Lenvatinib Combined With Transarterial

original reports Chemoembolization as First-Line Treatment for

Advanced Hepatocellular Carcinoma: A Phase III,
Randomized Clinical Trial (LAUNCH)
Zhenwei Peng, MD, PhD1,2; Wenzhe Fan, MD3; Bowen Zhu, MSc3; Guoying Wang, MD4; Junhui Sun, MD5; Chengjiang Xiao, MSc6;
Fuxi Huang, MSc7; Rong Tang, MSc8; Yu Cheng, MSc9; Zhen Huang, MSc10; Yuchuang Liang, MSc11; Huishuang Fan, MSc12;
Liangliang Qiao, MSc13; Fuliang Li, MSc14; Wenquan Zhuang, MD15; Baogang Peng, MD16; Jiping Wang, MD, PhD17; Jiaping Li, MD3;
and Ming Kuang, MD, PhD1,16

PURPOSE Lenvatinib (LEN) is a first-line therapy for patients with advanced hepatocellular carcinoma (HCC);
abstract

however, it has shown modest survival benefits. Therefore, we aimed to compare clinical outcomes of LEN
combined with transarterial chemoembolization (LEN-TACE) versus LEN monotherapy in patients with ad-
vanced HCC.
MATERIALS AND METHODS This was a multicenter, randomized, open-label, parallel group, phase III trial.
Patients with primary treatment-naive or initial recurrent advanced HCC after surgery were randomly assigned
(1:1) to receive LEN plus on-demand TACE (LEN-TACE) or LEN monotherapy. LEN was initiated within
3 days after random assignment (initial dose: 12 mg once daily for patients $ 60 kg; 8 mg once daily for
patients , 60 kg). TACE was initiated one day after LEN initiation. The primary end point was overall survival
(OS).
RESULTS Between June 2019 and July 2021, a total of 338 patients underwent random assignment at 12
centers in China: 170 to LEN-TACE and 168 to LEN. At a prespecified event-driven interim analysis after a
median follow-up of 17.0 months, the median OS was significantly longer in the LEN-TACE group
(17.8 v 11.5 months; hazard ratio, 0.45; P , .001). The median progression-free survival was 10.6 months in the
LEN-TACE group and 6.4 months in the LEN group (hazard ratio, 0.43; P , .001). Patients in the LEN-TACE
group had a higher objective response rate according to the modified RECIST (54.1% v 25.0%, P , .001).
Multivariable analysis revealed that portal vein tumor thrombus and treatment allocation were independent risk
factors for OS.
CONCLUSION The addition of TACE to LEN improves clinical outcomes and is a potential first-line treatment for
patients with advanced HCC.
J Clin Oncol 41:117-127. © 2022 by American Society of Clinical Oncology

INTRODUCTION phase III REFLECT trial, patients with advanced HCC

ASSOCIATED
CONTENT Hepatocellular carcinoma (HCC) is the sixth most receiving LEN achieved a significant improvement in
Data Supplement common cancer and the third most common cause of progression-free survival (PFS) and objective response
Protocol cancer-related death worldwide.1 More than 70% of rate (ORR) on the basis of the modified RECIST
Author affiliations patients with HCC have advanced cancer (Barcelona (mRECIST) criteria compared with sorafenib.9 However,
and support Clinic Liver Cancer stage C) at the time of diagnosis and the efficacy of LEN is unsatisfactory, with a median
information (if
are not eligible for treatments with curative intent in- overall survival (OS) of 13.6 months.9
applicable) appear
at the end of this cluding resection, transplantation, and ablation.2,3 The limited survival benefit provided by LEN in ad-
article. However, developments in targeted systemic thera- vanced HCC highlights the importance of investi-
Accepted on June 14, pies are providing hope for patients with advanced gating treatment strategies combining LEN with other
2022 and published at HCC.4-6 Targeted drugs that inhibit tyrosine kinases treatments. Intrahepatic tumor progression and as-
ascopubs.org/journal/ such as sorafenib and lenvatinib (LEN) are currently sociated hepatic failure remain the leading cause of
jco on August 3,
2022: DOI https://doi.
recommended as first-line treatments for advanced death after targeted therapy in patients with ad-
org/10.1200/JCO.22. HCC.7,8 Sorafenib was a mainstay of HCC treatment for vanced HCC.10,11 Thus, LEN combined with a local
00392 a decade until the introduction of LEN in 2018. In the therapy that targets intrahepatic tumors, such as

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 Peng et al

CONTEXT*
Key Objective
Although lenvatinib (LEN) represents a standard first-line therapeutic option for advanced hepatocellular carcinoma,
survival rates in this patient population still remain poor. Retrospective studies have suggested promising outcomes from
combining transarterial chemoembolization (TACE) with LEN; however, a large-scale clinical trial is required to confirm a
survival benefit.
Knowledge Generated
In this randomized phase III study, the LEN-TACE group showed significant improvement in overall survival, as well as in
progression-free survival and objective response rate, compared with the LEN group. Grade 3-4 hepatotoxicity was more
common in the LEN-TACE group. Rates of dose reduction or interruption of LEN were comparable between the two groups.
Relevance
This study demonstrates that combined LEN-TACE therapy is more effective than LEN alone in tumor control and prolonging
patient survival, with a manageable side effect profile.

