ABSTRACT
ABSTRACT
Introduction: Lenvatinib, a multi-kinase inhibitor, has demonstrated improved outcomes for patients with hepatocellular carcinoma (HCC) in clinical trials. The phase 3 REFLECT trial confirmed the noninferiority of lenvatinib to sorafenib for overall survival of HCC patients and indicated clinical benefits in efficacy over sorafenib. Adverse events (AEs) included hypertension, diarrhea, decreased appetite, decreased weight, fatigue, palmar-plantar erythrodysesthesia, and proteinuria.
Areas covered: AEs arising in HCC patients during lenvatinib treatment often lead to treatment interruption, dose reduction, or treatment discontinuation. However, reduced lenvatinib exposure may prevent patients from getting the full potential benefit of lenvatinib therapy. We first review the clinical data on lenvatinib, including efficacy and safety. Next, we review the common AEs associated with lenvatinib therapy and provide guidance on how to optimally prevent, detect, and manage these events while minimizing interruptions in lenvatinib treatment.
Expert opinion: By fully understanding the common AEs associated with lenvatinib therapy and the proper management of emerging AEs, clinicians may ensure that HCC patients can fully benefit from the potential clinical efficacy of lenvatinib, with fewer unnecessary safety risks.
1. Introduction
Hepatocellular carcinoma (HCC) is a leading cause of death around the world [1]. Current treatment options for early-stage disease include surgical resection, tumor ablation, and liver transplantation [2–4]. However, even after successful early treatment, most patients experience a recurrence of the disease [5]. The angiogenesis inhibitor sorafenib is used to treat patients with unresectable tumors [2–4]. The SHARP trial and the Asian-Pacific trial have shown that sorafenib, which targets multiple kinases, can extend survival in previously untreated patients with advanced stage disease [6–9]. Although the improvement in overall survival (OS) was statistically significant in these trials, the clinical benefit is only moderate, extending OS by only 2–3 months [6].
Several other angiogenesis inhibitors have been developed and tested in patients with HCC, but none have been found to be superior to sorafenib [7,8]. Lenvatinib is a novel oral angiogenesis inhibitor that targets vascular endothelial growth factor receptors (VEGFR)-1–3, fibroblast growth factor receptors (FGFR)-1–4, platelet-derived growth factor receptor (PDGFR)-β, and the RET and KIT oncogenes [10–12]. Lenvatinib has received approvals for the treatment of radioiodine-refractory differentiated thyroid cancer globally, and for unresectable differentiated, medullary and anaplastic thyroid cancer in Japan [13–15]. Lenvatinib in combination with everolimus, following one prior course of treatment, has been approved for advanced renal cell carcinoma in Western countries but not yet in Japan [16]. Additionally, phase 1 trials in patients with advanced solid tumors have demonstrated that lenvatinib has manageable toxicity and antitumor activity for durable disease control with a maximum tolerated dose (MTD) for solid tumors of 25 mg once daily [17–20]. Exposure to lenvatinib is increased in patients with severe hepatic impairment [21].
Phase 1 and 2 trials evaluating the MTD, efficacy, and safety of lenvatinib for HCC patients in Japan and Korea have produced promising results [22]. A phase 1 dose-escalation study concluded that the MTD of lenvatinib once daily was 12 mg in patients in Child–Pugh class A (CP-A) and 8 mg in patients in Child–Pugh class B (CP-B) [23]. A phase 2 study was then conducted to evaluate the 12-mg dose in CP-A patients who did not qualify for surgical resection or local therapies and demonstrated preliminary efficacy [24]. In the REFLECT phase 3 study, lenvatinib, with a median survival time of 13.6 months (95% confidence interval [CI] 12.1–14.9), was confirmed to be noninferior to sorafenib (12.3 months, range 10.4–13.9; hazard ratio [HR] 0.92, 95% CI 0.79–1.06) [25]. The median progression-free survival (PFS) was significantly longer in the lenvatinib group (7.4 months) than in the sorafenib group (3.7 months). Based on these results, lenvatinib was approved for the treatment of patients with unresectable HCC in Japan in March 2018 and subsequently approved in the United States and European Union in August 2018; it is under submission for approval in other countries.
In this review, the clinical results reported to date will be discussed. The data on the clinical activity of lenvatinib in patients with HCC are promising. The adverse events (AEs) commonly occurring in HCC patients must be identified and recognized by the medical community, to ensure long-term benefits for patients with early diagnosis and appropriate management. For this purpose, this review will provide an overview of the relevant AEs observed in HCC patients in clinical trials with lenvatinib and discuss their optimal management.
It must be noted that the use of lenvatinib in patients with or at risk of cardiovascular disease is not recommended. These patients are usually excluded from clinical trials of lenvatinib. Therefore, insufficient data are available with which to evaluate its efficacy and safety in this group, and further clinical experience with lenvatinib is needed.
2. Clinical efficacy of lenvatinib in hepatocellular carcinoma
2.1. Phase 1 and phase 2 trials
A phase 1, dose-escalation trial in 20 patients with HCC refractory to standard therapy found that the MTD was 12 mg once daily for CP-A patients and 8 mg for CP-B patients [23]. Pharmacokinetic analysis found that plasma concentrations of lenvatinib in these HCC patients were higher than concentrations previously seen in patients with other types of solid tumors. Additionally, the longer half-life of lenvatinib in CP-A and CP-B patients correlated with higher plasma concentration, as shown in the 12 mg dose groups (Table 1) [23]. Lenvatinib is primarily excreted through the liver; therefore, the increase in plasma concentrations is likely due to decreased clearance by the liver in HCC patients. Furthermore, the MTD of lenvatinib in other solid cancers is 25 mg/day, and that dose produces greater area under the plasma concentration–time curve (AUC) at steady state and maximum observed concentration (Cmax) values than the 12-mg and 8-mg doses do in CP-A and CP-B patients, respectively (Table 1, Figure 1). In the phase 1 trial, the dose of lenvatinib often had to be reduced in patients with reduced liver function, suggesting that lenvatinib is not as well tolerated in HCC patients as in other patients.
