, EOL management, and causes of death in patients who died from metastatic ALK-positive NSCLC. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0303/rc).

Methods

Study design and patient selection

This retrospective multicentric cohort study included all patients diagnosed with metastatic ALK-positive NSCLC and deceased before July 2024. There were seven participating centers in Paris and its surrounding area: Cochin Hospital, Tenon Hospital, Créteil Intercommunal Hospital, Georges Pompidou European Hospital, Bichat Hospital, Avicenne Hospital, and Ambroise Paré Hospital.

Recruitment methods varied across centers. Four centers relied on established local cohorts of ALK-positive NSCLC. In the remaining three centers, patients were identified through the AP-HP Clinical Data Warehouse (Entrepôt de Données de Santé) using the Cohort360 interface, which enables querying pseudonymized electronic health records across all AP-HP hospitals. Records were searched for prescriptions or administrations of ALK TKIs, including crizotinib, alectinib, brigatinib, ceritinib, and lorlatinib.

ALK rearrangement was assessed by ALK immunohistochemistry (IHC). Tumours with strong IHC staining (+++) were considered ALK-positive. For tumours with weaker staining (+ or ++), ALK positivity required confirmatory testing by either fluorescence in situ hybridization (FISH) (≥15% ALK-positive cells among ≥100 scored nuclei) or an RNA-based next-generation sequencing assay demonstrating an ALK rearrangement. Eligibility criteria included: age ≥18 years at diagnosis, follow-up in one of the participating centers, and death before the end of the recruitment period (July 2024).

Data collection

Demographic characteristics, cancer history, and histological and molecular data were obtained through review of medical records. The 8th edition of the tumor-node-metastasis (TNM) classification was used for staging. Past smokers were defined as those who had quit smoking at least 1 year before diagnosis. The following comorbidities were recorded: hypertension, heart disease, COPD, asthma, other malignancies, diabetes, and kidney failure. Data collection took place between June 2023 and July 2024. Overall survival (OS) was defined as the time between histological diagnosis and death.

For patients with CNS progression, we recorded the time from diagnosis to first CNS progression and site(s) of CNS involvement (supratentorial brain, cerebellum, and/or leptomeninges). We documented each patient’s consecutive lines of treatment from diagnosis to death. Treatment sequences were classified into five categories according to the generation of ALK-TKIs received: crizotinib was the only first-generation TKI; alectinib, ceritinib, and brigatinib were second-generation drugs; and lorlatinib was the only third-generation treatment. The five categories were: group 1, patients who received only first-generation TKI (crizotinib); group 2, patients who received only a second-generation TKI; group 3, patients who received both second and third-generation TKIs; group 4, patients who received crizotinib followed by a second-generation TKI and group 5, patients who received all three generations of TKIs.

EOL outcomes

Causes of death were classified as either lung cancer-related or non-cancer-related. Death was considered cancer-related if there was documented cancer progression accompanied by a decline in performance status (PS) prior to death. Cancer-related deaths were further subdivided into respiratory failure, neurological failure, cachexia, or other causes. Neurological failure was defined as death preceded by progressive neurological deterioration due to CNS disease progression. Respiratory failure was defined as death due to respiratory insufficiency related to pulmonary disease progression. Cachexia was defined as death in the context of severe weight loss as mentioned in the medical electronic file and functional decline without predominant respiratory or neurological symptoms. In the presence of combined causes, the condition that occurred first and acted as the triggering event was considered the primary cause of death. Non-cancer-related deaths were similarly subdivided according to their specific cause.

We recorded the circumstances of death, including place of death (hospital, home, or palliative care unit), ongoing cancer-specific treatment at the time of death and during the last 2 weeks of life, documentation of do-not-resuscitate decisions, multidisciplinary decisions to focus exclusively on palliative care, and any explicit requests for euthanasia. This 2-week cutoff was selected because mean EOL palliative care unit stay is 15 days in France.

Referral to a palliative care specialist was also documented.

Statistical analysis

Descriptive statistics were used to characterize the cohort and EOL outcomes. Univariable logistic regression was used for univariable analysis of categorical variables. Logistic regression was performed for multivariable analysis of predictive factors for in-hospital death and referral to palliative care specialists. Variables included in the multivariable analysis were those statistically significant in univariable analysis (P<0.05) and clinically relevant variables (PS, history of lorlatinib treatment, CNS metastases at diagnosis). All statistical analyses were completed using R software.

