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Table of Contents
DRUG REVIEW
Year : 2021  |  Volume : 4  |  Issue : 4  |  Page : 709-720

Lenvatinib: A narrative drug review


Department of Medical Oncology, Tata Memorial Center, Homi Bhabha Cancer Hospital, Sangrur, Punjab, India

Date of Submission02-Jul-2021
Date of Decision16-Nov-2021
Date of Acceptance11-Dec-2021
Date of Web Publication29-Dec-2021

Correspondence Address:
Alok Goel
Homi Bhabha Cancer Hospital, Sangrur, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/crst.crst_151_21

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  Abstract 


The discovery and clinical efficacy of imatinib in chronic myeloid leukemia opened a new and interesting avenue of oral small-molecule tyrosine kinase inhibitors. Thereafter, several such molecules with efficacy across multiple tumor types have been discovered. One of the oral multi-kinase inhibitors is lenvatinib, which started its journey in 2008 when it showed efficacy on stem cells in the laboratory setting and was first approved by the United States Food and Drug Administration in August 2015 for the management of radioiodine-refractory differentiated thyroid cancer. Since then, it has been approved for hepatocellular, endometrial, and renal cell carcinomas, and many more trials are underway for lenvatinib in multiple solid tumors, either alone or in combination with immunotherapy. In addition to the robust data on the efficacy of this drug, it is known for its tolerability with different dosing schedules in different tumor types, a feature unique to this drug. Therefore, an in-depth understanding of its mechanism of action, pharmacokinetics, pharmacodynamics, dosage in different tumor types, expected side effects, and predictors of response will go a long way in its safe and appropriate use in the clinics. In this review, we aim to summarize and collate these data in a reader-friendly manner, thus making it a ready reckoner for lenvatinib. We searched the PubMed database for full-text articles on lenvatinib published in the last 10 years using the search terms “lenvatinib,” “hepatocellular carcinoma,” renal cell carcinoma,” “thyroid carcinoma,” “and “endometrial carcinoma”. A total of 1053 studies were identified, of which 60 were included in this review.

Keywords: Hepatocellular carcinoma, lenvatinib, tyrosine kinase inhibitor


How to cite this article:
Goel A, Singla A. Lenvatinib: A narrative drug review. Cancer Res Stat Treat 2021;4:709-20

How to cite this URL:
Goel A, Singla A. Lenvatinib: A narrative drug review. Cancer Res Stat Treat [serial online] 2021 [cited 2022 Jan 20];4:709-20. Available from: https://www.crstonline.com/text.asp?2021/4/4/709/334174




  Introduction Top


Tyrosine kinases (TKs) constitute a very important and diverse group of molecules that play an important role in various cellular activities and functions, including cell cycle regulation and angiogenesis. They work in a strictly regulated manner as a component of intracellular signaling pathways, and their aberrant and dysregulated activity has been associated with the pathogenesis of cancer.[1],[2],[3],[4] This sparked an interest in the development of targeted agents and molecules which can inhibit the aberrant activity of these proteins, and may thus reverse the uncontrolled and aberrant cell growth.[5],[6] Lenvatinib is an oral small-molecule multi-kinase inhibitor of the vascular endothelial growth factor receptor (VEGFR) 1–3, platelet-derived growth factor receptor-alpha (PDGFR-α), fibroblast growth factor receptor (FGFR) 1–4, and the proto-oncogenes, KIT and rearranged during transfection (RET).[7] It has been shown in preclinical studies that by inhibiting VEGF and FGFR, lenvatinib can act as a potent antiangiogenic agent.[8],[9] Lenvatinib binds to the ATP-binding site of VEGFR2 in a way different than other TK inhibitors (TKIs) such as sorafenib.[10] In view of these differences, it is classified as a type I TKI.[11] Several studies have demonstrated the immunomodulatory activity of lenvatinib as well as its potential for synergistic activity with immune checkpoint inhibitors, thus providing the rationale for testing this combination.[12] Lenvatinib has shown clinically meaningful benefit and has been approved in multiple solid tumors, including differentiated thyroid, hepatocellular, renal cell, and endometrial carcinomas. In addition, it has demonstrated promising activity in various other tumor types as reported in several case reports, case series, and retrospective studies, including but not limited to medullary and anaplastic thyroid carcinomas, adenoid cystic carcinoma, non-small-cell lung cancer (NSCLC), head-and-neck squamous cell carcinoma, melanoma, gastric carcinoma, biliary tract cancers, gastrointestinal junction tumors, and thymic carcinomas. Apart from this, there are multiple ongoing clinical studies testing lenvatinib alone or in combination with immunotherapy in myriad tumor types. Therefore, we aimed to comprehensively review lenvatinib, its developmental journey, trial evidence, usage, dosing, side effect profile, future direction, and predictors of response.