Table 1. Summary of pharmacokinetic parameters for multiple doses of lenvatinib [23].
Published online:
12 October 2018Figure 1. Mean ± standard deviation plasma concentration–time curve of lenvatinib after multiple doses for HCC and solid tumor [23]. HCC, hepatocellular carcinoma.
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Figure 1. Mean ± standard deviation plasma concentration–time curve of lenvatinib after multiple doses for HCC and solid tumor [23]. HCC, hepatocellular carcinoma.
In the phase 2 trial, lenvatinib was administered at 12 mg/day to 46 HCC patients with liver function categorized as CP-A [24]. The objective response rate (ORR) was 37%, and the median time to progression was 7.4 months by independent radiologist assessment, demonstrating good efficacy. The AEs in the study were generally manageable with dose interruption and dose reduction. However, dose reductions and treatment discontinuations due to AEs were frequent, occurring in approximately 50% of patients during Cycle 1. By the end of the study, 75% of patients had a dose reduction. Although a strong correlation was not observed between body weight and the estimated concentration of lenvatinib in blood in patients with solid tumors, a strong correlation was confirmed in patients with HCC [26]. The relationship between the time to dose reduction and AUC or body weight was also investigated [26]. AUCs were found to be higher in patients with lower body weight, and the time to dose reduction was found to be shorter in patients with high AUCs or low body weight. The study authors found that an AUC cutoff value of 2430 ng∙h/mL could be used to identify patients at risk for requiring dose reduction. Based on the relationship between body weight, AUC, and dose, the AUC in patients weighing < 60 kg treated at 12 mg/day would be expected to exceed this cutoff value. Therefore, the recommended starting dose for patients weighing < 60 kg is 8 mg/day.
2.2. The REFLECT trial
The REFLECT trial (NCT01761266) was a randomized, open-label, comparative study to verify the noninferiority of lenvatinib to sorafenib in 954 previously untreated patients with unresectable HCC [25]. The patients received either lenvatinib at 12 mg/day (body weight ≥ 60 kg) or 8 mg/day (body weight < 60 kg) or sorafenib at 400 mg twice daily. The primary endpoint was OS. Secondary endpoints were PFS, time to progression (TTP), ORR, quality of life (QoL), and the pharmacokinetics of lenvatinib. Modified Response Evaluation Criteria in Solid Tumours (mRECIST), determined by the investigators, was used to assess tumor response. The major inclusion and exclusion criteria for the REFLECT trial must be considered during the interpretation of the study results and their implications for clinical practice [25]. The study enrolled only CP-A patients and excluded patients with portal vein invasion at the main portal branch (Vp4) or with gastric or esophageal varices requiring treatment in the 28 days before randomization. Additionally, patients with a platelet count below 75,000 cells/µL were excluded. This higher platelet count differentiated the REFLECT trial from sorafenib trials for HCC [25].
The median OS was 13.6 (95% CI 12.1–14.9) months in the lenvatinib group and 12.3 months (95% CI 10.4–13.9 months) in the sorafenib group, and the non-inferiority of lenvatinib to sorafenib was confirmed (HR 0.92, 95% CI 0.79–1.06). The median PFS (based on assessment by the investigator) was significantly longer in the lenvatinib group (7.4 months) than in the sorafenib group (3.7 months). The median TTP was also significantly longer in the lenvatinib group (8.9 months) than in the sorafenib group (3.7 months). The ORR was 24.1% in the lenvatinib group and 9.2% in the sorafenib group (Table 2).
Table 2. Efficacy measures in the REFLECT trial [25].
In masked independent imaging review, the median PFS was significantly longer in the lenvatinib group (7.3 months) than in the sorafenib group (3.6 months). Similarly, the median TTP was also significantly longer in the lenvatinib group (7.4 months) than in the sorafenib group (3.7 months). The ORR was 40.6% in the lenvatinib group and 12.4% in the sorafenib group (Table 2).
The HRs for TTP consistently seem to favor lenvatinib over sorafenib across patient subgroups stratified by baseline disease-related or demographic characteristics [25]. Specifically, the stratification analysis indicates that lenvatinib may be favorable over sorafenib in older patients (≥ 65 years) and patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 1, who may be more concerned about toxicity. However, a study in which the lenvatinib group and sorafenib group are balanced in terms of baseline patient characteristics would be needed to confirm this finding.
In the safety analysis, treatment-emergent AEs and serious treatment-emergent AEs occurred in 99% and 43%, respectively in the lenvatinib arm and 99% and 30%, respectively, in the sorafenib arm (Table 3). The common treatment-emergent AEs (incidence, > 25%) among patients receiving lenvatinib were hypertension, diarrhea, decreased appetite, decreased weight, fatigue, and palmar-plantar erythrodysesthesia (Table 3). In the sorafenib arm, the most common treatment-emergent AEs were palmar-plantar erythrodysesthesia, diarrhea, hypertension, and decreased appetite. Of all these AEs, patients who received lenvatinib experienced fewer instances of palmar-plantar erythrodysesthesia and diarrhea, and more instances of hypertension, decreased appetite, decreased weight, and fatigue than patients who received sorafenib.
