Kisplyx - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Kisplyx 4 mg hard capsules

Kisplyx 10 mg hard capsules

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Kisplyx 4 mg hard capsules

Each hard capsule contains 4 mg of lenvatinib (as mesilate).

Kisplyx 10 mg hard capsules

Each hard capsule contains 10 mg of lenvatinib (as mesilate).

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule.

Kisplyx 4 mg hard capsules

A yellowish-red body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with “C” on the cap, and “LENV 4 mg” on the body.

Kisplyx 10 mg hard capsules

A yellow body and yellowish-red cap, approximately 14.3 mm in length, marked in black ink with “C” on the cap, and “LENV 10 mg” on the body.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Kisplyx is indicated for the treatment of adults with advanced renal cell carcinoma (RCC):

• • in combination with pembrolizumab, as first-line treatment (see section 5.1).
• • in combination with everolimus, following one prior vascular endothelial growth factor (VEGF)-targeted therapy (see section 5.1).

4.2 Posology and method of administration

Treatment should be initiated and supervised by a healthcare professional experienced in the use of anticancer therapies.

Posology

Kisplyx in combination with pembrolizumab as first-line treatment

The recommended dose of lenvatinib is 20 mg (two 10-mg capsules) orally once daily in combination with pembrolizumab either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The daily dose of lenvatinib is to be modified as needed according to the dose/toxicity management plan. Lenvatinib treatment should continue until disease progression or unacceptable toxicity. Pembrolizumab should be continued until disease progression, unacceptable toxicity or the maximum duration of therapy as specified for pembrolizumab.

See the Summary of Product Characteristics (SmPC) for pembrolizumab for full pembrolizumab dosing information.

Kisplyx in combination with everolimus as second-line treatment

The recommended daily dose of lenvatinib is 18 mg (one 10-mg capsule and two 4-mg capsules) orally once daily in combination with 5 mg of everolimus once daily. The daily dose of lenvatinib and, if necessary, everolimus is to be modified as needed according to the dose/toxicity management plan.

See the SmPC for everolimus for full everolimus dosing information.

If a patient misses a dose of lenvatinib, and it cannot be taken within 12 hours, then that dose should be skipped and the next dose should be taken at the usual time of administration.

Treatment should continue as long as there is clinical benefit or until unacceptable toxicity occurs.

Dose adjustment and discontinuation for lenvatinib

Management of adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy (see section 4.4). Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of lenvatinib unless intolerable to the patient despite optimal management.

Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of lenvatinib until improvement of the reaction to Grade 0 to 1 or baseline.

Optimal medical management (i.e., treatment or therapy) for nausea, vomiting, and diarrhoea should be initiated prior to any lenvatinib therapy interruption or dose reduction; gastrointestinal toxicity should be actively treated in order to reduce the risk of development of renal impairment or renal failure (see section 4.4).

For toxicities thought to be related to lenvatinib (see Table 2), upon resolution/im­provement of an adverse reaction to Grade 0 to 1 or baseline, treatment should be resumed at a reduced dose of lenvatinib as suggested in Table 1.

Table 1 _____ Dose modifications from recommended lenvatinib daily dosea

	Lenvatinib dose in combination with pembrolizumab	Lenvatinib dose in combination with everolimus
Recommended daily dose	20 mg orally once daily (two 10-mg capsules)	18 mg orally once daily (one 10-mg capsule + two 4-mg capsules)
First dose reduction	14 mg orally once daily (one 10-mg capsule + one 4-mg capsule)	14 mg orally once daily (one 10-mg capsule + one 4-mg capsule)
Second dose reduction	10 mg orally once daily (one 10-mg capsule)	10 mg orally once daily (one 10-mg capsule)
Third dose reduction	8 mg orally once daily (two 4 mg capsules)	8 mg orally once daily (two 4-mg capsules)
a Limited data are available for doses below 8 mg

When used in combination with pembrolizumab, one or both medicines should be interrupted as appropriate. Lenvatinib should be withheld, dose reduced, or discontinued as appropriate. Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. No dose reductions are recommended for pembrolizumab.

For toxicities thought to be related to everolimus, treatment should be interrupted, reduced to alternate day dosing, or discontinued (see the SmPC for everolimus for dose adjustment recommendations regarding specific adverse reactions).

For toxicities thought to be related to both lenvatinib and everolimus, lenvatinib should be reduced (see Table 1) prior to reducing everolimus.

All treatments should be discontinued in case of life-threatening reactions (e.g., Grade 4) with the exception of laboratory abnormalities judged to be non-life-threatening, in which case they should be managed as severe reactions (e.g., Grade 3).

Grades are based on the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE).

Table 2 Adverse reactions requiring dose modification of lenvatinib

Adverse reaction	Severity	Action	Dose reduce and resume lenvatinib
Hypertension	Grade 3 (despite optimal antihypertensive therapy)	Interrupt	Resolves to Grade 0, 1 or 2. See detailed guidance in Table 3 in section 4.4.
	Grade 4	Discontinue	Do not resume
Proteinuria	> 2 gm / 24 hours	Interrupt	Resolves to less than 2 gm / 24 hours.
Nephrotic syndrome		Discontinue	Do not resume
Renal impairment or failure	Grade 3	Interrupt	Resolves to Grade 0–1 or baseline.
	Grade 4*	Discontinue	Do not resume
Cardiac dysfunction	Grade 3	Interrupt	Resolves to Grade 0–1 or baseline.
	Grade 4	Discontinue	Do not resume
PRES/RPLS	Any grade	Interrupt	Consider resuming at reduced dose if resolves to Grade 0–1.
Hepatotoxicity	Grade 3	Interrupt	Resolves to Grade 0–1 or baseline.
	Grade 4*	Discontinue	Do not resume
Arterial thromboembolisms	Any grade	Discontinue	Do not resume
Haemorrhage	Grade 3	Interrupt	Resolves to Grade 0–1.
	Grade 4	Discontinue	Do not resume
GI perforation or fistula	Grade 3	Interrupt	Resolves to Grade 0–1 or baseline.
	Grade 4	Discontinue	Do not resume
Non-GI fistula	Grade 4	Discontinue	Do not resume
QT interval prolongation	>500 ms	Interrupt	Resolves to <480 ms or baseline
Diarrhoea	Grade 3	Interrupt	Resolves to Grade 0–1 or baseline.
	Grade 4 (despite medical management)	Discontinue	Do not resume

*Grade 4 laboratory abnormalities judged to be non-life-threatening, may be managed as severe reactions (e.g., Grade 3)

Special populations

For information about clinical experience with the combination treatment of lenvatinib and pembrolizumab, see section 4.8.

Patients of age >65 years, with baseline hypertension or those with renal impairment appear to have reduced tolerability to lenvatinib (see section 4.8).

No data for the combination of lenvatinib and everolimus are available for most of the special populations. The following information is derived from clinical experience of single agent lenvatinib in patients with differentiated thyroid cancer (DTC; see SmPC for Lenvima).

All patients other than those with severe hepatic or renal impairment (see below) should initiate treatment at the recommended dose of 20 mg of lenvatinib daily with pembrolizumab or 18 mg of lenvatinib with 5 mg of everolimus taken once daily as indicated, following which the dose should be further adjusted on the basis of individual tolerability.

Patients with hypertension

Blood pressure should be well controlled prior to treatment with lenvatinib, and should be regularly monitored during treatment (see sections 4.4 and 4.8).

Patients with hepatic impairment

Limited data are available for the combination of lenvatinib with pembrolizumab in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily. Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment. Further dose adjustments may be necessary on the basis of individual tolerability. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see section 4.8).

