臨床研究等提出・公開システム

Safety and efficacy of lenvatinib in Child-Pugh A and B patients with advanced
hepatocellular carcinoma including high burden of intrahepatic tumor
(LAUNCH)

LAUNCH trial

59

Safety analysis: 59 cases Child-Pugh A group: 47 Child-Pugh B group: 12 (Figure 1) Group A (n = 47) Median age: 73 (50-88) years, 38 (80.9%) men, HBV: 10 (21.3%), HCV: 10 (21.3%), ECOG-PS 0: 40 (85.1%), Child-Pugh score 5: 26 (55.3%), Child-Pugh score 6: 21 (44.7%), intrahepatic tumour volume more than 50%: 5 cases 44.7%), intrahepatic tumour volume >50%: 5 cases (10.6%), portal trunk involvement: 7 cases (14.9%), bile duct involvement: 1 case (2.1%), extrahepatic metastases: 19 cases (40.4%), BCLC stage C: 28 cases (59.6%), AFP >400 mg/dL: 17 cases (36.2%) Group B (n = 12) Median age: 66 (51-85) years, 12 (100.0%) men, HBV: 2 (16.6%), HCV: 2 (16.6%), ECOG-PS 0: 7 (58.3%), Child-Pugh score 7: 9 (75.0%), Child-Pugh score 8: 3 (25.0%) Intrahepatic tumour volume >50%: 5 cases (41.7%), portal trunk involvement: 4 cases (33.3%), bile duct involvement: 1 case (8.3%), extrahepatic metastases: 5 cases (41.7%), BCLC stage C: 10 cases (83.3%), AFP >400 mg/dL: 6 cases (50.0%) (Table 1) Efficacy analysis included: 57 patients Child-Pugh A group: 45 cases Child-Pugh B group: 12 cases Group A: 11 patients with high burden, 12 patients on second-line treatment after atezolizumab/bevacizumab combination therapy Group A (n = 45) Median age: 73 (50-86) years, 36 (80.0%) men, HBV: 10 (22.2%), HCV: 9 (20.0%), ECOG-PS 0: 39 (86.7%), Child-Pugh score 5: 26 (57.8%), Child-Pugh score 6: 19 (19.2%), Child-Pugh score 6. 42.2%), intrahepatic tumour volume >50%: 5 cases (11.1%), portal trunk involvement: 7 cases (15.6%), bile duct involvement: 1 case (2.2%), extrahepatic metastases: 17 cases (37.8%), BCLC stage C: 26 cases (57.8%), AFP >400 mg/dL: 17 cases (37.8%) Group B (n = 12) Median age: 66 (51-85) years, 12 (100.0%) men, HBV: 2 (16.6%), HCV: 2 (16.6%), ECOG-PS 0: 7 (58.3%), Child-Pugh score 7: 9 (75.0%), Child-Pugh score 8: 3 (25.0%) ), Intrahepatic tumour volume >50%: 5 cases (41.7%), Portal trunk involvement: 4 cases (33.3%), Bile duct involvement: 1 case (8.3%), Extrahepatic metastases: 5 cases (41.7%), BCLC stage C: 10 cases (83.3%), AFP >400 mg/dL: 6 cases (50.0%).

Start date (26th April 2019) - 25th April 2020 Number of consent cases: 13 patients, Number of allocated cases: 13 patients, Number of discontinued cases: 4 patients, Number of dropout cases: 0 patient. 26th April 2020 - 25th April 2021 Number of consent cases: 38 patients, Number of allocated cases: 38 patients, Number of discontinued cases: 33 patients, Number of dropout cases: 0 patient. 26th April 2021 - 25th April 2022 Number of consent cases: 9 patients, Number of allocated cases: 8 patients, Number of discontinued cases: 21 patients, Number of dropout cases: 0 patient.