Table 3. Most frequent treatment-emergent adverse events (occurring in ≥15% of patients) in the REFLECT trial [25].
Quality of life was measured using the European Organisation for Research and Treatment of Cancer QoL Questionnaire C30 (EORTC QLQ-C30) and EORTC QLQ-HCC18 health questionnaires [25]. It declined during treatment in both treatment groups. Clinically meaningful worsening of role functioning, pain, and diarrhea (EORTC QLQ-C30) and nutrition and body image (EORTC QLQ-HCC18) were significantly delayed in patients treated with lenvatinib compared with those treated with sorafenib.
3. Management of lenvatinib-related AEs
3.1. Hypertension
In the REFLECT study, hypertension was the most frequent AE in the lenvatinib group [25]. The incidence was 42% (≥ Grade 3: 23%) in the lenvatinib group and 30% (≥ Grade 3: 14%) in the sorafenib group. In the SELECT phase 3 trial of lenvatinib conducted in patients with differentiated thyroid carcinoma, the incidence of hypertension tended to be higher in Japanese patients [27]. Therefore, appropriate management of hypertension may be particularly important for Asian patients. Based on our clinical experience, a calcium channel blocker might be the first choice, considering the potent hypotensive effects. An angiotensin II receptor blocker might be a second choice. Depending on the systolic and diastolic pressures, hypertension may be managed by an increased dose of the antihypertensive or the addition of another antihypertensive (Table 4) [28]. Grade 1 or 2 events can be managed without interrupting lenvatinib therapy, but lenvatinib should be discontinued while managing Grade 3 events.
Table 4. Management of adverse events before and during lenvatinib therapy.
3.2. Diarrhea
In the REFLECT study, the incidence of diarrhea was 39% (≥ Grade 3: 4%) in the lenvatinib group and 46% (≥ Grade 3: 4%) in the sorafenib group [25]. A prescription for loperamide can be provided to the patient before the start of lenvatinib treatment [28]. Clinicians should advise patients to report incidents of diarrhea so that the severity can be assessed, and care instructions provided. For Grade 1 diarrhea, the patient should be directed to take loperamide. For Grade 2 diarrhea, the patient should stop taking lenvatinib and continue taking loperamide. Patients experiencing Grade 3 or 4 diarrhea should go to the hospital for fluid management. Patients who have been taking lenvatinib safely for several weeks before an incident of Grade 2 or 3 diarrhea should resume lenvatinib at the same dose after the symptoms are alleviated. Patients in the early phase of lenvatinib treatment at the time of the incident should resume treatment at a lower dose. For patients on a diuretic for the treatment of hypertension, attention should be paid to the development of dehydration associated with diarrhea.
3.3. Decreased appetite and weight loss
Decreased appetite and decreased body weight are also common AEs associated with both lenvatinib and sorafenib treatment. In the REFLECT study, the incidence of decreased appetite was 34% (≥ Grade 3: 5%) in the lenvatinib group and 27% (≥ Grade 3: 1%) in the sorafenib group [25]. The incidence of decreased weight was 31% (≥ Grade 3: 8%) in the lenvatinib group and 22% (≥ Grade 3: 3%) in the sorafenib group. In thyroid cancer patients, decreased weight resulting from decreased appetite was also reported [13]. Dose interruption strategies are the most effective approach for alleviating decreased appetite. Grade 1 or 2 decreased appetite can be managed with dose interruption and lenvatinib treatment can be resumed at the same dose after symptoms are alleviated. Grade 3 decreased appetite occurring several days after starting lenvatinib can be managed with dose interruption and dose reduction (Table 4). However, decreased appetite occurring several months after starting lenvatinib is more difficult to manage, most likely because it is a consequence of the progression of HCC. In these cases, dose interruption should ideally be performed before progression to Grade 3, which typically requires tube feeding or total parenteral nutrition. Once the symptoms progress to Grade 3, the dose interruption can become prolonged, but a Grade 2 event can generally be resolved in under one week. In some cases, incidents of Grade 3 decreased weight were preceded by a decreased appetite that had already progressed to Grade 3. Therefore, early intervention is essential. Scheduled dose interruption was performed in other studies before the occurrence of these events in order to have patients regain appetite and weight, thereby reducing the patients’ burdens [29–31]. An antiemetic agent, such as prochlorperazine maleate or domperidone, can be prescribed to treat decreased appetite and weight loss. Oral nutrition support can also be offered.
3.4. Fatigue
Grade 1 fatigue is relieved by rest. Grade 2 and Grade 3 are not managed by rest and interfere with the activities of daily life (Table 4). The incidence of fatigue was similar in the lenvatinib and sorafenib groups in the REFLECT trial: 30% (≥ Grade 3: 4%) and 25% (≥ Grade 3: 4%), respectively [25]. In general, dose interruption can be used whenever an AE becomes intolerable to the patient. However, Grade 1 fatigue can generally be managed without dose interruption. If a patient with ≥ Grade 2 fatigue cannot tolerate the symptoms, the patient should be instructed to discontinue treatment. When ≥ Grade 2 fatigue occurs in the early phase of treatment, the treatment should be resumed at a reduced dose after the fatigue is improved. When ≥ Grade 2 fatigue occurs after several weeks of treatment, the treatment should be resumed at the same dose after the fatigue is improved. Studies of the multi-kinase inhibitor axitinib have suggested that malaise associated with hypothyroidism can be effectively managed with thyroid hormone replacement therapy [32]. This strategy may also be helpful for management of similar symptoms in patients taking lenvatinib.
