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Address for correspondence: Alexis Cortot, Université de Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de Lille, UMR9020–UMR-S 1277–Canther, Lille, France.
Université de Lille, CHU Lille, Thoracic Oncology Department, Centre National de la Recherche Scientifique, INSERM, Institut Pasteur de Lille, UMR9020–UMR-S 1277–Canther, Lille, France
METex14 NSCLC patients are typically older with complex treatment needs.
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MET TKIs are convenient and tolerable options for patients with METex14 NSCLC.
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MET TKIs currently in use are tepotinib, capmatinib, savolitinib, and crizotinib.
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Peripheral edema is the most common adverse event for MET TKIs.
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Understanding of MET TKI safety data is needed to optimize patient management.
Abstract
MET exon 14 (METex14) skipping mutations occur in 3% to 4% of non-small cell lung cancer (NSCLC) cases. Currently, four oral MET tyrosine kinase inhibitors (TKIs) are in use for the treatment of patients with METex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib). To support optimal management of METex14 skipping NSCLC in this typically older patient population, the safety profiles of these treatment options are reviewed here. Published safety data from prospective clinical trials with MET TKIs in patients with METex14 skipping NSCLC were reviewed. Treatment-related adverse events (TRAEs) occurring in ≥ 10% of patients were reported where feasible. Guidance on clinical monitoring and management of key MET TKI TRAEs and drug-drug interactions is provided. Across the clinical trials, safety data for MET TKIs were reported for 442 patients with METex14 skipping. Peripheral edema was the most reported TRAE (50%-63% of patients; grade ≥ 3: 1%-11%), followed by nausea (26%-46% of patients; grade ≥ 3: 0%-1%). TRAEs led to dose reductions in 33% to 38% of patients and to discontinuation in 7% to 14% of patients, across the MET TKIs. Considerations on interpreting available safety data are provided, along with insights into monitoring and managing specific MET TKI TRAEs of interest and drug-drug interactions. Overall, MET TKIs are tolerable treatment options for patients with METex14 skipping NSCLC, an older population for whom chemo- or immuno-therapy may not be an effective nor tolerable option. More data regarding the effectiveness of safety interventions and management strategies are needed.
Multiple targetable molecular alterations have been identified in NSCLC, including the MET receptor, a hepatocyte growth factor (HGF) receptor tyrosine kinase.
König D, Savic Prince S, Rothschild SI. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers (Basel). 2021;13:804. doi:10.3390/cancers13040804.
MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression.
Patients with METex14 skipping NSCLC tend to be older than patients with other oncogenic drivers (e.g., epidermal growth factor receptor, KRAS, anaplastic lymphoma kinase [ALK]) or pan-negative NSCLC.
MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression.
METex14 skipping NSCLC may also be associated with a poorer prognosis compared with patients whose tumors lack the METex14 skipping mutation, at least in the absence of targeted treatments.
As such, clinicians should consider the more complex management needs of older patients, and be more sensitive to the safety and tolerability profile of different treatment options. Additionally, when deciding on the most appropriate therapy, clinicians should consider the management of any potential adverse events (AEs).
Four oral MET tyrosine kinase inhibitors (TKIs) are currently in use for treating METex14 skipping NSCLC (tepotinib, capmatinib, savolitinib, and crizotinib).
Type I MET TKIs are ATP-competitive and interact with the MET activation loop to prevent the dysregulation of the MET/hepatocyte growth factor pathway involved in the proliferation, survival, and invasion of tumor cells; type Ia inhibitors (e.g., crizotinib) interact with Y1230, the hinge and G1163, while type Ib inhibitors (e.g., capmatinib, tepotinib, and savolitinib) do not interact with G1163 but have stronger interactions with Y1230 and the hinge, resulting in higher specificity for MET and fewer off-target interactions.
Type II inhibitors (e.g., cabozantinib, merestinib, glesatinib) are also ATP-competitive, but they bind to the ATP adenine binding site. Although type II MET TKIs may have some benefit for patients with METex14 skipping NSCLC, published data is currently limited and thus they are not included in this review.
Tepotinib and capmatinib are recommended by the National Comprehensive Cancer Network (NCCN) as the preferred options for first- and second-line treatment of METex14 skipping NSCLC.
has data available in METex14 skipping NSCLC but is not approved in this setting. However, owing to its approval in metastatic NSCLC with ROS-1 or ALK gene fusions,
crizotinib is often also used in the clinic for patients with METex14 skipping NSCLC.
With the recent approval of MET TKIs for the treatment of METex14 skipping NSCLC, it is important to consider their safety profiles to identify the most suitable management options for patients. Since the introduction of Common Terminology Criteria for Adverse Events (CTCAE) and MedDRA terminology,
safety documentation across clinical trials has become more standardized owing to a harmonization of similar reported events; however, when evaluating the safety of a drug, there remain several points of consideration, such as whether reported AEs are treatment-emergent (TEAEs) or treatment-related (TRAEs), the cut-off time point for reporting AEs, and the criteria for dose reductions. Unsurprisingly, different data will be collected across several clinical trials, not all these data are published, and how published data are reported will vary considerably. For example, there was wide variability in the presenting of Phase I and II lung cancer safety data across 209 American Society of Clinical Oncology (ASCO) presentations between 2017 and 2019.
