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\begin{document}

\title{Clinical usefulness of newly developed prognostic predictive score for
atezolizumab plus bevacizumab for hepatocellular carcinoma}



\author[1]{Hideko Ohama}%
\author[1]{Atsushi Hiraoka}%
\author[2]{Toshifumi Tada}%
\author[3]{Masashi Hirooka}%
\author[4]{Kazuya Kariyama}%
\author[5]{Takeshi Hatanaka}%
\author[6]{Joji Tani}%
\author[7]{Koichi Takaguchi}%
\author[8]{Masanori Atsukawa}%
\author[9]{Ei Itobayashi}%
\author[10]{Shinya Fukunishi}%
\author[11]{Kunihiko Tsuji}%
\author[12]{Kazuto Tajiri}%
\author[13]{Toru Ishikawa}%
\author[14]{Satoshi Yasuda}%
\author[14]{Hidenori Toyoda}%
\author[10]{Takashi Nishimura}%
\author[15]{Chikara Ogawa}%
\author[16]{Kakizaki Satoru}%
\author[17]{Noritomo Shimada}%
\author[16]{Atsushi Naganuma}%
\author[18]{Kazuhito Kawata}%
\author[19]{Hisashi Kosaka}%
\author[20]{Hidekatsu  Kuroda}%
\author[21]{Tomomitsu Matono}%
\author[22]{Yutaka Yata}%
\author[23]{Hironori Ochi}%
\author[1]{Fujimasa Tada}%
\author[4]{Kazuhiro Nouso}%
\author[6]{Asahiro Morishita}%
\author[8]{Norio Itokawa}%
\author[8]{Tomomi Okubo}%
\author[8]{Taeang Arai}%
\author[7]{Akemi Tsutsui}%
\author[7]{Takuya Nagano}%
\author[24]{Keisuke Yokohama}%
\author[24]{Hiroki Nishikawa}%
\author[13]{Michitaka Imai}%
\author[3]{Yohei Koizumi}%
\author[2]{Shinichiro Nakamura}%
\author[10]{Hiroko Iijima}%
\author[19]{Masaki Kaibori}%
\author[3]{Yoichi Hiasa}%
\author[25]{Takashi Kumada}%
\affil[1]{Ehime Kenritsu Chuo Byoin}%
\affil[2]{Himeji Sekijuji Byoin}%
\affil[3]{Ehime Daigaku Daigakuin Igakukei Kenkyuka Igakubu}%
\affil[4]{Okayama Shiritsu Shimin Byoin}%
\affil[5]{Gunma-ken Saiseikai Maebashi Byoin}%
\affil[6]{Kagawa Daigaku}%
\affil[7]{Kagawa Kenritsu Chuo Byoin}%
\affil[8]{Nihon Ika Daigaku}%
\affil[9]{Asahi Sogo Byoin}%
\affil[10]{Hyogo Ika Daigaku}%
\affil[11]{Teine Keijinkai Byoin}%
\affil[12]{Toyama Daigaku Fuzoku Byoin}%
\affil[13]{Saiseikai Niigata Byoin}%
\affil[14]{Ogaki Shimin Byoin}%
\affil[15]{Takamatsu Sekijuji Byoin}%
\affil[16]{Kokuritsu Byoin Kiko Takasaki Sogo Iryo Center Fuzoku Takasaki Kango Gakko}%
\affil[17]{Otakanomori Byoin}%
\affil[18]{Hamamatsu Ika Daigaku Igakubu Daigakuin Igakukei Kenkyuka Naikagaku Daini Koza}%
\affil[19]{Kansai Ika Daigaku Fuzoku Hirakata Byoin}%
\affil[20]{Iwate Ika Daigaku}%
\affil[21]{Himeji Sei Maria Byoin}%
\affil[22]{Hanwa Kinen Byoin}%
\affil[23]{Matsuyama Sekijuji Byoin}%
\affil[24]{Osaka Ika Yakka Daigaku Fuzoku Byoin}%
\affil[25]{Gifu Kyoritsu Daigaku}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Background/Aim: The present study aimed to develop detailed parameters
for prediction of prognosis for patients with unresectable
hepatocellular carcinoma (uHCC) receiving Atezolizumab plus Bevacizumab
(Atez/Bev). Methods: Between September 2020 and January 2023, the
patients treated with Atez/Bev were enrolled (n=719, males 577, median
age 74 years). Factors involved in overall survival (OS) were extracted
and a prognostic scoring system based on hazard ratio (HR) was created.
OS and progression-free survival (PFS) were examined retrospectively,
and the prognostic ability of the newly system was compared to CRAFITY
score using concordance index (c-index) and Akaike Information Criterion
(AIC) results. Results: Cox-hazards multivariate analysis showed BCLC
classification C/D (HR 1.4; 1 point), AFP [?]100 ng/mL (HR 1.4; 1 point),
mALBI 2a (HR 1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP [?]100
mAU/mL (HR 1.6; 1 point) as significant factors. The assigned points
were added and used for IMnunotherapy with AFP, BCLC staging, mALBI, and
DCP evaluation (IMABALI-De) scoring. For IMABALI-De scores of
0/1/2/3/4/5, OS was not applicable (NA)/NA/26.11/18.79/14.07/8.32 months
(P\textless{}0.001; AIC 2788.67, c-index 0.699), while for CRAFITY
scores of 0/1/2, OS was 26.11/20.29/11.32 months (p\textless{}0.001; AIC
2864.54, c-index 0.606). PFS for those IMABALI-De scores was
21.75/12.89/9.18/8.0/5.0/3.75 months (P\textless{}0.001; AIC 5203.32,
c-index 0.623) and for the CRAFITY scores was10.32/7.68/3.57 months
(p\textless{}0.001; AIC 5246.61, c-index 0.574). IMABALI-De score had
better AIC and c-index results as compared to CRAFITY score for both OS
and PFS. Conclusion: The proposed IMABALI-De score may have a favorable
prognostic predictive ability for uHCC patients with Atez/Bev.%
\end{abstract}%



