Overview Pembrolizumab with lenvatinib for previously treated advanced or recurrent endometrial cancer Guidance

M2′ and M3′, the major metabolites in human faeces, were formed from M2 and lenvatinib, respectively, by aldehyde oxidase. In vitro, the lenvatinib blood-to-plasma concentration ratio ranged from 0.589 to 0.608 (0.1 – 10 μ g/mL, mesilate). In case of suspected overdose, lenvatinib should be withheld and appropriate supportive care given as required. 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). Lenvatinib was embryotoxic and teratogenic when administered to rats and rabbits (see section 5.3).

• In the Phase 3 Study 309 (see section 5.1), cardiac dysfunction was reported in 1.0% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 0.5% of patients.
• Patients ≥ 75 years, of white race or female sex or those with worse baseline hepatic impairment (Child-Pugh A score of 6 compared to score of 5) appear to have reduced tolerability to lenvatinib.
• Lenvima for treatment of papillary thyroid cancer and treatment of follicular thyroid cancer was withdrawn from the Community register of orphan medicinal products in August 2018 upon request of the marketing authorisation holder.
• In the case of bleeding, dose interruptions, adjustments, or discontinuation may be required (see section 4.2, Table 3).
• No adjustment of starting dose is required on the basis of race (see section 5.2).
• Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab.
• No specific studies with lenvatinib have been conducted in animals to evaluate the effect on fertility.
• This is to help lower your risk of getting COVID-19 while having cancer treatment and until your immune system recovers from treatment.

LENVIMA 4 mg hard capsules

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 20 mg orally once daily in combination with pembrolizumab 200 mg intravenously every 3 weeks. When administering LENVIMA in combination with pembrolizumab, interrupt, dose reduce, or discontinue LENVIMA as appropriate (see Table 3). Withhold or discontinue pembrolizumab in accordance with the instructions in the SmPC for pembrolizumab. The Japanese company also recently signed an agreement with Merck & Co to test the combination of Lenvima and PD-1 inhibitor Keytruda (pembrolizumab) in thyroid cancer and other solid tumours. Thyroid cancer incidence rates have increased in the UK over the past few decades.

Information about lenvatinib

Events of gastrointestinal perforation were reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 3.0% of patients. Dose interruption and discontinuation of lenvatinib occurred in 0.5% and 3.0% of patients, respectively. In the Phase 3 Study 309 (see section 5.1), proteinuria was reported in 29.6% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 5.4% of patients. Dose interruption, reduction and discontinuation of lenvatinib occurred in 6.2%, 7.9% and 1.2% of patients, respectively. In the Phase 3 Study 309 (see section 5.1), hepatotoxicity was reported in 33.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 12.1% of patients. Dose interruption, reduction and discontinuation of lenvatinib occurred in 5.2%, 3.0% and 1.2 % of patients, respectively.

Lenvatinib for untreated advanced hepatocellular carcinoma

Dose interruption and discontinuation of lenvatinib occurred in 0.2% and 2.0% of patients, respectively. Dose reduction of lenvatinib due to adverse reactions occurred in 67.0% of patients. Discontinuation of lenvatinib occurred in 30.6% of patients, and discontinuation of both lenvatinib and pembrolizumab occurred in 15.3% of patients due to an adverse reaction.

Other medicines, foods and drinks

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). 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 for dosing in patients with renal impairment.

Changes since initial authorisation of medicine

In the pivotal Phase 3 SELECT trial (see section 5.1), QT/QTc interval prolongation was reported in 8.8% of lenvatinib-treated patients and 1.5% of patients in the placebo group. The incidence of QT interval prolongation of greater than 500 ms was 2% in the lenvatinib-treated patients compared to no reports in the placebo group. In the pivotal Phase 3 SELECT trial (see section 5.1), events of gastrointestinal perforation or fistula were reported in 1.9% of lenvatinib-treated patients and 0.8% of patients in the placebo group. Amongst 1,823 patients treated with lenvatinib monotherapy in clinical trials, there were 5 cases (0.3%) of PRES (0.2% were Grade 3 or 4), all of which resolved after treatment and/or dose interruption, or permanent discontinuation.