TRAEs were included in publications twice as often as TEAEs, AEs were reported across dose levels or by dose level, and few presentations defined key safety terms such as dose-limiting toxicity or serious AEs. Of note, dose-reduction strategies and denominators for laboratory tests were not defined in any of the 209 presentations reviewed.
Whilst considering these challenges, this review focuses on the published safety data for the four MET TKIs in use for the treatment of patients with METex14 NSCLC. Clinical monitoring and the management of key MET TKI TRAEs are also discussed, and guidance is provided on drug-drug interactions.
MET TKI Safety Data in METex14 Skipping NSCLC
We have focused our review on the TRAE safety data from prospective clinical trials of MET TKIs in METex14 skipping NSCLC. While the trials reviewed below used different cut-offs for presenting safety data (range, ≥ 5% to > 15%), we have for consistency opted to describe AEs (using MedDRA preferred terms) occurring in ≥ 10% of patients, where feasible. Data from case studies and other indications have been included where necessary to provide further background. In several instances, more safety data are described for crizotinib as this has been available as an NSCLC treatment option since 2012. Neutralizing MET or HGF antibodies, as well as type II MET TKIs, are not discussed in this review. Here, safety data are presented for tepotinib, capmatinib, savolitinib, and crizotinib from 442 patients with METex14 skipping across four Phase I or II clinical trials.
Patients received 500 mg tepotinib (450 mg active moiety) once daily in 21-day cycles; dose reductions to 250 mg once daily were permitted. At the primary analysis, median duration of treatment was 6.9 months (range: < 0.1-36.7), and outcomes in 99 patients from the efficacy population were reported. In these patients, median age was 74 years (range: 41-94), 55% were male, 46% had a history of smoking, 78% had an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 1, 90% had adenocarcinoma and 11% had brain metastases at baseline. The primary endpoint, objective response by independent review, was reported in 46% of patients (95% CI: 36, 57) and was consistent across all treatment lines.
Durable responses of nearly 1 year (median 11.1 months [95% CI: 7.2, not estimable]) were observed with tepotinib. Updated efficacy data, which includes data from a confirmatory cohort, have recently been presented and were consistent with the primary analysis; in this efficacy population (n = 275), objective response rate (ORR) by independent review was 49.1% (95% CI: 43.0, 55.2) and the duration of response was 13.8 months (95% CI: 9.9, 19.4).
ClinicalTrials.gov. Clinical study of oral cMET inhibitor INC280 in adult patients with EGFR wild-type advanced non-small cell lung cancer (Geometry Mono-1). https://www.clinicaltrials.gov/ct2/show/NCT02414139. Accessed March 23, 2021.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
ClinicalTrials.gov. A phase II study of HMPL-504 in lung sarcomatoid carcinoma and other non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02897479. Accessed January 6, 2022.
The most common TRAE was peripheral edema in 63% of patients (grade ≥ 3 in 7%). Other TRAEs with an incidence ≥ 10% (all grades) were nausea, diarrhea, increased blood creatinine, hypoalbuminemia, and increased amylase (Table 2). 15% of patients had serious TRAEs, the most common being pleural effusion and generalized edema. TRAEs led to dose reductions in 33% of patients (16% due to peripheral edema), and permanent discontinuation in 11% of patients (permanent discontinuation due to peripheral edema was uncommon [5%]). One patient died of respiratory failure and dyspnea secondary to interstitial lung disease (ILD), which was considered by investigators to be related to tepotinib. An exposure–safety analysis of tepotinib indicated no association with tepotinib exposure and first occurrence or severity of edema, lipase elevation, or any correlation with increased amylase or transient aspartate transaminase (AST)/alanine aminotransferase (ALT) increases; although risk of edema was associated with advanced age.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Capmatinib, another oral, ATP-competitive selective type Ib MET inhibitor, was first approved in 2020 in the US for treatment of METex14 skipping NSCLC,
ClinicalTrials.gov. Clinical study of oral cMET inhibitor INC280 in adult patients with EGFR wild-type advanced non-small cell lung cancer (Geometry Mono-1). https://www.clinicaltrials.gov/ct2/show/NCT02414139. Accessed March 23, 2021.
In the GEOMETRY mono-1 study, 364 patients with either METex14 skipping NSCLC or MET amplification were enrolled and treated with 400 mg capmatinib tablets twice daily for a 21-day cycle (the recommended Phase II dose [RP2D], either with or without fasting restrictions; a maximum of 2 dose reductions were permitted (to 300 mg twice daily, then 200 mg twice daily).
