Comprehensive management of MET tyrosine kinase inhibitor-induced peripheral edema in patients with MET-altered non-small-cell lung cancer: a narrative review

Introduction

Mesenchymal-epithelial transition factor (MET), also known as c-MET, is a proto-oncogene located on chromosome 7q21-q31 that encodes transmembrane receptor tyrosine kinase normally expressed on epithelial cells. The hepatocyte growth factor (HGF)/c-MET pathway is essential in several cell vital processes, including carcinogenesis and tumor progression. In non-small cell lung cancer (NSCLC), multiple MET alterations have been discovered, among which MET exon 14 skipping (METex14), MET-amplified (METamp) and MET protein overexpression after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance have attracted increased attention. These alterations may aberrantly activate MET oncogenic signaling pathway and promote tumor development (1). MET TKI has demonstrated the dramatic efficacy in patients with MET-altered NSCLCs (1).

MET TKIs are classified into three types: type I inhibitors compete with adenosine 5’-triphosphate (ATP) for the ATP binding pocket of the active form of MET, which can be further subdivided into non-selective type Ia inhibitors (e.g., crizotinib) and selective type Ib inhibitors (e.g., capmatinib, tepotinib, savolitinib, vebreltinib and glumetinib); type II inhibitors (e.g., cabozantinib), also ATP competitors, bind to the inactive conformation of MET; type III inhibitors are non-ATP competitors. Currently, only type Ib MET TKIs are approved for advanced NSCLC (aNSCLC) patients with METex14 (2).

Since the approval of tepotinib in Japan in March 2020, multiple MET TKIs have been approved worldwide, especially in China, where four MET TKIs have been approved. As MET TKI become widely used in clinical practice, peripheral edema (PE), one of the most common adverse events (AEs) reported in clinical trials, has attracted growing attention from clinicians and patients (3). Because PE is common in cancer patients and not necessarily caused by antitumor drugs, antitumor drug-related PE is usually difficult to define and is highly susceptible to misdiagnosis or under-recognition. In this review, by summarizing the relevant literature, we describe the incidence, potential pathophysiological mechanism, diagnosis, and comprehensive management of MET TKI-induced PE to improve recognition and standardize the management of PE. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-866/rc).

Methods

Literature search was conducted on PubMed, Wanfang Med Online, China National Knowledge Infrastructure (CNKI), and the official website of American Society of Clinical Oncology (ASCO), World Conference on Lung Cancer (WCLC), American Association for Cancer Research (AACR), Chinese Society of Clinical Oncology (CSCO) and European Society for Medical Oncology (ESMO) for publications from January 1, 2000, to December 31, 2023. Various relevant search terms were used, including non-small cell lung cancer, MET inhibitor, crizotinib, capmatinib, INC280, savolitinib, volitinib, AZD6094, HMPL-504, tepotinib, gumarontinib, glumetinib, SCC244, bozitinib, vebreltinib, APL-101, PLB-1001, CBT-101, supportive care, treatment, management, AEs and edema. The literature was limited to systematic reviews, meta-analysis, clinical studies and conference abstracts. The reference lists of identified studies were screened and reviewed (Table 1, Figure 1). Based on the evidence from published studies and the authors’ clinical experience, we performed this literature review of the comprehensive management MET TKI-induced PE in patients with MET-altered NSCLC.

Figure 1 Diagram of literature searches conducted in January 2024. AACR, American Association for Cancer Research; ASCO, American Society of Clinical Oncology; CSCO, Chinese Society of Clinical Oncology; CNKI, China National Knowledge Infrastructure; ESMO, European Society for Medical Oncology; WCLC, World Conference on Lung Cancer.

Incidence of PE in clinical trials

The exploration of MET TKI in MET-altered NSCLC mainly involves patients receiving MET TKI monotherapy or combination therapy with EGFR TKI. The results of the MET TKI monotherapy trials demonstrate that PE is one of the most common AEs, with an incidence of 10–74%, mostly mild-to-moderate (grade 1/2). Severe PE (grade ≥3) can occur in up to 13% of patients. The incidence of PE caused by type Ia inhibitors is relatively low, but type Ia inhibitors have not yet been approved globally for treating MET-altered NSCLC. Among patients treated with MET TKI plus EGFR TKI, the incidence of PE is 16% to 63.3% (Table 2). Interestingly, the incidence of PE in patients receiving tepotinib combined with EGFR TKI was lower than that in patients receiving tepotinib monotherapy, which may be related to the younger age of patients enrolled in the combination group (42), but the exact reasons need to be further explored.

