Incidence and risk factors of pneumonitis in ALK-rearranged non-small cell lung cancer patients treated with alectinib and thoracic radiotherapy

Introduction

Lung cancer is the most common cause of cancer-related mortality globally (1). More recently, precision medicine targeting gene mutations has played an increasingly important role in the treatment of lung cancer, especially non-small cell lung cancer (NSCLC). Of these, anaplastic lymphoma kinase (ALK) rearrangement occurs in 3.6–4.4% of NSCLC patients, predominantly in those with adenocarcinoma (2). These ALK-rearranged patients exhibit marked responses to ALK tyrosine kinase inhibitors (TKI) treatment and have significantly prolonged survival (3).

Alectinib (CH5424802) is the second-generation ALK-TKI applied to ALK-rearranged NSCLC (4). The phase III global ALEX trial has convincingly demonstrated the superiority of alectinib over crizotinib (median progression-free survival 34.8 vs. 10.9 months) (5,6). Based on this result, alectinib received Food and Drug Administration approval for the first-line treatment of advanced ALK-rearranged NSCLC patients. The J-ALEX and ALESIA trials also lent support to this conclusion in Asian populations (7,8). Although alectinib has an increasingly sturdy position among ALK-rearranged NSCLC treatments, the adverse reactions should not be underestimated. Pneumonitis occurred in 7 patients (4.6%) in the Alex trial, of which 4 (2.6%) of grade 3–5 (6), 8 patients (8%) in the J-ALEX trial developed interstitial lung disease (9), and 2 out of 125 patients (1.6%) in ALESIA trial discontinued alectinib due to lung injury (10).

Thoracic radiotherapy (TRT), as a classical means of locoregional treatment of lung cancer, occupies an important position in the field of anti-cancer therapy. The addition of consolidative radiotherapy to metastatic patients treated with ALK-TKI may also confer a survival benefit (11). Previous study has reported that 37.5% of patients treated with the combination of erlotinib and TRT developed grade 2 or higher pneumonitis (12). Concurrent treatment of Osimertinib and TRT was even worse, 63.6% of patients developed grade 2 or higher pneumonitis (13). However, no studies have investigated the incidence and risk factors of pneumonitis in combination with alectinib and TRT. Therefore, we retrospectively analyzed the clinical data and dosimetric parameters from 62 cases of ALK-rearranged NSCLC who received alectinib and TRT to evaluate the occurrence of pneumonitis and further identify the potential risk factors. We present this article in accordance with the TRIPOD reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-107/rc).

Methods

Patient selection

This retrospective study reviewed ALK-rearranged NSCLC patients who were treated with alectinib and TRT in the Shandong Cancer Hospital from January 2018 to December 2023. The enrollment criteria were as follows: (I) presence of histopathologically confirmed NSCLC; (II) identified as ALK rearrangement by genetic testing, including next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH); (III) received alectinib and sequential or concurrent TRT with an interval of fewer than 3 months. The exclusion criteria were: (I) received re-irradiation for recurrent lung cancer; (II) received prior immune checkpoint inhibitors; (III) with other simultaneous malignancies. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Shandong Cancer Hospital (No. SDTHEC2021003186) and individual consent for this retrospective analysis was waived.

Data collection

Standardized questionnaires were used to collect clinical data and dosimetric parameters. Available data included demographics, diagnoses, and treatment data. The duration of alectinib use was defined as the time from the initiation of alectinib therapy to treatment discontinuation due to treatment-related pneumonitis (TRP). The diagnosis of TRP was adjudicated by 3 radiation oncologists, each with more than 10 years of experience, through chest computed tomography (CT), hematological tests, symptoms, and clinical history, and excluding other etiologies, such as infection, tumor, or pulmonary edema. The severity of TRP was graded based on the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (14). We simultaneously collect the following dosimetric parameters: total dose, dose per fraction, planning target volume (PTV), ipsilateral and total lung V5, V10, V15, V20, V25, V30, and mean lung dose (MLD).

Statistical analysis

Data were expressed as median (range) for continuous variables and number (percentage) for categorical variables. In this study, the primary endpoint was the occurrence of TRP. Univariate and multivariate logistic regression analyses were employed to identify related risk factors of TRP from clinical and dosimetric characteristics. Missing data were handled using mean imputation. A nomogram was constructed to develop the TRP prediction model. Multicollinearity among independent variables was assessed using variance inflation factors (VIF). A VIF value exceeding 10 was considered indicative of severe multicollinearity, while values between 5 and 10 suggested moderate collinearity. Receiver operating characteristic (ROC) curves were plotted to compare the ability of different dosimetric parameters to predict TRP. In addition, the highest Youden index (sensitivity + specificity − 1) was calculated to determine optimal cut-off values for each dosimetric parameter. All statistical analyses were completed using Stata/MP Version 17.0 and SPSS Version 26. A P value <0.05 was considered statistically significant.