*The Context Summary was written by JCO Associate Editor Andrew H. Ko, MD.

transarterial chemoembolization (TACE), might improve MATERIALS AND METHODS

outcomes in patients with advanced HCC.12 Indeed, TACE
can effectively reduce tumor burden, and the effectiveness of
LEN may be improved when the tumor burden is relatively
low.13 In terms of mechanism of action, the combination of
LEN and TACE may have a synergistic antitumor effect. It is
known that TACE induces the upregulation of proangiogenic
factors by creating an ischemic tumor environment.14,15 LEN
is a multikinase inhibitor that targets vascular endothelial
growth factor receptors 1-3, fibroblast growth factor receptors
1-4, platelet-derived growth factor receptor a, RET, and KIT,
all of which play a key role in tumor recurrence and me-
tastasis after TACE. Therefore a potent antiangiogenic agent
such as LEN may inhibit angiogenesis and tumor growth after
TACE.
Recently, the efficacy of LEN combined with TACE (LEN-
TACE) has been investigated in several studies. A retro-
spective study showed that LEN provided better tumor
control than sorafenib in patients who previously received
TACE16 while another observational study reported that LEN-
TACE sequential therapy provided a survival benefit after
progression of advanced HCC during LEN therapy.17 In
addition, it has been indicated that LEN followed by TACE
leads to a favorable survival outcome and high tumor re-
sponse rate in patients with unresectable HCC.18 These
findings suggest that the combination of LEN-TACE has
potential synergistic efficacy and may be an effective ther-
apeutic option for patients with advanced HCC, and a large-
scale clinical trial is required to verify these observations.
Hence, we conducted a multicenter, randomized, open-
label, parallel group, phase III trial to assess the efficacy
and safety of LEN-TACE versus LEN monotherapy as a first-
line treatment for patients with advanced HCC.
Study Participants
This multicenter, randomized, open-label, parallel group,
phase III trial was performed from June 2019 to July 2021
at 12 hospitals in China. The study was registered at
ClinicalTrials.gov (identifier: NCT03905967). The trial
protocol was approved by the institutional review boards of
all participating hospitals, and all study participants gave
written informed consent before inclusion.
Patients with HCC were eligible for inclusion if they had the
following characteristics: (1) age 18-75 years; (2) advanced
primary HCC (consistent with the American Association for
the Study of Liver Diseases 2018 Guideline on Liver Cancer
Diagnosis6) without receipt of any previous treatment or with
initial recurrent advanced HCC after radical resection without
receipt of any postoperative treatment; (3) at least one
measurable lesion in the liver on the basis of mRECIST19; an
intrahepatic lesion consisting of a single tumor (# 10.0 cm)
or multiple tumors (# 10 foci) with the tumor burden , 50%;
(4) Eastern Cooperative Oncology Group performance status
score of 0 or 1; (5) Child-Pugh class A; (6) life expectancy of
at least 3 months; and (7) satisfactory blood, liver, and
kidney function parameters. The acceptable blood, liver, and
kidney parameters were (1) neutrophil count $ 1.5 3 109/L;
(2) platelet count $ 60 3 10 9 /L; (3) hemoglobin
concentration $ 90 g/L; (4) serum albumin
concentration $ 30 g/L; (5) bilirubin # 50 mmol/L; (6) AST
and ALT , 5 3 upper limit of normal (ULN) and alkaline
phosphatase , 4 3 ULN; (7) extended prothrombin time
, 6 seconds of ULN; and (8) serum creatinine , 1.5 3 ULN.
The main exclusion criteria were a medical history of hepatic
decompensation, such as hepatic encephalopathy and
esophageal or gastric variceal bleeding, CSF metastases,
other malignant diseases, contraindications for TACE, or
other criteria listed in the full-trial Protocol (online only).

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 Lenvatinib Plus TACE for Advanced HCC

Assessed for eligibility (N = 511)

Excluded (n = 173)
Did not meet eligibility criteria (n = 157)
Withdrew consent (n = 11)
Excluded for other reasons (n = 5)

Randomly assigned (n = 338)

Allocated to LEN plus TACE (n = 170) Allocated to LEN alone (n = 168)

Received allocated treatment (n = 170) Allocation Received allocated treatment (n = 168)
Did not receive allocated treatment (n = 0) Did not receive allocated treatment (n = 0)

Lost to follow-up (n = 3) Lost to follow-up (n = 4)

Discontinued treatment (n = 162) Discontinued treatment (n = 165)
Progression (n = 121) Follow-up Progression (n = 148)
AE (n = 15) AE (n = 14)
Surgical resection (n = 26) Surgical resection (n = 3)

Intention-to-treat Intention-to-treat
Analysis
LEN-TACE group (n = 170) LEN group (n = 168)

FIG 1. CONSORT diagram. AE, adverse event; LEN, lenvatinib; TACE, transarterial chemoembolization.