In the safety analysis population, there were 59 serious adverse events reported during the study. 18 events were attributable to the study and 41 events were not attributable to the study. The breakdown is as follows. Serious adverse events are defined in this study as follows. Serious adverse events are defined as any of the following. (1) Death. (2) May lead to death. (3) Disability (development of functional impairment to the extent that it interferes with daily life) (4) May lead to disability (5) Those requiring hospitalisation or prolonged hospitalisation in a hospital or clinic for treatment. (6) Cases that are as serious as those listed in (1) to (5) above*. (7) Congenital diseases or anomalies in later generations. Events resulting from: 18 cases. #1 Elevated AST: 1 case #2 Tumour collapse syndrome: 2 cases #3 Death: 1 event #4 Diarrhoea: 3 events #5 Hyperkalaemia and renal dysfunction: 1 case #6 Gastrointestinal haemorrhage: 1 case #7 Anorexia: 1 case #8 Fever: 2 cases #9 Ascites: 1 case #10 Hepatic encephalopathy: 1 case #11 Variceal haemorrhage: 2 cases #12 Pneumonia: 1 case #13 Renal failure: 1 case Unexplained events: 41 cases. #1 Exacerbation of primary disease: 19 cases #2 Skin ulcer: 1 case #3 Leg oedema: 2 events #4 Liver dysfunction: 2 events #5 Rupture of hepatocellular carcinoma: 2 events #6 Tumour collapse syndrome: 1 case #7 Anorexia: 3 cases #8 Bradycardia: 1 case #9 Myocardial ischaemia: 1 case #10 Renal failure: 1 case #11 Femur fracture: 1 case #12 Fever: 1 case #13 Atrioventricular block: 1 case #14 Constipation: 1 case #15 Peri-biliary abscess: 1 case #16 Enterocolitis: 1 case #17 Gastrointestinal haemorrhage: 1 case #18 Liver failure: 1 case All of the above events have been previously reported with lenvatinib and are not considered to interfere with the safety and scientific relevance of the study.

Trial Summary. Patient inclusion is as described above and also outlined in Figure 1. The background of the patients in each group is as described above for Child-Pugh A and B groups, and the subgroups in Group A are shown in Table 1. The epidemiology of hepatocellular carcinoma in the Japanese population included in the study is presented in Supplementary Table 1. Safety assessment The incidence of adverse events, the primary endpoint of this study, that occurred by 20% or more in either the Child-Pugh A or B groups are summarised in Figure 2. The main adverse events for each subgroup are summarised in Supplementary Table 2. In the Child-Pugh A group, the main adverse events of grade 3 or above were hypertension (29.8%), proteinuria (23.4%) and increased AST (10.6%); in the High burden group, the rate of grade 3 or above AST increases was higher at 27.3% Atezolizumab +. In the Child-Pugh B group, Grade 3 or higher adverse events included increased AST (41.7%), hyponaemia (41.7%) and increased bilirubin (16.7%). During the observation period, 83.0% and 83.3% of patients in Child-Pugh A and B groups required lenvatinib dose adjustment, respectively, and 17.0% and 33.3% of patients discontinued the study due to adverse events (Table 2). The main reasons for dose adjustment and discontinuation are summarised in Supplementary Table 3. Efficacy assessment The