Results

Patient characteristics

Over the duration of the study, a total of 519 patients were diagnosed with ALK-rearranged NSCLC through genetic testing. Of these, 262 patients received alectinib therapy. Sixty-six patients received TRT among these 262 patients, 4 patients were excluded due to re-radiotherapy, 62 patients who met the inclusion criteria were included in the final analysis. The detailed flow of the study is reported in Figure 1.

Figure 1 Flow chart of the patients screened. ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer; TRT, thoracic radiotherapy.

The clinical features of all 62 patients are listed in Table 1. The median age of participants was 50 (range, 26–76) years and the male-to-female ratio was generally consistent. The tumors were adenocarcinoma (n=60) or adenosquamous carcinomas (n=2). Thirty-six (58.1%) patients received concurrent alectinib and TRT (synchronous treatment is defined as overlapping time ≥1 day), and 26 (41.9%) patients received sequential therapy. Alectinib was administered as first-line treatment in 44 (71.0%) patients, second-line treatment in 17 (27.4%) patients and third-line treatment in only one patient. The dose of alectinib was administered as follows: 58 patients (93.5%) received the standard therapeutic dose of 600 mg twice daily (bid), while the remaining 4 patients (6.5%) were administered a reduced dose of 300 mg bid due to severe hepatic impairment as an adverse reaction. The median duration of alectinib treatment was 372 days (range, 109–878 days).

All patients had received TRT, which included 50 intensity modulated radiation therapy (IMRT) patients (80.6%), 4 simultaneous integrated boost (SIB) patients (6.5%), 6 conformal radiation therapy (CRT) patients (9.7%), and 2 helical tomotherapy (TOMO) patients (3.2%). The median total TRT dose was 50.2 Gy (range, 36.0–70.4 Gy), with a median single dose of 2.0 Gy (range, 1.8–8.0 Gy). The median ipsilateral lung V5, V20, V30 and MLD were 72.0% (range, 3.1–123.8%), 31.8% (range, 1.5–83.1%), 20.6% (range, 0.0–59.7%) and 1,559.1 Gy (range, 256.7–3,752.1 cGy), respectively. The total lung V5, V20, V30, and MLD were 44.7% (range, 8.0–94.5%), 19.0% (range, 1.2–46.4%), 9.3% (range, 0.0–33.0%), and 977.7 cGy (range, 59.3–2,602.1 cGy), respectively (Table S1).

Incidence, severity of treatment-related TRP

Thirty-nine out of 62 patients developed TRP, of whom 17 were grade 1, 12 were grade 2, 9 were grade 3, and 1 patient developed severe TRP of grade 5. We also describe other characteristics of TRP in Table 2. The median time between the last alectinib or TRT and TRP was 47 days (range, 0–179 days). The majority of patients were in stable disease (SD) status (61.5%) at the time of TRP occurrence. Seventeen patients were asymptomatic, but 22 patients experienced coughing, chest tightness, and dyspnea.

After developing TRP, most (58.9%) patients received systemic steroids, and 7 patients with co-infection received antibiotic therapy. Finally, 35 patients completely recovered or improved. However, a 45-year-old female patient with grade 5 TRP died of severe respiratory failure. This patient with stage IVB NSCLC progressed after receiving chemotherapy and oligoprogressed again after 4 months of alectinib treatment. Next, she received 45 Gy palliative TRT in 3 Gy daily fractions. The total lung V5, V20, V30 and MLD were 32.9%, 8.9%, 7.2% and 622.1 cGy, respectively. Eighty days after the end of TRT, the patient developed dyspnea and fever, and was diagnosed as TRP. As shown in Figure 2, the chest CT image depicts massive pleural effusion and diffuse infiltration lesions in the right lung. Three patients were lost to long-term follow-up.

