Tepmetko Adverse Reactions

Summary of the safety profile: The most common adverse reactions in ≥20% of exposed to tepotinib at the recommended dose in the target indication (N=313) are oedema (81.5% of patients), mainly peripheral oedema (72.5%), hypoalbuminaemia (32.9%), nausea (31.0%), increase in creatinine (29.1%) and diarrhoea (28.8%). The most common serious adverse reactions in ≥1% of patients are peripheral oedema (3.2%), generalised oedema (1.9%) and ILD (1.0%).
The percentage of patients who had adverse events leading to permanent treatment discontinuation is 24.9%. The most common adverse reactions leading to permanent discontinuation in ≥1% of patients are peripheral oedema (5.4%), oedema (1.3%), genital oedema (1.0%) and ILD (1.0%).
The percentage of patients who had adverse events leading to temporary treatment discontinuation is 52.7%. The most common adverse reactions leading to temporary discontinuation in ≥2% of patients are peripheral oedema (19.8%), increase in creatinine (5.8%), generalised oedema (4.8%), oedema (3.8%), increase in ALT (2.9%), nausea (3.2%) and increase in amylase (1.6%).
The percentage of patients who had adverse events leading to dose reduction is 36.1%. The most common adverse reactions leading to dose reduction in ≥2% of patients are peripheral oedema (15.7%), increase in creatinine (2.9%), generalised oedema (3.2%) and oedema (2.6%).
List of adverse reactions: Adverse reactions described in the list as follows reflect exposure to tepotinib in 506 patients with various solid tumours enrolled in five open-label studies, in which patients received tepotinib as a single agent at a dose of 450 mg once daily.
The frequencies of adverse reactions are based on all-cause adverse event frequencies identified in 313 patients exposed to tepotinib at the recommended dose in the target indication, whereas frequencies for changes in laboratory parameters are based on worsening from baseline by at least 1 grade and shifts to ≥grade 3. Median duration of treatment was 7.5 months (range 0 to 72).
Frequencies presented may not be fully attributable to tepotinib alone but may contain contributions from the underlying disease or from other medicinal products used concomitantly.
The severity of adverse reactions was assessed based on the Common Terminology Criteria for Adverse Events (CTCAE), defining grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening and grade 5 = death.
List of adverse reactions: An asterisk (*) indicates that additional information on the respective adverse reaction is provided after the table.
The following definitions apply to the frequency terminology used hereafter: Very common (≥1/10), Common (≥1/100 to <1/10), Uncommon (≥1/1,000 to <1/100), Rare (≥1/10,000 to <1/1,000), Very rare (<1/10,000), Frequency not known (cannot be estimated from the available data). (See Table 3.)

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Description of selected adverse reactions: Interstitial lung disease: Interstitial lung disease (ILD) or ILD-like reactions have been reported in 8 patients (2.6%), including 1 case of grade 3 or higher; serious cases occurred in 4 patients (1.3%), 1 case was fatal. Treatment was permanently discontinued in 5 patients and temporarily in 3 patients. Median time to onset of ILD was 9.4 weeks. For clinical recommendations, see Dosage & Administration and Precautions.
Increase in liver enzymes: ALT and/or AST increase led to permanent treatment discontinuation in 1 patient and infrequently led to temporary discontinuation (3.2%) or dose reduction (0.3%) of tepotinib. Median time to first onset for ALT and/or AST increase of any grade reported as an adverse event by investigators was 9.1 weeks. The median time to resolution was 3.6 weeks, 86% of events resolved. For clinical recommendations, see Dosage & Administration and Precautions.
ALP increase did not lead to any dose reductions, temporary treatment discontinuation or permanent discontinuation. The observed ALP increase was not associated with cholestasis. Median time to first onset for ALP increase of any grade reported as an adverse event by investigators was 9.1 weeks. The median time to resolution was 9.1 weeks, 80% of events resolved.
Oedema: The most frequently reported event was peripheral oedema (72.5% of patients), followed by oedema (8.3%) and generalised oedema (6.7%). Median time to onset of any-grade oedema was 9.1 weeks. The median time to resolution was 71 weeks, 39.2% of events resolved. 8% of patients had oedema events leading to permanent treatment discontinuation, of whom 5.4% had peripheral oedema. 28.4% of patients temporarily discontinued treatment and 21.7% of patients had dose reductions due to oedema. Most frequently peripheral oedema led to temporary treatment discontinuation and dose reductions (19.8% and 15.7%, respectively). Generalised oedema events led to a dose reduction in 3.2% of patients, to temporary treatment discontinuation in 4.8% and to permanent discontinuation in 0.6%.
Increase in creatinine: Increase in creatinine led to permanent treatment discontinuation in 2 patients (0.6%), temporary treatment discontinuation in 5.8% of patients and dose reduction in 2.9% of patients. Median time to onset of increase in creatinine reported as an adverse event by investigators was 3.4 weeks. The median time to resolution was 9.1 weeks, 78% of events resolved. The observed increases in creatinine are thought to occur mainly due to inhibition of renal tubular secretion (see Precautions).
Hypoalbuminaemia: Hypoalbuminaemia appeared to be long-lasting but did not lead to permanent treatment discontinuation. Dose reduction (1.6%) and temporary discontinuation (1.9%) were infrequent. Median time to onset of any-grade hypoalbuminaemia reported as an adverse event by investigators was 9.4 weeks. The median time to resolution was 28.9 weeks, 48% of events resolved.
Increase in amylase or lipase: Increases in amylase or lipase reported as an adverse event by investigators were asymptomatic and not associated with pancreatitis. 3.2% of patients temporarily discontinued treatment and there were no permanent treatment discontinuation or dose reduction. Median time to onset of any grade in lipase/amylase increase was 15 weeks. The median time to resolution was 6.1 weeks, 83% of events resolved.
QTc prolongation: QTcF prolongation to >500 ms was observed in 8 patients (2.6%) and a QTcF prolongation by at least 60 ms from baseline in 19 patients (6.1%) (see Precautions). The findings were isolated and asymptomatic; the clinical significance is unknown.
Additional information on special populations: Elderly: Of 313 patients with METex14 skipping alterations in the VISION study who received 450 mg tepotinib once daily, 79% were 65 years or older, and 8% were 85 years or older. The occurrence of grade ≥3 events increased with age. Treatment-related serious events were more frequent in patients aged ≥75 years and <85 years (21%) or those aged ≥85 years (20.8%) when compared to those younger than 65 years (10.4%), although this comparison is limited by the small sample size in patients aged ≥85 years.