  Methods Top


An extensive PubMed search was performed for full-text articles on lenvatinib published in the last 10 years, including meta-analyses, randomized controlled trials, case series, systematic reviews, and guidelines. The following search terms were used: “lenvatinib,” “hepatocellular carcinoma,” renal cell carcinoma,” “thyroid carcinoma”, and “endometrial carcinoma.” For chemical details of the drug, the United States Food and Drug Administration (FDA) website and the lenvatinib package insert were reviewed. Of the total 1053 identified studies, we excluded papers for various reasons and finally included a total of 60 studies [Figure 1].
Figure 1: Workflow of the selection process for articles included in this review

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The key features of lenvatinib are shown in [Table 1].
Table 1: Key features of lenvatinib

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  History Top


Various in vitro and in vivo models have been used to study lenvatinib's antitumor activity. Tumor vascularization grade (vascular score) has been shown to have a direct correlation with tumor shrinkage, which was used as a surrogate for its antitumor activity.[13] Initial preclinical data from 2008 show its potential as an inhibitor at nanomolar concentrations for multiple kinases (4–100 nM being its half maximal inhibitory concentration [IC50]).[14] In mouse models, it leads to tumor regression through the inhibition of angiogenesis. Furthermore, it has been shown to prevent breast cancer metastasis to lungs and nodes through studies on breast cancer models. This action has been attributed to lenvatinib's potential to inhibit VEGFR3 during lymphangiogenesis and angiogenesis.[13] It was subsequently tested in orthotopic malignant mesothelioma mouse models, where mice injected with three mesothelioma cell lines showed prolongation of survival when treated with lenvatinib.[15] Similar activity of lenvatinib has been shown in sarcoma xenograft mouse models.[16] Glen et al.[17] used patient-derived cell lines from prostate cancer, osteosarcoma, colorectal cancer, and melanoma and observed that lenvatinib reduced the tumor volume and capillary density in treated mice, thus delaying tumor growth, but did not have a direct effect on tumor cell proliferation.[18],[19] In recent years, preclinical studies have tested lenvatinib in other solid tumors including cancers of the endometrium, ovary, stomach, pancreas, and glioblastoma, among others.[19],[20],[21] Thereafter, phase I studies were conducted to explore its safety and efficacy. Phase I trials of lenvatinib were conducted in the US, Japan, and Europe simultaneously, wherein the drug resulted in tumor shrinkage in melanoma, renal cell carcinoma (RCC), thyroid cancer, endometrial cancer, sarcoma, and colon cancer.[22],[23],[24],[25],[26],[27] The maximal tolerated dose achieved in these studies was 25 mg. Fatigue, hypertension, and proteinuria were the main toxicities encountered. The dose established from these studies was 24 mg. Lenvatinib received the orphan drug status for the treatment of radioiodine-refractory thyroid cancers in Japan and the US in the year 2012 and in Europe in 2013. Further phase II and III studies led to its first approval by the FDA for radioiodine-refractory differentiated thyroid cancer on February 13, 2015, and subsequently in May 2016 for patients with advanced RCC in combination with everolimus. In August 2018, it received approval for unresectable hepatocellular carcinoma (HCC). It received its first accelerated approval in September 2019 in combination with pembrolizumab for patients with advanced endometrial carcinoma whose disease had progressed on prior systemic therapy, who were not amenable to curative radiation or surgery, and who did not have high microsatellite instability or mismatch repair deficiency.


  Chemistry Top


The details of the chemistry of lenvatinib are provided in [Table 2]. The chemical structure of lenvatinib is provided in [Figure 2].
Table 2: Basic chemistry of lenvatinib

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Figure 2: Chemical structure of lenvatinib (reproduced from https://pubchem.ncbi.nlm.nih.gov/compound/Lenvatinib)

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  Physical properties Top


  • It is a pale reddish yellow to white powder
  • It is practically insoluble in ethanol (dehydrated) and only slightly soluble in water
  • The dissociation constant (pKa value) is 5.05 at 25°C
  • Its partition coefficient (log P value) is 3.3.



