Impact of Long-Term Structured Exercise on Body Composition in an NTRK Fusion-Positive NSCLC Patient Treated With Entrectinib.

1
Introduction
Entrectinib is a first‐generation tropomyosin receptor kinase (TRK) inhibitor also approved for the treatment of patients with neurotrophic tyrosine receptor kinase (NTRK) gene fusions, a rare but recurrent oncogenic driver found in approximately 0.1%–0.2% of non‐small cell lung cancers (NSCLC). While generally well‐tolerated, entrectinib is associated with adverse events (AEs), including weight gain, reported in 25%–26.4% of patients [1, 2]. Although specific data for entrectinib are lacking, evidence from other tyrosine kinase inhibitors suggests that this weight gain is primarily driven by an increase in adipose tissue [3]. Excess fat is a recognized risk factor for cardiovascular and metabolic diseases, and it may negatively impact patients' overall well‐being, but also compromise the continuation of oncological treatment [4, 5]. Regarding management, limited data from patients treated with TRK inhibitors indicate that pharmacologic interventions may stabilize or slightly reduce weight [4]. A strong rationale supports the introduction of exercise in the amelioration of this side effect. Data from meta‐analyses indicate that exercise during cancer treatment may help to significantly preserve lean mass and attenuate fat gain [6, 7], thereby potentially counteracting adverse changes in body composition from entrectinib. However, no information is currently available on targeted modulation of body composition beyond body weight and non‐pharmacological strategies, such as exercise, in patients with NTRK fusion‐positive NSCLC. We present the case of a patient with NTRK fusion‐positive NSCLC undergoing entrectinib treatment who participated in a structured 2‐year exercise program, focusing on its impact on body composition.
1.1
Case Presentation
In May 2023, a 42‐year‐old patient with no relevant comorbidities presented with a persistent dry cough. Computed tomography (CT) scans revealed a 3 × 5 cm lesion in the left lower lobe, accompanied by mediastinal lymphadenopathy and bilateral pulmonary metastases, also confirmed by a positron emission tomography. In June 2023, a CT‐guided biopsy confirmed the diagnosis of lung adenocarcinoma harboring an NTRK gene fusion. Next‐generation sequencing (NGS) on liquid biopsy confirmed the SQSTM1‐NTRK1 fusion mutation. At baseline, the Eastern Cooperative Oncology Group (ECOG) performance status was 0, and the patient did not report weight loss. Treatment with entrectinib was initiated in July 2023 with early symptoms benefit (cough resolution) and concurrently, a physical exercise program was offered to preserve the patient's physical function and quality of life (QoL). Subsequent CT scans have consistently shown a marked reduction in the size of both the primary tumor and metastatic lesions, with sustained therapeutic benefit observed and without dose reductions or treatment interruptions to date.

1.2
Intervention
The exercise prescription is detailed in Figure 1 and was based on the current recommendations [8]. Overall, the intervention consisted of aerobic and resistance training twice a week, organized in macrocycles, and supervised by exercise specialists. This exercise frequency was selected based on the patient's availability, aiming to balance training demand and his adherence to avoid an overly burdensome schedule that could increase the risk of dropout. Despite its practicality, this frequency, as reported by le literature, still provides an adequate training stimulus to improve physical function and preserve muscle mass while minimizing patient burden, travel demands, and interference with oncologic care. Assessments occurred at the end of each macrocycle and included the following parameters: resting blood pressure and heart rate, functional capacity, muscle strength, flexibility, QoL, circulatory parameters (from medical records), body weight, and body composition via bioimpedance (BIA). Additionally, body composition was evaluated via routine staging CT scans at the third lumbar vertebra at the timepoints when the timing of assessments matched. Detailed descriptions of intervention and assessments are provided in the Supporting Information.

1.3
Results
Over the 2‐year intervention, exercise adherence was 91.6%, with only two mild AEs (nausea). Missed sessions were due to vacations and medical check‐ups. Figure 2 and Tables S1 and S2 show the results of weight, body composition, physical fitness, QoL domains and symptoms. From baseline, body weight increased by 12.65 and 13.05 kg at the 1st and 2nd evaluations, respectively, and then decreased, ranging from 2.85 to 3.60 kg, over the subsequent assessments. Body composition analysis revealed that the initial gain of body weight was nearly equally due to an increase in fat and muscle mass (1st assessment: BIA: +4.7 kg muscle, +5.65 kg fat; 2nd assessment: BIA: +4.5 kg muscle, +6.25 kg fat; CT scan: +26.0 cm2 visceral adipose tissue [VAT], +54.9 cm2 subcutaneous adipose tissue [SAT], +10.0 cm2 skeletal muscle [SM]). A reduction was reported at the 3rd evaluation for both components (BIA: +4.1 kg muscle, +3.37 kg fat; CT scan: +17.0 cm2 VAT, +45.0 cm2 SAT, +4.7 cm2 SM) and then fluctuations were observed, resulting in an overall major gain in muscle mass compared to fat tissue (8th evaluation: BIA: +4.1 kg, +3.27 kg fat) at the end of the intervention. The reduction was less evident with the CT scan (CT scan: 0.0 cm2 VAT, +35.1 cm2 SAT, +9.7 cm2 SM). Functional capacity and flexibility improved, while strength slightly declined. Some QoL domains improved (role, emotional, social functioning and insomnia), other symptoms slightly worsened (fatigue, pain, constipation, diarrhea). All these changes exceeded the corresponding minimally important difference (MID) thresholds. (Supporting Information).