MET TKI monotherapy

In the phase I dose-escalation trial of tepotinib, PE was one of most common treatment-related AEs (TRAEs) in patients with advanced solid tumors. Among 42 patients who received tepotinib with a recommended phase II dose (RP2D), 26.2% and 2.4% had any grade and grade ≥3 PE, respectively (4). In VISION trial of tepotinib in patients with MET-altered NSCLC, PE was the most common TRAE, reported in 67.1% of patients with METex14, and 11.2% of patients had grade ≥3 PE (5). In a pool analysis of 228 patients with advanced solid tumors treated with tepotinib, including 81 Asian patients, PE occurred in 33.8% of patients overall and in 24.7% of Asian patients (grade ≥3: 3.5% and 0%, respectively) (43). PE was mostly grade 1/2 and the incidence was essentially the same irrespective of patient characteristics (44).

PE was the most frequently reported AE in phase I clinical trials of capmatinib (also known as INC280) for advanced solid tumors (10-12). This result was replicated in GEOMETRY mono-1 study and GeoMETry-III trial (13,16). In the real-world RECAP study of capmatinib, PE was also the most common TRAE in patients with METex14 aNSCLC, 13% of patients had grade 3/4 PE and led to dose reduction in 23 patients (28%), treatment interruption in 10 patients (12%), and treatment discontinuation in 6 patients (7%) (17). In another real-world IFCT-2104 CapmATU study of capmatinib for METex14 NSCLC patients, PE was the most common TRAE of grade ≥3, occurring in 8.2% of patients, and 18 patients were discontinued due to toxicity, with edema accounting for 66.7% of the patients (18).

In two phase I trials of savolitinib (also known as volitinib, AZD6094 or HMPL-504) in patients with advanced solid tumors, treatment-related PE (TRPE) was reported in 23% and 21% of patients (19,20). In the phase II and phase IIIb confirmatory trials of savolitinib for METex14 aNSCLC, PE occurred in 56% and 59.8% of patients respectively (21,22). In the pivotal phase II global trial of glumetinib (also known as gumarontinib or SCC244) in patients with METex14 aNSCLC, the most common TRAE was edema (80%), with 62 (74%) patients having PE (23). In two studies of vebreltinib (also known as bozitinib, APL-101, PLB-1001 or CBT-101) for MET-altered aNSCLC and solid tumors, TRPE was observed in 32.4% and 24% of patients (24,25). KUNPENG trial was a pivotal phase II study of vebreltinib in patients with MET-altered aNSCLC, and PE was the most common TRAE of any grade (56.6%) and grade ≥3 (7.1%) (26).

For crizotinib and ensartinib, only preliminary explorations have been conducted. In PROFILE 1001 trial for METex14 NSCLCs (27,28), METROS trial for METex14 or METamp patients (29), edema occurred in 31% of patients, and AcSé trial for METamp or MET-mutated patients demonstrated the similar safety profile of crizotinib (30). In the study of ensartinib for METex14 NSCLC, 10% of patients had TRPE (31).

MET TKI combined with EGFR TKI

METamp is an important mechanism of EGFR TKI resistance in EGFR mutation (EGFRm) NSCLC. MET TKI plus EGFR TKI is an effective therapy to overcoming MET mediated resistance.

The efficacy and safety of tepotinib plus gefitinib or osimertinib of EGFRm NSCLC patients with METamp were explored in INSIGHT (32) and INSIGHT2 studies (33). PE was one of the most common TRAEs in both studies, occurring in 29% and 40.6% of the patients respectively (grade ≥3: 6.5% and 4.7%).

In a phase Ib/II study of capmatinib plus gefitinib in patients with EGFRm, METamp NSCLC after progression on EGFR TKIs, the incidence of TRPE was 22% (34). In another study of capmatinib plus erlotinib for MET-altered aNSCLC, the incidence of TRPE was 37% (35).

Currently, several studies on savolitinib plus EGFR TKI have been published. In a phase Ib study of savolitinib plus gefitinib, TRPE occurred in 16% of the patients (36). The efficacy and safety of savolitinib in combination with osimertinib in patients with aNSCLC have been explored in the TATTON, SAVANNAH, and ORCHARD trials. In cohort B, cohort C, and cohort D of the TATTON study, the incidence of TRPE was similar (31–36%) and rarely for grade ≥3 (0–3%) (37,38). This result was subsequently validated in the SAVANNAH study (39) and ORCHARD study (40). Interestingly, in cohort B and cohort D of the TATTON study, five patients experienced osimertinib-related PEs, but these AEs were not reported in the previous AURA3 study (45), FLAURA study (46), and ADAURA study (47). Therefore, the role of osimertinib in the development of PE is unclear. So far, only a phase Ib/II study of glumetinib plus osimertinib has been published, where edema was the most common TRAE, with a high incidence of grade ≥3 of 10% of patients (41).

