Hypoalbuminemia, pleural effusion... MET-TKI adverse event management method, do you know?

*Only for medical professionals to read and reference, learn quickly! Targeted therapy plays an important role in the comprehensive treatment of non-small cell lung cancer (NSCLC)
.

In recent years, in addition to the classic EGFR, ALK, ROS and other well-researched driver gene targets, the targeted therapy of mesenchymal epithelial transition factor (MET) exon 14 (MET ex14) skipping mutations has also achieved impressive results.
Notable results
.

As the fourth most common type of gene mutation in NSCLC, MET ex14 skipping mutation is common in elderly patients and is significantly associated with poor prognosis of patients
.

With the approval of MET tyrosine kinase inhibitors (MET-TKIs), the therapeutic prospects of MET ex14 skipping mutations have become increasingly clear, and the management of adverse events (AEs) of these drugs has become increasingly important
.

Overview of MET-TKI drugs At present, there are four related drugs that can be used to target MET ex14 skipping mutation treatment at home and abroad, namely crizotinib, capmatinib, tepotinib and sivotinib, among which gram Zotinib is a type Ia small-molecule inhibitor, while capmatinib, tepotinib, and sivotinib are type Ib small-molecule inhibitors
.

The latter has stronger inhibitory effect and lower off-target rate than the former [1, 2] (Fig.
1)
.

Figure 1 Clinical research and efficacy evaluation of MET-TKI, a drug targeting MET ex14 skipping mutation (95%CI 36%-57%), the duration of efficacy was about 1 year (median 11.
1 months)
.

Data analysis based on data from the benefit population-based cohort (n=275) showed that the population-based independent review objective response rate (ORR) was 49.
1% (95% CI 43.
0%-55.
2%), and the duration of response was 13.
8 Month (95%CI 9.
9-19.
4)
.

2.
Capmatinib: The results of the GEOMETRY mono-1 study [5, 6] showed that among the 128 patients included in the analysis, the ORR was 41% (95%CI 29%-53) for patients who had received prior first- or second-line therapy.
%), while the ORR was 48% (95%CI 30%-67%) and 68% (95%CI 48%-84%) for patients who had received only first-line therapy and naïve patients, respectively
.

The results of the subsequent study showed that the ORR of independent review was 44.
0% (95% CI 34.
1%-54.
3%) for patients who had previously received first- or second-line therapy (n=100), while the ORR for treatment-naïve patients (n=60) was 44.
0% (95% CI 34.
1%-54.
3%).
was 66.
7% (95%CI 53.
3%-78.
3%)
.

3.
The results of the savatinib NCT02897479 study [7] showed that the ORR of the patients included in the efficacy analysis (n=70) was 42.
9% (95%CI 31.
1%-55.
3%)
.

4.
The results of the crizotinib PROFILE 1001 study [8, 9] showed that the ORR of patients included in the efficacy analysis (n = 65) was 32% (95% CI 21%-45%)
.

Table 1: Overview of clinical studies of major targeted drugs for MET ex14 skipping mutations Open-label, single-dose, multi-center open-label, single-dose, multi-center open-label, multi-center open-label, multi-dose, multi-center Primary completion time 2021-122022-022021-122020-07 Total 33736476596 Treatment regimen 500 mg OD21 days A course of 400 mg BID for 21 days for a course of 400 mg (<50 kg) or 600 mg (≥50 kg) for OD21 days for a course of 250 mg BID for 28 days for a course of treatment Main outcome indicators Objective response rate (ORR) Objective response rate (ORR) Objective response rate ( ORR) Objective response rate (ORR) AEs of MET-TKI should not be ignored The overall AE rates of currently available clinical MET ex14 skipping mutation-targeted drugs are roughly the same, and common AEs mainly include fluid retention (peripheral edema, Pleural effusion), hypoalbuminemia, abnormal liver enzymes (ALT/AST elevation), gastrointestinal reactions (nausea, vomiting, diarrhea, etc.
), etc.
Common AEs and their incidence are shown in Table 2
.

Table 2 MET ex14 skipping mutation-targeted drugs Common AEs Drugs Total AE incidences Most common common AEs Minor common AEs (incidence > 10%) Serious AEs-related drug reduction incidence AE-related drug discontinuation incidence Tepotit 89% (≥ grade 3: 28%) peripheral edema (incidence: 63%, > grade 3: 7%) nausea, diarrhea, elevated serum creatinine, hypoalbuminemia, elevated serum amylase pleural Effusion and generalized edema (incidence: 15%) 33% 11% capmatinib 88% (≥Grade 3: 46%) Peripheral edema (incidence: 50%, >Grade 3: 11%) Nausea , Elevated serum creatinine, vomiting, decreased appetite, fatigue, increased ALT Drug-associated pneumonia Not reported Not reported Peripheral edema > 25% with sivotinib (incidence: 54%; > Grade 3 incidence: 9%) Nausea, elevated ALT, elevated AST, vomiting, hypoalbuminemia, decreased appetite, abnormal liver function, and drug hypersensitivity (incidence: 24%) Not reported 14% Crizotinib 94% (≥Grade 3: 29% ) Peripheral edema (incidence: 51%; > Grade 3 incidence: 1%) visual disturbance, nausea, diarrhea, vomiting, fatigue and constipation Interstitial pneumonia 38% 7% Note: ALT: alanine aminotransferase; AST: aspartate aminotransferase How to deal with the adverse reactions of MET-TKI? [10] 1.
Characteristics of peripheral edema: ① Peripheral edema is the most common adverse reaction of MET-TKI, which is mostly delayed (ranging from 8 weeks to 5 months), and is mild to moderate edema.
in the elderly drug population
.