  Mechanism of action Top


It is a small-molecule multi-kinase inhibitor with activity against VEGFR1–3, FGFR1–4, PDGFR-α, RET, and KIT. Lenvatinib, as per a study in syngeneic mouse tumor models, can lead to reduction in tumor-associated macrophages and increased cytotoxic T-cell activity, thus exerting a synergistic effect and increasing the antitumor activity when combined with anti-programmed cell death protein 1 (PD-1) antibody.[28],[29],[30]


  Pharmacokinetics Top


Absorption

  • It achieves peak plasma concentration (Tmax) at 4 h
  • Absorption follows first- and zero-order kinetics
  • There is no effect of stomach pH on absorption
  • No drug accumulation is seen after daily dose
  • Oral bioavailability of the capsule is 90%.


Food effect

When taken with a high-fat meal, absorption is delayed, but there is no effect on the extent of absorption. It can be taken on an empty stomach or with meals.

Distribution

About 98%–99% of the drug is plasma protein bound.

Elimination

Its terminal half-life is 28 h.

Metabolism

It is majorly metabolized enzymatically through the cytochrome P450, family 3, subfamily A, and aldehyde oxidase as well as non-enzymatically to a minor extent.

Excretion

64% of the drug is excreted through feces and 25% through urine.


  Dosage forms and strength Top


Oral capsule in 2 doses of 4 and 10 mg.


  Administration Top


  • Oral administration
  • Capsule to be swallowed whole, not to be chewed, opened, or crushed
  • No relationship with meals
  • To be taken at the same time everyday
  • Take skipped dose within 12 h; if not possible, take the next dose at the usual time
  • Can be dissolved in a tablespoon full of water or apple juice if swallowing is not possible; capsule to be left for 10 min to allow proper dissolution and then stirred properly for at least 3 min.


The dosing details of lenvatinib are presented in [Table 3], and the recommended dose reductions are presented in [Table 4].
Table 3: Dosing of lenvatinib

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Table 4: Recommended dose reductions of lenvatinib as per indication

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A global phase I trial in patients with various solid tumors identified 24 mg once daily as the single-agent dose for lenvatinib based on the safety, maximum tolerated dose, pharmacodynamics and pharmacokinetic properties, and antitumor activity across three different dosing schedules.[22],[24]

Pharmacokinetic studies with lenvatinib in subjects with normal and impaired hepatic function revealed that a reduced dose is required in those with hepatic impairment.[31]

Study 202, a multicentric, open-label, phase I/II study, was conducted to find the appropriate lenvatinib dose for patients with HCC. It included a phase I dose-escalation part and a phase II expansion part. The maximum tolerated dose was found to be 12 mg daily in phase I in patients with Child–Pugh score A. Phase II showed promising efficacy at this dose.[32]

A phase II dose assessment study was performed in patients with HCC and Child–Pugh score A. A significant exposure–response relationship was shown between low body weight and high area under the curve. Based on these results, a weight-based dosing of 8 mg for those weighing <60 kg and 12 mg for those weighing ≥60 kg was reached at.[33]


  Dose Modifications for Adverse Effects Top


Hypertension

  • Grade 3: Need to withhold if grade 3 hypertension persists despite adequate and optimal antihypertensive therapy
  • Grade 4: Permanent discontinuation.


Cardiac dysfunction

  • Grade 3: Withhold, rechallenge when cardiac toxicity improves to ≤ grade 1, restart at reduced dose
  • Grade 4: Permanent discontinuation.


Arterial thromboembolic event

Any grade – permanent discontinuation.

Hepatotoxicity

  • Grade 3/4: Withhold, rechallenge when hepatotoxicity improves to ≤ grade 1, restart at reduced dose
  • Hepatic failure: Permanent discontinuation.


Renal impairment or failure

Grade 3/4: Withhold, rechallenge when renal dysfunction improves to ≤ grade 1, restart at reduced dose.