3.5. Palmar-plantar erythrodysesthesia syndrome (hand-foot syndrome)
Palmar-plantar erythrodysesthesia syndrome affects the hands and the soles of the feet and is characterized by swelling, numbness, and reddening and peeling of the skin. It is a common adverse reaction to certain chemotherapeutic drugs. Grade 1 involves minimal skin changes or dermatitis without any associated pain (Table 4). Skin changes are more extensive and painful in Grade 2 and Grade 3 events and limit activities of daily living. In the REFLECT study, the incidence of palmar-plantar erythrodysesthesia syndrome was 27% (≥ Grade 3: 3%) in the lenvatinib group and 52% (≥ Grade 3: 11%) in the sorafenib group [25]. In the SELECT study, the frequency of palmar-plantar erythrodysesthesia syndrome associated with lenvatinib was higher in the Japanese subgroup than in the overall study population [27]. Although the incidence is generally higher in the early phase of treatment, palmar-plantar erythrodysesthesia syndrome can also occur during Cycles 5–15 [26]. As recommended with sorafenib therapy [33], patients should be given guidance on prophylactic moisturizing with urea-based cream and should continue lenvatinib treatment as long as no pain occurs [28]. If pain does occur, lenvatinib treatment can be interrupted while the condition is treated with a steroid. If the dose interruption occurs within one week of initiating lenvatinib treatment, the treatment should be resumed at a reduced dose after the pain is alleviated. If the pain occurs after several weeks of pain-free treatment, the treatment should be resumed at the same dose after the pain is alleviated.
3.6. Proteinuria
Proteinuria is characterized by abnormal quantities of protein in the urine, indicating potential kidney damage. It is one of the most serious lenvatinib-related AEs, because it may lead to hypoalbuminemia in patients with advanced HCC and liver cirrhosis.
Patients receiving lenvatinib require monitoring for proteinuria. This should be carried out by semiquantitative urine dipstick testing, weekly in the first month of treatment and every two weeks thereafter. Proteinuria is graded based primarily on the amount of protein in the urine (Table 4). Both the incidences of proteinuria of any grade and of ≥ Grade 3 were higher in the lenvatinib group than the sorafenib group in the REFLECT trial: 25% (≥ Grade 3: 6%) in the lenvatinib group and 11% (≥ Grade 3: 2%) in the sorafenib group [25]. Patients with Grade 1 or 2 proteinuria can continue lenvatinib treatment. For ≥ Grade 3 proteinuria, the urinary protein-to-creatinine ratio (UPCR) should be determined. Lenvatinib treatment should be interrupted for patients with a UPCR of ≥ 3.5. Dose interruption may also be appropriate for patients with a UPCR < 3.5 if other symptoms such as edema, pleural effusion, ascites, or increased blood creatinine levels are observed. After the proteinuria is improved to Grade 0 or 1, lenvatinib treatment can be resumed [28].
No treatments specifically for lenvatinib-related proteinuria are available. The most effective management is suspension of treatment followed by resumption at a lower dose. Additional diagnostic investigations for proteinuria, for example requiring specific tests (e.g. measurement of urinary β2 – macroglobulin or N-acetyl-β-d-glucosaminidase), are not routinely carried out. However, in serious cases of proteinuria, patients are referred to a nephrologist.
Proteinuria induced by tyrosine kinase inhibitors rarely leads to renal failure, and persistent proteinuria alone does not lead to a fatal outcome. Therefore, from a risk-benefit viewpoint, lenvatinib treatment should not be discontinued due to the occurrence of proteinuria only.
3.7. Decreased platelet count and management of bleeding
In the REFLECT trial, only patients with a baseline platelet count > 75,000 cells/µL were eligible [25]. The incidence of decreased platelet count was 18% (≥ Grade 3: 5%) in the lenvatinib group and 12% (≥ Grade 3: 3%) in the sorafenib group. In the majority of patients with decreased platelet count, the platelet count decreased from approximately 100,000 cells/µL to 45,000–48,000 cells/µL and returned to around 80,000 cells/µL after dose interruption for about one week.
In clinical settings, when lenvatinib is administered to patients with a platelet count of 50,000–60,000 cells/µL and the platelet count is reduced by half, there will be an increased risk for serious bleeding. Therefore, physicians must be aware of the risk for decreased platelet count and exercise particular caution when prescribing lenvatinib to patients with platelet count between 50,000 and 75,000 cells/µL, because the methods for escalation from a lower dose of lenvatinib have not been established. A blood cell count is required weekly for the first month of treatment and twice monthly thereafter. In the REFLECT trial, the first onset of decrease in platelet count occurred at median 29 days, however, it resolved after dose interruption. For patients requiring surgical intervention, lenvatinib should be stopped one week before surgery and resumed one week after.
Lenvatinib is not recommended for patients with platelet count < 50,000 cells/µL.
3.8. Hypothyroidism
Grade 1 hypothyroidism is asymptomatic. Grade 2 hypothyroidism limits some activities of daily living and may require thyroid replacement. Grade 3 has severe symptoms and may require hospitalization. Grade 4 is life threatening. The incidence of hypothyroidism in HCC patients receiving lenvatinib was 16% in the REFLECT trial (no Grade 3 events) [25]. In the SELECT study, the incidence of increased thyroid-stimulating hormone level among patients treated with lenvatinib was 30.0% in the Japanese population, while it was 5.7 % in the general population [27]. In the REFLECT trial [25], patients experiencing hypothyroidism were treated with levothyroxine. Because patients with Grade 2 hypothyroidism tend to have no symptoms, patients requiring levothyroxine can be hard to identify. In Japan, thyroid-stimulating hormone levels must be monitored and appropriate information on how to manage hypothyroidism must be provided to clinicians.