Changes to levels of thyroid hormones

• Management of some adverse reactions may require dose interruption, adjustment, or discontinuation of lenvatinib therapy.
• If urine dipstick proteinuria ≥ 2+ is detected, dose interruptions, adjustments, or discontinuation may be necessary (see section 4.2).
• The early detection and effective management of hypertension are important to minimise the need for lenvatinib dose interruptions and reductions.
• There are not sufficient data for HCC patients with Child-Pugh B (moderate hepatic impairment, 3 patients treated with lenvatinib in the pivotal trial) and no data available in Child-Pugh C HCC patients (severe hepatic impairment).
• Experts estimate that there are approximately 250 people in the UK living with RAI refractory DTC.
• 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.

In the Phase 3 REFLECT trial (see section 5.1), 7.1% of lenvatinib-treated patients developed a renal failure/impairment event. Grade 3 or greater reactions occurred in 1.9% of lenvatinib-treated patients. The safety profile of lenvatinib as combination therapy is based on data from 530 EC patients treated with lenvatinib in combination with pembrolizumab (see section 5.1). The safety profile of lenvatinib as monotherapy is based on data from 452 DTC patients and 496 HCC patients; allowing characterisation only of common adverse drug reactions in DTC and HCC patients. The adverse reactions presented in this section are based on safety data of both DTC and HCC patients (see section 5.1). No adjustment of starting dose is required on the basis of hepatic function in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment.

Changes to your blood pressure

In the Phase 3 REFLECT trial (see section 5.1), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group. 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. For use in combination with pembrolizumab, refer to the SmPC for pembrolizumab. Treatment 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).

Recommended

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.

How do you have lenvatinib?

• It’s a worrying time for many people and we want to be there for you whenever – and wherever – you need us.
• A larger proportion of Asian patients had a lenvatinib dose reduction compared to Caucasian patients.
• Adverse reactions that most commonly led to dose reductions (in ≥ 5% of patients) were hypertension, proteinuria, diarrhoea, fatigue, PPE, decreased weight, and decreased appetite.
• Cases of nephrotic syndrome have been reported in patients using lenvatinib.
• For the full list of side effects with Lenvima, see the package leaflet.
• Your doctor will discuss the results of these tests with you and decide whether you can be given LENVIMA.
• 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).

In the Phase 3 REFLECT trial (see section 5.1), diarrhoea was reported in 38.7% of patients treated with lenvatinib (4.2% were Grade ≥ 3). In the Phase 3 REFLECT trial (see section 5.1), arterial thromboembolic events were reported in 2.3% of patients treated with lenvatinib. In the Phase 3 REFLECT trial (see section 5.1), cardiac dysfunction (including congestive cardiac failure, cardiogenic shock, and cardiopulmonary failure) was reported in 0.6% of patients (0.4% were Grade ≥ 3) in the lenvatinib-treated group. In the pivotal Phase 3 SELECT trial (see section 5.1), decreased ejection fraction/cardiac failure was reported in 6.5% of patients (1.5% were Grade ≥ 3) in the lenvatinib-treated group, and 2.3% in the placebo group (none were Grade ≥ 3). If patients have severe renal impairment, the initial dose of lenvatinib should be adjusted (see sections 4.2 and 5.2). Data in HCC patients with moderate hepatic impairment (Child-Pugh B) are very limited and there are currently no data available in HCC patients with severe hepatic impairment (Child-Pugh C).