Study Design and Interventions
Patients were randomly assigned to receive LEN-TACE or
LEN monotherapy in a 1:1 ratio using a computerized
minimization technique. Random assignment was stratified
by Eastern Cooperative Oncology Group performance
status (0 v 1), tumor thrombus (present v absent), body
weight (, 60 v $ 60 kg), and trial site. The study schema is
presented in the Data Supplement (online only).
Patients in each group initiated LEN within 3 days of random
assignment orally at an initial dose of 12 mg once daily
(body weight $ 60 kg) or 8 mg once daily (body weight
, 60 kg). LEN treatment would be terminated if there was
disease progression or unacceptable toxicity during treat-
ment. In the LEN-TACE group, TACE was received 1 day
after oral administration of LEN and then repeated if there
was incomplete necrosis and tumor regrowth. Only one of
two TACE approaches was allowed during initial or repeated
TACE: either (1) injection of an emulsion of anticancer agent
with lipiodol, followed by embolization of the feeding artery
with an embolization agent or (2) injection of drug-eluting
beads preloaded with a chemotherapy agent. Selection of
TACE was decided by the investigators, and each patient
was required to use the same chemoembolization agent
throughout the study duration. LEN was continuously ad-
ministered without interruption during TACE. The details of
interventions are provided in the Data Supplement.
End Points, Assessments, and Safety Analyses
See the Data Supplement.
Statistical Analyses
Sample size was calculated for the primary end point
using the log-rank method. This study used a 1:1 parallel
design. In a previous international phase III study,7 the
median OS for patients with advanced HCC (Barcelona
Clinic Liver Cancer stage C) who received LEN was
11.8 months. However, at diagnosis, patients with HCC in
China typically have a heavier tumor burden and more
advanced disease stage than their counterparts from
western developed countries, which may result in a
shorter median OS after targeted therapy. Therefore, the
median OS for patients receiving LEN was conservatively
estimated to be 10 months. For patients with advanced
HCC who receive LEN-TACE, the median OS may be
expected to be 15 months, with an equivalent hazard ratio
(HR) of 0.67 versus LEN. Assuming a two-sided type I
error rate (a) of 5%, a type II error rate (b) of 10% (ie, 90%
power), recruitment and follow-up periods expected to
last 24 months, a total study duration of 48 months, and a
10% loss to follow-up or noncompliance rate, a total
sample of 336 patients was needed. A single interim
analysis in the intention-to-treat population was planned
when approximately 2/3 (66.7%) of the 258 expected

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 Peng et al

TABLE 1. Baseline Characteristics of Patients in the Two Groups

Characteristic LEN-TACE Group (n 5 170) LEN Group (n 5 168)
Age, years, median (IQR) 54.0 (46.0-64.0) 56.0 (48.0-63.0)
60 and younger, No. (%) 113 (66.50) 117 (69.60)
Older than 60, No. (%) 57 (33.50) 51 (30.40)
Sex, No. (%)
Male 139 (81.80) 132 (78.60)
Female 31 (18.20) 36 (21.40)
Bodyweight, kg, No. (%)
, 60 60 (35.30) 65 (38.70)
$ 60 110 (64.70) 103 (61.30)
Etiology, No. (%)
Hepatitis B 148 (87.10) 144 (85.70)
Hepatitis C 4 (2.40) 6 (3.60)
Others 18 (10.60) 18 (10.70)
ECOG-PS score, No. (%)
0 89 (52.40) 99 (58.90)
1 81 (47.60) 69 (41.10)
WBC, 3 109/L, mean (SD) 6.2 (1.60) 6.0 (1.40)
Hemoglobin, g/L, mean (SD) 130 (18.00) 126 (20.00)
Platelet count, 3 10 /L, mean (SD)
9
191 (80.00) 189 (78.00)
AFP, ng/mL, mean (SD) 55,979 (224,434.00) 31,752 (119,316.00)
, 400, No. (%) 87 (51.20) 81 (48.20)
$ 400, No. (%) 83 (48.80) 87 (51.80)
ALT, IU/L, mean (SD) 41.9 (22.20) 45.1 (22.30)
AST, IU/L, mean (SD) 47.8 (19.20) 50.6 (20.90)
GGT, mean (SD) 169.2 (187.10) 176.0 (237.90)
ALB, g/dL, mean (SD) 37.2 (3.50) 38.0 (4.40)
TBil, mg/dL, mean (SD) 16.5 (6.90) 15.9 (6.30)
PT, seconds, mean (SD) 13.0 (1.20) 13.2 (1.20)
ALBI score, mean (SD) 22.38 (0.33) 22.46 (0.40)
ALBI grade, No. (%)
Grade 1 41 (24.10) 53 (31.50)
Grade 2 129 (75.90) 115 (68.50)
Intrahepatic tumors, No. (%)
Single 30 (17.60) 38 (22.60)
Multiple 140 (82.40) 130 (77.40)
Main tumor size, cm, median (IQR) 8.4 (4.5-9.5) 7.4 (4.1-9.7)
, 5, No. (%) 47 (27.60) 58 (34.50)
$ 5, No. (%) 123 (72.40) 110 (65.50)
Primary tumor, No. (%)
Yes 157 (92.40) 142 (84.50)
No 13 (7.60) 26 (15.50)
Macroscopic portal vein invasion, No. (%)
Yes 122 (71.80) 117 (69.60)
(continued on following page)

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 Lenvatinib Plus TACE for Advanced HCC

TABLE 1. Baseline Characteristics of Patients in the Two Groups (continued)

Characteristic LEN-TACE Group (n 5 170) LEN Group (n 5 168)
No 48 (28.20) 51 (30.40)
Extrahepatic spread, No. (%)
Yes 94 (55.30) 95 (56.50)
No 76 (44.70) 73 (43.50)
Involved disease sites, No. (%)
Liver 170 (100.00) 168 (100.00)
Lung 55 (32.40) 54 (32.10)

Abbreviations: AFP, a-fetoprotein; ALB, albumin; ALBI, albumin-bilirubin score; ECOG-PS, Eastern Cooperative Oncology Group performance status; GGT,
g-glutamyltranspeptidase; IQR, interquartile range; LEN, lenvatinib; PT, prothrombin time (international ratio); SD, standard deviation; TACE, transarterial
chemoembolization; TBil, total bilirubin.