Factors and potential mechanisms of MET TKI-induced edema

PE is the result of a perturbation in fluid homeostasis among the vascular, lymphatic, and interstitial spaces. Many drugs can cause PE via multiple synergistic mechanisms, the main ones being: increased capillary permeability (permeability edema), sodium/water retention (renal edema), lymphatic insufficiency (lymphedema) and precapillary arteriolar vasodilation (vasodilatory edema) (48). Despite the high incidence of MET TKI-induced PE, the exact mechanism has not been elucidated, and may be related to the following mechanisms.

Increased capillary permeability

MET TKI-induced edema is most likely due to increased vascular permeability. In physiological conditions, HGF in the vascular endothelium helps to protect vascular endothelial cells from vascular endothelial growth factor (VEGF)-induced endothelial cell hyper-permeability. MET TKI action on the HGF/MET signaling pathway may disrupt this balance, leading to increased endothelial cell permeability, as well as promoting edema development (48). A study in healthy volunteers treated with capmatinib demonstrated that the drug was largely distributed to the peripheral tissues, which could contribute to the development of PE (49). Alao MET inhibition could reduce the proteasomal degradation of VEGFR2 and increases its expression, leading to increased permeability (44,50).

Effect on renal function

Another potential mechanism of MET TKI-induced edema is through effects on renal function. Elevated serum creatinine levels during treatment have been observed in several clinical trials of MET TKIs, and the effect appears to be dose-dependent (3,5). However, serum creatinine level is influenced by a number of factors, in addition to glomerular filtration, and it can also be affected by active renal tubular secretion and clearance of renal transport proteins, such as multidrug and toxic extrusion (MATE) transporter proteins and organic anion transporter (51). The increase in creatinine observed during capmatinib or tepotinib treatment could be due to the inhibition of the MATE proteins 1 and 2-K (3,52). Therefore, elevated serum creatinine is not necessarily a marker of impaired renal function, and data from several studies also demonstrated that MET TKI-induced elevated serum creatinine does not seem to be accompanied by clinically meaningful renal impairment (53,54). In the GLORY study of glumetinib, 13 patients with elevated serum creatinine developed edema, yet 81% of patients with edema did not have elevated serum creatinine, suggesting that elevated serum creatinine may not be the primary mechanism of edema, but the effects on renal function may exacerbated the development of edema in some patients (23).

Hypoalbuminemia

Hypoalbuminemia is another common AE during MET TKI treatment and may be an independent risk factor for edema pathogenesis (55). The mechanism of MET TKI-related hypoalbuminemia is not fully understood but may be due to that MET TKI blocks the HGF pathway in albumin production in hepatocyte (23). To date, there is no clear evidence that MET TKI-induced hypoalbuminemia is secondary to hepatic or renal impairment. Studies have demonstrated that the serum albumin level is correlated with the risk and severity of edema, and there is also a significant positive trend between the magnitude of serum albumin decline and the severity of edema, with more severe edema observed in patients with the greatest reduction in serum albumin (55).

The exact mechanism of MET TKI-induced PE is not well defined and may be related to one or more potential mechanisms. In cancer patients, the mechanisms of edema are more complex and may be the result of synergistic effect of multiple etiologies and mechanisms.

Clinical manifestations and diagnosis of MET TKI‑induced PE

Clinical manifestations

MET TKI-induced edema is predominantly PE, which can manifest as edema of peripheral tissues, such as the face and extremities. Swollen extremities are the most bothersome symptom for patients, followed by pain and weight gain, and some patients may also have sensory abnormalities and skin infections. Patients with severe PE are more likely to have pain and skin lesions than those with mild-to-moderate PE (56).

MET TKI-induced edema may not be immediately symptomatic, and the time to onset and time to remission may differ across agents. In the GEOMETRY mono-1 study of capmatinib, the median time to first grade ≥2 PE was 3.5 months, and the median time to first grade 3/4 PE was 5.0 months (57). Crizotinib-induced edema occurred at approximately 2 months, and the median time from therapy initiation to the onset of edema with savolitinib was 50 days (58,59). For tepotinib, the median time to first onset of edema was 7.9 weeks and 18.9 weeks for grade 3 edema (44). The median time from the first dose of glumetinib to the onset of edema was 42 days, and the median time to the onset of grade 3 edema was 75 days (23). When patients were treated with tepotinib combined with EGFR TKI, the median time to onset of PE of any grade was 12.1 weeks in the INSIGHT study and 9.9 weeks in the INSIGHT2 study (42).