In 496 patients with HCC, dose modification (interruption or reduction) and discontinuation were the actions taken for an adverse reaction in 62.3% and 20.2% of patients, respectively. Adverse reactions that most commonly led to dose modifications (in ≥ 5% of patients) were decreased appetite, diarrhoea, proteinuria, hypertension, fatigue, PPE and decreased platelet count. Adverse reactions that most commonly led to discontinuation of lenvatinib were hepatic encephalopathy, fatigue, increased blood bilirubin, proteinuria and hepatic failure. Hypertension has been reported in patients treated with lenvatinib, usually occurring early in the course of treatment (see section 4.8).

Lenvima has demonstrated significantly prolonged progression-free survival

Side effects reported with Lenvima are carefully evaluated and any necessary action taken to protect patients. The active substance in Lenvima, lenvatinib, is a tyrosine-kinase inhibitor. This means that it blocks the activity of enzymes known as tyrosine kinases. These enzymes can be found in certain receptors (such as VEGF, FGFR and RET receptors) in cancer cells, where they activate several processes including cell division and the growth of new blood vessels. By blocking these enzymes, lenvatinib can block the formation of new blood vessels and hence cut off the blood supply that keeps cancer cells growing, and reduce their growth. Lenvatinib may also alter the activity of the immune system (the body’s natural defences).

More information about this treatment

This means that it is a medicine of major interest for public health, so its timeframe for review was 150 evaluation days rather than 210. Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Lenvima have been included in the summary of product characteristics and the package leaflet. To manage side effects, the doctor may decide to reduce the dose or stop treatment temporarily. Lenvima can only be obtained with a prescription and treatment must be started and supervised by a doctor who is experienced in using cancer medicines. You might have liver changes that are usually mild and unlikely to cause symptoms.

Increased risk of infection

In the Phase 3 Study 309 (see section 5.1), there was one event of PRES (Grade 1) in the lenvatinib plus pembrolizumab-treated group for which lenvatinib was interrupted. For additional safety information when lenvatinib is administered in combination, refer to the SmPC for the respective combination therapy component (pembrolizumab). 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. No adjustment of starting dose is required on the basis of race (see section 5.2). Limited data are available on use in patients from ethnic origins other than Caucasian or Asian (see section 4.8).

Lenvatinib (Lenvima, Kisplyx)

• Amongst 1,823 patients treated with lenvatinib monotherapy in clinical trials, there were 10 cases (0.5%) of arterial thromboembolisms (5 cases of myocardial infarction and 5 cases of cerebrovascular accident) with a fatal outcome.
• LENVIMA as monotherapy is indicated for the treatment of adult patients with progressive, locally advanced or metastatic, differentiated (papillary/follicular/Hü rthle cell) thyroid carcinoma (DTC), refractory to radioactive iodine (RAI).
• Lenvatinib should be used with caution in such patients, given the reduced tolerability of lenvatinib in Asian and elderly patients (see section 4.8).
• In the Phase 3 REFLECT trial (see section 5.1), there was 1 event of PRES (Grade 2) in the lenvatinib-treated group.
• This treatment can change the levels of potassium, magnesium, calcium, creatinine and cholesterol in your blood.
• This means that it is a medicine of major interest for public health, so its timeframe for review was 150 evaluation days rather than 210.
• In the Phase 3 Study 309 (see section 5.1), hepatotoxicity was reported in 33.7% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 12.1% of patients.

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). It will compete in Europe with Bayer’s kinase inhibitor Nexavar (sorafenib), which was approved for radioactive-iodine refractory DTC by the EMA last year and by the US FDA in 2013. At the time Nexavar was reported to be the first targeted therapy to become available for refractory DTC in four decades. The EMA gave a green light to the product late last month for use progressive, locally advanced or metastatic differentiated (papillary, follicular, Hürthle cell) thyroid carcinoma (DTC) after an accelerated, nine-month review. Lenvima, discovered and developed by Eisai, is an oral molecular tri-specific targeted therapy that possesses a potent selectivity and a binding mode different to other tyrosine kinase inhibitors (TKI). Lenvima simultaneously inhibits the activities of several different molecules including vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR) RET KIT and platelet-derived growth factor receptors (PDGFR).