total death events had been observed in the required 336
patients enrolled. To control the type I error rate at the
interim analysis, superiority boundaries were calculated
using the O’Brien-Fleming spending function,20 giving a
P value boundary of .016 for OS and an upper boundary
of the 95% CI for the OS HR , 0.697.
Continuous variables were expressed as mean 6 standard
deviation or median (interquartile range) and categorical data
as frequencies. Efficacy was assessed in all patients who
were randomly assigned (intention-to-treat population). The
safety evaluations included all patients who received at least
one dose of study treatment. Time-to-event survival variables
in the two treatment groups were estimated using the Kaplan-
Meier method, and the statistical significance of between-
group differences was tested using a log-rank test. HRs were
estimated with a Cox proportional hazards model. In addition,
a stratified log-rank test was performed, and stratified HRs
were estimated, which is the primary analysis of this study. All
stratified analyses used the prespecified random assignment
stratification factors. In an exploratory data-driven approach,
all covariates with a P , .10 in a univariable Cox proportional
hazards model were included in a multivariable analysis to
evaluate the effect of treatment assignment on survival
outcomes by estimating HRs and corresponding 95% CIs.
Subgroup analyses were conducted according to the random
assignment stratification factors and other baseline charac-
teristics. The statistical significance of differences in tumor
response and safety variables between subgroups were
evaluated using Pearson’s chi-squared or Fisher’s exact test;
all subgroup statistical tests were two-sided, and between-
group differences were considered significant when P was
below .05, unless otherwise specified. Programming and
statistical analyses were performed using STATA version 15.0
software (Stata Corporation, College Station, TX) and R
version 4.0.2 (Stanford University, Stanford, CA).
RESULTS
Patient Characteristics and Treatment
We initially screened 511 patients between June 2019 and
July 2021 at 12 hospitals in China and ultimately randomly
assigned 338 eligible patients to receive LEN-TACE
(n 5 170) or LEN alone (n 5 168), all of whom were in-
cluded in the intention-to-treat population (Fig 1). In
general, the two groups had balanced baseline charac-
teristics (Table 1). The majority of patients had hepatitis B
virus infection (148 [87.1%] in the LEN-TACE group and
144 [85.7%] in the LEN group). There were 122 (71.8%)
patients with portal vein tumor thrombus (PVTT) in the LEN-
TACE group and 117 (69.6%) in the LEN group. Extra-
hepatic spread was observed in 94 (55.3%) and 95

TABLE 2. Best Tumor Response After Treatment

RECIST 1.1 mRECIST

Group, No. (%) Group, No. (%)

Variable LEN-TACE Group (n 5 170) LEN Group (n 5 168) P LEN-TACE Group (n 5 170) LEN Group (n 5 168) P
Objective response 78 (45.9) 35 (20.8) , .001 92 (54.1) 42 (25.0) , .001
Complete response 1 (0.6) 1 (0.6) 5 (2.9) 1 (0.6)
Partial response 77 (45.3) 34 (20.2) 87 (51.2) 41 (24.4)
Stable disease 79 (46.5) 87 (51.8) 68 (40.0) 81 (48.2)
Disease control rate 157 (92.4) 122 (72.6) , .001 160 (94.1) 123 (73.2) , .001
Progressive disease 13 (7.6) 46 (27.4) 10 (5.9) 45 (26.8)

Abbreviations: LEN, lenvatinib; mRECIST, modified RECIST; TACE, transarterial chemoembolization.

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 Peng et al

A
Group
1.00
LEN group
OS (probability) LEN-TACE group No.of Events/ Median OS OS OS OS
0.75 No.of Patients (95% CI), at 6 Months, at 12 Months, at 24 Months,
(%) months % (95% CI) % (95% CI) % (95% CI)

LEN-TACE 75/170 (44.1) 17.8 (16.1 to 19.5) 95.9 (91.5 to 98.0) 81.5 (74.0 to 87.0) 26.1 (16.8 to 36.4)
0.50
LEN 104/168 (61.9) 11.5 (10.3 to 12.7) 87.4 (81.3 to 91.6) 46.9 (38.2 to 55.0) 17.8 (11.0 to 26.0)

0.25
HR = 0.45 (95% CI, 0.33 to 0.61)
Log-rank P < .001

0 10 20 30 Stratified HR = 0.33 (95% CI, 0.23 to 0.50)

Stratified log-rank P < .001
Time (months)
No. at risk:
LEN group 168 78 15 0
LEN-TACE group 170 112 25 0

1.00 Group
LEN group
PFS (probability)

LEN-TACE group No.of Events/ Median PFS PFS PFS

0.75 No.of Patients (95% CI), at 6 Months, at 12 Months,
(%) months % (95% CI) % (95% CI)

0.50 LEN-TACE 122/170 (71.8) 10.6 (9.5 to 11.7) 88.2 (82.3 to 92.2) 39.2 (31.2 to 47.0)

LEN 149/168 (88.7) 6.4 (5.8 to 7.0) 54.8 (46.9 to 61.9) 14.3 (9.1 to 20.6)
0.25
HR = 0.43 (95% CI, 0.34 to 0.55)
Log-rank P < .001
0 10 20 30
Stratified HR = 0.36 (95% CI, 0.27 to 0.49)
Time (months) Stratified log-rank P < .001
No. at risk:
LEN group 168 33 6 0
LEN-TACE group 170 73 7 0

FIG 2. Kaplan-Meier curves of (A) OS and (B) PFS for patients in the LEN-TACE and LEN groups. Shadow areas: 95% CIs. HR, hazard ratio; LEN,
lenvatinib; OS, overall survival; PFS, progression-free survival; TACE, transarterial chemoembolization.