ClinicalTrials.gov. Clinical study of oral cMET inhibitor INC280 in adult patients with EGFR wild-type advanced non-small cell lung cancer (Geometry Mono-1). https://www.clinicaltrials.gov/ct2/show/NCT02414139. Accessed March 23, 2021.
In the efficacy population, 84% were over 65 years, 58% were female, 74% had an ECOG PS of ≥ 1, 60% had never smoked, 80% had adenocarcinoma and 16% had brain metastases at baseline.
ORR by independent review was 41% (95% CI: 29, 53) in patients previously treated with one or two lines of therapy, 48% (30, 67) in patients previously treated with one line of therapy and 68% (48, 84) in treatment-naïve patients. Updated analysis of the GEOMETRY mono-1 study has also been recently presented, which includes additional preliminary efficacy analyses of patients in expansion cohorts; ORR by independent review was 44.0% (95% CI: 34.1, 54.3) in patients previously treated with one or two lines of therapy (n = 100) and 66.7% (95% CI: 53.3, 78.3) in treatment-naïve patients (n = 60).
AEs, including individual TRAEs occurring in ≥ 10% of patients, were reported for all 151 patients in the primary analysis, with the duration of treatment in these patients ranging from 0.4 to 136 weeks.
TRAEs were reported in 88% of patients (grade ≥ 3 in 46%). The most common TRAE was peripheral edema in 50% of patients (grade ≥ 3 in 11%). Other TRAEs with an incidence ≥ 10% were nausea, increased blood creatinine, vomiting, decreased appetite, fatigue, and increased ALT (Table 2). Serious TRAEs occurred in 15% of patients (grade ≥ 3 in 13%), 12% of patients discontinued treatment due to TRAEs (grade ≥ 3 in 8%), and one patient died of pneumonitis, which was suspected to be treatment-related. TRAEs leading to dose reductions were not reported for METex14 skipping patients.
Capmatinib is being evaluated further in pretreated patients with METex14 skipping NSCLC in the ongoing, randomized, open-label, Phase III GeoMETry-III trial (NCT04427072) of capmatinib vs. docetaxel.
ClinicalTrials.gov. Study of capmatinib efficacy in comparison with docetaxel in previously treated participants with non-small cell lung cancer harboring MET exon 14 skipping mutation. https://clinicaltrials.gov/ct2/show/NCT04427072. Accessed March 23, 2021.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Patients received 600 mg or 400 mg savolitinib once daily in 21-day cycles; median duration of treatment was 6.9 months (interquartile range, 2.2-13.8) or 6.5 months (2.7-10.5), respectively; for 600 mg, 3 dose reductions were allowed (400 mg, then 300 mg, then 200 mg, all once daily) and for 400 mg, 2 dose reductions were allowed (300 mg then 200 mg, both once daily). For the 70 patients in the full analysis set, median age was 69 years (range: 65-75), 59% were male, 60% had never smoked, 83% had an ECOG PS of ≥ 1, 57% had adenocarcinoma, whilst 36% had pulmonary sarcomatoid carcinoma, and 21% had brain metastases at baseline. ORR (primary endpoint) was 42.9% (95% CI: 31.1, 55.3).
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
The most common TRAE was peripheral edema in 54% of patients (grade ≥ 3 in 9%). Other TRAEs with an incidence > 15% were nausea, increased ALT, increased AST, vomiting, hypoalbuminemia, and decreased appetite. Grade ≥ 3 TRAEs were experienced by 41% of patients, most frequently increased AST or ALT. Serious TRAEs were documented for 24% of patients (the most frequently reported being abnormal hepatic function and drug hypersensitivity). One patient died of tumor lysis syndrome, which was considered treatment-related. TRAEs leading to discontinuation occurred in 14% of patients; TRAEs leading to dose reduction were not reported.
Crizotinib
Crizotinib is an oral, ATP-competitive, type Ia inhibitor of MET, ALK and c-ros oncogene 1 (ROS1) approved for the treatment of ALK-positive NSCLC in 2011 and ROS1-positive NSCLC in 2016.
(Table 1; NCT00585195). Patients were treated with 250 mg crizotinib twice daily in 28-day cycles. A maximum of 2 dose reductions, to 200 mg twice daily and 250 mg once daily, was permitted. Median duration of treatment over which AE data were reported was 7.4 months. Patients in the safety population, who had received at least one dose of crizotinib, had a median age of 72 years (range: 34-91), 58% were female, 62% had a history of smoking, 72% had an ECOG PS of ≥ 1, and 84% had adenocarcinoma. ORR among evaluable patients (n = 65) was 32% (95% CI: 21, 45).
Any-grade TRAEs occurred in 94% of patients (grade ≥ 3 in 29%), with the most common TRAE being peripheral edema in 51% of patients (grade ≥ 3 in 1%). Other TRAEs with an incidence ≥ 10% were vision disorders, nausea, diarrhea, vomiting, fatigue, and constipation (Table 2). TRAEs leading to dose reduction occurred in 38% of patients, and discontinuations in 7%. One patient died of ILD, which was considered to be related to crizotinib.