No data for the combination of lenvatinib with everolimus are available in patients with hepatic impairment. No adjustment of starting dose of the combination is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose of lenvatinib is 10 mg taken once daily in combination with the dose of everolimus recommended for patients with severe hepatic impairment in the SmPC for everolimus. Further dose adjustments may be necessary on the basis of individual tolerability. The combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk (see section 4.8).

Patients with renal impairment

No adjustment of starting dose is required on the basis of renal function in patients with mild or moderate renal impairment. In patients with severe renal impairment, the recommended starting dose is 10 mg of lenvatinib taken once daily. Please refer to the SmPC for pembrolizumab or everolimus for dosing in patients with renal impairment. Further dose adjustments may be necessary based on individual tolerability. Patients with end-stage renal disease have not been studied, therefore the use of lenvatinib in these patients is not recommended (see section 4.8).

Elderly population

No adjustment of starting dose is required on the basis of age. Limited data are available on use in patients aged >75 years (see section 4.8).

Paediatric population

Lenvatinib should not be used in children younger than 2 years of age because of safety concerns identified in animal studies (see section 5.3). The safety and efficacy of lenvatinib in children aged 2 to <18 years have not yet been established (see section 5.1). No data are available.

Ethnic Origin

No adjustment of starting dose is required on the basis of race (see section 5.2). Currently available data are described in section 4.8).

Body weight below 60 kg

No adjustment of starting dose is required on the basis of body weight. Limited data are available on treatment with lenvatinib in combination with everolimus in patients with a body weight below 60 kg with RCC (see section 4.8).

Performance status

Patients with an ECOG (Eastern Cooperative Oncology Group) performance status of 2 or higher were excluded from RCC Study 205 (see section 5.1). Patients with a KPS (Karnofsky Performance Status) <70 were excluded from Study 307 (CLEAR). Benefit-risk in these patients has not been evaluated.

Method of administration

Lenvatinib is for oral use. The capsules should be taken at about the same time each day, with or without food (see section 5.2). The capsules can be swallowed whole with water. Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.

Alternatively, the lenvatinib capsules may be added without breaking or crushing them to a tablespoon of water or apple juice in a small glass to produce a suspension. The capsules must be left in the liquid for at least 10 minutes and stirred for at least 3 minutes to dissolve the capsule shells. The suspension is to be swallowed. After drinking, the same amount of water or apple juice (one tablespoon) must be added to the glass and swirled a few times. The additional liquid must be swallowed.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Breast-feeding (see section 4.6).

4.4 Special warnings and precautions for use

Hypertension

Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). Blood pressure (BP) should be well controlled prior to treatment with lenvatinib and, if patients are known to be hypertensive, they should be on a stable dose of antihypertensive therapy for at least 1 week prior to treatment with lenvatinib. Serious complications of poorly controlled hypertension, including aortic dissection, have been reported. The early detection and effective management of hypertension are important to minimise the need for lenvatinib dose interruptions and reductions.

Antihypertensive agents should be started as soon as elevated BP is confirmed. BP should be monitored after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months, and monthly thereafter. The choice of antihypertensive treatment should be individualised to the patient’s clinical circumstances and follow standard medical practice. For previously normotensive patients, monotherapy with one of the classes of antihypertensive should be started when elevated BP is observed. For those patients already on an antihypertensive medicinal product, the dose of the current agent may be increased, if appropriate, or one or more agents of a different class of antihypertensive should be added. When necessary, manage hypertension as recommended in Table 3.

Table 3 ______ Recommended management of hypertension

Blood pressure (BP) level	Recommended action
Systolic BP >140 mmHg up to <160 mmHg or diastolic BP >90 mmHg up to <100 mmHg	Continue lenvatinib and initiate antihypertensive therapy, if not already receiving OR Continue lenvatinib and increase the dose of the current antihypertensive therapy or initiate additional antihypertensive therapy
Systolic BP >160 mmHg or diastolic BP >100 mmHg despite optimal antihypertensive therapy	1. W ithhold lenvatinib 2. When systolic BP <150 mmHg, diastolic BP <95 mmHg, and patient has been on a stable dose of antihypertensive therapy for at least 48 hours, resume lenvatinib at a reduced dose (see section 4.2)
Life-threatening consequences (malignant hypertension, neurological deficit, or hypertensive crisis)	Urgent intervention is indicated. Discontinue lenvatinib and institute appropriate medical management.

Aneurysms and artery dissections

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating lenvatinib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Women of childbearing potential

Women of childbearing potential must use highly effective contraception while taking lenvatinib and for one month after stopping treatment (see section 4.6). It is currently unknown if lenvatinib increases the risk of thromboembolic events when combined with oral contraceptives.

Proteinuria

Proteinuria has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). Urine protein should be monitored regularly. If urine dipstick proteinuria >2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2). Cases of nephrotic syndrome have been reported in patients using lenvatinib. Lenvatinib should be discontinued in the event of nephrotic syndrome.

Renal failure and impairment

Renal impairment and renal failure have been reported in patients treated with lenvatinib (see section 4.8). The primary risk factor identified was dehydration and/or hypovolemia due to gastrointestinal toxicity. Gastrointestinal toxicity should be actively managed in order to reduce the risk of development of renal impairment or renal failure. Caution should be taken in patients receiving agents acting on the reninangiotensin aldosterone system given a potentially higher risk for acute renal failure with the combination treatment. Dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 and 5.2).

Cardiac dysfunction

Cardiac failure (<1%) and decreased left ventricular ejection fraction have been reported in patients treated with lenvatinib (see section 4.8). Patients should be monitored for clinical symptoms or signs of cardiac decompensation, as dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

Posterior reversible encephalopathy syndrome (PRES) / Reversible posterior leucoencephalopathy syndrome (RPLS)

PRES, also known as RPLS, has been reported in patients treated with lenvatinib (<1%; see section 4.8). PRES is a neurological disorder which can present with headache, seizure, lethargy, confusion, altered mental function, blindness, and other visual or neurological disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging is necessary to confirm the diagnosis of PRES. Appropriate measures should be taken to control blood pressure (see section 4.4, Hypertension). In patients with signs or symptoms of PRES, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

Hepatotoxicity

Liver-related adverse reactions most commonly reported in patients treated with lenvatinib included increases in alanine aminotransferase, increases in aspartate aminotransferase, and increases in blood bilirubin. Hepatic failure and acute hepatitis (<1%; see section 4.8) have been reported in patients treated with lenvatinib. The hepatic failure cases were generally reported in patients with progressive liver metastases. Liver function tests should be monitored before initiation of treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. In the case of hepatotoxicity, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

If patients have severe hepatic impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 and 5.2).

Arterial thromboembolisms

Arterial thromboembolisms (cerebrovascular accident, transient ischaemic attack, and myocardial infarction) have been reported in patients treated with lenvatinib (see section 4.8). Lenvatinib has not been studied in patients who have had an arterial thromboembolism within the previous 6 months, and therefore should be used with caution in such patients. A treatment decision should be made based upon an assessment of the individual patient's bene­fit/risk. Lenvatinib should be discontinued following an arterial thrombotic event.

Haemorrhage

Serious tumour related bleeds, including fatal haemorrhagic events have occurred in clinical trials and have been reported in post-marketing experience (see section 4.8). In post-marketing surveillance, serious and fatal carotid artery haemorrhages were seen more frequently in patients with anaplastic thyroid carcinoma (ATC) than in DTC or other tumour types. The degree of tumour invasion/infil­tration of major blood vessels (e.g. carotid artery) should be considered because of the potential risk of severe haemorrhage associated with tumour shrinkage/necrosis following lenvatinib therapy. Some cases of bleeding have occurred secondarily to tumour shrinkage and fistula formation, e.g. tracheo-oesophageal fistulae. Cases of fatal intracranial haemorrhage have been reported in some patients with or without brain metastases. Bleeding in sites other than the brain (e.g. trachea, intra-abdominal, lung) has also been reported.