Proteinuria

  • ≥2 g/24 h: Withhold, resume at a reduced dose when proteinuria decreases to <2 g/24 h
  • Nephrotic syndrome: Permanent discontinuation.


Gastrointestinal perforation or fistula formation

Permanent discontinuation.

QT prolongation

>500 ms or >60 ms increase over baseline: Withhold, resume at reduced dose when <480 ms.

Other adverse reactions

  • Grade 4 laboratory abnormality: Withhold, restart at reduced dose when the adverse reaction improves to ≤ grade 1
  • Grade 4 adverse reaction: Discontinue permanently.



  Special Populations Top


Pregnancy

  • Lenvatinib has been shown to be embryotoxic in animal studies, and thus is not recommended during pregnancy (category D)
  • Women in the reproductive age group should use effective contraception during and for up to a month after the last dose.


Lactation

No data from human studies on drug secretion in breast milk are available, but mouse studies show a higher concentration in breast milk as compared to plasma. Hence, it is advisable to avoid lactation while on lenvatinib and for 1 week after its cessation.

Pediatric population

  • No human studies have been conducted in the pediatric population
  • Animal studies show severe growth and developmental abnormalities, and hence, lenvatinib should be avoided in this population.


Geriatric population

Safety and effectiveness of lenvatinib seem to be similar in young as well as geriatric population. No dose reduction is needed because of age. Patients with HCC aged >75 years show decreased tolerability.

Renal impairment

  • No dose reduction is needed for mild or moderate renal dysfunction
  • In case of severe renal dysfunction, dose reduction is recommended, except in those with HCC, where no data are available. Lenvatinib has also not been studied in patients with end-stage renal disease.


Hepatic impairment

  • No dose reduction is needed for mild or moderate hepatic dysfunction (Child–Pugh score A/B)
  • In case of severe hepatic dysfunction (Child–Pugh score C), dose reduction is recommended
  • Lenvatinib is not indicated in patients with HCC and Child–Pugh score B/C.



  Indications for use Top


Differentiated thyroid carcinoma

Lenvatinib was shown to have clinically meaningful efficacy in a phase II study involving patients with advanced, radioiodine-refractory differentiated thyroid cancer, including papillary thyroid cancer, follicular thyroid cancer, or Hurthle cell cancer. With manageable toxicities, it showed a remarkable progression-free survival (PFS) of 12.6 months with a median duration of response of 12.7 months. Anti-VEGF therapy-naïve patients showed a higher objective response rate (ORR) as compared to those who had received prior VEGF therapy (54% vs. 41%).[34] About 35% of patients harbored rat sarcoma virus (RAS) mutations, and they showed better response to lenvatinib with an ORR of 100% and 80% PFS at 14 months as compared to 20% PFS in those with wild-type RAS.[35]

On the basis of these results, a phase III study called the SELECT study[36] was conducted in patients with radioiodine-refractory differentiated thyroid cancer who progressed within 13 months of their last radioiodine therapy. It was a multicentric study that enrolled 392 patients across 23 countries. Patients were randomized in a 2:1 ratio to receive either lenvatinib at 24 mg or placebo. Both crossover and one prior line of anti-VEGFR therapy were allowed. The primary endpoint of the study was PFS. The secondary endpoints were ORR, overall survival (OS), and safety. Lenvatinib showed a 79% relative improvement in PFS which was statistically significant (median PFS: 18.3 vs. 3.6 months, hazard ratio (HR), 0.21; 99% confidence interval [CI], 0.14–0.31; P < 0.001). All the pre-specified subsets showed improvement. Disease control rate (DCR), which is the sum of the complete responses (CRs) and partial responses (PRs), was noted in 64.8% in the lenvatinib group and only 1.5% in the placebo group (P < 0.001). At the time of the 3-year analysis, the median OS was not reached in either group. Although lenvatinib demonstrated remarkable efficacy, there were significantly higher side effects in the lenvatinib group. Grade 3 or greater side effects occurred in 9.9% of patients in the placebo group as compared to 75.9% in the lenvatinib group, with hypertension, proteinuria, diarrhea, fatigue, and thromboembolic events being significantly more frequent in the lenvatinib group. Drug discontinuation was observed in 14.2% and 3.2% in the lenvatinib and placebo groups, respectively. Six treatment-related deaths occurred in the lenvatinib group, while there were none in the placebo group. Based on these results, the FDA approved lenvatinib in August 2015 for patients with radioiodine-refractory differentiated thyroid cancer.[37]