Patients with METex14 skipping were also included in the MET alteration arm of the Phase II METROS study (9/26 patients; NCT02499614).
For all patients with MET alterations, the most frequent TRAEs were respiratory symptoms (including dyspnea and cough), peripheral edema, nausea, fatigue, transaminase elevation, visual disorders, and pain. The safety profile for crizotinib in PROFILE 1001 was similar to Phase III data reported in patients with ALK-positive NSCLC.
Overall, published safety data from the four MET TKIs in clinical use suggest that the most common TRAE with these treatments is peripheral edema, reported in 50% to 63% patients across the clinical trials, followed by nausea reported in 26% to 46% patients (Table 2). The most reported grade ≥3 TRAEs were increased AST (2%-13%), increased ALT (3%-10%) and peripheral edema (1%-11%). TRAEs which led to a reduction in the dose of the MET TKI, or discontinuation of the study, occurred in 33% to 38% (not reported for capmatinib or savolitinib) or 7% to 14% patients, respectively.
While these published safety data are valuable, it is equally important to consider them in the context of the clinical trial protocol and how they have been presented. For example: What was the cut-off point for presenting AEs (e.g., ≥ 5%, ≥ 10%, or ≥ 20% of patients)? What was the denominator? What was the timeframe for collecting safety data? What was the dose-reduction strategy? When did dose reductions occur? And, how might dose reductions or treatment discontinuations have affected the reported safety data? If 40% of patients had their doses halved due to TRAEs within 2 weeks of a 12-month trial, the reported 12-month safety data using the starting RP2D would be misleading. Regarding the denominator used, in an analysis of 209 lung cancer Phase I and II presentations disclosing toxicity data at ASCO between 2017 and 2019, it was unclear whether all patients, or a subset, were tested for the reported laboratory data.
Nonindustry single and multicenter studies reported reduced testosterone with crizotinib in 100% and 84% of men, respectively, who had testosterone levels checked. In comparison, the crizotinib US label reports reduced testosterone in < 1% of patients from PROFILE 1014 and 1007
Ideally, only men with evaluated testosterone levels should comprise the denominator for any reduction in testosterone from baseline levels.
Therefore, before making final treatment decisions, clinicians should consider the context for information reported in the product label or trial papers. An example of this can be taken from crizotinib. Reports published in 2014 highlighted a creatinine-driven reduction in estimated glomerular filtration rate (eGFR) with crizotinib,
Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.
but this was not added to the US label until April 2016. This was obviously not ideal for clinicians who were not experts in targeted therapies, who might have relied more on the label than publications to guide their treatment decisions. An increase in creatinine is reported in the US label for tepotinib,
Monitoring and management considerations for selected AEs are summarized in Figure 1. The sections below discuss monitoring and management considerations for AEs associated with MET TKIs that are not usually typical of other pharmacologic treatments for NSCLC, such as chemotherapy.
Figure 1Overview of monitoring and management considerations for key adverse events. Abbreviations. GFR = glomerular filtration rate; GI = gastrointestinal; ILD = interstitial lung disease; TKI = tyrosine kinase inhibitor.
Although the precise mechanism is unknown, mild-to-moderate peripheral edema is a common, class-effect AE of MET TKIs in patients with METex14 skipping NSCLC.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Across the studies reviewed here, peripheral edema was the most reported TRAE (50%-63% patients [grade ≥3: 1%-11%]). In contrast to the onset of most TRAEs, edema appears to be a cumulative AE with a delay in onset.
While several other drug classes are also associated with peripheral edema (including chemotherapies, antidepressants, antihypertensives, antivirals, hormones, cytokines, and nonsteroidal anti-inflammatories), it is unclear whether the etiology for MET TKIs is the same.
In addition, for patients with comorbid diseases, edema can be confounded by other systemic (e.g., cardiac, hepatic or renal disease) or local (e.g., secondary lymphedema) causes.
; for example, in the GEOMETRY mono-1 trial of capmatinib, peripheral edema was reported by 50% patients in the METex14 skipping population (84% were over 65 years), compared with 37.6% of the patients with MET amplification (42% over 65 years).