2
Discussion
Entrectinib may lead to weight gain, at least partially related to hyperphagia, by inhibiting hypothalamic TrkB receptors, which are typically activated by brain‐derived neurotrophic factors that promote satiety (Figure 3A,B) [9]. This imbalance inevitably leads to an increase in energy intake, resulting in a rapid weight increase. In this case, the patient gained 11 kg over approximately 9 months from the entrectinib initiation. However, compared to prior reports, which described an accumulation mainly in the adipose tissue, we found that about half of the increase occurred in muscle mass. This could have been mediated by exercise. Muscle hypertrophy requires both mechanical stimulus and a positive energy balance, indeed. Therefore, exercise, combined with entrectinib‐induced hyperphagia, may have created the optimal anabolic environment for this initial and rapid lean mass gain. Nevertheless, given the sustained caloric surplus, some degree of fat accumulation is physiologically unavoidable and was also documented in this case.
Moreover, beyond this initial modulation of body composition, a structured exercise resulted in being effective in the long‐term control of this AE. Indeed, after the initial peak of gain, the patient gradually lost weight, approximately 3.45 kg, primarily due to fat loss. Although the data reported by CT and BIA show slightly different body composition values, this was probably due to the high specificity of training, which was primarily targeted at the limbs. However, the observed weight change is of utmost relevance, especially considering that weight gain induced by TRKs typically increases over time, and that pharmacological interventions often result in stabilization of weight, and their impact on body composition change remains to be defined [4]. From this perspective, exercise may help manage long‐term entrectinib‐induced weight gain in several ways: regulating appetite, increasing energy expenditure through exercise, improving metabolic adaptations, and enhancing basal metabolism through muscle mass gain (Figure 3C). A prior study in patients treated with ALK tyrosine kinase inhibitors describes a similar weight gain. In a retrospective cohort of 53 ALK+ NSCLC patients receiving alectinib, de Leeuw et al. reported a median weight increase of +9.6 kg after 12 months of treatment. Detailed body‐composition assessment by CT demonstrated that such gain was primarily due to an increase of VAT, +39%, and SAT +33%, with a slight decline in SM, −0.4% [3]. In our case, the 2 years of intervention resulted in an overall increase of +33% of SAT, +5.7% of SM, and no changes in VAT, supporting the hypothesis that long‐term exercise can manage body composition trajectories during TRK inhibitor therapy.
Moreover, beyond the impact on body composition, the intervention demonstrated improving functional capacity and maintaining several high QoL domains. On one side, the maintenance and even improvement in several QoL domains observed in this case mirror findings from the STARTRK‐2 global phase II/III study, in which patients with NTRK‐fusion positive solid tumors or ROS1‐fusion positive NSCLC receiving entrectinib reported moderate‐to‐high baseline functioning and health‐related QoL scores that were either improved or maintained over time [10]. In our case, improvements in role, emotional, and social functioning, alongside reduced insomnia, are consistent with this trajectory and further support that integrating exercise into the management of patients on long‐term targeted therapy may reinforce these favorable QoL outcomes. On the other hand, the improvement in the 6‐min walking test by 34.9 m over the intervention period may have important clinical implications. In this sense, a decline of ≥ 50 m in this test is associated with an increased mortality risk in patients with NSCLC [11], and, additionally, it is also known that functional capacity usually deteriorates during systemic therapy [12]. The observed increase is in line with prior evidence testing exercise in patients with NSCLC [12], and further reinforces the potential of such intervention in maintaining long‐term cardiorespiratory fitness during systemic treatments.
This study has some limitations that should be acknowledged. As this is a single case report, the generalizability of the findings is limited, and some lifestyle‐related variables were not comprehensively captured. In this sense, data on unsupervised physical activity and longitudinal dietary intake were not systematically monitored, which may limit the interpretation of body‐composition changes. Future studies could evaluate the effects of a combined exercise and nutritional intervention to better elucidate their impact on body composition.

3
Conclusion
We report a unique case of a patient with NTRK fusion‐positive NSCLC, in which 2 years of structured exercise resulted in an overall long‐term mitigation of entrectinib‐induced weight gain and favorably influenced body composition.

Author Contributions

Alice Avancini: conceptualization, supervision, investigation, methodology, resources, writing – review and editing, writing – original draft, visualization. Marco Sposito: investigation, methodology, resources, writing – review and editing, writing – original draft, visualization. Gloria Adamoli: investigation, methodology, resources, writing – review and editing, writing – original draft, visualization. Anita Borsati: validation, writing – review and editing. Christian Ciurnelli: validation, writing – review and editing. Ilaria Mariangela Scaglione: validation, writing – review and editing. Serena Eccher: validation, writing – review and editing. Linda Toniolo: validation, writing – review and editing. Daniela Tregnago: validation, writing – review and editing. Lucia Longo: validation, writing – review and editing. Jessica Insolda: validation, writing – review and editing. Michele Milella: validation, writing – review and editing. Federico Schena: validation, writing – review and editing. Sara Pilotto: conceptualization, supervision, investigation, methodology, resources, writing – review and editing, writing – original draft, visualization. Lorenzo Belluomini: conceptualization, supervision, investigation, methodology, resources, writing – review and editing, writing – original draft, visualization.

Consent
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.

Conflicts of Interest
The authors declare no conflicts of interest.

Supporting information

Supporting Information: 1 Description of the exercise intervention.

Supporting Information: 2: Description of assessment methods and tools.

Table S1: Absolute scores of physical fitness parameters, quality of life domains, and symptoms scale.

Table S2: Circulatory parameters.