3.9. Hepatic disorder
In the REFLECT trial [25], some patients in the lenvatinib group developed liver dysfunction reflected by increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin levels and decreased albumin levels. According to the inclusion criteria of REFLECT study, lenvatinib should be avoided in patients with fivefold increases in the levels of AST, ALT, and alkaline phosphatase above the normal range, in those with serum albumin levels less than 2.8 g/dL, and in those with total bilirubin levels exceeding 3.0 mg/dL. Thus, for patients who develop liver dysfunction, appropriate intervention, such as dose reduction, interruption, or discontinuation, should be undertaken. The criteria for dose interruption, reduction, and discontinuation for patients who developed liver dysfunction in the REFLECT trial [25], were as follows: patients who developed a tolerable Grade 2 event could continue treatment; for patients who developed a Grade 3 or intolerable Grade 2 event, treatment was resumed at a dose reduced by one dose level after an improvement in liver dysfunction to the lower grade was confirmed; in cases of 10-fold decreases in ALT, AST, or γ-glutamyl transpeptidase levels below the normal ranges, the treatment could be continued when the physician deemed it appropriate. Treatment was to be discontinued in patients who developed a Grade 4 event.
Underlying liver disease, for example alcoholic cirrhosis or hepatitis, must be adequately managed. Abnormalities in the results of liver function tests are interpreted differently and require different approaches to management depending on the individual patient. Therefore, consultation with a hepatologist is strongly recommended.
3.10. Hepatic encephalopathy
Hepatic encephalopathy occurs when the liver fails to remove toxins from the blood. These toxins then accumulate and cause impairment of brain function. A previous report suggested that HCC patients are at risk of suffering complications with hepatic encephalopathy regardless of the type of treatment [34]. Additionally, hepatic encephalopathy is more likely to occur in patients with more advanced disease and higher serum ammonia levels.
Because the presence of esophageal varices is a risk factor for hepatic encephalopathy, an upper gastrointestinal endoscopy to screen for high-risk varices is mandatory for patients who have not had this investigation in the past 6 months, and for patients not already receiving beta-blocker therapy for prevention of variceal hemorrhage. It is particularly relevant in cases of portal vein invasion (which increases portal pressure), so that the appropriate prophylaxis against bleeding (i.e. band ligation or the use of beta-blockers) can be applied.
Hepatic encephalopathy can also be the result of portosystemic shunting; it has been reported that up to 71% of patients with intractable hepatic encephalopathy have portosystemic shunts. The diagnosis of shunt-induced hepatic encephalopathy is based on clinical symptoms such as intellectual impairment, reduced level of consciousness, and flapping tremor (asterixis), accompanied by increased serum ammonia level, after other causes of hepatic encephalopathy, such as gastrointestinal bleeding and infection, have been excluded.
Hepatic encephalopathy is a serious complication, and its management requires the expertise of a hepatologist. Its onset necessitates identification of any precipitating factors, such as dehydration, gastrointestinal hemorrhage, infection (e.g. spontaneous bacterial peritonitis), and portal vein thrombosis.
In cases of hepatic encephalopathy, medications such as lactulose, lactitol, or rifaximin are administered. However, many cases improve only with lenvatinib dose interruption or dose reduction, so this is the first step in management. Hepatic encephalopathy can also be managed (improved) by administration of amino acid preparations. Hepatic encephalopathy can also be managed (improved) by administration of amino acid preparations.
Hepatic encephalopathy can occur several days after starting lenvatinib. A phase 2 study of lenvatinib reported that hepatic encephalopathy was the most frequent serious AE, occurring in 11% of patients [24]. Even patients with a baseline CP score of 5, who appear to have no significant issues with liver function, can develop hepatic encephalopathy. Patients at high risk of developing hepatic encephalopathy several days after starting lenvatinib may be identified to some extent according to their baseline liver function or by monitoring the serum ammonia levels. Therefore, patients should be carefully monitored, including an assessment of serum ammonia levels, every week during the first month of treatment. After long-term treatment, the development of hepatic encephalopathy may be associated with cancer progression. Physicians should be aware that the risk of developing hepatic encephalopathy increases particularly when a diuretic is used or when dehydration or diarrhea occurs.
4. Conclusion
Clinicians should ensure that HCC patients can fully benefit from the potential clinical efficacy of lenvatinib without any unnecessary safety risks by fully understanding the common AEs associated with lenvatinib therapy and their appropriate management.
5. Expert opinion: long-term management of AEs in lenvatinib-treated HCC patients
To date, the trials of lenvatinib for the treatment of patients with HCC have clearly defined some clinical advantages to lenvatinib over sorafenib. The studies have also established the need for a lower starting dose of lenvatinib for HCC patients than for patients with other solid tumors. Appropriate and informed management is particularly important for hepatic encephalopathy and decreased platelet count, both of which occur often with lenvatinib treatment in this patient population.
Regarding patient selection, lenvatinib is not recommended for patients with or at risk of cardiovascular disease, because of the lack of data on its efficacy and safety in this group, and the potential for increased risk of cardiovascular events. It is also not recommended for patients with platelet count < 50,000 cells/µL.