In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see section 4.2, Table 2).

Gastrointestinal perforation and fistula formation

Gastrointestinal perforation or fistulae have been reported in patients treated with lenvatinib (see section 4.8). In most cases, gastrointestinal perforation and fistulae occurred in patients with risk factors such as prior surgery or radiotherapy. In the case of a gastrointestinal perforation or fistula, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).

Non-gastrointestinal fistula

Patients may be at increased risk for the development of fistulae when treated with lenvatinib. Cases of fistula formation or enlargement that involve other areas of the body than stomach or intestines were observed in clinical trials and in post-marketing experience (e.g. tracheal, tracheo-oesophageal, oesophageal, cutaneous, female genital tract fistulae). In addition, pneumothorax has been reported with and without clear evidence of a bronchopleural fistula. Some reports of fistula and pneumothorax occurred in association with tumour regression or necrosis. Prior surgery and radiotherapy may be contributing risk factors. Lung metastases may also increase the risk of pneumothorax. Lenvatinib should not be started in patients with fistulae to avoid worsening and lenvatinib should be permanently discontinued in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula (see section 4.2); limited information is available on the use of dose interruption or reduction in management of other events, but worsening was observed in some cases and caution should be taken. Lenvatinib may adversely affect the wound healing process as do other agents of the same class.

QT interval prolongation

QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than in patients treated with placebo (see section 4.8). Electrocardiograms should be monitored in all patients with a special attention for those with congenital long QT syndrome, congestive heart failure, bradyarrhythmics, and those taking medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics. Lenvatinib should be withheld in the event of development of QT interval prolongation greater than 500 ms. Lenvatinib should be resumed at a reduced dose when QTc prolongation is resolved to < 480 ms or baseline.

Electrolyte disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia increase the risk of QT prolongation; therefore electrolyte abnormalities should be monitored and corrected in all patients before starting treatment. Periodic monitoring of ECG and electrolytes (magnesium, potassium and calcium) should be considered during treatment. Blood calcium levels should be monitored at least monthly and calcium should be replaced as necessary during lenvatinib treatment. Lenvatinib dose should be interrupted or dose adjusted as necessary depending on severity, presence of ECG changes, and persistence of hypocalcaemia.

Impairment of thyroid stimulating hormone suppression / Thyroid dysfunction

Hypothyroidism has been reported in patients treated with lenvatinib (see section 4.8). Thyroid function should be monitored before initiation of, and periodically throughout, treatment with lenvatinib. Hypothyroidism should be treated according to standard medical practice to maintain euthyroid state.

Lenvatinib impairs exogenous thyroid suppression (see section 4.8). Thyroid stimulating hormone (TSH) levels should be monitored on a regular basis and thyroid hormone administration should be adjusted to reach appropriate TSH levels, according to the patient’s the­rapeutic target.

Diarrhoea

Diarrhoea has been reported frequently in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8). Prompt medical management of diarrhoea should be instituted in order to prevent dehydration. Lenvatinib should be discontinued in the event of persistence of Grade 4 diarrhoea despite medical management.

Wound healing complications

No formal studies of the effect of lenvatinib on wound healing have been conducted. Impaired wound healing has been reported in patients receiving lenvatinib. Temporary interruption of lenvatinib should be considered in patients undergoing major surgical procedures. There is limited clinical experience regarding the timing of reinitiation of lenvatinib following a major surgical procedure. Therefore, the decision to resume lenvatinib following a major surgical procedure should be based on clinical judgment of adequate wound healing.

Osteonecrosis of the jaw (ONJ)

Cases of ONJ have been reported in patients treated with lenvatinib. Some cases were reported in patients who had received prior or concomitant treatment with antiresorptive bone therapy, and/or other angiogenesis inhibitors, e.g. bevacizumab, TKI, mTOR inhibitors. Caution should therefore be exercised when lenvatinib is used either simultaneously or sequentially with antiresorptive therapy and/or other angiogenesis inhibitors.

Invasive dental procedures are an identified risk factor. Prior to treatment with lenvatinib, a dental examination and appropriate preventive dentistry should be considered. In patients who have previously received or are receiving intravenous bisphosphonates, invasive dental procedures should be avoided if possible (see section 4.8).

Special populations

Limited data are available for patients of ethnic origin other than Caucasian or Asian, and in patients aged >75 years. Lenvatinib should be used with caution in such patients, given the reduced tolerability of lenvatinib in Asian and elderly patients (see section 4.8).

There are no data on the use of lenvatinib immediately following sorafenib or other anticancer treatments and there may be a potential risk for additive toxicities unless there is an adequate washout period between treatments. The minimal washout period in clinical trials was of 4 weeks.

4.5 Interaction with other medicinal products and other forms of interaction

Effect of other medicinal products on lenvatinib

Chemotherapeutic agents

Concomitant administration of lenvatinib, carboplatin, and paclitaxel has no significant impact on the pharmacokinetics of any of these 3 substances. Additionally, in patients with RCC the pharmacokinetics of lenvatinib was not significantly affected by concomitant everolimus.

Effect of lenvatinib on other medicinal products

CYP3A4 substrates

A clinical drug-drug interaction (DDI) study in cancer patients showed that plasma concentrations of midazolam (a sensitive CYP3A and Pgp substrate) were not altered in the presence of lenvatinib. Additionally, in patients with RCC the pharmacokinetics of everolimus was not significantly affected by concomitant lenvatinib. No significant drug-drug interaction is therefore expected between lenvatinib and other CYP3A4/Pgp substrates.

Oral contraceptives

It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method (see section 4.6).

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/ Contraception in females

Women of childbearing potential should avoid becoming pregnant and use highly effective contraception while on treatment with lenvatinib and for at least one month after finishing treatment. It is currently unknown whether lenvatinib may reduce the effectiveness of hormonal contraceptives, and therefore women using oral hormonal contraceptives should add a barrier method.

Pregnancy

There are no data on the use of lenvatinib in pregnant women. Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits (see section 5.3).

Lenvatinib should not be used during pregnancy unless clearly necessary and after a careful consideration of the needs of the mother and the risk to the foetus.

Breast-feeding

It is not known whether lenvatinib is excreted in human milk. Lenvatinib and its metabolites are excreted in rat milk (see section 5.3).

A risk to newborns or infants cannot be excluded and, therefore, lenvatinib is contraindicated during breast-feeding (see section 4.3).

Fertility

Effects in humans are unknown. However, testicular and ovarian toxicity has been observed in rats, dogs, and monkeys (see section 5.3).

4.7 Effects on ability to drive and use machines

Lenvatinib has minor influence on the ability to drive and use machines, due to undesirable effects such as fatigue and dizziness. Patients who experience these symptoms should use caution when driving or operating machines.

4.8 Undesirable effects

Summary of the safety profile

The safety profile of lenvatinib is based on pooled data from 497 RCC patients treated with lenvatinib in combination with pembrolizumab, including Study 307 (CLEAR); 62 RCC patients treated with lenvatinib in combination with everolimus in Study 205; 458 DTC patients and 496 HCC patients treated with lenvatinib as single-agent therapy.

Lenvatinib in combination with pembrolizumab in RCC

The safety profile of lenvatinib in combination with pembrolizumab is based on data from 497 RCC patients. The most frequently reported adverse reactions (occurring in >30% of patients) were diarrhoea (61.8%), hypertension (51.5%) fatigue (47.1%), hypothyroidism (45.1%), decreased appetite (42.1%), nausea (39.6%), stomatitis (36.6%), proteinuria (33.0%), dysphonia (32.8%), and arthralgia (32.4%).

