KISPLYX Hard capsule Ref.[27667] Active ingredients: Lenvatinib

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 PDGFRα, 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 hypercholesterolaemia 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). Lenvatinib in combination with pembrolizumab demonstrated statistically significant improvements in PFS, OS and ORR compared with sunitinib at the prespecified interim analysis (final analysis for PFS). The median PFS for lenvatinib in combination with pembrolizumab was 23.9 months (95% CI: 20.8, 27.7) compared with 9.2 months (95% CI: 6.0, 11.0) for sunitinib, with HR 0.39 (95% CI: 0.32, 0.49; P value <0.0001). For OS, HR was 0.66 (95% CI: 0.49, 0.88; P value 0.0049) with the median OS follow-up time of 26.5 months and the median duration of treatment for lenvatinib plus pembrolizumab of 17.0 months. The ORR for lenvatinib in combination with pembrolizumab was 71% (95% CI: 66, 76) vs 36% (95% CI: 31, 41) P value <0.0001 for sunitinib. Efficacy results for PFS, OS and ORR at the protocol-specified final analysis (median follow-up time of 49.4 months) are summarised in Table 5, Figure 1 and Figure 2. 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.

The final OS analysis was not adjusted to account for subsequent therapies, with 195/357 (54.6%) patients in the sunitinib arm and 56/355 (15.8%) patients in the lenvatinib plus pembrolizumab arm receiving subsequent anti-PD-1/PD-L1 therapy.

Table 5. Efficacy Results in Renal Cell Carcinoma Per IRC in CLEAR:

Median in months (range) 26.7 (1.64+, 55.92+) 14.7 (1.64+, 54.08+)

Tumour assessments were based on RECIST 1.1; only confirmed responses are included for ORR.
Data cutoff date (DCO) = 31 July 2022
CI = confidence interval; NE = Not estimable
^* 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. Nominal 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).

Figure 1. Kaplan-Meier Curves for Progression-Free Survival in CLEAR*:

DCO: 31 July 2022
^* Based on updated PFS analysis conducted at the time of the protocol-specified final OS analysis.

Figure 2. Kaplan-Meier Curves for Overall Survival in CLEAR*:

NE = Not estimable.
DCO: 31 July 2022 ^* Based on the protocol-specified final OS analysis

The CLEAR study was not powered to evaluate efficacy of individual subgroups. Table 6 summarises the efficacy measures by MSKCC prognostic group based on the final OS analysis at a median follow-up of 49.4 months.

Table 6. Efficacy Results in CLEAR by MSKCC Prognostic Group:

^a Median follow up 49.4 months (DCO – 31 July 2022)

Open-label, single arm Phase 2 study

Additional data are available from the open-label, single-arm, Phase 2 study KEYNOTE-B61 of lenvatinib (20 mg OD) in combination with pembrolizumab (400 mg every 6 weeks) for the first-line treatment of patients with advanced or metastatic RCC with non-clear cell histology (n=158), including 59% papillary, 18% chromophobe, 4% translocation, 1% medullary, 13% unclassified, and 6% other. The ORR was 50.6% (95% CI (42.6, 58.7)), and the median duration of response was 19.5 months (95% CI 15.3, NR).

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)|

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
^a Point estimates are based on Kaplan-Meier method and 95% CIs are based on the Greenwood formula using log-log transformation.
^b Stratified 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.
^c Data cut-off date = 31 Jul 2015

Figure 3. Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment):

Figure 4. Kaplan-Meier Plot of Overall Survival:

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).

Paediatric studies

The efficacy of lenvatinib was assessed but not established in two open-label studies (for additional paediatric information see also Lenvima SmPC section 5.1):

Study 216 was a multicentre, open-label, single-arm, Phase ½ study to determine the safety, tolerability, and antitumour activity of lenvatinib administered in combination with everolimus in paediatric patients (and young adults aged ≤21 years) with relapsed or refractory solid malignancies, including CNS tumours. A total of 64 patients were enrolled and treated. In Phase 1 (combination dose-finding), 23 patients were enrolled and treated: 5 at Dose Level –1 (lenvatinib 8 mg/m² and everolimus 3 mg/m²) and 18 at Dose Level 1 (lenvatinib 11 mg/m² and everolimus 3 mg/m²). The recommended dose (RD) of the combination was lenvatinib 11 mg/m² and everolimus 3 mg/m², taken once daily. In Phase 2 (combination expansion), 41 patients were enrolled and treated at the RD in the following cohorts: Ewing Sarcoma (EWS, n=10), Rhabdomyosarcoma (RMS, n=20), and High-grade glioma (HGG, n=11). The primary efficacy outcome measure was objective response rate (ORR) at Week 16 in evaluable patients based on investigator assessment using RECIST v1.1 or RANO (for patients with HGG). There were no objective responses observed in the EWS and HGG cohorts; 2 partial responses (PRs) were observed in the RMS cohort for an ORR at Week 16 of 10% (95% CI: 1.2, 31.7).

Study 231 is a multicentre, open-label, Phase 2 basket study to evaluate the antitumour activity and safety of lenvatinib in children, adolescents, and young adults between 2 to ≤21 years of age with relapsed or refractory solid malignancies, including EWS, RMS, and HGG. A total of 127 patients were enrolled and treated at the lenvatinib RD (14 mg/m²) in the following cohorts: EWS (n=9), RMS (n=17), HGG (n=8), and other solid tumours (n=9 each for diffuse midline glioma, medulloblastoma, and ependymoma; all other solid tumours n=66). The primary efficacy outcome measure was ORR at Week 16 in evaluable patients based on investigator assessment using RECIST v1.1 or RANO (for patients with HGG). There were no objective responses observed in patients with HGG, diffuse midline glioma, medulloblastoma, or ependymoma. Two PRs were observed in both the EWS and RMS cohorts for an ORR at Week 16 of 22.2% (95% CI: 2.8, 60.0) and 11.8% (95% CI: 1.5, 36.4), respectively. Five PRs (in patients with synovial sarcoma [n=2], kaposiform hemangioendothelioma [n=1], Wilms tumour nephroblastoma [n=1], and clear cell carcinoma [n=1]) were observed among all other solid tumours for an ORR at Week 16 of 7.7% (95% CI: 2.5, 17.0).