With proper management, the optimal sequence of drug therapy for HCC can be ensured. The following aspects need to be considered to ensure such an optimal therapy sequence for the treatment of HCC: (A) an appropriate risk assessment for AEs before lenvatinib treatment, (B) careful and continuous monitoring during lenvatinib treatment and (C) appropriate dose modification upon the onset of AEs during lenvatinib treatment. The approach for the optimal management of AEs should account for the type and severity of the event and its potential impact on the patient’s daily life activities.
The assessment of risk before starting lenvatinib treatment will help enable the prediction of AEs. It is important to check the baseline laboratory data of patients to determine treatment eligibility. Patients with a history of hypertension and proteinuria may be at higher risk of these occurring as AEs during lenvatinib treatment compared with those who do not have these baseline comorbidities. Reportedly, patients with hepatic impairment have higher plasma concentrations of lenvatinib, and therefore, may have an increased risk of AEs compared with patients without hepatic compromise. However, the phase 3 study of lenvatinib only enrolled CP-A patients [25]; thus, the AE risk of patients with worsened hepatic function (e.g. CP-B patients) remains to be clarified. An upper gastrointestinal endoscopy is mandatory for patients who have not had this investigation recently, and for those not already receiving beta-blocker therapy for prevention of variceal hemorrhage, to identify patients at increased risk of hepatic encephalopathy.
The continuous monitoring of AEs during lenvatinib treatment may facilitate the detection of AEs at an earlier stage and allow early management of symptoms. Whenever possible, lenvatinib treatment should be continued while managing the AEs to improve treatment outcomes for HCC patients. Use of the maximum initial dose is important, and it is ideal to consider dose interruption or reduction and maintain the appropriate dose. For patients who present with low-grade AEs that can be managed by either monitoring the patient carefully or providing standard supportive care, we recommend continuing lenvatinib treatment at the same dose whenever possible.
Dose modifications, including interruption of treatment and resumption at the same or a reduced dose after recovery of the AE may have an impact on both the safety and potential efficacy of the treatment with lenvatinib. In clinical practice, HCC patients who developed AEs are usually managed with dose interruptions and/or reductions to help manage the symptoms and alleviate the condition. However, patients who have to interrupt or discontinue treatment may not fully benefit from the therapy. Progressive disease can result either when the disease does not initially respond to the drug or when the drug is ineffective because the resulting dose after dose reduction is too low. To ensure long-term disease control, the dose intensity of lenvatinib should be maintained as much as possible while managing AEs even in patients with HCC. In the case of treatment interruption, lenvatinib should be resumed without dose reduction as long as supportive therapy can effectively control the symptoms. These recommendations should ensure careful management of the AE without an undue risk of disease progression.
For some patients, dose escalation may be appropriate, particularly in those with progressive disease and acceptable tolerability. A recent report on lenvatinib-treated thyroid cancer patients demonstrated that dose escalation after disease progression was associated with remarkable efficacy [35]. Additionally, dose escalation of axitinib, another kinase inhibitor, was used in select patients with progressive metastatic renal cell carcinoma. A reduction in tumor burden and an extension of the duration of therapy were reported [36]. A similar approach should be further evaluated in patients with HCC treated with lenvatinib in future studies. Nonetheless, if clinicians consider the above-mentioned aspects for careful patient selection, symptom surveillance, and dose adjustments, and apply the recommended approaches for the management of the relevant AEs upon onset, we expect that HCC patients can fully experience the potential benefits of lenvatinib treatment.
| Parameter | HCC, Child–Pugh A | HCC, Child–Pugh B | Solid tumor | |||
|---|---|---|---|---|---|---|
| 12 mg (MTD) | 16 mg | 8 mg (MTD) | 12 mg | 12 mg | 25 mg (MTD) | |
| AUC(0-τ) (ng*h/mL) | 3120 (566) n = 5 | 5110 (976) n = 2 | 1770 (340) n = 6 | 3960 (1990) n = 2 | 2059 (792) n = 8 | 4236 (1127) n = 4 |
| Css, max (ng/mL) | 346 (75.4) n = 5 | 402 (62.9) n = 2 | 167 (40.4) n = 6 | 349 (180) n = 2 | 291 (146) n = 8 | 545 (183) n = 4 |
| C24 h (ng/mL) | 43.1 (21.7) n = 5 | 84.6 (33.1) n = 2 | 29.9 (13.4) n = 6 | 64.0 (34.7) n = 2 | 22.3 (7.4) n = 10 | 45.1 (20.2) n = 5 |
| t 1/2, ss (h) | 8.76 (2.62) n = 5 | 8.98 (2.15) n = 2 | 10.2 (3.1) n = 6 | 9.74 (0.933) n = 2 | 6.9 (1.2) n = 8 | 6.0 (0.7) n = 4 |
Parameters on day 15 of multiple dosing were summarized. AUC(0-τ), area under the concentration–time curve over the dosing interval for multiple dosing; Css, max, maximum observed concentration at steady state; ; C24 h, plasma concentration at 24 h after administration; HCC, hepatocellular carcinoma; MTD, maximum tolerated dose; t1/2, terminal elimination phase half-life; . Data are mean (standard deviation).