MET TKI-induced edema was more common in elderly. In the GEOMETRY mono-1 trial, 84% of patients with METex14 NSCLC who developed PE were older than 65 years (52). This phenomenon may be related to the fact that METex14 is more common in older patients (60). Advanced age was an independent risk factor for the development of edema in patients treated with tepotinib and was not associated with drug exposure (55). In the VISION study, the incidence of edema was higher in patients aged ≥65 years than in those aged <65 years, and also the incidence was higher in patients aged ≥75 years than in those aged <75 years (44). White patients, a high body mass index (BMI), low mobility and time on treatment were also reported as common risk factors for PE (44,56).

Diagnosis

The etiology of edema is complex, a comprehensive medical history should be taken when PE appears in order to facilitate diagnosis, and that includes: the timing of PE, unilateral or bilateral, whether PE changed with body position and accompanied by other systemic disease, and patient medication history. Acute edema is commonly associated with deep venous thrombosis (DVT), cellulitis, and acute compartment syndrome from trauma, whereas the chronic generalized edema is due to the onset or exacerbation of chronic systemic conditions, such as congestive heart failure (CHF), renal disease, or hepatic disease. Edema caused by venous insufficiency is more likely to be found in low-hanging parts of the body and can vary with position. Unilateral edema is often caused by impaired venous or lymphatic drainage, commonly due to DVT, venous insufficiency, venous or lymphatic obstruction secondary to the tumor or filariasis. Bilateral or generalized swelling usually suggests a systemic cause (61) (Figure 2A).

Figure 2 Comprehensive management of MET TKI-induced peripheral edema. Algorithm for the differential diagnosis (A) and clinical management of MET TKI-induced peripheral edema (B). CTCAE, Common Terminology Criteria for Adverse Events; DVT, deep venous thrombosis; MET, mesenchymal-epithelial transition factor; PE, peripheral edema; TKI, tyrosine kinase inhibitor.

MET TKI-induced PE should be considered in patients who develop or experience a significantly worsening of PE during MET TKI treatment. Therefore, the diagnosis of MET TKI-induced PE should include a clear history of MET TKI administration and PE-related clinical symptoms temporally associated with therapy (3,59). At the same time, relevant laboratory tests and examinations should be performed to exclude other diseases, such as cardiac disease, renal disease, hepatic disease, endocrine disease, and DVT (61) (Figure 2A). PE should be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 (Table 3).

Comprehensive management of MET TKI-induced PE

Although not life-threatening, MET TKI-induced edema can negatively impact quality of life (QoL) and treatment adherence, and once edema develops, it is long-lasting and difficult to relieve (44). Real-world experience has shown that the resolution time for PE is up to 3 months in patients with mild-to-moderate PE and up to 6 months in patients with severe PE (56). Therefore, it is crucial to manage PE comprehensively, which includes prevention, early recognition and timely intervention. PE can be prevented or alleviated by lifestyle intervention or physical therapy before onset or for grade 1/2; for grade 3 PE, pharmacological intervention may be required by the clinical judgment (59) (Figure 2A).

Prevention

Before initiating MET TKI treatment, patients and their families should be informed of the possible risk of edema. PE can be monitored at the beginning and in the course of MET TKI treatment by proactively measuring body weight, limb circumference, and detecting whether limb swelling or skin erosions is present, which is conducive in reducing clinical symptoms due to PE exacerbation, such as pain, paresthesia, and skin infections.

Non-pharmacological treatment

Non-pharmacological interventions, including lifestyle intervention or physical therapy, such as low-salt and light diet, moderate exercises, raising the limb swelling, wearing elastic stockings, lymphatic massage, are recommended for patients with mild-to-moderate PE to alleviate symptoms, one or more interventions may be used based on the grade of PE (3,59).

Pharmacological treatment

When patients develop severe edema, diuretics can be used according to clinical judgment. Severe PE can lead to hypovolemia and special attention must be paid when using diuretics to avoid excessive diuresis, worsening of renal hypoperfusion and acute renal injury. Therefore, it is recommended that daily weight loss should be ≤0.5 kg, especially in elderly patients. In patients who already have renal insufficiency, potassium-sparing diuretics and osmotic diuretics should be used with caution. When the estimated glomerular filtration rate is less than 30 mL/min, the diuretic effect of thiazide diuretics is poor, and loop diuretics are recommended. For patients with PE combined with hyponatremia, tolvaptan can be considered, but currently there is a lack of evidence-based medical proof from large sample studies. During the application of diuretics, attention should be given to maintaining the electrolyte and acid‒base balance, alerting to AEs such as hyponatremia, hypokalemia and hypotension, and the dosage should be adjusted timely (59). Pain is an important symptom of PE, especially for severe PE, and appropriate analgesic drugs can be used according to the patient conditions (56). Pharmacological treatment can only temporarily alleviate the symptoms, and if PE is to be eliminated, it is necessary to rely on the dose adjustment of MET TKI, such as dosage reduction and temporary interruption of treatment.