(56.5%) patients in the LEN-TACE and LEN groups,
respectively.
The 170 patients in the LEN-TACE group received 560
TACE treatments, and the median number of TACE ses-
sions per patient was 3 (range, 1-6 sessions, Data Sup-
plement). We also compared subsequent treatments after
discontinuation (Data Supplement). Twenty-six patients
(15.3%) in the LEN-TACE group received curative surgical
resection because of downstaging, and two patients ex-
perienced pathologic complete responses. Three patients
(1.8%) in the LEN group received curative surgery, and
none of them experienced a pathologic complete response.
Efficacy
At the time of data cutoff on October 10, 2021, a total of 179
deaths had been observed (69% of expected deaths), and
the prespecified interim analysis was performed. Because
of the time interval of the follow-up period, the proportion of
deaths that had occurred at the time of the interim analysis
(69%) was slightly higher than the prespecified 66.7%. At
the interim analysis, the P value for the difference in median
OS between the LEN-TACE and LEN groups was , .001,
and the upper boundary of the 95% CI of the corresponding
HR was 0.61, which crossed the superiority boundary
(P 5 .016; HR, 0.697). Thus, on October 20, 2021, the
Data and Safety Monitoring Committee agreed with the
recommendation of the statistician regarding the superior
OS for participants who received LEN-TACE versus TACE
and released the results to the principal investigator.
The overall responses in the two treatment groups, evalu-
ated using RECIST 1.1 and mRECIST, were compared
(Table 2). The ORR was 45.9% in the LEN-TACE group
and 20.8% in the LEN group according to RECIST 1.1
(P , .001) and was 54.1% in the LEN-TACE group, and
25.0% in the LEN group according to mRECIST (P , .001).
After a median follow up of 17.0 months, 75 patients
(44.1%) in the LEN-TACE group and 104 patients (61.9%)
in the LEN group had died. The median OS was
17.8 months (95% CI, 16.1 to 19.5) in the LEN-TACE group
and 11.5 months (95% CI, 10.3 to 12.7) in the LEN group.
The corresponding HR for OS was 0.45 (95% CI, 0.33 to
0.61; P , .001), and the stratified HR was 0.33 (95% CI,
0.23 to 0.50; P , .001; Fig 2A).
At the data cutoff, a total of 122 patients (71.8%) in the
LEN-TACE group and 149 patients (88.7%) in the LEN

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 Lenvatinib Plus TACE for Advanced HCC

A
Events
Subgroup All LEN–TACE LEN HR (95% CI)
Overall 338 75 104 0.45 (0.33 to 0.61)
Age, years
60 and younger 230 50 75 0.42 (0.29 to 0.61)
older than 60 108 25 29 0.52 (0.30 to 0.89)
Sex
Male 271 60 82 0.43 (0.31 to 0.60)
Female 67 15 22 0.52 (0.27 to 1.00)
Bodyweight, kg
< 60 125 29 38 0.46 (0.28 to 0.76)
! 60 213 46 66 0.43 (0.30 to 0.63)
Aetiology
HBV 292 66 88 0.47 (0.34 to 0.64)
Others 46 9 16 0.34 (0.15 to 0.78)
ECOG–PS
0 188 32 59 0.40 (0.26 to 0.62)
1 150 43 45 0.45 (0.29 to 0.70)
AFP, ng/mL
< 400 168 38 50 0.50 (0.33 to 0.77)
! 400 170 37 54 0.39 (0.26 to 0.61)
ALBI grade
Grade 1 94 20 35 0.47 (0.27 to 0.82)
Grade 2 244 55 69 0.44 (0.31 to 0.63)
No. of tumor
Single 68 13 20 0.55 (0.27 to 1.11)
Multiple 270 62 84 0.43 (0.31 to 0.60)
Main tumor size, cm
<5 105 14 35 0.38 (0.20 to 0.71)
!5 233 61 69 0.47 (0.33 to 0.66)
Primary tumor
Yes 299 73 89 0.44 (0.32 to 0.61)
No 39 2 15 0.30 (0.07 to 1.34)
PVTT
Yes 239 53 80 0.34 (0.24 to 0.49)
No 99 22 24 0.72 (0.40 to 1.29)
EHS
Yes 189 50 59 0.56 (0.38 to 0.82)
No 149 25 45 0.32 (0.19 to 0.52)