Ethical considerations

We reviewed medical records for written opposition to participate in retrospective studies. In the absence of such documentation, patients were included. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the French Society of Respiratory Diseases (Société de Pneumologie de Langue Française, SPLF, CEPRO 2021-024). Informed consent was waived in this retrospective study.

Results

Demographic characteristics

Between March 2009 and June 2023, 232 patients with a diagnosis of ALK-positive metastatic NSCLC were identified across participating centers. Of these, 143 were excluded: 67 were still alive at the end of the study period, 27 did not have confirmed ALK rearrangement, 52 were lost to follow-up, and 5 had cancers of non-pulmonary origin. The final cohort included 89 deceased patients (Figure S1).

Patient characteristics are summarized in Table 1. The clinical characteristics of the cohort were consistent with those typically observed in ALK-positive NSCLC patients: 58.4% were female, median age at diagnosis was 59.9 years [interquartile range (IQR), 47.5–70.2 years], and 62.9% were never-smokers. Comorbidities were infrequent, with 41.7% of patients having no documented comorbidity. As expected, most tumours were adenocarcinomas (80.9%), and 34.8% of patients presented with CNS metastases at diagnosis.

Molecular characterization beyond ALK rearrangement was performed in 58 patients (65.2%). Co-mutations were identified in 11 cases (19.0% of tested patients), while 47 patients had no documented co-mutations and 31 patients had no additional molecular testing.

Consecutive lines of treatment

To describe the evolution of treatment strategies over time, patients were stratified into five groups based on the generations of ALK-TKIs they received during their disease course (Figure 1).

Figure 1 Distribution of treatment sequence groups by year of diagnosis.

The number of patients, median OS, and median year at diagnosis for each group are summarized in Table 2. Patients who received all three generations of TKIs (group 5) had the longest median OS (71 months), while those treated with only first-generation (group 1) or only second-generation TKIs (group 2) had the shortest median OS (6 and 9.5 months, respectively). Two patients did not receive any treatment and were not classified into any group.

In the overall cohort, median OS from diagnosis was 26 months (range, 1–143 months). CNS disease progression occurred in 53 of 89 patients (59.6%), with a median time to first CNS progression of 14.5 months from diagnosis. The most frequent site of CNS progression was the cerebrum (n=46, 87.3% of patients with CNS progression), followed by leptomeningeal involvement (n=20, 38.2%) and cerebellar metastases (n=20, 38.2%). Multiple CNS sites were affected in 27 patients (30.3%). The median time from first CNS progression to death was 11 months.

Causes of death

Cancer-related deaths accounted for 79.8% of all deaths (71/89). Among these cancer-related deaths, the most common causes were neurological failure (n=26, 36.6%), respiratory failure (n=21, 29.6%), and cachexia (n=21, 29.6%) (Figure 2).

Figure 2 Distribution of causes of death among patients who died from metastatic ALK-positive NSCLC. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer.

Eighteen deaths (20.2%) were not directly related to cancer progression. The reported causes were: bacterial pneumonia (n=6), heart failure (n=2), septic shock (n=2), viral pneumonia (n=1), lupus shrinking lung syndrome (n=1), cardiac arrest during upper gastrointestinal endoscopy for dysphagia assessment (n=1), cardiac arrest during neurosurgery (n=1), stroke (n=1), road traffic accident (n=1), and progression of non-lung malignancy (n=1). Cause of death was unknown for one patient. As he had been reassessed with a contrast-enhanced computed tomography (CT) of the chest, abdomen, pelvis and brain, which showed no evidence of disease progression; and presented no new symptom or worsening of PS, he was classified as a non-cancer-related death.

EOL management

Treatment at end of life

In the 2 weeks preceding death, 64 patients (71.9%) were still receiving cancer-specific treatment: crizotinib (n=11, 17.2%), a second-generation inhibitor (n=21, 32.8%), lorlatinib (n=21, 32.8%), or chemotherapy (n=8, 12.5%). Among the 25 patients who had discontinued cancer-specific treatment, the median time from treatment cessation to death was 1 month (range, 0–9 months).

Place and circumstances of death

Most patients (n=53, 59.6%) died in a medical ward, while 14 patients (15.7%) died in a palliative care unit, 12 (13.5%) in an intensive care unit, and 10 (11.2%) at home.