Medullary thyroid carcinoma

Based on lenvatinib's inhibitory activity against RET in preclinical and animal studies,[14],[38],[39] a phase II study of lenvatinib was planned in 59 patients with unresectable or metastatic medullary thyroid carcinoma. DCR in this study was 80%, with 36% showing PR. Prior anti-VEGF therapy had no effect on the response, and the median PFS was 9 months in responders. The outcomes did not differ based on the RET mutation status. However, an inverse correlation was found between angiopoietin-2 levels and tumor reduction. Lenvatinib is not FDA approved for this indication.[40]

There are no phase III trials of lenvatinib in medullary thyroid carcinoma. However, in view of lenvatinib's activity on VEGF and RET, with the concentration for 50% inhibition (IC50) for RET being even lower than that of vandetanib, it is likely to be effective in medullary thyroid carcinoma as well.

There have been several case reports with the use of lenvatinib as neoadjuvant therapy in patients with unresectable thyroid cancer (both differentiated and medullary thyroid carcinoma).[41],[42]

Anaplastic thyroid carcinoma

Two retrospective studies showed some activity of lenvatinib in anaplastic thyroid carcinoma[43],[44] with DCR ranging from 40% to 60%, albeit in a selected and very small group of 5 and 13 patients, in these 2 studies respectively. A total of 17 patients with anaplastic thyroid cancer were included in a single-arm, phase II study of lenvatinib in thyroid cancer. A median PFS of 7.4 months and OS of 10.6 months were observed. A DCR of 88% and ORR of 24% were achieved. There were significant grade 3/4 toxicities.[45] In Japan, lenvatinib is approved for use in patients with anaplastic thyroid cancer.

Hepatocellular carcinoma

In a phase I study of lenvatinib involving 20 patients with HCC and Child–Pugh score A/B (12 mg and 8 mg doses, respectively), 17 showed some tumor shrinkage, with 3 attaining PRs.[32] In a subsequent phase II study in patients with HCC not eligible for local therapy and with Child–Pugh score A, lenvatinib was administered at a dose of 12 mg. DCR was 78%, with 37% achieving PR. The median OS was 18.7 months and the median time to progression was 7.4 months. Two-thirds of the patients developed hypertension, palmar–plantar erythrodysesthesia, decreased appetite, or proteinuria; 22% required drug discontinuation, and 74% required dose reduction.[46] Based on these encouraging data in the early phase studies, a phase III trial (REFLECT) was conducted.[47] It was an international, multicenter, randomized, open-label, non-inferiority trial across 154 sites in 20 countries. It included patients with previously untreated, unresectable, or metastatic HCC, Child–Pugh score A, and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1. A total of 954 patients were randomized 1:1 to receive either sorafenib 400 mg twice daily or lenvatinib 12 mg (>60 kg of body weight) or 8 mg once daily (<60 kg). OS was the primary endpoint with a non-inferiority margin of 1.08; the secondary endpoints were PFS and ORR; superiority could be tested if non-inferiority of OS was proved. The study achieved its primary endpoint. The median OS was 13.6 months in the lenvatinib arm as compared to 12.3 months in the sorafenib arm (HR, 0.92; 95% CI, 0.79–1.06). The median PFS was 7.3 months versus 3.6 months with lenvatinib and sorafenib, respectively (HR, 0.64; 95% CI, 0.55–0.75; P < 0.001). A significantly higher proportion of patients achieved an objective response in the lenvatinib arm (24% vs. 9%). About 43% of patients in the lenvatinib arm experienced serious adverse events as compared to 30% in the sorafenib arm. Diarrhea, hypertension, weight loss, and a decrease in appetite were the most commonly observed adverse effects in the lenvatinib arm, whereas they were palmar–plantar erythrodysesthesia, decreased appetite, diarrhea, and hypertension in the sorafenib arm; 11 patients experienced fatal events with lenvatinib and 4 with sorafenib.

Drug interruption, reduction in dose, and discontinuation were seen in 40%, 32%, and 37%, respectively, in the lenvatinib arm and in 38%, 9%, and 7%, respectively, in the sorafenib arm. Quality-of-life parameters were similar with both drugs. Based on these results, lenvatinib received FDA approval for unresectable HCC in the first-line setting.