MET-inhibitor-induced edema may not be immediately symptomatic. Time to onset may differ among the agents: edema has been reported from ∼8 weeks with tepotinib,
and ∼2 months with crizotinib (based on clinical experience), although this has not been clinically investigated; however, monitoring should be proactive from initiation for all agents. Early and vigilant monitoring (e.g., weight) is recommended to reduce the potential complexities related to management of advanced edema, which may be resistant to MET TKI dose reduction and use of diuretics. Prophylactic measures, such as support stockings, bed elevation, and reduction in dietary salt intake, should be considered, along with lymphedema massage. Patients should be encouraged to continue with usual daily activities, with increased movement or specialized exercises promoted upon onset of symptoms. Skin should also be closely monitored to avoid the development of lesions. Management of edema should balance the need to reduce excess fluid with continuing to treat NSCLC as effectively as possible; diuretics may be transiently effective (although there is a need to consider that mild diuretics may be required in older patients and MET TKI-increased creatinine levels can affect the ability to assess the tolerability of diuretics), and corticosteroids might reduce severity. To manage edema while retaining treatment effectiveness, lymphatic drainage (manual or mechanical) may be required. MET TKI dose reduction, interruption or intermittent dosing schedules should be considered; data from patients with dose reductions of tepotinib show that they remained on treatment for prolonged periods.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Most cases of hypoalbuminemia reported with tepotinib were mild-to-moderate in severity (all grades: 16%; grade ≥ 3: 2%); with savolitinib, all cases were mild-to-moderate (all grades: 23%; grade ≥ 3: 0%).
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
The mechanism for hypoalbuminemia is unclear, although it is recognized that in patients with cancer, vascular permeability is increased and serum albumin levels and half-life are decreased.
Edema itself may decrease plasma oncotic pressure leading to hypoalbuminemia, and systemic causes of edema such as renal or hepatic failure may also cause hypoalbuminemia.
Whether hypoalbuminemia contributes to edema is uncertain. Given these potential mechanisms of hypoalbuminemia in patients with NSCLC treated with MET TKIs, high protein diets may not be effective in managing this event.
Albumin transfusion or furosemide may provide transient benefits and/or prevent deterioration, however hypoalbuminemia is unlikely to resolve until the underlying cause is addressed (Figure 1). For grade ≥ 3 hypoalbuminemia, dose reduction or interruption of the MET TKI should be considered.
Whether treatment-related pleural effusion occurred with capmatinib, crizotinib or savolitinib is unclear, as all used higher cut-offs than tepotinib for presenting TRAEs; although, a case report of a patient with pleural effusion with ROS1-rearranged NSCLC treated with crizotinib has been published.
This patient experienced contralateral pleural effusion, predominantly composed of lymphocytes, that was considered related to crizotinib as it disappeared with continued drug withdrawal. Pleural effusion can occur as part of disease progression and therefore must be ruled out by thoracentesis and cytological testing to distinguish if it is truly non-malignant and TKI-related; if so, grade ≥ 3 pleural effusion should be managed with dose reduction or interruption.
Other anticancer therapies, including systemic chemotherapy and radiotherapy, are also associated with pleural effusion and should be considered as a potential cause, in addition to TKIs.
The most common gastrointestinal (GI) TRAEs reported in patients with METex14 skipping NSCLC treated with MET TKIs were mild-to-moderate nausea (26%-46%), vomiting (6%-29%), diarrhea (9%-39%) and constipation (20%).
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
GI events may be reduced when MET TKIs are taken with food; this should be recommended if patients experience GI events. The occurrence of GI events is common in patients undergoing cancer treatment,
including the treatment of METex14 skipping with MET TKIs (Table 2); although reported GI AEs with epidermal growth factor receptor TKI treatments are typically higher (25%-95%).
Diarrhea is of greater concern in older patients, and can often be managed effectively with standard antidiarrheal therapies. The causes of GI disturbance should be investigated to ensure that other underlying reasons are appropriately treated.
Raised creatinine is typically associated with renal impairment; however, MET TKIs are known to inhibit creatinine transporters, causing creatinine levels to rise by approximately 20% to 25%.
Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.
Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.
Once treatment was stopped, eGFR recovered to baseline levels or above in 56% of patients; the remainder recovered to within 84% to 97% of their baseline eGFR.
Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.
In patients with METex14 skipping NSCLC, mild-to-moderate treatment-related increases in blood creatinine have been reported for capmatinib and tepotinib.
In an 84-year old patient with METex14 skipping treated with capmatinib, serum creatinine rose from 1.6 mg/dL to 2.44 mg/dL, representing acute kidney injury (AKI), however the rise was asymptomatic and reversible with treatment interruption and pseudo-AKI was diagnosed, supporting the probable inhibition of creatinine transporters by capmatinib rather than renal impairment.
Alternative markers for measuring GFR can help determine whether creatinine elevation in fact reflects renal impairment. For example, 51Cr-EDTA or 123I-iothalamate assessments can be used to confirm or rule out renal impairment and, thus, guide management
Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations.
Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations.
Cystatin C may also be of use when estimating GFR in some patients (e.g., those with extremes in muscle mass, weight, or age), as limitations associated with serum creatinine use, such as diet, muscle mass, rapidly changing kidney function, and certain medications, may be avoided.
For example, tissue inhibitor of metalloproteinase (TIMP)-2 and insulin-like growth factor binding protein 7 (IGFBP7), both biomarkers of cell cycle arrest, can accurately predict AKI.
Kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) have also shown potential in predicting AKI depending on the etiology.