0.2 0.5 0.8 1.0 1.2

Favours LEN–TACE Favours LEN

FIG 3. Forest plots of (A) overall survival and (B) progression-free survival in different patient subgroups. AFP,
a-fetoprotein; ALBI, albumin-bilirubin score; ECOG-PS, Eastern Cooperative Oncology Group performance
status; EHS, extrahepatic spread; HBV, hepatitis B virus; HR, hazard ratio; LEN, lenvatinib; PVTT, portal vein
tumor thrombus; TACE, transarterial chemoembolization. (continued on following page)

group had experienced disease progression or death, and
median PFS was significantly longer in the LEN-TACE
group (10.6 months; 95% CI, 9.5 to 11.7) versus the
LEN group (6.4 months; 95% CI, 5.8 to 7.0; HR, 0.43; 95%
CI, 0.34 to 0.55; P , .001; stratified HR, 0.36; 95% CI,
0.27 to 0.49; P , .001; Fig 2B).
We also compared survival outcomes between patients in
the LEN-TACE group who received LEN drug-eluting
beads-TACE versus LEN-conventional TACE. There was
no significant difference between the two types of TACE,
either in terms of median OS, PFS, or local tumor response
(Data Supplement).
Multivariable analyses identified that PVTT (HR, 2.04;
P , .001) and treatment allocation (HR, 0.41; P , .001)
were independent risk factors for OS and that PVTT (HR,
1.90; P , .001) and treatment allocation (HR, 0.38;
P , .001; Data Supplement) were independent risk
factors for PFS. In addition, the multivariable Cox model
adjusted using the data-driven variables were consistent
(Data Supplement). Subgroup analysis showed that
LEN-TACE was associated with better median OS and PFS
than LEN across most of the patient subgroups (Fig 3).
Safety
The grade 3-4 adverse events (AEs) more common in
the LEN-TACE group included ALT elevation (17.6% v 1.2%,
P , .001), AST elevation (22.9% v 1.8%, P , .001), and
hyperbilirubinemia (9.4% v 3.0%, P 5 .014; Table 3).

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 Peng et al

B
Events
Subgroup All LEN–TACE LEN HR (95% CI)
Overall 338 122 149 0.43 (0.34 to 0.55)
Age, years
60 and younger 230 82 106 0.37 (0.27 to 0.50)
older than 60 108 40 43 0.55 (0.35 to 0.84)
Sex
Male 271 100 116 0.43 (0.33 to 0.56)
Female 67 22 33 0.46 (0.27 to 0.80)
Bodyweight, kg
< 60 125 42 56 0.42 (0.28 to 0.64)
! 60 213 80 93 0.44 (0.32 to 0.59)
Aetiology
HBV 292 108 130 0.43 (0.33 to 0.56)
Others 46 14 19 0.44 (0.22 to 0.89)
ECOG–PS
0 188 60 86 0.46 (0.33 to 0.64)
1 150 62 63 0.33 (0.22 to 0.48)
AFP, ng/mL
< 400 168 64 70 0.53 (0.38 to 0.75)
! 400 170 58 79 0.35 (0.25 to 0.51)
ALBI grade
Grade 1 94 29 45 0.36 (0.22 to 0.58)
Grade 2 244 93 104 0.46 (0.34 to 0.61)
No. of tumor
Single 68 20 34 0.44 (0.25 to 0.76)
Multiple 270 102 115 0.44 (0.34 to 0.58)
Main tumor size, cm
<5 105 30 48 0.46 (0.29 to 0.73)
!5 233 92 101 0.42 (0.32 to 0.56)
Primary tumor
Yes 299 115 123 0.44 (0.34 to 0.57)
No 39 7 26 0.37 (0.16 to 0.86)
PVTT
Yes 239 86 107 0.31 (0.23 to 0.41)
No 99 36 42 0.67 (0.43 to 1.05)
EHS
Yes 189 69 86 0.46 (0.33 to 0.63)
No 149 53 63 0.40 (0.28 to 0.59)

0.2 0.5 0.8 1.0 1.2

Favours LEN–TACE Favours LEN

FIG 3. (Continued).

Analysis of the causes of dose reductions or interruption of
LEN (Data Supplement) indicated that 90 patients (52.9%)
in the LEN-TACE group and 75 (44.6%) in the LEN group
received dose reductions because of severe AEs
(P 5 .127). The median duration of treatment was
8.2 months in the LEN-TACE group and 5.1 months in the
LEN group. In the LEN-TACE group, the mean LEN dose
intensity was 7.6 mg in the low-dose group (8 mg/d) and
10.9 mg in the high-dose group (12 mg/d); the corre-
sponding dose intensities in the LEN group were 6.9 mg
and 10.6 mg (Data Supplement).
DISCUSSION
To the best of our knowledge, the present trial is the first
randomized phase III study to demonstrate an improved OS
and PFS with LEN-TACE combination treatment versus LEN
monotherapy in patients with systemic treatment-naive
advanced HCC. Moreover, we found that this survival benefit
was generally consistent across multiple patient subgroups.
Our results show that combined LEN-TACE therapy is more
effective than LEN alone in the control of intrahepatic tumors
and in prolonging patient survival.
In our study, we demonstrated a promising tumor response
for patients in the LEN-TACE group, with an ORR of 54.1%
on the basis of mRECIST. This favorable treatment response
might be partially due to increased efficacy of LEN from
debulking of tumor burden by TACE. Previous studies have
implied that intrahepatic tumor burden affects survival
outcomes in patients with advanced HCC, indicating that
debulking of the liver tumor increases patients’ survival
time.21,22 The present study also provides a rationale for the
concurrent use of LEN-TACE to control intrahepatic tumors.
Notably, our subgroup analyses found that LEN-TACE
treatment was associated with favorable survival outcomes

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 Lenvatinib Plus TACE for Advanced HCC

TABLE 3. AEs After Treatment

Any Grade Grade 3-4

Group, No. (%) Group, No. (%)