Lenvatinib plus pembrolizumab in hepatocellular carcinoma

The combination of lenvatinib with pembrolizumab was studied for safety and antitumor activity in Study 116, a phase Ib trial. This trial enrolled 100 patients with advanced HCC, Child–Pugh score A, and an ECOG PS 0 or 1.[48] The ORR in 100 evaluable patients was 46%, which was much higher than the ORR of 24% and 17% attained with single-agent lenvatinib and pembrolizumab, respectively. A median PFS of 9.3 months and OS of 22 months were achieved. There were no new safety signals with this combination. The phase III multicenter, randomized, double-blind, active-controlled, LEAP-002 trial is planned to test the above combination. Similarly, a trial for this combination with transarterial chemoembolization (TACE) called 1016TiP-LEAP-012 is planned for patients with unresectable intermediate-stage HCC, localized to the liver with no portal vein thrombosis, and not amenable to curative therapy.

Renal cell carcinoma

Several phase I studies have shown encouraging results for lenvatinib in RCC. A median PFS of median PFS of 500 days was achieved in one of these studies.[22],[23] A subsequent phase Ib study also tested the combination of lenvatinib with everolimus in unresectable/metastatic RCC, yielding a DCR of 83% with PR rate of 33%.[49] Based on this proof-of-principle study, an open-label, multicentric phase II randomized controlled trial[50] was planned involving patients with advanced clear cell RCC, including those who had received anti-VEGF therapy and had progressed during or within 9 months of it. A total of 153 patients were randomized equally into 3 groups, lenvatinib (24 mg/day), everolimus (10 mg/day), and the combination of lenvatinib with everolimus (18 mg/day and 5 mg/day, respectively). PFS was the primary endpoint. The median PFS was 14.6, 5.5, and 7.4 months for the combination (lenvatinib + everolimus), everolimus alone, and lenvatinib alone groups, respectively. Both the combination and lenvatinib alone achieved greater PFS as compared to everolimus alone with an HR of 0.40 and 0.68, respectively. ORR was also significantly higher at 43% with the combination, 27% with lenvatinib alone, and only 6% with everolimus alone. OS was the secondary endpoint and was significantly better in both the lenvatinib-containing groups (25.5 months vs. 19.1 months vs. 15.4 months in the combination, lenvatinib alone, and everolimus alone groups). Highergrade 3/4 toxicities were seen in the lenvatinib-containing groups as compared to the everolimus alone group (50% vs. 79% vs. 71%). Diarrhea (20%), proteinuria (19%), and anemia (12%) were the most commonly observed adverse effects in the combination, lenvatinib alone, and everolimus alone groups, respectively. A higher proportion of patients in the combination arm experienced grade 4 adverse events. The FDA approved the combination of everolimus and lenvatinib (5 mg and 18 mg once daily, respectively) as a post anti-VEGF second-line therapy in clear cell RCC based on these trial results.[51]

Phase II studies have shown the activity of lenvatinib in combination with pembrolizumab in advanced RCC. Based on these initial efficacy reports, the phase III CLEAR trial[52] was conducted. It was a multicentric, open-label, randomized controlled, three-arm study which compared sunitinib alone (50 mg once daily, 4 weeks on, 2 weeks off) with lenvatinib (20 mg once daily) plus pembrolizumab (200 mg once every 3 weeks) and lenvatinib (18 mg once daily) plus everolimus (5 mg once daily) as first-line therapy for advanced RCC. In this study, 1069 treatment-naïve patients with advanced RCC were randomized 1:1:1 to receive lenvatinib plus pembrolizumab or lenvatinib plus everolimus, or sunitinib. PFS was the primary endpoint, and OS and ORR were the main secondary endpoints. The median PFS was statistically significantly higher in the lenvatinib combination arms as compared to the sunitinib arm (23.9 vs. 9.2; HR, 0.39; 95% CI, 0.32–0.49 for pembrolizumab plus lenvatinib vs. sunitinib, and 14.7 vs. 9.2; HR, 0.65; 95% CI, 0.53–0.80 for everolimus plus lenvatinib vs. sunitinib). A difference in OS was not observed between the lenvatinib plus everolimus and sunitinib arms. In the lenvatinib plus pembrolizumab arm, OS benefit was seen in intermediate- and poor-risk disease but not in favorable-risk disease. The response rates and duration of response were also higher in the lenvatinib combination arms vs. the sunitinib arm, with the pembrolizumab combination being better with regard to all parameters as compared to the everolimus combination.

