Insight

Combination therapy with lenvatinib and everolimus in metastatic renal cell carcinoma - why did this combination succeed where others failed?
Katrina Mountfort, Touch Medical Media, Reading, UK

Metastatic renal cell carcinoma (mRCC) is associated with a poor prognosis, with a 5-year survival rate of only 8%.1 Within the last 10 years, a number of potent inhibitors of vascular endothelial growth factor receptors (VEGFR), which decrease angiogenesis, have been approved for the first-line treatment of mRCC. However, a substantial proportion of patients fail to respond to targeted therapies,2,3 and many patients acquire resistance to these treatments over time,4 largely due to the re-establishment of tumour vasculature. This has led to the investigation of combined therapeutic approaches targeting multiple pathways. In presentations at an Eisai sponsored meeting held at the 2017 European Cancer Congress (ECCO), held on 27-30 January in Amsterdam, the Netherlands, Professor Viktor Grünwald of Hanover, Germany and Professor Manuela Schmidinger of Vienna, Austria, discussed the history of combination therapy in mRCC and explored the factors behind the success of the combination of lenvatinib and everolimus, which has received approval from the European Medicines Agency (EMA) for the treatment of mRCC patients who have failed one prior vascular endothelial growth factor (VEGFR)-inhibitor treatment.

Combination therapeutic strategies have the potential to improve response rates and efficacy, as well as improving overall survival. There is also a need to balance toxicity and demonstrate superiority over sequential treatment before considering combination treatment. Until study 205, the use of combination remedies in mRCC following prior VEGF targeted therapy had been disappointing, with numerous clinical studies showing modest efficacy but also excess toxicity, leading to dose reductions that eliminated any benefits.5,6 Lenvatinib (Kisplyx® ▼ in the European Union) is a tyrosine kinase inhibitor (TKI) of VEGFR and fibroblast growth factor receptors, as well as targeting multiple receptors at the cell surface. 7 The combination of lenvatinib and everolimus results in synergistic antiangiogenic activity as well as direct anti-tumour effects.8 The efficacy and safety of the combination was demonstrated in a registrational study (study 205) in which second-line treatment with the combination improved progression-free survival (PFS), objective response rate, and overall survival (OS) compared with everolimus alone.9 The PFS was almost 15 months, around three times the expected PFS for a single agent, and the overall response rate (ORR) was the longest ever reported in second line in mRCC after failure of a VEGFR TKI. For lenvatinib in combination with everolimus, the most common any-grade treatment-emergent adverse events (TEAEs) reported in the lenvatinib plus everolimus group were diarrhoea, decreased appetite and fatigue. The most common TEAEs of Grade 3 or higher were diarrhoea, fatigue and hypertension.

According to Prof Schmidinger, the reason for the success of this combination was that the right targets were chosen. Multikinase inhibitors such as sunitinib and sorafenib inhibit many potential therapeutic targets, but VEGF is the most relevant target in RCC. The depth of the remission is vital to drive outcomes in mRCC. The combination of lenvatinib and everolimus increases efficacy substantially versus everolimus alone and has been shown to reduce tumour burden,9 which is an independent prognostic factor in mRCC.10 Professor Grünwald also noted that the pharmacological activity of lenvatinib differs from other VEGF receptor inhibitors.

Professor Grünwald also presented several case studies demonstrating the effectiveness of the combination in clinical practice. Real-world experience of a combination of lenvatinib plus everolimus to date is consistent with the findings of the Phase II clinical trial.


This article and filmed interviews have been initiated and funded by Eisai.
Revised: 04/2017