The most common severe (Grade >3) adverse reactions (>5%) were hypertension (26.2%), lipase increased (12.9%), diarrhoea (9.5%), proteinuria (8.0%), amylase increased (7.6%), weight decreased (7.2%), and fatigue (5.2%).

Discontinuation of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 33.4% of patients; 23.7% lenvatinib, and 12.9 % both drugs. The most common adverse reactions (>1%) leading to discontinuation of lenvatinib, pembrolizumab, or both were myocardial infarction (2.4%), diarrhoea (2.0%), proteinuria (1.8%), and rash (1.4%). Adverse reactions that most commonly led to discontinuation of lenvatinib (>1%) were myocardial infarction (2.2%), proteinuria (1.8%), and diarrhoea (1.0%).

Dose interruptions of lenvatinib, pembrolizumab, or both due to an adverse reaction occurred in 80.1% of patients; lenvatinib was interrupted in 75.3%, and both drugs in 38.6% of patients. Lenvatinib was dose reduced in 68.4% of patients. The most common adverse reactions (>5%) resulting in dose reduction or interruption of lenvatinib were diarrhoea (25.6%), hypertension (16.1%), proteinuria (13.7%), fatigue (13.1%), appetite decreased (10.9%), palmar-plantar erythrodysaesthesia syndrome (PPE) (10.7%), nausea (9.7%), asthenia (6.6%), stomatitis (6.2%), lipase increased (5.6%), and vomiting (5.6%).

Lenvatinib in combination with everolimus in RCC

The safety profile of lenvatinib in combination with everolimus is based on data from 62 patients, allowing characterisation only of common adverse drug reactions in RCC patients from Study 205. The adverse reactions presented in this section are based on the combined safety data of 62 RCC patients from Study 205 (see section 5.1) and 458 DTC patients (see SmPC for Lenvima).

The most frequently reported adverse reactions in the Study 205 RCC and DTC patient populations (occurring in >30% of patients) were diarrhoea (80.6%), hypertension (70.1%), fatigue (59.7%), decreased appetite (53.7%), weight decreased (52.6%), vomiting (48.4%), nausea (45.2%), proteinuria (38.9%), stomatitis (36.9%), headache (35.8%), dysphonia (35.6%), palmar-plantar erythrodysaesthesia syndrome (34.1%), peripheral oedema (33.9%), and hypercholeste­rolemia (30.6%). Hypertension and proteinuria tend to occur early during lenvatinib treatment (see sections 4.4 and 4.8; the asterisked frequencies are from the DTC patient population).

The most important serious adverse reactions included renal failure and impairment (11.3%), arterial thromboembolisms (3.9%), cardiac failure (1.6%), cerebral haemorrhage (1.6%), intracranial tumour haemorrhage (0.7%), PRES / RPLS (0.2%), and hepatic failure (0.2%)* (the asterisked frequencies are from the DTC patient population).

In RCC Study 205 (see section 5.1), adverse reactions led to dose reductions in 67.7% of patients and 18 (29.0%) patients discontinued the treatment. The most common adverse reactions (>5%) resulting in dose reductions in the lenvatinib plus everolimus treated group were diarrhoea (21.0%), thrombocytopenia (6.5%), and vomiting (6.5%).

Tabulated list of adverse reactions for RCC, DTC and HCC studies

Similar adverse reactions were observed in clinical trials in RCC and DTC. Adverse reactions that occur more frequently with lenvatininb and everolimus combination therapy compared to lenvatinib monotherapy are hypothyroidism, (including increased blood thyroid stimulating hormone), hypercholeste­rolaemia, and severe diarrhoea.

Adverse reactions that occured more frequently with lenvatinib and pembrolizumab combination therapy compared to lenvatinib monotherapy were hypothyroidism (including increased blood thyroid stimulating hormone), hypercholeste­rolaemia, diarrhoea, lipase increased, amylase increased, rash (including maculopapular rash), and blood creatinine increased.

Adverse reactions observed in clinical trials and reported from post-marketing use of lenvatinib are listed in Table 4. Adverse reactions known to occur with lenvatinib or combination therapy components given alone may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical studies with combination therapy.

For additional safety information when lenvatinib is administered in combination, refer to the SmPC for the respective combination therapy components.

Frequencies are defined as:

• Very common • Common • Uncommon • Rare • Very rare • Not known

(>1/10) (>1/100 to <1/10) (>1/1,000 to <1/100) (>1/10,000 to <1/1,000) (<1/10,000) (cannot be estimated from the available data)

Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Table 4 Adverse reactions reported in patients treated with lenvatinib§

System organ class (MedDRA terminology)	Monotherapy/com­bination with everolimus	Combination with pembrolizumab
Infections and in	estations
Very common	Urinary tract infection
Common		Urinary tract infection
Uncommon	Perineal abscess	Perineal abscess
Blood and lymphatic disorders
Very common	Thrombocytopenia3 Leukopenia3 Neutropenia3
Common	Lymphopenia3	Thrombocytopenia3 Leukopenia3 Neutropeniaa Lymphopeniaa
Uncommon	Splenic infarction
Endocrine disorc	ers
Very common	Hypothyroidism* Blood thyroid stimulating hormone increased*,	Hypothyroidism Blood thyroid stimulating hormone increased*,
Metabolism and nutrition disorders
Very common	Hypocalcaemia Hypercholeste­rolaemiab" * Hypokalaemia Decreased appetite Decreased weight	Decreased appetite Decreased weight Hypercholeste­rolaemiab
Common	Dehydration Hypomagnesaemiab	Hypocalcaemia Hypokalaemia Dehydration Hypomagnesaemiab
Psychiatric disorders
Very common	Insomnia	Insomnia
Nervous system disorders
Very common	Dizziness Headache Dysgeusia	Dizziness Headache Dysgeusia
Common	Cerebrovascular accident
Uncommon	Posterior reversible encephalopathy syndrome Monoparesis Transient ischaemic attack	Cerebrovascular accident Posterior reversible encephalopathy syndrome Transient ischaemic attack

Cardiac disorders

Common	Myocardial infarction0,* Cardiac failure Prolonged electrocardiogram QT Decreased ejection fraction	Myocardial infarction6, * Prolonged electrocardio­gram QT
Uncommon		Cardiac failure* Decreased ejection fraction
Vascular disorders
Very common	Haemorrhaged, , * Hypertension6, Hypotension	Haemorrhaged, , * Hypertensione, ,
Common		Hypotension
Not known	Aneurysms and artery dissections	Aneurysms and artery dissections
Respiratory, thoracic and mediastinal disorders
Very common	Dysphonia	Dysphonia
Common	Pulmonary embolism	Pulmonary embolism
Uncommon	Pneumothorax	Pneumothorax
Gastrointestinal disorders
Very common	Diarrhoea*, * Gastrointestinal and abdominal painsf Vomiting Nausea Oral inflammation8 Oral painh Constipation Dyspepsia Dry mouth	Diarrhoea*, * Gastrointestinal and abdominal painsf Vomiting Nausea Oral inflammationg Oral painh Constipation Dyspepsia Dry mouth Lipase increased* Amylase increased*
Common	Anal fistula Flatulence Lipase increased Amylase increased	Pancreatitisi Flatulence
Uncommon	Pancreatitisi	Anal fistula
Hepatobiliary disorders
Very common	Blood bilirubin increasedj, * Hypoalbuminaemia* Aspartate aminotransferase increased* Alanine aminotransferase increased*	Aspartate aminotransferase increased* Alanine aminotransferase increased
Common	Hepatic failurek, , * Hepatic encephalopathy , * Cholecystitis Blood alkaline phosphatase increased Hepatic function abnormal Gamma-glutamyltransferase increased	Cholecystitis Hepatic function abnormal Hypoalbuminaemia Blood bilirubin increasedj, * Blood alkaline phosphatase increased Gamma-glutamyltransferase increased
Uncommon	Hepatocellular damage/hepatitism	Hepatic failurek, ,