② The mechanism of peripheral edema is unknown, and it needs to be differentiated from edema caused by other diseases: such as cardiac, hepatic, renal edema, and local secondary lymph node edema; in addition, it needs to be differentiated from peripheral edema caused by other drugs Phase identification: such as chemotherapy, antidepressants, antihypertensive drugs, hormones, antiviral drugs,
etc.

Treatment suggestions: ① Pay attention to early prevention to avoid the reduction of drugs and the use of diuretics
.

Preventive measures include: use of leggings and stockings during medication, raising the bed, reducing salt intake, and supplementing with edema lymph node massage
.

②For patients with peripheral edema, maintain daily activities during the encouragement period and increase the amount of exercise appropriately
.

Do specific exercises while closely monitoring your skin to avoid damage
.

In addition, diuretics and lymphatic drainage (manual or mechanical) may be considered as appropriate
.

③ For patients with poor preventive and therapeutic interventions, dose reduction, interruption or intermittent dosing regimens of targeted drugs should be considered
.

2.
Hypoalbuminemia (1) Occurrence characteristics: ① The mechanism of occurrence is unknown, which may be related to the tumor patient's own blood vessel homogeneity, serum albumin level and shortened half-life
.

The decrease in plasma osmolality caused by edema induced by MET-TKI may also be one of the causes of hypoalbuminemia
.

② MET-TKI-induced hypoalbuminemia is mostly mild to moderate
.

It needs to be differentiated from hypoalbuminemia caused by abnormal liver and kidney function
.

(2) Treatment suggestions: ① For hypoproteinemia not caused by MET-TKI, timely treatment should be carried out
.

②The infusion of albumin and the use of diuretics as appropriate can help relieve the condition in the short term and prevent the deterioration of the condition
.

3.
Pleural effusion (1) Occurrence characteristics: The mechanism of pleural effusion is unknown, and a case report shows that the cytological characteristics of pleural effusion caused by MET-TKI are mainly lymphocytes [11]
.

(2) Management suggestions: ①If a patient develops pleural effusion during the use of MET-TKI, the possibility of pleural effusion due to disease progression should be excluded first
.

In addition, other anticancer therapies, such as chemotherapy and radiotherapy, may also trigger pleural effusions, which also need to be identified
.

Identification by thoracentesis and cytology is recommended
.

② It is recommended to reduce the dose of MET-TKI or interrupt the treatment for grade ≥3 pleural effusion
.

4.
Gastrointestinal reactions (1) Occurrence characteristics: Most of the gastrointestinal reactions caused by MET-TKI in the literature are mild to moderate, and the incidence rates from high to low are: mild to moderate nausea (26%).
-46%), vomiting (6%-29%), diarrhea (9%-39%) and constipation (20%)
.

(2) Handling suggestions: ① It is recommended to take MET-TKI with food to reduce gastrointestinal reactions
.

Mild to moderate gastrointestinal reactions caused by MET-TKIs generally do not require dose reduction or discontinuation, but should be considered for grade ≥3 gastrointestinal adverse reactions
.

② Attention should be paid to elderly patients with diarrhea after medication, and other incentives should be excluded
.

5.
Elevated serum creatinine (1) Occurrence characteristics: The increased serum creatinine after the use of MET-TKI is usually related to the inhibition of creatinine transporter by MET-TKI, and does not indicate renal damage
.

Under normal circumstances, taking MET-TKI will increase the serum creatinine level by 20%-25% compared with the normal baseline, mostly manifested as mild-moderate increase
.

Note: Creatinine passes through the glomerulus via drug transporters such as organic anion transporter 2 (OAT2), organic cation transporter 2 (OCT2), OCT3, multidrug toxin extrusion protein 1 (MATE1), MATE2-K, etc.
Filtration and tubular secretion into the urine [12]
.

(2) Management suggestions: ① In the first few months of treatment, the patient's renal function should be closely monitored, so that the MET-TKI drug dose can be adjusted or discontinued
.

If a patient's serum creatinine increases rapidly within a short period of time using MET-TKI, but decreases rapidly (≤1 week) and returns to normal after drug discontinuation, it usually indicates inhibition of creatinine transporter by MET-TKI rather than renal impairment
.

②It is recommended that a nephrology specialist assist in evaluation when necessary to systematically evaluate the renal function of patients
.

③ Consider using cystatin C (Cystatin C) as an indicator for monitoring renal function
.