AE LEN-TACE Group (n 5 170) LEN Group (n 5 168) P LEN-TACE Group (n 5 170) LEN Group (n 5 168) P
Hand-foot skin reaction 53 (31.2) 54 (32.1) .849 7 (4.1) 6 (3.6) .794
Abdominal pain 86 (50.6) 18(10.7) , .001 6 (3.5) 1 (0.6) .058
Nausea 61 (35.9) 17 (10.1) , .001 1 (0.6) 1 (0.6) .993
Diarrhea 80 (47.1) 76 (45.2) .737 9 (5.3) 7 (4.2) .626
Fever 66 (38.8) 9 (5.4) , .001 1 (0.6) 0 .319
Hypertension 110 (64.7) 111 (66.1) .792 35 (20.6) 33 (19.6) .828
Alopecia 13 (7.6) 8 (4.8) .272 3 (1.8) 1 (0.6) .320
Ascites 22 (12.9) 7 (4.2) .004 4 (2.4) 2 (1.2) .418
Vomiting 30 (17.6) 9 (5.4) , .001 1 (0.6) 2 (1.2) .555
Fatigue 55 (32.4) 50 (29.8) .607 6 (3.5) 4 (2.4) .533
Dysphonia 43 (25.3) 44 (26.2) .851 1 (0.6) 2 (1.2) .555
Decreased appetite 75 (44.1) 68 (40.5) .498 8 (4.7) 8 (4.8) .981
Proteinuria 62 (36.5) 54 (32.1) .402 7 (4.1) 8 (4.8) .774
Weight decrease 63 (37.1) 64 (38.1) .844 13 (7.6) 12 (7.1) .859
Rash 22 (12.9) 22 (13.1) .966 4 (2.4) 2 (1.2) .418
ALT increase 36 (21.2) 9 (5.4) , .001 30 (17.6) 2 (1.2) , .001
AST increase 45 (26.5) 11 (6.5) , .001 39 (22.9) 3 (1.8) , .001
Hyperbilirubinemia 30 (17.9) 16 (9.5) .029 16 (9.4) 5 (3.0) .014
Hypoalbuminemia 24 (14.3) 7 (4.2) .001 1(0.6) 1 (0.6) .993
Constipation 31 (18.2) 30 (17.9) .928 2 (1.2) 3 (1.8) .643

Abbreviations: AE, adverse event; LEN, lenvatinib; TACE, transarterial chemoembolization.

versus LEN monotherapy in patients with significant tumor
burden, such as those who had PVTT, a-fetoprotein levels
of $ 400 ng/mL, three or more intrahepatic tumors, and main
tumor size of $ 5 cm, supporting the hypothesis that tumor
debulking through TACE might improve the efficacy of LEN.
Theoretically, control of the intrahepatic tumor burden would
be expected to improve liver function and allow LEN to be
continued for a longer time, thereby increasing PFS. In this
regard, our results demonstrated that the median duration of
treatment in the LEN-TACE group (8.2 months) was longer
than that in the LEN group (5.1 months). Taken together, this
evidence from our randomized controlled trial suggests that
tumor debulking with TACE may improve the efficacy of
systemic LEN treatment and allow longer treatment duration
in patients with advanced HCC. A high ORR is considered to
be one of the most important predictors of downstaging and
conversion to surgical therapy.23 Indeed, in the present study,
curative surgical resection was achieved by 26 patients
(15.3%) in the LEN-TACE group because of downstaging,
and two patients (1.2%) achieved pathologic complete re-
sponses. In this respect, LEN-TACE combination treatment
could be used in routine clinical practice as an effective
downstaging/conversion treatment. This strategy can offer
patients with advanced HCC a greater chance to receive
subsequent radical treatments, such as surgical resection,
which might subsequently improve survival outcomes.
The improved efficacy outcomes among patients receiving
LEN-TACE in our study may also be due to synergistic effects
of combining TACE and LEN. First, LEN inhibits vascular
endothelial growth factor receptors 1-3 and fibroblast growth
factor receptors 1-4 and may, therefore, reduce tumor re-
currence and metastasis after TACE. Second, LEN promotes
tumor vascular normalization, which would be expected to
enhance response rates by improving embolism agent de-
livery and optimizing the embolization effect,24 as well as
optimizing delivery of systemic anticancer drugs within the
tumor through reduction of tumor vascular permeability and
interstitial pressure.25
In addition to favorable efficacy outcomes, LEN-TACE was
demonstrated to be safe, with a similar incidence of dose
reductions or interruption to LEN monotherapy. In addition,
the most common LEN-related AEs were similar in the two
treatment groups, suggesting that the on-demand TACE
procedure had little effect on toxicities due to LEN. How-
ever, patients treated with LEN-TACE had a significantly
elevated incidence of abdominal pain, nausea and fever,
probably related to postembolization syndrome.26

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 Peng et al

Furthermore, a higher incidence of liver enzyme increases
and hyperbilirubinemia were observed in the LEN-TACE
group versus the LEN group, which may be due to im-
pairment of hepatic liver function by TACE. However, these
AEs were mild and manageable and did not lead to LEN
dose reductions or interruptions.
Our study had several limitations. First, we used an open-
label design. However, this was necessary to ensure the
safety of all participants because of the distinct toxicities
and dose-management requirements in the two treatment
groups. Second, all patients in this study were enrolled in
China, and a more geographically diverse study is needed
to further validate our findings in other patient populations.
In conclusion, the results of this phase III study show that
LEN-TACE is a safe and effective treatment for patients with
advanced HCC and provided significant improvements in
OS, PFS, and ORR compared with LEN monotherapy
without a clinically meaningful increase in toxicity or AEs.