Lenvatinib exposure, based on dose-adjusted AUC0-t and AUC0-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. A single 32-mg dose of lenvatinib did not prolong the QT/QTc interval based on results from a thorough QT study in healthy volunteers; however, QT/QTc interval prolongation has been reported at a higher incidence in patients treated with lenvatinib than in patients treated with placebo (see sections 4.4 and 4.8). In Study 231, the most frequently reported (≥ 15%) adverse drug reactions were hypothyroidism, hypertension, proteinuria, decreased appetite, diarrhoea, and platelet count decreased. In the OLIE study (Study 230), the most frequently (≥ 35%) reported adverse drug reactions were hypothyroidism, anaemia, nausea, platelet count decreased, proteinuria, vomiting, back pain, febrile neutropenia, hypertension, constipation, diarrhoea, neutrophil count decreased, and pyrexia. In the pivotal Phase 3 SELECT trial (see section 5.1), arterial thromboembolic events were reported in 5.4% of lenvatinib-treated patients and 2.3% of patients in the placebo group.

Pembrolizumab with lenvatinib for previously treated advanced or recurrent endometrial cancer

Limited data are available on use in patients aged ≥ 75 years (see section 4.8). Patients ≥ 75 years, of white race or female sex or those with worse baseline hepatic impairment (Child-Pugh A score of 6 compared to score of 5) appear to have reduced tolerability to lenvatinib. Initiate medical management for nausea, vomiting, or diarrhoea prior to interruption or dose reduction. For lenvatinib-related erlotinib price in philippines toxicities (see Table 4), 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. The recommended daily dose of lenvatinib is 24 mg (two 10-mg capsules and one 4-mg capsule) once daily. The daily dose is to be modified as needed according to the dose/toxicity management plan.

The choice of antihypertensive treatment should be individualised to the patient’s clinical circumstances and follow standard medical practice. For previously normotensive subjects, monotherapy with one of the classes of antihypertensives 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. In the Phase 3 Study 309 (see section 5.1), 18.2% of lenvatinib plus pembrolizumab-treated patients developed a renal failure/impairment event. Dose interruption, reduction and discontinuation of lenvatinib occurred in 3.0%, 1.7% and 1.2% of patients, respectively. In the pivotal Phase 3 SELECT trial (see section 5.1), proteinuria was reported in 33.7% of lenvatinib-treated patients and 3.1% of patients in the placebo-treated group.

The majority of cases recovered following dose interruption or reduction, which occurred in 6.9% and 2.5% of patients, respectively. Proteinuria led to permanent treatment discontinuation in 0.6% of patients. In the Phase 3 Study 309 (see section 5.1), events of fistula formation were reported in 2.5% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 2.5% of patients.

In patients with severe (Child-Pugh C) hepatic impairment, the recommended starting dose is 14 mg taken once daily. “As a disease with few treatment options the launch of lenvatinib in the UK helps address the significant medical need for those people living with this aggressive form of thyroid cancer. The data show lenvatinib’s proven benefits in progression-free survival which means patients will now have more time before their cancer progresses something we know is incredibly important for people with an advanced cancer” commented Dr Kate Newbold Consultant Clinical Oncologist at The Royal Marsden London. 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. In the Phase 3 REFLECT trial (see section 5.1), 89.6% of patients had a baseline TSH level of less than the upper limit of normal. Elevation of TSH above the upper limit of normal was observed post baseline in 69.6% of lenvatinib-treated patients.

• Evidence-based recommendations on lenvatinib (Lenvima) for untreated advanced hepatocellular carcinoma in adults.
• LENVIMA blocks the action of proteins called receptor tyrosine kinases (RTKs), which are involved in the development of new blood vessels that supply oxygen and nutrients to cells and help them to grow.
• 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.
• Please refer to the SmPC for pembrolizumab for dosing in patients with hepatic impairment.
• “The launch of Lenvima represents great news for both Eisai and for patients who will now have access to this significant new treatment.
• In the Phase 3 REFLECT trial (see section 5.1), hypocalcaemia was reported in 1.1% of patients, with grade 3 reactions occurring in 0.4%.