Close and more frequent monitoring in the early months of treatment will help identify clinically relevant increases in creatinine, and whether dose reduction or interruption is needed. Some creatinine increase and plateau would be expected with MET TKIs and might not require dosing changes. Clinicians could also consider the kinetics of creatinine increases and decreases. For example, if creatinine increased rapidly following MET TKI treatment, and then rapidly decreased (≤ 1 week) with return to normal values following treatment withdrawal, this is likely to be due to inhibition of creatinine transporters rather than renal impairment. Additionally, a nephrology referral should be made to gain assistance in determining GFR, since alternative markers of GFR are esoteric.
Increased Liver Transaminases and Phosphatases
Increased ALT, AST, and alkaline phosphatase (ALP) levels (mostly mild-to-moderate severity) have been reported in patients with METex14 skipping NSCLC treated with MET inhibitors.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Monitoring for liver function parameters is essential; however, most events are low grade and reversible. In asymptomatic patients, increases do not usually require dose reduction or interruption, and it is not clear whether switching MET inhibitors might be a useful strategy for management of elevated ALT and AST levels.
Interstitial Lung Disease
Although rare, ILD has been reported following lung cancer treatment with TKIs; onset tends to occur quickly (e.g., ≤ 3 months), but late presentation (e.g., > 2 years) has been reported across four PROFILE clinical trials of crizotininb.
Between 2.2% and 4.5% of patients with METex14 skipping NSCLC treated with capmatinib, tepotinib or crizotinib developed ILD; 0.4% to 1.8% had grade ≥ 3 ILD, and 0.3% to 0.5% died.
Of note, higher rates of ILD have been reported in Japan than in other countries, which is linked to ILD rates in other antineoplastic and immunomodulatory drugs (gefitinib, erlotinib, everolimus, nivolumab, etc.) and differences in postmarketing pharmacovigilance.
The labels for tepotinib and capmatinib in METex14 skipping NSCLC, and crizotinib in other indications, mandate immediate discontinuation of study drug for incidences of ILD.
It is important to rule out other potential causes of ILD if possible (e.g., tumor progression, auto-immune ILD, hypersensitivity pneumonitis, or ILD due to other drugs such as immune checkpoint inhibitors [ICIs], radiation, and infection) in case MET TKIs are not the cause and ongoing benefit could continue. For example, immune-related AEs affecting the lungs have been associated with ICIs,
with 58% being fatal. A meta-analysis of patients treated with ICIs reported a 4.1% incidence of all-grade pneumonitis in NSCLC patients (1.8% developed grade ≥ 3 pneumonitis; 0.4% died), with the risk for developing pneumonitis significantly higher with combination versus monotherapy.
It is also worth noting that these pulmonary events can be late-onset, occurring after ICI treatment has stopped. Patients previously treated with ICIs should be monitored carefully; although, overall data from the MET TKI clinical trials suggest that MET TKIs have a similar safety profile in patients with prior ICI treatment to those without.
Referral to pulmonary specialists should also be made in cases where drug-induced ILD is suspected. Biological tests, pulmonary function tests, bronchoalveolar lavage and bronchoscopy may be necessary in some cases to assist in diagnosis, along with the initiation of steroids.
Other TRAEs of Interest and Special Populations
Other agent-specific AEs are highlighted in the labels for MET TKIs approved to treat NSCLC: tepotinib has additional warnings for hepatotoxicity and embryo-fetal toxicity
Therefore, testosterone levels in men following crizotinib treatment should be monitored and testosterone replacement considered as needed. In VISION, amylase and lipase increases were reported in 11% and 9% of patients treated with tepotinib, respectively; however, these were mild or moderate in severity and were not accompanied by symptoms of pancreatitis.
Ethnicity can also affect the safety of MET TKIs, as shown by a higher rate of permanent discontinuations due to crizotinib-related AEs after treatment with crizotinib in Asian vs. non-Asian populations (PROFILE 1007: 11.4% vs. 2.2%; PROFILE 1014: 6.5% vs. 3.2%).
In Asian patients treated with tepotinib in the VISION study (n = 50), TRAEs of grade ≥ 3 were reported in 26% patients (vs. 28% in the overall VISION population [N = 152; Table 2]) and TRAEs led to treatment discontinuations in 10% patients (vs. 11% in the overall VISION population),
although individual TRAEs have not been reported. In GEOMETRY mono-1, TRAEs in the Japanese cohort (n = 45) were comparable to those in the overall cohort shown in Table 2, although it is worth noting that this cohort also contains patients with MET amplification.
In the VISION study, Japanese patients (n = 15) with METex14 skipping treated with tepotinib reported mostly mild-to-moderate AEs that were in line with the overall VISION population, as well a low rate of TRAEs leading to discontinuation.
However, blood creatinine increase (any grade) was the most commonly reported TRAE in Japanese patients in both VISION and GEOMETRY mono-1 (63.2% and 53.3%, respectively).