Nearly all patients had some treatment-related adverse events, which were higher in the combination arms as compared to the sunitinib alone arm. Dose reductions and treatment discontinuations due to treatment-related adverse events were more common in the combination arms than in the sunitinib arm. For lenvatinib plus pembrolizumab, grade 3 or higher toxicities included hypertension (28%), diarrhea (10%), weight loss or proteinuria (8% each), and palmar–plantar erythrodysesthesia (4%).

Endometrial carcinoma

There were 4 patients with endometrial cancer in a phase I dose-escalation study of lenvatinib in 77 patients with advanced solid tumors.[23] In this study, promising antitumor activity was shown by lenvatinib in patients with endometrial cancer. A subsequent phase II, single-arm, open-label, multicentric, international trial[53] evaluated lenvatinib as a second-line agent in patients with unresectable endometrial carcinoma that had progressed on platinum-based chemotherapy. ORR was the primary endpoint, and OS, PFS, and clinical benefit rate were the secondary endpoints. Patients were given lenvatinib 24 mg once daily. The ORR was 14.3% (95% CI, 8.8–21.4), and 31 patients had durable stable disease (≥23 weeks) with a clinical benefit rate of 37.6% (95% CI, 29.3–46.4). The median PFS and OS were 5.6 months and 10.6 months, respectively. Commonly observed adverse effects were hypertension (49%), fatigue/asthenia (48%), decreased appetite (32%), nausea/vomiting (32%), and diarrhea (31%). Higher ORR and longer OS and PFS were noted in patients with lower baseline levels of angiopoietin-2. Simultaneously, an open-label, single-arm, phase II study[54] assessing the combination of pembrolizumab plus lenvatinib post two prior lines of therapy was conducted in patients with metastatic endometrial cancer unselected for programmed death-ligand 1 (PD-L1) expression and microsatellite instability. Patients received oral lenvatinib 20 mg daily plus intravenous pembrolizumab 200 mg every 3 weeks. Results of the interim analysis were published in 2019 for 53 patients, of which 25% were PD-L1 positive and 85% (45/53) were microsatellite stable (MSS). The primary endpoint of this interim analysis was the ORR at 24 weeks. About 39.6% of patients had an objective response at 24 weeks. The ORR was found to be 35.6% in MSS patients which was significantly higher than that reported in previous studies in this cohort. This led to the FDA approval of this combination in patients with advanced endometrial carcinoma.[55] The final analysis of the above trial showed 38% ORR at 24 weeks, with an ORR of 63.6% (30.8%–89.1%) in patients with high microsatellite instability (MSI-H) tumors (n = 11) and 36.2% (26.5%–46.7%) in MSS tumors (n = 94). The median duration of response, PFS, and OS were 21.2, 7.4, and 16.7 months, respectively. Grade 3/4 treatment-related adverse events were seen in 66.9% of patients.[56]

KEYNOTE-775/Study 309 is a phase III randomized controlled trial studying the combination of pembrolizumab plus lenvatinib in advanced, metastatic, or recurrent, post platinum endometrial cancer. Patients could have received two prior regimens if one was given in the neoadjuvant or adjuvant setting. A total of 827 patients were enrolled (130 – mismatch repair deficient and 697 – proficient in mismatch repair). Patients were randomized 1:1 to receive either pembrolizumab plus lenvatinib (200 mg intravenously every 3 weeks up to a maximum of 35 cycles plus 20 mg once daily, respectively) or physician's choice chemotherapy (doxorubicin 60 mg/m2 every 3 weeks or paclitaxel 80 mg/m2 once-a-week for 3 weeks, every 4 weeks). The primary endpoints, PFS and OS, were achieved. At a median follow-up of 11.4 months in all comers, the median PFS was 7.2 versus 3.8 months (HR, 0.56; P < 0.0001) and the median OS was 18.3 versus 11.4 months (HR, 0.63; P < 0.0001) in favor of lenvatinib plus pembrolizumab.