		Hepatic encephalopathy1, Hepatocellular damage and hepatitism
Skin and subcutaneous tissue disorders
Very common	Palmar-plantar erythrodysaesthesia syndrome Palmar erythema Rash Alopecia	Palmar-plantar erythrodysaesthesia syndrome Rash
Common	Hyperkeratosis	Alopecia Hyperkeratosis
Uncommon		Palmar erythema
Musculoskeletal and connective tissue disorders
Very common	Back pain Arthralgia Myalgia Pain in extremity Musculoskeletal pa­in	Back pain Arthralgia Myalgia Pain in extremity Musculoskeletal pa­in
Uncommon	Osteonecrosis of jaw
Renal and urinary disorders
Very common	Proteinuria*	Proteinuria* Blood creatinine increased*,
Common	Renal failure n, , Renal impairment Blood creatinine increased Blood urea increased	Renal failuren Blood urea increased
Uncommon	Nephrotic syndrome	Renal impairment Nephrotic syndrome
General disorders and administration site conditions
Very common	Fatigue Asthenia Oedema peripheral	Fatigue Asthenia Oedema peripheral
Common	Malaise	Malaise
Uncommon	Impaired healing	Non-gastrointestinal fistulao Impaired healing
Not Known	Non-gastrointestinal fistulao

§: Adverse reaction frequencies presented in Table 4 may not be fully attributable to lenvatinib alone but may contain contributions from the underlying disease or from other medicinal products used in a combination.

: These adverse reactions occur more frequently with combination therapy compared to lenvatinib monotherapy.

• e: Hypertension includes: hypertension, hypertensive crisis, increased blood pressure diastolic, orthostatic hypertension and increased blood pressure.

• f: Gastrointestinal and abdominal pain include: abdominal discomfort, abdominal pain, lower abdominal pain, upper abdominal pain, abdominal tenderness, epigastric discomfort, and gastrointesti­nal pain.

• g: Oral inflammation includes: aphthous stomatitis, aphthous ulcer, gingival erosion, gingival ulceration, oral mucosal blistering, stomatitis, glossitis, mouth ulceration, and mucosal inflammation.

• h: Oral pain includes: oral pain, glossodynia, gingival pain, oropharyngeal discomfort, oropharyngeal pain and tongue discomfort.

• i: Pancreatitis includes: pancreatitis and acute pancreatitis.

• j: Blood bilirubin increased includes: hyperbilirubi­naemia, increased blood bilirubin, jaundice and increased bilirubin

conjugated. Hypoalbuminaemia includes hypoalbuminaemia and decreased blood albumin.

• k: Hepatic failure includes: hepatic failure, acute hepatic failure and chronic hepatic failure.

• l: Hepatic encephalopathy includes: hepatic encephalopathy, coma hepatic, metabolic encephalopathy and encephalopathy.

• m: Hepatocellular damage and hepatitis include: drug-induced liver injury, hepatic steatosis, and cholestatic liver injury.

• n: Renal failure includes: acute prerenal failure, renal failure, renal failure acute, acute kidney injury, and renal tubular necrosis.

4.9 Overdose

The highest doses of lenvatinib studied clinically were 32 mg and 40 mg per day. Accidental medication errors resulting in single doses of 40 to 48 mg have also occurred in clinical trials. The most frequently observed adverse drug reactions at these doses were hypertension, nausea, diarrhea, fatigue, stomatitis, proteinuria, headache, and aggravation of PPE. There have also been reports of overdose with lenvatinib involving single administrations of 6 to 10 times the recommended daily dose. These cases were associated with adverse reactions consistent with the known safety profile of lenvatinib (i.e., renal and cardiac failure), or were without adverse reactions.

There is no specific antidote for overdose with lenvatinib. In case of suspected overdose, lenvatinib should be withheld and appropriate supportive care given as required.

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, protein kinase inhibitors, ATC code: L01EX08

Mechanism of action

Lenvatinib is a receptor tyrosine kinase (RTK) inhibitor that selectively inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4), in addition to other proangiogenic and oncogenic pathway-related RTKs including fibroblast growth factor (FGF) receptors FGFR1, 2, 3, and 4, the platelet derived growth factor (PDGF) receptor PDGFRa, KIT, and RET. In syngeneic mouse tumour models, lenvatinib decreased tumour-associated macrophages, increased activated cytotoxic T cells, and demonstrated greater antitumour activity in combination with an anti-PD-1 monoclonal antibody compared to either treatment alone.

The combination of lenvatinib and everolimus showed increased antiangiogenic and antitumour activity as demonstrated by decreased human endothelial cell proliferation, tube formation, and VEGF signalling in vitro and tumour volume in mouse xenograft models of human renal cell cancer greater than each substance alone.

Although not studied directly with lenvatinib, the mechanism of action (MOA) for hypertension is postulated to be mediated by the inhibition of VEGFR2 in vascular endothelial cells. Similarly, although not studied directly, the MOA for proteinuria is postulated to be mediated by downregulation of VEGFR1 and VEGFR2 in the podocytes of the glomerulus.

The mechanism of action for hypothyroidism is not fully elucidated.

The mechanism of action for the worsening of hypercholeste­rolemia with the combination of lenvatinib and everolimus has not been studied directly and is not fully elucidated.

Although not studied directly, the MOA for the worsening of diarrhoea with the combination of lenvatinib and everolimus is postulated to be mediated by the impairment of intestinal function related to the MOAs for the individual agents – VEGF/VEGFR and c-KIT inhibition by lenvatinib coupled with mTOR/NHE3 inhibition by everolimus.

Clinical efficacy and safety

First-line treatment of patients with RCC (in combination with pembrolizumab)

The efficacy of lenvatinib in combination with pembrolizumab was investigated in Study 307 (CLEAR), a multicentre, open-label, randomized trial that enrolled 1069 patients with advanced RCC with clear cell component including other histological features such as sarcomatoid and papillary in the first-line setting. Patients were enrolled regardless of PD-L1 tumour expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomisation was stratified by geographic region. (North-America and Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favourable, intermediate and poor risk).

Patients were randomized to lenvatinib 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks (n=355), or lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily (n=357), or sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks (n=357). All patients on the lenvatinib plus pembrolizumab arm were started on lenvatinib 20 mg orally once daily. The median time to first dose reduction for lenvatinib was 1.9 months. The median average daily dose for lenvatinib was 14 mg. Treatment continued until unacceptable toxicity or disease progression as determined by the investigator and confirmed by independent radiologic review committee (IRC) using Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST 1.1). Administration of lenvatinib with pembrolizumab was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. Pembrolizumab was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months.

Assessment of tumour status was performed at baseline and then every 8 weeks.

The study population (355 patients in the lenvatinib with pembrolizumab arm and 357 in the sunitinib arm) characteristics were: median age of 62 years (range: 29 to 88 years); 41% age 65 or older, 74% male; 75% White, 21% Asian, 1% Black, and 2% other races; 17% and 83% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by IMDC (International Metastatic RCC Database Consortium) risk categories was 33% favourable, 56% intermediate and 10% poor, and MSKCC prognostic groups was 27% favourable, 64% intermediate and 9% poor. Metastatic disease was present in 99% of the patients and locally advanced disease was present in 1%. Common sites of metastases in patients were lung (69%), lymph node (46%), and bone (26%).