Drug-drug Interactions
Tepotinib is a substrate of CYP3A4 and CYP2C8, and transported by P-glycoprotein (P-gp)
; thus, concomitant use with strong CYP3A inducers should be avoided owing to a potential reduction in tepotinib efficacy, and use with dual strong CYP3A inhibitors and P-gp inhibitors should be avoided owing to a potential increase in the frequency and severity of adverse events with tepotinib. Additionally, as tepotinib is a P-gp inhibitor, concomitant use of drugs that are P-gp substrates may increase the concentration of the concomitant drug and should either be avoided in case of a narrow therapeutic window or may demand dose adjustment of the P-gp substrate, according to its approved prescribing information.
The use of capmatinib with moderate and strong CYP3A inducers should be avoided owing to potential reductions in capmatinib exposure (and hence efficacy), and if used with strong CYP3A inhibitors, patients should be monitored for adverse reactions due to potential increases in capmatinib exposure. Capmatinib inhibits the metabolism of drugs that are substrates of CYP1A2 and may also inhibit the transport of drugs which are substrates of P-gp, breast cancer resistance protein (BCRP), as well as the multidrug and toxin extrusion transporter (MATE) 1 and MATE2K. Therefore, coadministration of capmatinib with these drugs should only be used if unavoidable, and a decrease in substrate dosage, according to the approved prescribing information, may be necessary.
; concomitant use with strong CYP3A inducers should be avoided, but exposure is not affected by CYP3A4 inhibitors or gastric pH inducers. Savolitinib and its metabolites have a moderate inhibitory effect on CYP2C8 and caution is required when used concomitantly with CYP2C8 substrates with narrow therapeutic windows.
Savolitinib also has a definite inhibitory effect on MATE1 and MATE2K and a weak inhibitory effect on P-gp, therefore, caution should be used when prescribing metformin (a MATE1/2K substrate) or sensitive P-gp substrates for patients receiving savolitinib. Savolitinib may cause QTc prolongation, thus, concomitant use with other drugs that cause QTc prolongation should be performed with caution and with close monitoring of the patient.
Crizotinib is primarily metabolized by CYP3A, is a moderate CYP3A inhibitor, and inhibits the transporters P-gp, organic cation transporter (OCT) 1 and OCT2.
Crizotinib: A novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond.
Concomitant use with strong CYP3A inhibitors should be avoided and caution should be used with moderate CYP3A inhibitors, owing to the increased risk of adverse reactions to crizotinib. Grapefruit or grapefruit juice should be avoided, as these may also increase the plasma concentrations of crizotinib.
Concomitant use with strong CYP3A inducers which may decrease the efficacy of crizotinib should be avoided, and, use of crizotinib with CYP3A substrates where minimal concentration changes may lead to serious adverse reactions with these substrates should be avoided as well.
Crizotinib has been reported to prolong the QT/QTc interval and cause bradycardia, thus, concomitant use with drugs that cause these effects, including beta-blockers and digoxin, should also be avoided.
MET TKI inhibitors provide an effective treatment option for patients with METex14 skipping NSCLC, an older patient population with potentially complex needs. From published clinical trial data, MET TKIs have been shown to be generally well tolerated, with relatively few patients discontinuing treatment due to AEs. Data show that peripheral edema and nausea are the most common TRAEs for each MET TKI to date, and that while some TRAEs might occur early in therapy (e.g., GI effects), peripheral edema does not. The etiology for some MET TKI TRAEs (e.g., increased creatinine) is known, but not for others (e.g., hypoalbuminemia). Additionally, some class effects of MET TKIs, such as edema, hypoalbuminemia and pleural effusion seem to be biologically related, perhaps via vascular permeability,
although further investigations are required to confirm this.
As clinicians, it is vital to know not only the TRAEs reported (and their severity), but also when those TRAEs occurred, what the dose reduction strategies were, and when dose reductions and discontinuations occurred in order to place the safety data in better context. Understanding the denominator used to analyze TRAE percentages is crucial to gain insight into whether the data reported accurately reflect a specific TRAE (e.g., testosterone levels in the overall population, or in men with testosterone data available). Of equal importance is providing advice for the management for TRAEs. All of these factors are essential so clinicians can know when to be vigilant of specific TRAEs and how to manage them. While most MET TKI TRAEs can be managed primarily without dose reduction or interruption, both should be used where necessary, with additional clinical management dependent on the TRAE. Finally, more data regarding the effectiveness of safety interventions and management strategies are needed.
Acknowledgments
Medical writing assistance for the development of this manuscript was provided by Syneos Health Medical Communications, and funded by the healthcare business of Merck KGaA, Darmstadt, Germany.
Funding
Funded by the healthcare business of Merck KGaA, Darmstadt, Germany.
Author disclosures
A.C. reports acting in an advisory role for AstraZeneca, BMS, Novartis, Pfizer, Roche, Takeda, receiving research funding from Novartis and the healthcare business of Merck KGaA, Darmstadt, Germany, and receiving honoraria and/or travel expenses from AstraZeneca, BMS, Novartis, MSD, Pfizer, Roche and Takeda.