ORR was also higher in the lenvatinib plus pembrolizumab arm (31.9% vs. 14.7%) as were the CR rate (6.6% vs. 2.6%) and median duration of response (14.4 vs. 5.7 months). The benefit was seen in all comers across all pre-defined subgroups as well as in patients proficient in mismatch repair. Grade 3 or higher adverse events were observed in 88.9% of patients in the combination arm and 72.7% in the chemotherapy arm. Hypertension was the most common toxicity reported in patients receiving lenvatinib plus pembrolizumab and was grade 3 or higher in 37.9% of patients.

The combination of pembrolizumab and lenvatinib is being compared in two ongoing phase III trials in patients with advanced endometrial cancer and known microsatellite instability status. The comparator arm in both these studies is physicians' choice chemotherapy (paclitaxel/carboplatin/doxorubicin) (NCT03517449, NCT03884101).

Adenoid cystic carcinoma

A phase II trial of lenvatinib at a dose of 24 mg once daily was conducted in 33 patients with recurrent/metastatic adenoid cystic carcinoma. The primary endpoint of the study was ORR. The DCR was 90%, and 15% of patients achieved PR. The median PFS was 17.5 months, but the response was offset by very high rates of adverse events leading to dose modification in 72% of patients and drug discontinuation in 56%. Hypertension was the most common grade 3/4 side effect seen in 28% of patients.[57]

Other tumors

Various trials are already underway to study the combination of neoadjuvant lenvatinib with pembrolizumab in patients with NSCLC and Merkel cell carcinoma.


  Adverse Effects Top


The adverse effects of lenvatinib seen in more than 10% of the study population are shown in [Table 5].
Table 5: Adverse effects of lenvatinib seen in more than 10% of the study population

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Other important but less frequent adverse events include the following:

  • Arterial thromboembolic events
  • Cardiac failure
  • QTc prolongation
  • Gastrointestinal fistula/perforation
  • Anemia, neutropenia, thrombocytopenia, and lymphocytopenia
  • Hepatic encephalopathy and hepatic failure
  • Reversible posterior leukoencephalopathy syndrome.


The management of common adverse events associated with lenvatinib is shown in [Table 6].
Table 6: Management of common adverse events

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  Drug Interactions Top


Lenvatinib has the potential to prolong the QTc interval and, hence, should be avoided with drugs with QT prolongation as an adverse effect, as shown in [Table 7].
Table 7: Drugs associated with QTc prolongation

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  Warnings/precautions Top


  • Control blood pressure (BP) before therapy initiation
  • In view of the risk of QTc prolongation, correct electrolyte abnormalities in all patients
  • Serious and fatal hemorrhagic events may occur with lenvatinib, epistaxis, and hematuria being the most common
  • Fatal intracranial hemorrhage was observed in a patient with central nervous system metastases at baseline who received lenvatinib in the SELECT trial[36]
  • For women in the reproductive age group, rule out pregnancy before starting lenvatinib.



  Monitoring patients on lenvatinib Top


  1. Liver function tests: At baseline, every 2 weeks for the first 2 months, and at least once a month thereafter
  2. Renal function tests and electrolytes: At baseline and then at least once a month
  3. Serum calcium: At baseline and then at least once a month
  4. Thyroid-stimulating hormone levels: At baseline and monthly or as clinically indicated
  5. Proteinuria: At baseline and monthly or as clinically indicated (check urine dipstick: If 2+, then obtain a 24-h urine protein)
  6. Check pregnancy status: Prior to treatment initiation
  7. BP monitoring: Check the BP after 1 week, then every 2 weeks for 2 months, and at least once a month thereafter
  8. Electrocardiogram to be checked in select patients with congenital long QT syndrome, bradyarrhythmias, heart failure, or those on concomitant medications with potential for QTc prolongation: It should be considered at baseline, 7 and 15 days after initiation of lenvatinib or after changing the dose, monthly during the first 3 months, and then periodically during treatment depending on the patient status.[58]



  Conclusion Top


With its ever-expanding indications and approval in various cancer types, lenvatinib has now become an essential tool in the armamentarium of a medical oncologist. Thus, an in-depth understanding and knowledge about this novel TKI, its unique dosing regimen, and management of side effects will go a long way in better managing patients on this drug.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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