The primary efficacy outcome measure was progression free survival (PFS) based on RECIST 1.1 per IRC. Key secondary efficacy outcome measures included overall survival (OS) and objective response rate (ORR). Median duration of treatment for lenvatinib plus pembrolizumab was 17.0 months. Lenvatinib in combination with pembrolizumab demonstrated statistically significant improvements in PFS, OS and ORR compared with sunitinib. Efficacy results for CLEAR are summarised in Table 5 and Figure 1, at a median OS follow-up time of 26.5 months. PFS results were consistent across pre-specified subgroups, MSKCC prognostic groups and PD-L1 tumour expression status. Efficacy results by MSKCC prognostic group are summarised in Table 6.

Table 5 Efficacy Results in Renal Cell Carcinoma Per IRC in CLEAR
	Lenvatinib 20 mg with Pembrolizumab 200mg N=355	Sunitinib 50mg N=357
Progression-Free Survival (PFS)
Number of events, n (%)	160 (45%)	205 (57%)
Median PFS in months (95% CI)a	23.9 (20.8, 27.7)	9.2 (6.0, 11.0)
Hazard Ratio (95% CI)b, c	0.39 (0.32, 0.49)
p-Valuec	<0.0001
Overall Survival (OS)
Number of deaths, n (%)	80 (23%)	101 (28%)
Median OS in months (95% CI)	NR (33.6, NE)	NR (NE, NE)
Hazard Ratio (95% CT)b, c	0.66 (0.49, 0.88)
p-Valuec	0.0049
Objective Response Rate (Confirmed)
Objective response rate, n (%)	252 (71%)	129 (36%)
(95% CI)	(66, 76)	(31, 41)
Number of complete responses (CR), n (%)	57 (16%)	15 (4%)
Number of partial responses (PR), n (%)	195 (55%)	114 (32%)
p-Valued	<0.0001
Duration of Response3
Median in months (range)	26 (1.6+, 36.8+)	15 (1.6+, 33.2+)
Tumour assessments were based on RECIST 1.1; only confirmed responses are included for ORR. Data cutoff date = 28 Aug 2020 CI = confidence interval; NE= Not estimable; NR= Not reached The primary analysis of PFS included censoring for new anti-cancer treatment. Results for PFS with and without censoring for new anti-cancer treatment were consistent. a Quartiles are estimated by Kaplan-Meier method. b Hazard ratio is based on a Cox Proportional Hazards Model including treatment group as a factor; Efron method is used for ties. c Stratified by geographic region (Region 1: Western Europe and North America, Region 2: Rest of the World) and MSKCC prognostic groups (favourable, intermediate and poor risk) in IxRS. Two-sided p-value based on stratified log-rank test. d  Nominal two-sided p-value based on the stratified Cochran-Mantel-Haenszel (CMH) test. At the earlier pre-specified final analysis of ORR (median follow-up time of 17.3 months), statistically significant superiority was achieved for ORR comparing lenvatinib plus pembrolizumab with sunitinib, (odds ratio: 3.84 (95% CI: 2.81, 5.26), p-value <0.0001).

The primary OS analysis was not adjusted to account for subsequent therapies.

Time (months)

Number of subjects at risk:

L+P=Lenvatinib + Pembrolizumab; S = Sunitinib. Data cut-off date: 28 Aug 2020

An updated OS analysis was performed when patients receiving lenvatinib and pembrolizumab or sunitinib had a median follow-up of 33.4 months. The hazard ratio was 0.72 (95% CI 0.55, 0.93) with 105/355 (30%) deaths in the combination arm and 122/357 (34%) deaths in the sunitinib arm (see Figure 2). This updated OS analysis was not adjusted to account for subsequent therapies.

L+P = Lenvatinib + Pembrolizumab; S = Sunitinib. NE = Not estimable. Data cut-off date: 31 Mar 2021

The CLEAR study was not powered to evaluate efficacy of individual subgroups. Table 6 summarises the efficacy measures by MSKCC prognostic group from the pre-specified primary analysis and the updated OS analysis.

Table 6 Efficacy Results in CLEAR by MSKCC Prognostic Group

	Lenvatinib + Pembrolizumab (N=355)		Sunitinib (N=357)		Lenvatinib + Pembrolizumab vs. Sunitinib
	Number of Patients	Number of Events	Number of Patients	Number of Events
Progression-Free Surviva	(PFS) by IRCa				PFS HR (95% CI)
Favourable	96	39	97	60	0.36 (0.23, 0.54)
Intermediate	227	101	228	126	0.44 (0.34, 0.58)
Poor	32	20	32	19	0.18 (0.08, 0.42)
Overall Survival (OS)a					OS HR (95% CI)
Favourableb	96	11	97	13	0.86 (0.38, 1.92)
Intermediate	227	57	228	73	0.66 (0.47, 0.94)
Poor	32	12	32	15	0.50 (0.23, 1.08)
Updated OS c					OS HR (95% CI)
Favourableb	96	17	97	17	1.00 (0.51, 1.96)
Intermediate	227	74	228	87	0.71 (0.52, 0.97)
Poor	32	14	32	18	0.50 (0.25, 1.02)

a Median follow up 26.5 months (DCO – 28 August 2020)

b Interpretation of HR is limited by the low number of events (24/193 and 34/193)

cMedian follow up 33.4 months (DCO – 31 March 2021)

Second-line treatment of patients with RCC (in combination with everolimus)

Study 205, a multicentre, randomised, open-label, trial was conducted to determine the safety and efficacy of lenvatinib administered alone or in combination with everolimus in patients with unresectable advanced or metastatic RCC. The study consisted of a Phase 1b dose finding and a Phase 2 portion. The Phase 1b portion included 11 patients who received the combination of 18 mg of lenvatinib plus 5 mg of everolimus. The Phase 2 portion enrolled a total of 153 patients with unresectable advanced or metastatic RCC following 1 prior VEGF-targeted treatment. A total of 62 patients received the combination of lenvatinib and everolimus at the recommended dose. Patients were required, among others, to have histological confirmation of predominant clear cell RCC, radiographic evidence of disease progression according to RECIST 1.1, one prior VEGF-targeted therapy and Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1.

Patients were randomly allocated to one of 3 arms: 18 mg of lenvatinib plus 5 mg of everolimus, 24 mg of lenvatinib or 10 mg of everolimus using a 1:1:1 ratio. Patients were stratified by haemoglobin level (<13 g/dL vs. >13 g/dL for males and <11.5 g/dL vs >11.5 g/dL for females) and corrected serum calcium (>10 mg/dL vs. <10 mg/dL). The median of average daily dose in the combination arm per patient was 13.5 mg of lenvatinib (75.0% of the intended dose of 18 mg) and 4.7 mg of everolimus (93.6% of the intended dose of 5 mg). The final dose level in the combination arm was 18 mg for 29% of patients, 14 mg for 31% of patients, 10 mg for 23% of patients, 8 mg for 16% of patients and 4 mg for 2% of patients.