median PFS in Child-Pugh A and B groups was 6.4 (95% CI 4.5-8.3) and 2.5 (95% CI 1.0-5.1) months in mRECIST respectively (Table 2). The ORR and DCR in mRECIST were 57.8% and 88.9% in the Child-Pugh A and B groups, respectively (Table 2). Supplementary Table 4 shows the results in RECIST ver 1.1. Figure 3A shows a Swimmer's plot of treatment duration and best response in mRECIST, with some patients in Child-Pugh A, 1st line able to continue treatment for more than 12 months. Figure 3B shows the maximum reduction of the target lesion in mRECIST for each group, with good major reduction in both 1st and 2nd line patients in group A. In group B, some patients were able to continue treatment for more than 12 months. A similar analysis for RECIST ver 1.1 is shown in Supplementary figure 1. The median OS was 19.7 (95% CI 11.9-NE) and 4.1 (95% CI 2.2-9.1) months in Child-Pugh A and B groups, respectively (Figure 4A), and 21.6 (95% CI 13.1-NE) months in group A when restricted to the 1st line ( In group A, 1st line patients with and without a high burden, the difference was 14.5 (95% CI 11.2-NE) months in the high burden group and 21.6 (95% CI 11.9-NE) months in the low burden group (Figure 4C), In the second line patients, OS was 10.1 months from the start of lenvatinib and 14.3 months from the start of atezolizumab + bevacizumab. Supplementary figure 2 shows the change in Child-Pugh score at the start and end of lenvatinib: 84.4% of patients in Child-Pugh A group remained in A at the end of the study, while 41.7% of patients in Child-Pugh B group had a Child-Pugh score of 9 or higher at the end of the study. 71.1% of patients in group A and 33.3% of patients in group B were transferred to the next line of treatment after completion of lenvatinib. The breakdown is shown in Table 3. Figure 5 shows the 4-week relative dose intensities (RDI) by Child-Pugh class and lenvatinib starting dose. 24-week RDI averages were 59.0%, 79.1% and 63.7% for Group A (starting 12 mg, 8 mg and 8 mg) and Group B (all starting 8 mg), respectively. Analysis of the association between RDI and survival in three 8-week periods showed a trend towards longer PFS in mRECIST in the group with higher RDI at 9-16 weeks, but no clear association between initial RDI at 1-8 weeks and lenvatinib efficacy (Supplementary table 5). Exploratory evaluation Figure 6 shows lenvatinib blood concentration trends; data for Days 22 and 29 were analysed up to Day 15 due to a high number of exclusions due to withdrawal or dose reduction. The correlation between the trough values on Days 8 and 15 and the RDI every 4 weeks showed a negative correlation. The correlations were negative. When looking at the proportion of lenvatinib withdrawal and dose reductions at Day 8 and 15 troughs, which were divided into two groups based on median values, the proportion of withdrawal and dose reductions was higher in the group with the highest blood levels in both groups (Supplementary table 6). (Supplementary figure 3). Furthermore, a comparison of the RDI every four weeks in the two groups according to the presence or absence of portal hypertension showed that the RDI tended to be lower in patients with portal hypertension (Supplementary figure 4).