Documentation of EOL care planning varied: a multidisciplinary consultation recommending exclusive palliative care was documented in 23 cases (25.8%), specific treatment limitation orders [e.g., no vasopressors, no cardiopulmonary resuscitation, no intensive care unit (ICU) transfer] were recorded in 51 cases (57.3%), and family meetings were documented in 56 cases (62.9%). Consultation with palliative care specialists was requested for 46 patients (51.1%), and 30 patients (33.8%) accepted psychological support. Median time from referral to palliative care specialist to death was 16 days. Continuous intravenous morphine and benzodiazepines were administered at the time of death in 57% of patients.

Factors associated with palliative care referral

Patients were classified into two groups based on referral to specialist palliative care: referred (n=46) and not referred (n=43). Clinical and demographic characteristics were similar between groups (Table S1), except for prior lorlatinib use, which was more frequent among patients referred to palliative care.

Statistical analysis of palliative care referral associated factors are presented in Table 3. Two factors were positively associated with palliative care referral in univariable analysis: history of third-generation TKI [odds ratio (OR) 3.46, P=0.007] and multidisciplinary discussion recommending exclusive palliative care (OR 4.89, P=0.005). On the contrary active treatment within 2 weeks before death was strongly associated with a lower chance of palliative care referral (OR 0.12, P<0.001); 45% of patients referred to palliative care vs. 9% had discontinued treatment in the last 2 weeks of life (median 4.5 vs. 2 weeks before death). In multivariable analysis, absence of active treatment [OR 0.15, 95% confidence interval (CI): 0.03–0.55, P=0.01], absence of CNS metastases at diagnosis (OR 0.31, 95% CI: 0.09–0.91, P=0.04) and history of lorlatinib treatment (OR 3.32, 95% CI: 1.12–10.6, P=0.04) were significantly associated with more frequent palliative care referral (Table 3).

Factors associated with in-hospital death

Several factors were associated with in-hospital death in univariable analysis: poor PS at diagnosis increased the odds (OR 4.10, P=0.04), while palliative care referral (OR 0.33, P=0.03) and multidisciplinary discussion (OR 0.20, P=0.003) were protective. Notably, patients receiving active anti-cancer treatment within 2 weeks before death had markedly higher odds of dying in hospital (OR 17.30, 95% CI: 5.77–58.60, P<0.001). After multivariable adjustment, active treatment within the final 2 weeks remained the only independent predictor of in-hospital death (OR 16.4, 95% CI: 4.19–83.4, P<0.001) (Table 4).

Discussion

This retrospective multicentre real-world study provides new insights into EOL trajectories in patients with ALK-positive NSCLC. Despite major therapeutic advances, most patients (79.8%) died from cancer-related causes, at rates comparable to those reported in the overall NSCLC population (8). Several factors may explain this observation. First, patients with ALK-positive NSCLC are typically younger and present with better PS and fewer comorbidities than unselected stage IV NSCLC populations, resulting in a lower competing risk of death from non-cancer causes. In addition, because this retrospective analysis included only deceased patients, the observed median OS of 26 months suggests that many patients did not survive long enough for competing causes of death to predominate. In line with this interpretation, a large retrospective study across multiple cancer types reported that non-cancer deaths exceeded cancer-related deaths only after approximately 8 years of disease evolution (9).

Although ALK-targeted therapies have substantially prolonged survival, the disease remains ultimately fatal in most patients, with progression occurring despite sequential lines of treatment. Importantly, routine first-line use of lorlatinib largely followed the update of the CROWN study in 2024. Our study does not include patients who received lorlatinib as first-line therapy, which may influence future outcomes and patterns of EOL trajectories in this population.

The observed median OS of 26 months appears relatively short but should be interpreted with caution given the inherent selection bias of a study restricted to deceased patients. In addition, outcomes in group 1 likely reflect historical treatment practices, as 31% of these patients received first-line chemotherapy before the widespread adoption of ALK inhibitors (data not shown). Conversely, patients diagnosed more recently (groups 3 and 4) who died during the study period probably represent a subset with more aggressive disease biology or limited response to newer-generation TKIs, whereas patients with more favourable outcomes were still alive at data cutoff and therefore excluded by design. Overall, 18% and 57% of patients were not exposed to second- or third-generation TKIs, respectively. These findings therefore reflect both genuine therapeutic advances over time and the unavoidable selection bias inherent to a retrospective study restricted to deceased patients.