Of the 153 patients randomly allocated, 73% were male, the median age was 61 years, 37% were 65 years or older, 7% were 75 years or older, and 97% were Caucasian. Metastases were present in 95% of the patients and unresectable advanced disease was present in 5%. All patients had a baseline ECOG PS of either 0 (55%) or 1 (45%) with similar distribution across the 3 treatment arms. Memorial Sloan Kettering Cancer Centre (MSKCC) poor risk was observed in 39% of patients in the lenvatinib plus everolimus arm, 44% in the lenvatinib arm and 38% in the everolimus arm. International mRCC Database Consortium (IMDC) poor risk was observed in 20% of patients in the lenvatinib plus everolimus arm, 23% in the lenvatinib arm, and 24% in the everolimus arm. The median time from diagnosis to first dose was 32 months in the lenvatinib plus everolimus-treatment arm, 33 months in the lenvatinib arm and 26 months in the everolimus arm. All patients had been treated with 1 prior VEGF-inhibitor; 65% with sunitinib, 23% with pazopanib, 4% with tivozanib, 3% with bevacizumab, and 2% each with sorafenib or axitinib.

The primary efficacy outcome measure, based on investigator assessed tumour response, was PFS of the lenvatinib plus everolimus arm vs the everolimus arm and of the lenvatinib arm vs the everolimus arm. Other efficacy outcome measures included OS and investigator-assessed ORR. Tumour assessments were evaluated according to RECIST 1.1.

The lenvatinib plus everolimus arm showed a statistically significant and clinically meaningful improvement in PFS compared with the everolimus arm (see Table 7 and Figure 3). Based on the results of a post-hoc exploratory analysis in a limited number of patients per subgroup, the positive effect on PFS was seen regardless of which prior VEGF-targeted therapy was used: sunitinib (Hazard ratio [HR] = 0.356 [95% CI: 0.188, 0.674] or other therapies (HR = 0.350 [95% CI: 0.148, 0.828]). The lenvatinib arm also showed an improvement in PFS compared with the everolimus arm. Overall survival was longer in the lenvatinib plus everolimus arm (see Table 7 and Figure 4). The study was not powered for the OS analysis.

The treatment effect of the combination on PFS and ORR was also supported by a post-hoc retrospective independent blinded review of scans. The lenvatinib plus everolimus arm showed a statistically significant and clinically meaningful improvement in PFS compared with the everolimus arm. Results for ORR were consistent with that of the investigators’ assessments, 35.3% in the lenvatinib plus everolimus arm, with one complete response and 17 partial responses; no patient had an objective response in the everolimus arm (P < 0.0001) in favour of the lenvatinib plus everolimus arm.

Table 7 Efficacy results following one prior VEGF targeted therapy in RCC Study 205

	lenvatinib 18 mg + everolimus 5 mg (N=51)	lenvatinib 24 mg (N=52)	everolimus 10 mg (N=50)
Progression-free survival (PFS)a by investigator assessment
Median PFS in months (95% CI)	14.6 (5.9, 2O.1)	7.4 (5.6, 10.2)	5.5 (3.5, 7.1)
Hazard Ratio (95% CI)b lenvatinib + everolimus vs everolimus	O.4O (O.24, 0.67)	–	–
P Value lenvatinib + everolimus vs everolimus	0.0005	–	–
Progression-free survival (PFS)a by post-hoc retrospective independent review
Median PFS in months (95% CI)	12.8 (7.4, 17.5)	9.0 (5.6, 1O.2)	5.6 (3.6, 9.3)
Hazard Ratio (95% CI)b lenvatinib + everolimus vs everolimus	0.45 (O.26, O.79)	–	–
P Value lenvatinib + everolimus vs everolimus	0.003	–	–
Overall Survivalc
Number of deaths, n (%)	32 (63)	34 (65)	37 (74)
Median OS in months (95% CI)	25.5 (16.4, 32.1)	19.1 (13.6, 26.2)	15.4 (11.8, 20.6)
Hazard Ratio (95% CI) b lenvatinib + everolimus vs everolimus	0.59 (O.36, O.97)	–	–
Objective Response Rate n (%) by investigator assessment
Complete responses	1 (2)	0	0
Partial responses	21 (41)	14 (27)	3 (6)
Objective Response Rate	22 (43)	14 (27)	3 (6)
Stable disease	21 (41)	27 (52)	31 (62)
Duration of response, months, median (95% CI)	13.O (3.7, NE)	7.5 (3.8, NE)	8.5 (7.5, 9.4)

Tumour assessment was based on RECIST 1.1 criteria. Data cut-off date = 13 Jun 2014

Percentages are based on the total number of patients in the Full Analysis Set within relevant treatment group.

CI = confidence interval, NE = not estimable

aPoint estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation. bStratified hazard ratio is based on a stratified Cox regression model including treatment as a covariate factor and haemoglobin and corrected serum calcium as strata. The Efron method was used for correction for tied events.

cData cut-off date = 31 Jul 2015

Figure 4 Kaplan-Meier Plot of Overall Survival

Time (months)

Number of subjects at risk:

L(18mg + E (5mg)	51	48	46	44	37	35	32	30	26	17	11	7	2	0	0
L(24mg)	52	50	45	42	37	31	28	23	19	12	7	3	2	1	0
E(10mg)	50	46	42	38	30	27	20	17	13	10	9	5	1	0	0

L(18mg) + E(5mg)=Lenvatinig 18mg + Everolimus 5mg; L(24mg)=Lenvatinib 24; E(10mg)=Everolimus 10mg Data Cutoff Date: 31JUL2015

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with lenvatinib in one or more subsets of the paediatric population in the treatment of renal cell carcinoma (RCC) (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Pharmacokinetic parameters of lenvatinib have been studied in healthy adult subjects, adult subjects with hepatic impairment, renal impairment, and solid tumours.

Absorption

Lenvatinib is rapidly absorbed after oral administration with tmax typically observed from 1 to 4 hours postdose. Food does not affect the extent of absorption, but slows the rate of absorption. When administered with food to healthy subjects, peak plasma concentrations are delayed by 2 hours. Absolute bioavailability has not been determined in humans; however, data from a mass-balance study suggests that it is in the order of 85%.

Distribution

In vitro binding of lenvatinib to human plasma proteins is high and ranged from 98% to 99%

(0.3 – 30 pg/mL, mesilate). This binding was mainly to albumin with minor binding to a1-acid glycoprotein and Y—globulin. A similar plasma protein binding (97% to 99%) with no dependencies on lenvatinib concentrations (0.2 to 1.2 pg/mL) was observed in plasma from hepatically impaired, renally impaired, and matching healthy subjects.

In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 pg/mL, mesilate).

In vitro studies indicate that lenvatinib is a substrate for P-gp and BCRP. Lenvatinib shows minimal or no inhibitory activities toward P-gp mediated and BCRP mediated transport activities. Similarly, no induction of P-gp mRNA expression was observed. Lenvatinib is not a substrate for OAT1, OAT3, OATP1B1, OATP1B3, OCT1, OCT2, or the BSEP. In human liver cytosol, lenvatinib did not inhibit aldehyde oxidase activity.

In patients, the median apparent volume of distribution (Vz/F) of the first dose ranged from 50.5 L to 92 L and was generally consistent across the dose groups from 3.2 mg to 32 mg. The analogous median apparent volume of distribution at steady-state (Vz/Fss) was also generally consistent and ranged from 43.2 L to 121 L.

Biotransformation

In vitro, cytochrome P450 3A4 was demonstrated as the predominant (>80%) isoform involved in the P450-mediated metabolism of lenvatinib. However, in vivo data indicated that non-P450-mediated pathways contributed to a significant portion of the overall metabolism of lenvatinib. Consequently, in vivo, inducers and inhibitors of CYP 3A4 had a minimal effect on lenvatinib exposure (see section 4.5).

In human liver microsomes, the demethylated form of lenvatinib (M2) was identified as the main metabolite. M2’ and M3’, the major metabolites in human faeces, were formed from M2 and lenvatinib, respectively, by aldehyde oxidase.