References

1. American Cancer Society. Survival rates for kidney cancer by stage http://www.cancer.org/cancer/kidneycancer/detailedguide/kidney-cancer-adult-survival-rates Accessed February 2017.
2. Motzer RJ, Escudier B, Oudard S, et al., Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial, Lancet, 2008;372:449-56.
3. Hutson TE, Lesovoy V, Al-Shukri S, et al., Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial, Lancet Oncol, 2013;14:1287-94.
4. Rini BI, Atkins MB, Resistance to targeted therapy in renal-cell carcinoma, Lancet Oncol, 2009;10:992-1000.
5. MCDermott D, Manola, J., Pins, M. et al, The BEST trial (E2804): A randomized phase II study of VEGF, RAF kinase, and mTOR combination targeted therapy (CTT) with bevacizumab (bev), sorafenib (sor), and temsirolimus (tem) in advanced renal cell carcinoma (RCC), J Clin Oncol, 2013;31:suppl 6;abstr 345. 6. 6. Rini B, Szczylik C, Tannir NM, et al., AMG 386 in combination with sorafenib in patients with metastatic clear cell carcinoma of the kidney: a randomized, double-blind, placebo-controlled, phase 2 study, Cancer, 2012;118:6152-61.
7. . Matsui J, Funahashi Y, Uenaka T, et al., Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase, Clin Cancer Res, 2008;14:5459-65.
8. Kimura T, et al. The Antitumor Activity of Lenvatinib (LEN) in combination with Everolimus (EVE) in Human Renal Cell Carcinoma (RCC) Xenograft Models Is Dependent on VEGFR and FGFR Signaling. European Society for Medical Oncology 2016; Poster: 6P
9.Motzer RJ, Hutson TE, Glen H, et al., Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial, Lancet Oncol, 2015;16:1473-82.
10. Iacovelli R, Lanoy E, Albiges L, et al., Tumour burden is an independent prognostic factor in metastatic renal cell carcinoma, BJU Int, 2012;110:1747-53.