| Lenvatinib (n = 478) | Sorafenib (n = 476) | Effect size (95% CI) | p value | |
|---|---|---|---|---|
| Investigator review according to mRECIST | ||||
| PFS (months) | 7.4 (6.9–8.8) | 3.7 (3.6–4.6) | HR 0.66 (0.57−0.77) | <0.0001 |
| TTP (months) | 8.9 (7.4–9.2) | 3.7 (3.6–5.4) | HR 0.63 (0.53–0.73) | <0.0001 |
| ORR (%) | 24.1 (20.2–27.9) | 9.2 (6.6–11.8) | OR 3.13 (2.15–4.56) | <0.0001 |
| DCR (%) | 75.5 (71.7–79.4) | 60.5 (56.1–64.9) | ||
| Masked independent imaging review according to mRECIST | ||||
| PFS (months) | 7.3 (5.6–7.5) | 3.6 (3.6–3.7) | HR 0.64 (0.55–0.75) | <0.0001 |
| TTP (months) | 7.4 (7.2–9.1) | 3.7 (3.6–3.9) | HR 0.60 (0.51–0.71) | <0.0001 |
| ORR (%) | 40.6 (36.2–45.0) | 12.4 (9.4–15.4) | OR 5.01 (3.59–7.01) | <0.0001 |
| DCR (%) | 73.8 (69.9–77.8) | 58.4 (54.0–62.8) | ||
DCR, disease control rate; HR, hazard ratio; mRECIST, modified Response Evaluation Criteria in Solid Tumours; OR, odds ratio; ORR, objective response rate; PFS, progression-free survival; TTP, time to progression
Data are presented as median (95% CI) or % (95% CI) unless otherwise indicated.
Reprinted from reference [25], copyright (2018), with permission from Elsevier.
| Lenvatinib (n = 476) | Sorafenib (n = 475) | |||
|---|---|---|---|---|
| Any grade n (%) | Grade ≥ 3 n (%) | Any grade n (%) | Grade ≥ 3 n (%) | |
| Treatment-emergent adverse events | 470 (99%) | 357 (75%) | 472 (99%) | 316 (67%) |
| Treatment-related treatment-emergent adverse events | 447 (94%) | 270 (57%) | 452 (95%) | 231 (49%) |
| Serious treatment-emergent adverse events | 205 (43%) | 144 (30%) | ||
| Serious treatment-related treatment-emergent adverse events | 84 (18%) | 48 (10%) | ||
| Hypertension | 201 (42%) | 111 (23%) | 144 (30%) | 68 (14%) |
| Diarrhea | 184 (39%) | 20 (4%) | 220 (46%) | 20 (4%) |
| Decreased appetite | 162 (34%) | 22 (5%) | 127 (27%) | 6 (1%) |
| Decreased weight | 147 (31%) | 36 (8%) | 106 (22%) | 14 (3%) |
| Fatigue | 141 (30%) | 18 (4%) | 119 (25%) | 17 (4%) |
| Palmar-plantar erythrodysesthesia | 128 (27%) | 14 (3%) | 249 (52%) | 54 (11%) |
| Proteinuria | 117 (25%) | 27 (6%) | 54 (11%) | 8 (2%) |
| Dysphonia | 113 (24%) | 1 (< 1%) | 57 (12%) | 0 |
| Nausea | 93 (20%) | 4 (1%) | 68 (14%) | 4 (1%) |
| Decreased platelet count | 87 (18%) | 26 (5%) | 58 (12%) | 16 (3%) |
| Abdominal pain | 81 (17%) | 8 (2%) | 87 (18%) | 13 (3%) |
| Hypothyroidism | 78 (16%) | 0 | 8 (2%) | 0 |
| Vomiting | 77 (16%) | 6 (1%) | 36 (8%) | 5 (1%) |
| Constipation | 76 (16%) | 3 (1%) | 52 (11%) | 0 |
| Increased blood bilirubin | 71 (15%) | 31 (7%) | 63 (13%) | 23 (5%) |
| Elevated aspartate aminotransferase | 65 (14%) | 24 (5%) | 80 (17%) | 38 (8%) |
| Rash | 46 (10%) | 0 | 76 (16%) | 2 (< 1%) |
| Alopecia | 14 (3%) | 0 | 119 (25%) | 0 |
Reprinted from reference [25], copyright (2018), with permission from Elsevier.
| Adverse event and grade definition* | Before lenvatinib therapy | During lenvatinib therapy |
|---|---|---|
| Hypertension Grade 1: Prehypertension (systolic BP 120–139 mmHg or diastolic BP 80–89 mm Hg) Grade 2: Stage 1 (systolic BP 140–159 mmHg or diastolic BP 90–99 mmHg); medical intervention indicated; recurrent or persistent (≥24 h); symptomatic increase by >20 mmHg (diastolic) or to >140/90 mmHg if previously within normal limits; monotherapy indicated Grade 3: Stage 2 (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg); medical intervention indicated; more than one drug or more intensive therapy than previously used indicated Grade 4: Life-threatening consequences, urgent intervention indicated | Do not start lenvatinib until BP is controlled with an antihypertensive to a systolic BP of ≤ 140 mmHg and a diastolic BP of ≤ 90 mmHg. |
|
| Diarrhea Grade 1: Increase of <4 stools per day over baseline Grade 2: Increase of 4–6 stools per day over baseline Grade 3: Increase of 7–9 stools per day over baseline; incontinence; hospitalization indicated Grade 4: Life-threatening consequences; urgent intervention indicated | Prescribe loperamide for use on an as-needed basis. |
|
| Decreased appetite/decreased weight Grade 1: Loss of appetite without alteration in eating habits; weight loss of 5–10% from baseline; intervention not indicated Grade 2: Oral intake altered without significant weight loss or malnutrition; weight loss of 10%–20% from baseline; nutritional support indicated Grade 3: Weight loss ≥20% from baseline; tube feeding, or total parenteral nutrition indicated Grade 4: Life-threatening consequences; urgent intervention indicated | Monitor appetite and weight. |
|
| Fatigue Grade 1: Relieved by rest Grade 2: Not relieved by rest; limiting instrumental ADL Grade 3: Not relieved by rest, limiting self-care ADL | Monitor fatigue. |
|