DTC accounts for 95% of the 52,000 cases of thyroid cancer that are diagnosed each year in Europe, according to Eisai, which is also testing the drug in other cancers, including hepatocellular carcinoma (phase III) as well as renal cell carcinoma and non-small cell lung cancer (phase II). The launch of Lenvima (lenvatinib mesylate) in the UK comes just days after it was approved by the European Medicines Agency (EMA) for the treatment of adults with advanced thyroid cancer refractor to treatment with radioactive iodine. Lenvima is indicated for the treatment of adult patients with progressive locally advanced or metastatic differentiated (papillary follicular Hürthle cell) thyroid carcinoma (DTC) refractory to radioactive iodine (RAI). Lenvima® (lenvatinib) launches in the UK today as a treatment option for people with radioactive iodine refractory differentiated thyroid cancer (RAI refractory DTC).

The majority of cases recovered or resolved following dose interruption or reduction, which occurred in 13.0% and 13.4% of patients, respectively. In 1.1% of patients, hypertension led to permanent treatment discontinuation. The safety of lenvatinib in combination with pembrolizumab has been evaluated in 530 patients with advanced EC receiving 20 mg lenvatinib once daily and 200 mg pembrolizumab every 3 weeks. In the Phase 3 REFLECT trial (see section 5.1), hypertension (including hypertension, increased blood pressure, increased diastolic blood pressure and orthostatic hypertension) was reported in 44.5% of lenvatinib-treated patients and Grade 3 hypertension occurred in 23.5%. The majority of cases recovered following dose interruption or reduction, which occurred in 3.6% and 3.4% of patients, respectively.

In the Phase 3 Study 309 (see section 5.1), hypocalcaemia was reported in 3.9% of lenvatinib plus pembrolizumab-treated patients and Grade ≥ 3 reactions occurred in 1.0% of patients. The most common (occurring in ≥ 5% of patients) severe (Grade ≥ 3) adverse reactions were hypertension (37.2%), decreased weight (9.1%), diarrhoea (8.1%), increased lipase (7.7%), decreased appetite (6.4%), asthenia (6%), fatigue (6%), hypokalaemia (5.7%), anaemia (5.3%) and proteinuria (5.1%). These patients also had a higher incidence of renal reactions and a trend towards a higher incidence of liver reactions.

The SELECT study is a randomised, double-blind, multicentre trial for people with progressive radioactive iodine refractory differentiated thyroid cancer. Lenvima significantly improves objective response rate versus placebo. 2.2 The daily dose of lenvatinib in the summary of product characteristics is 8 mg (2×4 mg capsules) given orally for patients who weigh less than 60 kg, and 12 mg (3×4 mg capsules) orally for patients who weigh 60 kg or over (based on company submission). The summary of product characteristics advises that dose adjustments are not needed on the basis of hepatic function in people with Child–Pugh grade A liver 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.

The most common (occurring in ≥ 1% of patients) adverse reactions leading to discontinuation of lenvatinib were hypertension (1.9%), diarrhoea (1.3%), asthenia (1.3%), decreased appetite (1.3%), proteinuria (1.3%) and decreased weight (1.1%). Dose interruption of lenvatinib due to an adverse reaction occurred in 63.2% of patients. Dose interruption of lenvatinib and pembrolizumab due to an adverse reaction occurred in 34.3% of patients. The most common (occurring in ≥ 5% of patients) adverse reactions leading to interruption of lenvatinib were hypertension (12.6%), diarrhoea (11.5%), proteinuria (7.2%), vomiting (7%), fatigue (5.7%), and decreased appetite (5.7%).