Dosage modifications for MET TKI

Among patients treated with MET TKI, the majority of patients had mild-to-moderate PE, and only a small proportion required treatment interruption or discontinuation. Patients with grade 1/2 PE can continue therapy, whereas treatment for patients with grade 3 PE should be interrupted until edema recovers to grade 1 or below, therapy is then resumed at a reduced dose. If PE failed to recover to grade 1 or below, permanent discontinuation of the therapy is needed (3,59) (Table 3). The dose adjustments for different MET TKIs are presented in Table 4. When patients are treated with MET TKI in combination with other regimen (e.g., EGFR TKI), MET TKIs are similarly modified in the following regimens.

Since PE is a class effect, changing to another MET inhibitor is unlikely to be beneficial. Reducing the dose and/or interrupting treatment, including taking frequent short breaks, seems to be the most effective approach for managing edema and should be initiated early to minimize its severity (44). A temporary pause in treatment, as opposed to reducing the dosage, might be a more effective strategy for addressing edema (55). When MET TKI-induced PE occurs, patients should be managed according to clinical symptoms and the grade of PE as soon as possible.

Future directions

Patients receiving MET TKIs often face PE as an adverse reaction, with its high incidence becoming an issue of significant concern in clinical practice. The present review provides comprehensive insights into MET TKI-induced PE, including its potential molecular mechanisms, diagnostic criteria, and management strategies. Further research into the molecular mechanisms and the management strategies is necessary to enhance the treatment of MET TKI-induced PE. This includes preclinical studies on mechanisms and clinical studies on innovative management approaches. A survey reveals two primary challenges in the management of MET TKI-induced PE: firstly, the lack of effective treatment strategies; secondly, the inadequate understanding of the complex interaction mechanisms between PE and MET TKIs (56). Addressing these unmet needs, future directions in the management of MET TKI-induced PE may involve exploration and innovation across multiple frontier areas.

Firstly, researchers will embark on an in-depth exploration of the molecular mechanisms underlying PE. They will utilize molecular biology tools to elucidate the key molecules and signaling pathways involved in PE. This process not only expands the boundaries of basic science but also establishes a robust theoretical foundation for the development of novel and precise therapeutic agents. Simultaneously, continued enhancements in the chemical composition of MET TKIs by pharmaceutical companies, or the finding of efficacious practical therapeutic observed in clinical practice, will result in a comprehensive solution to MET TKI-induced PE. Finally, enhancing patient education is recognized as a pivotal measure to elevate the management of MET TKI-induced PE. To address gaps in patient awareness in this area, some educational resources may aid patients in developing accurate understanding. Additionally, with the development of telemedicine and digital health technologies, the management tools may undergo revolutionary changes, such as mobile applications, will provide real-time feedback and foster close interaction between patients and physicians.

Conclusions

MET TKIs provide a new treatment option for patients with MET-altered NSCLC (62). PE, a common adverse event of MET TKI, has a high incidence but is generally mild-to-moderate in most patients. However, if PE is not treated in a timely manner and develops into severe PE, the duration time will be prolonged, and become difficult to manage, which is likely to have a negative impact on patients’ QoL and treatment adherence. Therefore, once MET TKI-induced edema occurs, we should actively perform a comprehensive management including non-pharmacological treatment, pharmacological treatment and dosage modifications (Figure 2B), which are essential for alleviating patients suffering and reinforcing treatment adherence.

Acknowledgments

Medical writing assistance and figure processing for this manuscript was provided by Yafang Zhang, of Merck Serono Co., Ltd., Beijing, China, an affiliate of Merck KGaA.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-866/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-866/prf

Funding: This work was funded by the National Natural Science Foundation of China (No. 82202997 to S.Y.M.L.) and Guangdong Provincial Key Lab of Translational Medicine in Lung Cancer (No. 2017B030314120 to Y.L.W.).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-866/coif). Y.L.W. reports the grants from AstraZeneca, BMS, and Pfizer and speaker fees from Roche, AstraZeneca, Eli Lilly, Boehringer Ingelheim, Sanofi, MSD, Hengrui, Pfizer, and BMS. 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.

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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