A concerning finding was that 71.9% of patients received systemic anti-cancer treatment in the last 2 weeks of life, which was independently associated with in-hospital death. While ALK-TKIs are well-tolerated oral therapies, and disease flare upon discontinuation has been described (17,18) and represents a true concern when deciding to stop a TKI, continuing treatment until death may not align with patient-centered EOL goals. This pattern mirrors observations with immune checkpoint inhibitors, where administration in the last 30 days of life was associated with decreased palliative care referral and increased in-hospital deaths (19). Treatment discontinuation discussions should be prioritized as patients approach end of life, focusing on quality of life rather than survival prolongation alone.

Only half of patients were referred to palliative care specialists, despite documented benefits including fewer in-hospital deaths, earlier treatment discontinuation, more frequent multi-disciplinary consultations, and more consistent documentation of treatment limitation decisions. Moreover, the median interval between referral to palliative care and death was 16 days, reflecting a relatively short timeframe. This aligns with the average length of stay in palliative care units in France and suggests referrals predominantly occurred at an advanced stage of disease, rather than earlier in the disease trajectory when integration of palliative care might have enabled more comprehensive longitudinal support. These findings align with broader evidence that early palliative care integration improves outcomes in stage IV NSCLC, including reduced ICU admissions and improved OS (20,21). The younger age and prolonged survival of ALK-positive patients should not delay palliative care referral; rather, it underscores the importance of early integration to optimize quality of life throughout the disease trajectory.

Limitations

Our study has some limitations. The retrospective design precluded systematic quality-of-life assessment due to heterogeneous documentation. Of note, assessment of the patient’s or his family’s satisfaction with the treatment and with the decision to maintain or stop active anticancer treatment was not possible. The restriction to deceased patients before June 2024 created selection bias favouring poor responders to second- and third-generation TKIs, resulting in lower median OS than contemporary patients will likely experience with current therapies. We deemed the analysis of OS prognostic factors to be inappropriate. Another limitation is that we lacked the statistical power to analyse the impact of the last TKI received on the decision to pursue treatment, even though some may be better tolerated than others and thus influence this choice. Finally, 52 patients were lost to follow-up and did not have any information concerning disease progression or EOL management, which may have induced a selection bias. Nevertheless, our findings suggest that palliative care referral reflects a more holistic approach benefiting patients beyond survival metrics, particularly regarding place of death.

Conclusions

In this cohort of 89 deceased patients with ALK-positive NSCLC, most deaths were cancer-related, and patients benefited from palliative care specialist referral. The pursuit of cancer-specific treatment or hope for prolonged TKI response should not delay such referral nor obscure emerging EOL symptoms.

Acknowledgments

ChatGPT 5.0 was used to generate text and improve quality of our formulations.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0303/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0303/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-0303/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-2026-0303/coif). V.F. reports receiving personal fees from Pfizer, Takeda, AstraZeneca, Janssen, Novocure, Regeneron, Amgen, BMS, Sanofi, and Pierre Fabre, and support to attend meetings from Pfizer, AstraZeneca, Regeneron, Takeda, and Janssen. G.R.B. reports receiving honoraria for lectures from BMS, Roche, Sanofi, Takeda, AstraZeneca, and Johnson & Johnson, and support for attending meetings from Boehringer Ingelheim, Takeda, Pfizer, Lilly, AstraZeneca, Sanofi, MSD, Pierre Fabre, and Regeneron. B.D. reports receiving honoraria from Roche, Pfizer, AstraZeneca, Amgen, and Lilly and support for attending meetings from Oxyvie and Pfizer. E.G.L. reports receiving consulting fees from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Janssen, Lilly, MSD, Pfizer, Roche, Sanofi, and Takeda, and support for attending meetings from Roche, Pfizer, and Takeda. H.B. reports receiving honoraria for lectures from Amgen, Janssen, AstraZeneca, and MSD. M.W. reports receiving honoraria for lectures, support for attending meetings, and participation on a data safety monitoring board from Pfizer, Takeda, Novartis, and F. Hoffmann-La Roche. The other 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. The study was approved by the French Society of Respiratory Diseases (Société de Pneumologie de Langue Française, SPLF, CEPRO 2021-024). Informed consent was waived in this retrospective study.

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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