| Palmar-plantar erythrodysesthesia syndrome Grade 1: Minimal skin changes or dermatitis without pain Grade 2: Skin changes with pain; limiting instrumental ADL Grade 3: Severe skin changes with pain; limiting self-care ADL | Start prophylactic treatment with a moisturizer; provide guidance to the patient. |
|
| Proteinuria Grade 1: 1+ proteinuria; urinary protein < 1.0 g/24 h Grade 2: 2+ proteinuria; urinary protein 1.0–3.4 g/24 h Grade 3: urinary protein ≥ 3.5 g/24 h | Check renal function; check for the presence or absence of proteinuria. |
|
| Decreased platelet count Grade 1: Below lower limit of normal and > 75,000/µL Grade 2: 50,000–75,000/µL Grade 3: 25,000–50,000/µL Grade 4: < 25,000/µL | Check platelet counts to identify patients at risk. If platelet count is < 50,000/µL, lenvatinib is not recommended. |
|
| Hypothyroidism Grade 1: Asymptomatic; clinical or diagnostic observations only; intervention not indicated Grade 2: Symptomatic; thyroid replacement indicated; limiting instrumental ADL Grade 3: Severe symptoms; limiting self-care ADL; hospitalization indicated Grade 4: Life-threatening consequences; urgent intervention indicated | Perform thyroid function tests. |
|
| Hepatic disorder Alanine aminotransferase increased Grade 1: > ULN – 3.0 × ULN Grade 2: > 3.0 – 5.0 × ULN Grade 3: > 5 – 20.0 × ULN Grade 4: > 20.0 × ULN Alkaline phosphatase increased Grade 1: > ULN – 2.5 × ULN Grade 2: > 2.5 – 5.0 × ULN Grade 3: > 5 – 20.0 × ULN Grade 4: > 20.0 × ULN Aspartate aminotransferase increased Grade 1: > ULN – 3.0 × ULN Grade 2: > 3.0 – 5.0 × ULN Grade 3: > 5 – 20.0 × ULN Grade 4: > 20.0 × ULN Blood bilirubin increased Grade 1: > ULN – 1.5 × ULN Grade 2: > 1.5 – 3.0 × ULN Grade 3: > 3 – 10.0 × ULN Grade 4: > 10.0 × UL Hypoalbuminemia Grade 1: < LLN – 3.0 g/dL; < LLN – 30 g/L Grade 2: < 3 – 2 g/dL; < 30 – 20 g/L Grade 3: < 2 g/dL; < 20 g/L Grade 4: Life-threatening consequences; urgent intervention indicated | Perform liver function tests and consult a hepatologist if necessary |
|
| Encephalopathy Grade 1: Mild symptoms Grade 2: Moderate symptoms; limiting self-care ADL Grade 3: Severe symptoms; limiting self-care ADL Grade 4: Life-threatening consequences; urgent intervention indicated | Measure serum ammonia levels; identify risk factors, such as the presence of esophageal varices; evaluate the patient for portosystemic shunting and rule out other possible causes of altered mental status |
|
ADL, activities of daily living; BCAA, branched-chain amino acids; BP, blood pressure; UPCR, urinary protein-to-creatinine; ULN, upper limit of normal; LLN, lower limit of normal
*CTC-AE ver 4.0
Acknowledgments
The authors thank Susan Cottrell, PhD, of Edanz Medical Writing for providing medical writing support. We would like to thank all the patients and families that have participated in the clinical trials of lenvatinib.
Article highlights
• The phase 3 REFLECT trial in patients with hepatocellular carcinoma has demonstrated the noninferiority of lenvatinib to sorafenib for overall survival and indicated that progression-free survival, tumor response, and disease control may be improved with lenvatinib.
• Adverse events in the REFLECT trial included hypertension, diarrhea, decreased appetite and weight, fatigue, palmar-plantar erythrodysesthesia, and proteinuria.
• For each of these event types, guidance is provided on when lenvatinib treatment should be interrupted, when it is appropriate to resume treatment, and when dose reduction is necessary.
• To ensure long-term disease control, the dose intensity of lenvatinib must be maintained while managing AEs even in patients with HCC. If treatment interruption is necessary, the previous lenvatinib dose should be maintained as long as supportive therapy can effectively control the symptoms.
• With informed treatment of emerging events, patients can fully benefit from the clinical efficacy of lenvatinib while minimizing safety risks.
This box summarizes key points contained in the article.
Declaration of interest
MI is a member of an advisory board or board of directors of Bayer Yakuhin, Eisai, Novartis Pharma, Shire and MSD; involved in researches sponsored by Bayer Yakuhin, Kyowa Hakko Kirin, Yakult, Eli Lilly Japan, Ono Pharmaceutical, Eisai, AstraZeneca, Baxalta Japan Limited, Chugai Pharmaceutical, Bristol Myers Squibb, Merck Serono, Nano Carrier, ASLAN Pharmaceuticals, Novartis Pharma and Takara Bio. The other authors have no competing interests to declare.
Reviewer disclosures
Peer reviewers on this manuscript have received an honorarium from Expert Opinion on Drug Safety for their review work and a reviewer on this manuscript has declared the following, Bayer: advisory board and speaker bureau honoraria, Bracco: speaker bureau honoraria, EISAI: advisory board and speaker bureau honoraria, ESAOTE: research contract, Guerbet: speaker bureau honoraria.