The serum concentration of CysC is not affected by factors such as inflammation, infection, tumor and liver function, and has no relationship with age, gender, diet, body surface area, and muscle mass, and has high sensitivity and specificity
.

④ If possible, it is recommended to measure other indicators for evaluating the glomerular filtration rate, such as 51 chromium-ethylenediaminetetraacetic acid (Cr-EDTA) and 125I iodophthalate [13]
.

6.
Abnormalities of liver enzymes (1) Occurrence characteristics: Abnormalities of liver enzymes (ALT/AST elevation) associated with MET-TKI are mostly mild to moderate, and are reversible under the condition of passing
.

(2) Management suggestions: ① Closely monitor the patient's liver function during medication, and it is usually not necessary to reduce or stop MET-TKI for mild asymptomatic patients
.

② Based on evidence-based medicine, the 2015 edition of the Guidelines for the Diagnosis and Treatment of Drug-Induced Liver Injury in China [14] does not recommend the preventive use of hepatoprotective drugs to reduce the occurrence of drug-induced liver injury
.

It is recommended to strengthen biochemical tests during the use of the drug, especially the first 3 months of the drug, to detect liver damage in time and give reasonable treatment
.

7.
Interstitial lung disease (1) Occurrence characteristics: Interstitial lung disease (ILD) associated with MET-TKI medication is rare, but the disease progresses rapidly once it occurs
.

MET-TKI-related ILD needs to be differentiated from tumor progression, autoimmune ILD, and ILD caused by other drugs (eg, immune checkpoint inhibitors)
.

(2) Treatment suggestions: ① For patients with ILD caused by drugs, it is recommended to ask a pulmonology specialist to assist in diagnosis and treatment
.

② Actively improve relevant examinations, such as lung biopsy, pulmonary function test, bronchoalveolar lavage and bronchoscopy to assist in diagnosis, and initiate hormone therapy
.

8.
Other adverse reactions: Figure 2 MET ex14 skipping mutation targeting drug MET-TKI other adverse reactions Note the interaction between MET-TKI and other drugs The metabolism of MET-TKI drugs in vivo depends on cytochrome P450 enzymes in the liver (including CYP1A2 , CYP2C8, CYP3A4) and P-glycoprotein (P-gp) and other enzymes, so if the substrate drugs, inhibitors or inducers of the above enzymes are used in combination during MET-TKI medication, it may affect the efficacy of MET-TKI.

.

Table 3 Metabolic characteristics and precautions of MET-TKIs Drug metabolism characteristics Capmatinib combined with CYP3A4 and aldehyde oxidase metabolism, is a substrate of P-gp; can inhibit the metabolism of CYP1A2 substrate drugs, and may inhibit breast cancer resistance protein (BCRP), toxin extrusion transporter (MATE) 1 and MATE2K Substrate Metabolism Avoid concomitant use with moderate and strong CYP3A inducers; Avoid concomitant use with CYP1A2/BCRP/MATE 1/MATE2K substrate drugs; Substrate of CYP3A4 and CYP1A2 enzymes; uridine Diphosphoglucuronosyltransferase and aldehyde oxidase substrates; avoid concomitant use with potent CYP3A inducers; avoid concomitant use with MATE1 and/MATE2K substrate drugs; sivotinib may cause QTc prolongation, and may cause QTc prolongation with other drugs that cause QTc prolongation Crizotinib is metabolized by CYP3A and is a moderate CYP3A inhibitor; inhibits the transporter P-gp, organic cation transporter (OCT) 1 and OCT2; avoids combination with strong CYP3A inhibitors Concomitant use, with caution Concomitant use with moderate CYP3A inhibitors; avoid concomitant use with CYP3A substrate drugs Table 4 MET-TKI concomitant drug effects on drug types Butin, dexamethasone, phenytoin and carbamazepine or phenobarbital may accelerate the metabolism of MET-TKIs and reduce their plasma concentrations.
CYP1A2 inducers such as montelukast, omeprazole and moricizine are strong CYP3A4/5 Inhibitors such as ketoconazole, itraconazole, clarithromycin, voriconazole, telithromycin, saquinavir, and ritolavir may slow down MET-TKI metabolism and increase their plasma concentrations of ciproflox, a strong CYP1A2 inhibitor P-gp-inhibiting drugs such as celiac, enoxacin and fluvoxamine, amiodarone, lidocaine, nifedipine, verapamil and other P-gp substrate drugs, digoxin, etoposide, cardiotonic In addition, commonly used foods such as citrus, star fruit, grapefruit and grapefruit juice will affect the activity of cytochrome P450, so avoid eating during the medication
.

Conclusion MET-TKI is an important treatment option for NSCLC with MET ex14 skipping mutation, and its efficacy is worthy of recognition.
Although the current research evidence shows that the adverse reactions of MET-TKI are generally well tolerated, clinicians still need to use this type of drug.
Strengthen the management of its adverse reactions, pay attention to the early prevention and early treatment of adverse reactions, in order to further benefit the patients
.

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