In plasma samples collected up to 24 hours after administration, lenvatinib constituted 97% of the radioactivity in plasma radiochromatograms while the M2 metabolite accounted for an additional 2.5%. Based on AUC(o — inf), lenvatinib accounted for 60% and 64% of the total radioactivity in plasma and blood, respectively.

Data from a human mass balance/excretion study indicate lenvatinib is extensively metabolised in humans. The main metabolic pathways in humans were identified as oxidation by aldehyde oxidase, demethylation via CYP3A4, glutathione conjugation with elimination of the O-aryl group (chlorophenyl moiety), and combinations of these pathways followed by further biotransformations (e.g., glucuronidation, hydrolysis of the glutathione moiety, degradation of the cysteine moiety, and intramolecular rearrangement of the cysteinylglycine and cysteine conjugates with subsequent dimerisation). These in vivo metabolic routes align with the data provided in the in vitro studies using human biomaterials.

In vitro transporter studies

Please see distribution section.

Elimination

Plasma concentrations decline bi-exponentially following Cmax. The mean terminal exponential half-life of lenvatinib is approximately 28 hours.

Following administration of radiolabelled lenvatinib to 6 patients with solid tumours, approximately two-thirds and one-fourth of the radiolabel were eliminated in the faeces and urine, respectively. The M3 metabolite was the predominant analyte in excreta (~17% of the dose), followed by M2’ (~11% of the dose) and M2 (~4.4 of the dose).

Linearity/non-linearity

Dose proportionality and accumulation

In patients with solid tumours administered single and multiple doses of lenvatinib once daily, exposure to lenvatinib (Cmax and AUC) increased in direct proportion to the administered dose over the range of 3.2 to 32 mg once-daily.

Lenvatinib displays minimimal accumulation at steady state. Over this range, the median accumulation index (Rac) ranged from 0.96 (20 mg) to 1.54 (6.4 mg).

Special populations

Hepatic impairment

The pharmacokinetics of lenvatinib following a single 10-mg dose were evaluated in 6 subjects each with mild and moderate hepatic impairment (Child-Pugh A and Child-Pugh B, respectively). A 5-mg dose was evaluated in 6 subjects with severe hepatic impairment (Child-Pugh C). Eight healthy, demographically matched subjects served as controls and received a 10-mg dose. The median half-life was comparable in subjects with mild, moderate, and severe hepatic impairment as well as those with normal hepatic function and ranged from 26 hours to 31 hours. The percentage of the dose of lenvatinib excreted in urine was low in all cohorts (<2.16% across treatment cohorts).

Lenvatinib exposure, based on dose-adjusted AUC(0-t) and AUC(0-inf) data, was 119%, 107%, and 180% of normal for subjects with mild, moderate, and severe hepatic impairment, respectively. It has been determined that plasma protein binding in plasma from hepatically impaired subjects was similar to the respective matched healthy subjects and no concentration dependency was observed. See section 4.2 for dosing recommendation.

Renal impairment

The pharmacokinetics of lenvatinib following a single 24-mg dose were evaluated in 6 subjects each with mild, moderate, and severe renal impairment, and compared with 8 healthy, demographically matched subjects. Subjects with end-stage renal disease were not studied.

Lenvatinib exposure, based on AUC(0-inf) data, was 101%, 90%, and 122% of normal for subjects with mild, moderate, and severe renal impairment, respectively. It has been determined that plasma protein binding in plasma from renally impaired subjects was similar to the respective matched healthy subjects and no concentration dependency was observed. See section 4.2 for dosing recommendation.

Age, sex, weight, ethnic origin

Based on a population pharmacokinetic analysis of patients receiving up to 24 mg lenvatinib once daily, age, sex, weight, and race (Japanese vs. other, Caucasian vs. other) had no significant effects on clearance (see section 4.2).

Paediatric population

Paediatric patients have not been studied.

5.3 Preclinical safety data

In the repeated-dose toxicity studies (up to 39 weeks), lenvatinib caused toxicologic changes in various organs and tissues related to the expected pharmacologic effects of lenvatinib including glomerulopathy, testicular hypocellularity, ovarian follicular atresia, gastrointestinal changes, bone changes, changes to the adrenals (rats and dogs), and arterial (arterial fibrinoid necrosis, medial degeneration, or haemorrhage) lesions in rats, dogs, and cynomolgus monkeys. Elevated transaminase levels asociated with signs of hepatotoxicity, were also observed in rats, dogs and monkeys. Reversibility of the toxicologic changes was observed at the end of a 4-week recovery period in all animal species investigated.

Genotoxicity

Lenvatinib was not genotoxic.

Carcinogenicity studies have not been conducted with lenvatinib.

Reproductive and developmental toxicity

No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility.

However, testicular (hypocellularity of the seminiferous epithelium) and ovarian changes (follicular atresia) were observed in repeated-dose toxicity studies in animals at exposures 11 to 15 times (rat) or 0.6 to 7 times (monkey) the anticipated clinical exposure (based on AUC) at the maximum tolerated human dose. These findings were reversible at the end of a 4-week recovery period.

Administration of lenvatinib during organogenesis resulted in embryolethality and teratogenicity in rats (foetal external and skeletal anomalies) at exposures below the clinical exposure (based on AUC) at the maximum tolerated human dose, and rabbits (foetal external, visceral or skeletal anomalies) based on body surface area; mg/m2 at the maximum tolerated human dose. These findings indicate that lenvatinib has a teratogenic potential, likely related to the pharmacologic activity of lenvatinib as an antiangiogenic a­gent.

Lenvatinib and its metabolites are excreted in rat milk.

Juvenile animal toxicity studies

Mortality was the dose-limiting toxicity in juvenile rats in which dosing was initiated on postnatal day (PND) 7 or PND21 and was observed at exposures that were respectively 125– or 12-fold lower compared with the exposure at which mortality was observed in adult rats, suggesting an increasing sensitivity to toxicity with decreasing age. Therefore mortality may be attributed to complications related to primary duodenal lesions with possible contribution from additional toxicities in immature target organs.

The toxicity of lenvatinib was more prominent in younger rats (dosing initiated on PND7) compared with those with dosing initiated on PND21 and mortality and some toxicities were observed earlier in the juvenile rats at 10 mg/kg compared with adult rats administered the same dose level. Growth retardation, secondary delay of physical development, and lesions attributable to pharmacologic effects (incisors, femur [epiphyseal growth plate], kidneys, adrenals, and duodenum) were also observed in juvenile rats.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Capsule contents

Calcium carbonate

Mannitol

Microcrystalline cellulose

Hydroxypropyl­cellulose

Low-substituted hydroxypropyl­cellulose

Talc

Capsule shell

Hypromellose

Titanium dioxide (E171)

Yellow iron oxide (E172)

Red iron oxide (E172)

Printing ink

Shellac

Black iron oxide (E172)

Potassium hydroxide

Propylene glycol

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

4 years.

6.4 Special precautions for storage

Do not store above 25°C.

Store in the original blister in order to protect from moisture.

6.5 Nature and contents of container

Polyamide/Alu­minium/PVC/Alu­minium blisters containing 10 capsules. Each carton contains

30, 60, or 90 hard capsules. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Caregivers should not open the capsule, in order to avoid repeated exposure to the contents of the capsule.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

Eisai GmbH

Edmund-Rumpler-StraBe 3

60549 Frankfurt am Main

Germany

E-mail:

8. MARKETING AUTHORISATION NUMBER(S)

Kisplyx 4 mg hard capsules

EU/1/16/1128/001

EU/1/16/1128/003

EU/1/16/1128/004

Kisplyx 10 mg hard capsules

EU/1/16/1128/002

EU/1/16/1128/005

EU/1/16/1128/006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 25 August 2016

ZDate of latest renewal: 17 June 2021