Lenvatinib is expected to be safe and effective in patients with advanced HCC who have a high tumor burden and second-line treatment after atezolizumab plus bevacizumab, whereas liver function was maintained with Child-Pugh A. However, in Child-Pugh B, this study found lower efficacy and higher discontinuation rates due to adverse events compared with Child-Pugh A.

Feb. 20, 2024

No

None

https://jrct.niph.go.jp/latest-detail/jRCTs031190017

Kato Naoya

Chiba University

1-8-1, Inohana, Chuo-ku, Chiba city, Chiba, Japan

kato.naoya@chiba-u.jp

Ogasawara Sadahisa

Chiba University

1-8-1, Inohana, Chuo-ku, Chiba city, Chiba, Japan

+81-43-222-7171

ogasawaras@chiba-u.jp

Complete

Jan. 15, 2019

Interventional

non-randomized controlled trial

open(masking not used)

no treatment control/standard of care control

parallel assignment

treatment purpose

Patients must meet all of the following criteria to be included in this study:
1) Patients must have been diagnosed with HCC base on either of the following assessments:
a) Histological or cytological diagnosis of HCC
b) Radiographic image diagnosis of HCC by the typical findings of a hypervascular tumor on dynamic CT, CTHA/CTAP, dymamic MRI.
2) Patients must meet all of the following criteria on treatment of HCC:
a) Not applicable for surgical resection.
b) Not applicable for any local therapies (radio frequency ablation, percutaneous ethanol injection, microwave ablation).
c) Not applicable for transarterial chemoembolization (TACE).
3) EOCG Performance Status (PS) of 0 or 1.
4) Liver function status is Child-Pugh class A or B (only less than 9).
a) HCC is classified into Child-Pugh class A to C, employing the added score of 5 clinical parameters.
b) Child-Pugh classification: A (5-6), B (7-9), and C (10-15)
5) Patients must meet all of the following criteria of clinical lab tests.
a) White blood cell>=2000/uL
b) Neutrophil>=1000/uL
c) Hemoglobin>=8.5g/dl
d) Platelet>=50000/mm3
e) Total bilirubin<=3.0mg/dl
f) AST, ALT<=5 times the upper limit of the facility reference
g) Serum Creatinine<=1.5 times the upper limit of the facility reference
h) Serum albumin>=2.8g/dl
i) Prothrombin time (PT-INR)<=2.3
6) Patients must have measurable lesion with RECIST version 1.1 and modified RECIST (mRECIST).
7) Systemic chemotherapy including lenvatinib, sorafenib, regorafenib has not been administerd(Combination therapy of atezolizumab and bevacizumab is permitted).
8) More than four weeks after the last treatment(In the case of combination therapy of atezolizumab and bevacizumab, more than two weeks have passed after the last treatment and adverse events have improved to grade 1 or less).
9) Ages 20 and older (any gender).
10) Patients with written consent after receiving sufficient explanation for this study. The consent is based on free will.

Patients who fall under any of the following criteria, will be excluded from the study.
1) Patients with a history of malignant tumors except for the following cases.
a) Early stage cancers with a low risk of relapse after appropriate radical treatment such as intraepithelial cervical cancer, basal cell carcinoma, superficial bladder tumor [Ta, Tis and T1] and early gastric cancer.
b) Malignant tumors that have been given radical treatment for more than three years prior to the study and is considered to have not relapsed since then.
2) Patients on kidney dialysis.
3) Heart disease which falls under any of the following.
a) Heart failure of NYHA class 3 or higher.
b) Coronary artery disease with symptoms. History of myocardial infarction within 24 weeks prior to enrollment.
c) Arrhythmias requiring control with antiarrhythmic drugs such as beta blocker and digoxin (CTCAE version 4.0 Grade 3 or higher).
d) Poor control hypertension.
4) Severe and active infections (CTCAE version 4.0 Grade 3 or higher).
5) History of HIV infection.
6) Portosystemic shunt with hepatic encephalopathy.
7) History of hepatic encephalopathy (Grade2 or higher).
8) Esophageal and gastric varices requiring treatment.
9) History of esophageal and gastric variceal bleeding.
10) Refractory ascites.
11) Detectable HBV-DNA without nucleic acid analog treatment.
12) Thromboembolism (cerebrovascular disorder including transient cerebral ischemic attack, deep vein thrombosis, pulmonary embolism etc.) within 6 months before the start of the study
13) Patients with the following medical history,
a) Use of CYP3A4 inducer (rifampicin etc.)
b) Use of Warfarin
c) History of gastrointestinal bleeding which needs to be treated within 4 weeks prior to study enrollment
d) Medical history with invasive surgery within 4 weeks prior to study enrollment
e) History of homologous organ transplantation
14) Gastrointestinal disorders which may affect drug absorption and pharmacokinetics
15) Use of drugs which may affect drug absorption and pharmacokinetics
16) Pregnant or lactating woman; woman of child bearing age unless using effective contraception (In case of suspected pregnancy, pregnancy test should be conducted)
17) Possibility of allergic reaction to the study drug
18) Drug abuse. Health, psychological, social conditions that interfere with the participation of the study or evaluation of the results
19) Any condition that in the opinion of the investigators could impair the patient's safety or make the study difficult to comply with the protocol by participating in the study.

Both

Hepatocellular carcinoma

Lenvatinib

Chemotherapy

Molecular targeted agent

013

Safety
For evaluation of adverse events, we use "Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Japanese version)"

Secondary outcomes of efficacy.
As secondary outcomes of efficacy, we evaluate overall survival (OS), progression free survival (PFS), time to progression (TTP) and objective response rate (ORR). Both RECIST version 1.1 and mRECIST are used for evaluation of efficacy.
Secondary outcomes of safety
As secondary outcomes of safety, we evaluate the discontinuation rate due to adverse events. For evaluation of adverse events, we use "Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Japanese version)"

+81-43-226-2616

Dec. 19, 2018

none