X.L. reports acting in an advisory role for AstraZeneca, Eli Lilly, EMD Serono, and receiving research funding from Eli Lilly and Boehringer Ingelheim.
E.S. reports acting in an advisory role for Eli Lilly, AstraZeneca, Boehringer Ingelheim, Roche/Genentech, Bristol-Myers Squibb, MSD Oncology, Takeda, Bayer, Regeneron, Novartis, Daiichi Sankyo, Seattle Genetics, and the healthcare business of Merck KGaA, Darmstadt, Germany, and receiving research funding from Boehringer Ingelheim, Bayer, Roche/Genentech, AstraZeneca and Bristol-Myers Squibb.
S.V. reports acting in an advisory role to AbbVie, BMS, Roche, Takeda, AstraZeneca and MSD, receiving speaker fees and/or travel expenses from BMS, MSD, Roche, AstraZeneca, OSE Pharma, EMD Serono, Puma Biotechnology, Janssen Cilag, and the healthcare business of Merck KGaA, Darmstadt, Germany.
T.K. reports receiving grants and personal fees from AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Chugai, Eli Lilly, the healthcare business of Merck KGaA, Darmstadt, Germany, MSD, Novartis, Ono, Pfizer, Taiho, Boehringer Ingelheim, Daiichi-Sankyo, Nippon Kayaku, Takeda and Regeneron.
H.S. reports receiving speaker fees from BMS, Ono Pharmaceutical, MSD K.K., AstraZeneca, Chugai Pharma, Taiho Pharmaceutical, Boehringer Ingelheim and the healthcare business of Merck KGaA, Darmstadt, Germany.
K.P. reports acting in an advisory role for AstraZeneca, Boehringer Ingelheim, Clovis, Eli Lilly, Hanmi Pharmaceutical, Novartis, Ono and Roche.
R.C reports acting in an advisory role for Anchiano, Amgen, Takeda, Roche, EMD Serono, Sanofi, Pfizer, CBT Pharmaceuticals, Daiichi Sankyo, G1 Therapeutics, Bio Thera, Blueprint, AbbVie, Achilles, BeyondSpring, Apollomics, 14ner/Elevation, Archer, Helssin, Bristol-Myers Squibb, Eli Lilly, Medtronic, Ribon, AstraZeneca, Takeda, Arrys/Kyn, Regeneron, Hengrui, Hansoh, Bio Thera, Roche/Genentech and Inivata, and has received research funding from Takeda, AbbVie, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Hansoh, Inhibrx, Lycera, Medimmune, Pfizer, Phosplatin, Psioxus, Rain, Roche/Genentech, Seattle Genetics, Symphogen, Tolero, and the healthcare business of Merck KGaA, Darmstadt, Germany.
K.B. and S.V. are employed by the healthcare business of Merck KGaA, Darmstadt, Germany.
P.P. reports acting in an advisory role for AbbVie, AstraZeneca, Calithera, Celgene, Lilly, Takeda, EMD Serono, Xencor, Bicara, Boehringer Ingelheim, GlaxoSmithKline, and has received research expenses from Celgene and EMD Serono.
References
Zheng D
Wang R
Ye T
et al.
MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.
König D, Savic Prince S, Rothschild SI. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers (Basel). 2021;13:804. doi:10.3390/cancers13040804.
MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression.
ClinicalTrials.gov. Clinical study of oral cMET inhibitor INC280 in adult patients with EGFR wild-type advanced non-small cell lung cancer (Geometry Mono-1). https://www.clinicaltrials.gov/ct2/show/NCT02414139. Accessed March 23, 2021.
ClinicalTrials.gov. Study of capmatinib efficacy in comparison with docetaxel in previously treated participants with non-small cell lung cancer harboring MET exon 14 skipping mutation. https://clinicaltrials.gov/ct2/show/NCT04427072. Accessed March 23, 2021.
Once-daily savolitinib in chinese patients with pulmonary sarcomatoid carcinomas and other non-small-cell lung cancers harbouring MET exon 14 skipping alterations: A multicentre, single-arm, open-label, phase 2 study.
Drug-induced reduction in estimated glomerular filtration rate in patients with ALK-positive non-small cell lung cancer treated with the ALK inhibitor crizotinib.
Assessing glomerular filtration rate (GFR) in critically ill patients with acute kidney injury - true GFR versus urinary creatinine clearance and estimating equations.
Crizotinib: A novel and first-in-class multitargeted tyrosine kinase inhibitor for the treatment of anaplastic lymphoma kinase rearranged non-small cell lung cancer and beyond.
ClinicalTrials.gov. A phase II study of HMPL-504 in lung sarcomatoid carcinoma and other non-small cell lung cancer. https://clinicaltrials.gov/ct2/show/NCT02897479. Accessed January 6, 2022.
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