Figure 2 CT images of a 45-year-old female who began palliative thoracic radiotherapy after the progression of disease on second-line alectinib treatment. (A) The lung fields were clear before thoracic radiotherapy. (B) Received local lung tumor irradiation (15×3 Gy) and isodose distribution of the treatment plan. Red line: gross tumor volume; green line: planning target volume; dose escalation: maximum dose reached 106.6% of prescribed dose, due to multiple irradiation fields, high-dose regions (hotspots) were observed in some areas. (C) Eighty days after thoracic radiotherapy, she developed dyspnea and fever. CT showed a large amount of pleural effusion and diffuse infiltration of the right lung. CT, computed tomography.

Risk factors of treatment-related TRP

The results of univariate and multivariate logistic regression analyses are shown in Table 3 and Figure 3. Advanced age [odds ratio (OR) =1.103, 95% confidence interval (CI): 1.027–1.185, P=0.007], central-type cancer (OR =0.170, 95% CI: 0.035–0.816, P=0.03), long-term alectinib (OR =1.006, 95% CI: 1.002–1.011, P=0.006), and higher total lung V30 (OR =1.149, 95% CI: 1.040–1.269, P=0.006) are risk factors for TRP in NSCLC patients with ALK rearrangement who received alectinib combined with TRT treatment. A nomogram was constructed with a C-index of 0.846 (0.733–0.958) (Figure 4A) and calibration was satisfactory (Figure 4B). The VIF values for all variables ranged from 1.02 to 1.07 (mean VIF =1.04), well below the threshold of 10, indicating no substantial multicollinearity concerns (Table S2). Other parameters are not significant predictive risk factors, such as Karnofsky performance score (KPS), clinical stage, and PTV size. Twelve patients developed ≥ Grade 2 TRP in patients undergoing concurrent treatment but treatment sequencing was not a statistically significant risk factor for TRP (OR =1.607, 95% CI: 0.554–4.659, P=0.38).

Figure 3 Forest plot of independent risk factors for pneumonitis. Multivariate logistics regression analysis indicated that NSCLC patients with central tumor were more likely to develop TRP. Age, duration of alectinib, and total lung V30 were independent risk factors. CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer; TRP, treatment-related pneumonitis.

Figure 4 Nomogram (A) and calibration curve (B) for TRP in ALK-rearranged non-small cell lung cancer patients. ALK, anaplastic lymphoma kinase; TRP, treatment-related pneumonitis.

ROC curve analysis

Given the importance of dosimetric parameters for TRP, separate analyses were conducted for each parameter. The ROC curves were used to compare the ability of different dosimetric parameters to predict TRP, and the area under ROC curve (AUC) was rendered for each parameter. As shown in Table 4 and Figure 5, the average AUC was 66.83%, the minimum AUC was 64.4%, and the maximum AUC was 68.9%.

Figure 5 The receiver operating characteristic curves and AUC values for the lung dosimetric parameters. (A) Ipsilateral lung dosimetric parameters. (B) Total lung dosimetric parameters. AUC, area under the curve; FPR, false positive rate; TPR, true positive rate.

The patient dosimetric parameters were illustrated in Table S1 and the optimal cut-offs were calculated based on the best Youden index. Results are described in Table 4. The best thresholds of ipsilateral V5, V10, V15, V20, V25, V30 and MLD were <52.9%, <52.8%, <41.1%, <34.1%, <27.7%, <15.5%, and <1,825.3 cGy, respectively. The best thresholds of total lung V5, V10, V15, V20, V25, V30 and MLD were <44.2%, <30.9%, <22.4%, <16.7%, <14.0%, <9.8%, and <980.2 cGy, respectively.

Discussion

Pneumonitis is a potential adverse effect of both alectinib and TRT (5,6,9,15). The incidence of pneumonitis in patients with locally advanced lung cancer treated by TRT is 16% (16). For non-ALK rearranged NSCLC patients, the incidence of radiotherapy-related pneumonitis was 10–30% (17), and the incidence of pneumonitis associated with alectinib was 4.6–8.0% (6,9). Thus, the combination of alectinib and TRT warrants further investigation. In this study, we explored the clinical and radiological features of TRP patients receiving alectinib and TRT, and the management of this toxicity. Further, we analyzed the risk predictors of TRP in this subset of patients.