AFFILIATIONS PRIOR PRESENTATION

1
Cancer Center, The First Affiliated Hospital of Sun Yat-sen University, Presented in part at the ASCO Gastrointestinal Cancers Symposium, San
Guangzhou, China Francisco, CA, January 20-22, 2022.
2
Clinical Trials Unit, The First Affiliated Hospital of Sun Yat-sen
University, Guangzhou, China
SUPPORT
3
Department of Interventional Oncology, The First Affiliated Hospital of
Supported by Science and Technology Innovation 2030 Major Projects
Sun Yat-Sen University, Guangzhou, China
(No. 2020AAA0109504, M.K.), the National Science Fund for
4
Department of Hepatic Surgery, The Third Affiliated Hospital of Sun Yat-
Distinguished Young Scholars (No. 81825013, M.K.), Key Program of
Sen University, Guangzhou, China
the National Natural Science Foundation of China (No. 82130083,
5
Division of Hepatobiliary and Pancreatic Surgery, Hepatobiliary and
M.K.), the National Natural Science Foundation of China (No.
Pancreatic Interventional Treatment Center, The First Affiliated Hospital,
82072029, Z.P.), and the National high level talents special support
Zhejiang University School of Medicine, Hangzhou, China
plan—“Ten thousand plan”—Young top-notch talent support program
6
Department of Interventional Radiology, Guangdong Second Provincial
(Z.P.). Merck purchased commercial insurance for the study subjects free
General Hospital, Guangzhou, China
of charge.
7
Department of Medical Oncology, Guangzhou Panyu Central Hospital,
Guangzhou, China
8
Department of Hepatopancreatobiliary Surgery, Hainan General CLINICAL TRIAL INFORMATION
Hospital, Haikou, China NCT03905967 (LAUNCH)
9
Department of Hepatobiliary Surgery, Huizhou Municipal Central
Hospital, Huizhou, China
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF
10
Department of Interventional Angiology, Huizhou First People’s
Hospital, Huizhou, China
INTEREST
11
Department of Interventional Medicine, Jiangmen Central Hospital, Disclosures provided by the authors are available with this article at DOI
Jiangmen, China https://doi.org/10.1200/JCO.22.00392.
12
Interventional Department, Dongguan People’s Hospital, Dongguan,
China AUTHOR CONTRIBUTIONS
13
Department of Interventional Oncology, Jinshazhou Hospital of Conception and design: Zhenwei Peng, Bowen Zhu, Junhui Sun,
Guangzhou University of Chinese Medicine, Guangzhou, China Yu Cheng, Jiaping Li, Ming Kuang
14
Hepatobiliary Surgical Department, Gaozhou People’s Hospital, Financial support: Zhenwei Peng, Jiaping Li, Ming Kuang
Gaozhou, China Administrative support: Zhenwei Peng, Jiaping Li, Ming Kuang
15
Department of Interventional Radiology, The First Affiliated Hospital of Provision of study materials or patients: Zhenwei Peng, Wenzhe Fan,
Sun Yat-sen University, Guangzhou, China Guoying Wang, Junhui Sun, Chengjiang Xiao, Fuxi Huang, Rong Tang,
16
Center of Hepato-Pancreato-Biliary Surgery, The First Affiliated Zhen Huang, Yuchuang Liang, Huishuang Fan, Liangliang Qiao, Fuliang
Hospital of Sun Yat-sen University, Guangzhou, China Li, Wenquan Zhuang, Baogang Peng, Jiaping Li, Ming Kuang
17
Division of Surgical Oncology, Hepatobiliary Cancer, Brigham and Collection and assembly of data: Zhenwei Peng, Wenzhe Fan, Bowen Zhu,
Women’s Hospital, Harvard Medical School, Boston, MA Guoying Wang, Junhui Sun, Fuxi Huang, Rong Tang, Yu Cheng, Zhen
Huang, Yuchuang Liang, Huishuang Fan, Fuliang Li, Wenquan Zhuang,
CORRESPONDING AUTHOR Jiaping Li, Ming Kuang
Ming Kuang, MD, PhD, Cancer Center, Center of Hepato-Pancreato- Data analysis and interpretation: Zhenwei Peng, Wenzhe Fan, Bowen Zhu,
Biliary Surgery, The First Affiliated Hospital of Sun Yat-sen University, 58 Junhui Sun, Chengjiang Xiao, Yu Cheng, Liangliang Qiao, Baogang Peng,
Zhongshan 2nd Rd, Guangzhou 510080, China; e-mail: kuangm@mail. Jiping Wang, Jiaping Li, Ming Kuang
sysu.edu.cn. Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
EQUAL CONTRIBUTION
Z.P., W.F., and B.Z. contributed equally to this work as first authors. Z.P.,
J.W., J.L., and M.K. contributed equally to this work as senior authors.

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 Lenvatinib Plus TACE for Advanced HCC

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n n n

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 Peng et al

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Lenvatinib Combined With Transarterial Chemoembolization as First-Line Treatment for Advanced Hepatocellular Carcinoma: A Phase III, Randomized Clinical
Trial (LAUNCH)
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted.
Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript.
For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Jiping Wang
Honoraria: GenomiCare
Consulting or Advisory Role: GenomiCare
Research Funding: GenomiCare
No other potential conflicts of interest were reported.

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