PRESCRIBING INFORMATION
Kisplyx® ▼ (lenvatinib) Please refer to the Summary of Product Characteristics (SPC) before prescribing.
Presentation: 4mg and 10mg hard capsules.
Indication: Used in combination with everolimus for the treatment of adult patients with advanced renal cell carcinoma (RCC) following one prior vascular endothelial growth factor (VEGF)-targeted therapy.
Dose and administration: For oral use. Should be initiated and supervised by a health care professional experienced in the use of anticancer therapies. 18 mg lenvatinib once daily in combination with 5 mg everolimus once daily at about the same time each day, with or without food. Swallow the capsules whole with water or dissolve in water or apple juice without breaking or crushing - see SPC for guidelines. If dose missed, and it cannot be taken within 12 hours, skip dose until following day. Continue treatment as long as clinical benefit observed or unacceptable toxicity occurs. Initiate medical management for nausea, vomiting, and diarrhoea prior to interruption or dose reduction. Manage GI toxicity to reduce risk of renal impairment or failure. Dose adjustment: Mild to moderate adverse reactions (e.g., Grade 1 or 2) generally do not warrant interruption of the combination, unless intolerable to the patient despite optimal management. Severe (e.g., Grade 3) or intolerable adverse reactions require interruption of the combination of medicines until improvement of the reaction to Grade 0-1 or baseline. For toxicities thought to be related to lenvatinib, upon resolution/improvement of an adverse reaction to Grade 0-1 or baseline, resume treatment at a reduced dose of lenvatinib: First dose reduction 14 mg once daily; second dose reduction 10 mg once daily; third dose reduction 8 mg once daily. For toxicities thought to be related to everolimus, interrupt the treatment, reduce to alternate day dosing, or discontinue (see the everolimus SPC). For toxicities thought to be related to both lenvatinib and everolimus, reduce lenvatinib dose prior to reducing everolimus. Discontinue treatment in case of life-threatening reactions (e.g., Grade 4) except if laboratory abnormalities judged to be non-life-threatening, then manage as severe reactions (e.g., Grade 3). Special populations: Patients with hypertension: Control blood pressure prior to treatment and monitor regularly during treatment. Patients with hepatic impairment: No data with the combination. No adjustment of starting dose of the combination required in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. In patients with severe (Child-Pugh C) hepatic impairment, lenvatinib starting dose is 10 mg once daily in combination with everolimus dose for patients with severe hepatic impairment in the everolimus SPC. Adjust dose further based on individual tolerability. Combination should be used in patients with severe hepatic impairment only if the anticipated benefit exceeds the risk. Patients with renal impairment: No adjustment of starting dose is required in patients with mild or moderate renal impairment. In patients with severe renal impairment starting dose is 10 mg of lenvatinib with 5 mg of everolimus once daily. Adjust dose further based on individual tolerability. Use of lenvatinib in patients with end-stage renal disease is not recommended. Elderly population: No adjustment of starting dose is required. Paediatric population: No data in children aged 2 to 18 years. Do not use in children Patients with high ECOG performance status: Benefit-risk in these patients has not been evaluated. Contra-Indications: Hypersensitivity to active substance or any of the excipients. Breast-feeding. Special warnings and precautions: Control blood pressure prior to treatment with lenvatinib and, if patients are known to be hypertensive, control with stable dose of antihypertensive therapy for at least 1 week prior to treatment with lenvatinib. Start antihypertensive agents as soon as elevated blood pressure is confirmed. Monitor blood pressure after 1 week of treatment with lenvatinib, then every 2 weeks for the first 2 months and monthly thereafter. When necessary, manage hypertension as recommended in SPC. Women of childbearing potential must use highly effective contraception while taking lenvatinib and for one month after stopping treatment. Monitor urine protein regularly. Interrupt, adjust or discontinue dose if urine dipstick proteinuria ≥2+ detected. Discontinue in the event of nephrotic syndrome. Interrupt, adjust or discontinue dose in patients receiving agents acting on the renin-angiotensin aldosterone system due to a potentially higher risk for acute renal failure with the combination treatment. Monitor for clinical symptoms or signs of cardiac decompensation, dose interruption, adjustment or discontinuation may be necessary. Dose interruption, adjustment or discontinuation may be necessary in patients with signs or symptoms of PRES. Monitor liver function tests before starting treatment, then every 2 weeks for the first 2 months and monthly thereafter during treatment. In the case of hepatotoxicity, bleeding, gastrointestinal perforation or fistula, dose interruptions, adjustments, or discontinuation may be necessary. Use lenvatinib with caution in patients who have had an arterial thromboembolism within the previous 6 months. Discontinue following an arterial thrombotic event. Do not start lenvatinib in patients with fistulae to avoid worsening and discontinue permanently in patients with oesophageal or tracheobronchial tract involvement and any Grade 4 fistula. Monitor ECGs in all patients particularly those with congenital long QT syndrome, congestive heart failure, bradyarrhythmias, and those taking medicinal products known to prolong the QT interval, including Class Ia and III antiarrhythmics. Withhold lenvatinib in QT interval prolongation greater than 500 ms. Resume lenvatinib at a reduced dose when QTc prolongation is resolved to Drug Interactions: Cannot exclude risk that lenvatinib could induce CYP3A4 or P-gp. Administer CYP3A4 substrates known to have a narrow therapeutic index with caution. Unknown if lenvatinib reduces effectiveness of hormonal contraceptives. Women using oral hormonal contraceptives should add a barrier method. Pregnancy and lactation: Do not use during pregnancy unless clearly necessary. Women of childbearing potential should avoid becoming pregnant and use highly effective contraception during and for at least one month after treatment. Fertility effects in human are unknown. Effects on ability to drive and use machines: Use caution when driving or operating machines if experiencing fatigue or dizziness. Undesirable effects:Consult the SPC for information on all side effects. The adverse reactions presented in this section are based on the combined safety data of 62 RCC patients and 458 differentiated thyroid carcinoma patients. Very common (≥1/10): Urinary tract infection, thrombocytopenia, hypothyroidism, blood thyroid stimulating hormone increased, hypocalcaemia, hypercholesterolaemia, hypokalaemia, decreased appetite, weight decreased, insomnia, dizziness, headache, dysgeusia, haemorrhage, hypertension, hypotension, dysphonia, diarrhoea, gastrointestinal and abdominal pains, vomiting, nausea, oral inflammation, oral pain, constipation, dyspepsia, dry mouth, palmar-plantar erythrodysaesthesia syndrome, palmar erythema, rash, alopecia, back pain, arthralgia, myalgia, pain in extremity, musculoskeletal pain, proteinuria, fatigue, asthenia, oedema peripheral. Common (≥1/100 to Overdose: No specific antidote. In case of suspected overdose, lenvatinib should be withheld and appropriate supportive care given as required. Legal Category: POM Cost: UK NHS list price: 4mg capsules pack of 30: £1,437.00; 10mg capsules pack of 30: £1,437.00 Marketing authorisation (MA) numbers: 4mg capsules: EU/1/16/1128/001; 10mg capsules: EU/1/16/1128/002 MA holder: Eisai Europe Ltd. Further information from: Eisai Ltd., Mosquito Way, Hatfield, Hertfordshire, AL10 9SN, United Kingdom Date of preparation: March 2017



Kisplyx PI – Date of Preparation March 2017

Kispyx PI – Job Code: Kisplyx UK0028