TRP occurred in 62.9% of patients treated with alectinib combined with TRT, and the incidence of grade 2 and above TRP was 35.5%, including concurrent and sequential treatment. Peng et al. (18) proposed that the incidence of pneumonitis in patients with crizotinib combined with TRT was beyond expectation. All 4 patients in the concurrent treatment group developed grade 2 or 3 pneumonitis, and the incidence of grade 2 pneumonitis in the sequential group was 37.5%. In our study, the incidence of grade 2 or higher TRP was 33.3% and 38.4% in the concurrent and sequential groups, respectively, which shows that ALK-TKIs may aggravate the damage to the lungs. Patients receiving sequential therapy appeared to have higher risks of TRP, but there was no statistical difference, potentially reflecting sampling bias due to the limited cohort size. Clinical symptoms were absent at the onset of TRP in 27.4% of patients, so timely diagnosis is difficult. Considering asymptomatic patients, the true incidence of TRP may be higher than observed—much higher than that with alectinib alone (19)—which reminds clinicians to be cautious when considering the combination of these two treatments and exercise constant vigilance to the symptoms and signs of TRP throughout therapy. In the present study, patients with TRP responded favorably to the combination therapy, and 79.4% of patients exhibited SD or partial response (PR) when TRP set in. After being treated with corticosteroid and antibiotic treatment, the TRP resolved or improved in most patients, but one patient died of respiratory failure.

Patients with advanced age are more likely to have TRP due to poor physical activity, which is consistent with a previous study on ALK-TKI (20). On one hand, central-type tumors may be more likely to cause tracheal obstruction, and on the other hand, it is not conducive to radiotherapy planning, resulting in a significantly higher incidence of TRP than peripheral-type tumors. The risk of TRP increased along with the duration of alectinib use, demonstrating that alectinib indeed poses an additional risk of TRP with radiotherapy. Most dosimetric parameters influence the risk of TRP, with total lung V30 being the most significant risk factor. ROC curve analysis confirmed that limiting the total lung V30 to 9.8% may reduce the risk of TRP. Given the small patient cohort, we just recommend that radiotherapists be more judicious in formulating radiotherapy plans. Dosimetric parameters have been linked with the TRP risk in many studies of targeted therapy combined with TRT. Jia et al. found that ipsilateral lung V30 >34% is a predictive factor of grade ≥2 pneumonitis in patients treated with osimertinib and TRT (21). A study of concurrent erlotinib and TRT concluded that all lung dosimetric parameters can be used to predict radiation pneumonitis, with AUC greater than 0.8 (22). The increased TRP rate caused by the combination of alectinib and TRT can be explained by some therapeutic mechanisms. The activation of ALK is related to cell proliferation (23), and the blockade of ALK by alectinib can lead to poor repair of alveolar epithelial injury caused by radiotherapy. On the other hand, radiotherapy exerts its cytotoxic effects by inducing DNA double-strand breaks in tumor cells. Alectinib may concurrently suppress DNA damage repair pathways such as ATR signaling, prolonging repair delays in lung tissue and exacerbating pulmonary injury (24).

There were some limitations to this study. Due to the low frequency of ALK rearrangements in NSCLC and the use of alectinib, only 62 eligible patients were included in this analysis. Moreover, the retrospective nature of this study may have introduced selection or information bias.

In summary, this study reported for the first time the high incidence of TRP in ALK-rearranged NSCLC patients treated with alectinib and TRT. Age, tumor location, duration of alectinib use, and total lung V30 are risk factors for TRP. Clinicians should be cautious when choosing the combination therapy of alectinib and TRT and adjust the relevant dosimetric parameters and duration of alectinib to reduce the TRP rate. At the same time, it is imperative to pay more attention to the monitoring of related symptoms for early identification and intervention.

Conclusions

The combined use of alectinib and TRT significantly increased the risk of TRP. Clinicians should consider the elevated risks and related dosimetric factors when deciding on combination treatment for ALK-rearranged NSCLC patients.

Acknowledgments

The authors are grateful to all the patients who participated in this study. Part of this work was previously presented as a conference abstract at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-107/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-107/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-107/prf

Funding: This study was supported by National Key Technologies Research and Development Program (grant number 2022YFC2404605), Post-Marketing Clinical Research Special Project on Innovative Drugs (grant number WKZX2023Cx020012), National Natural Science Foundation of China (grant numbers 82172865 and 82404083), China Postdoctoral Science Foundation (grant number 2023M732127), Natural Science Foundation of Shandong Province (grant numbers ZR2023LZL002, ZR2024MH007, and ZR2021LZL009), and Clinical Research Special Fund of Wu Jieping Medical Foundation (grant numbers 320.6750.2021-02-51 and 320.6750.2021-17-13).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-107/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. The study was approved by the Ethics Committee of Shandong Cancer Hospital (No. SDTHEC2021003186) and individual consent for this retrospective analysis was waived.

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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