\sloppy


Clinical usefulness of newly developed prognostic predictive score for
atezolizumab plus bevacizumab for hepatocellular carcinoma

Hideko Ohama\textsuperscript{1}, Atsushi Hiraoka\textsuperscript{1}+,
Toshifumi Tada\textsuperscript{2}, Masashi Hirooka\textsuperscript{3},
Kazuya Kariyama\textsuperscript{4}, Takeshi Hatanaka\textsuperscript{5},
Joji Tani\textsuperscript{6}, Koichi Takaguchi\textsuperscript{7},
Masanori Atsukawa\textsuperscript{8}, Ei Itobayashi\textsuperscript{9},
Takashi Nishimura\textsuperscript{10}, Kunihiko
Tsuji\textsuperscript{11}, Kazuto Tajiri\textsuperscript{13}, Toru
Ishikawa\textsuperscript{12}, Satoshi Yasuda\textsuperscript{14},
Hidenori Toyoda\textsuperscript{14}, Shinya
Fukunishi\textsuperscript{10}, Chikara Ogawa\textsuperscript{15}, Satoru
Kakizaki\textsuperscript{16}, Noritomo Shimada\textsuperscript{17},
Atsushi Naganuma\textsuperscript{18}, Kazuhito
Kawata\textsuperscript{19},Hisashi Kosaka\textsuperscript{20}, Hidekatsu
Kuroda\textsuperscript{21}, Tomomitsu Matono\textsuperscript{22}, Yutaka
Yata\textsuperscript{23}, Hironori Ochi\textsuperscript{24}, Fujimasa
Tada\textsuperscript{1}, Kazuhiro Nouso\textsuperscript{4}, Asahiro
Morishita\textsuperscript{6}, Norio Itokawa\textsuperscript{8}, Tomomi
Okubo\textsuperscript{8}, Taeang Arai\textsuperscript{8}, Akemi
Tsutsui\textsuperscript{7}, Takuya Nagano\textsuperscript{7}, Keisuke
Yokohama\textsuperscript{25}, Hiroki Nishikawa\textsuperscript{25},
Michitaka Imai\textsuperscript{12}, Yohei Koizumi\textsuperscript{3},
Shinichiro Nakamura\textsuperscript{2}, Hiroko
Iijima\textsuperscript{10}, Masaki Kaibori\textsuperscript{20}, Yoichi
Hiasa\textsuperscript{3}, Takashi Kumada\textsuperscript{26}

Representing the Real-life Practice Experts for HCC Study Group with
Hepatocellular Carcinoma experts from 48 clinics in Japan (RELPEC/ HCC
48 Group).

Affiliations:

\begin{enumerate}
\tightlist
\item
  Ehime Prefectural Central Hospital, Gastroenterology Center, Ehime,
  Japan
\item
  Japanese Red Cross Himeji Hospital, Department of Internal Medicine,
  Hyogo, Japan
\item
  Ehime University Graduate School of Medicine, Department of
  Gastroenterology and Metabology, Ehime, Japan
\item
  Okayama City Hospital, Department of Hepatology, Okayama, Japan
\item
  Gunma Saiseikai Maebashi Hospital, Department of Gastroenterology,
  Gunma, Japan
\item
  Kagawa University, Department of Gastroenterology and Hepatology,
  Kagawa, Japan
\item
  Kagawa Prefectural Central Hospital, Department of Hepatology, Kagawa,
  Japan
\item
  Nippon Medical School, Division of Gastroenterology and Hepatology,
  Department of Internal Medicine, Tokyo, Japan
\item
  Asahi General Hospital, Department of Gastroenterology, Chiba, Japan
\item
  Hyogo Medical University, Department of Gastroenterology and
  Hepatology, Hyogo, Japan
\item
  Teine Keijinkai Hospital, Center of Gastroenterology, Hokkaido, Japan
\item
  Saiseikai Niigata Hospital, Department of Gastroenterology, Niigata,
  Japan
\item
  Toyama University Hospital, Department of Gastroenterology, Toyama,
  Japan
\item
  Ogaki Municipal Hospital, Department of Gastroenterology and
  Hepatology, Gifu, Japan
\item
  Japanese Red Cross Takamatsu Hospital, Department of Gastroenterology,
  Kagawa, Japan
\item
  National Hospital Organization Takasaki General Medical Center,
  Department of Clinical Research, Gunma, Japan
\item
  Otakanomori Hospital, Division of Gastroenterology and Hepatology,
  Chiba, Japan
\item
  National Hospital Organization Takasaki General Medical Center,
  Department of Gastroenterology, Gunma, Japan
\item
  Hamamatsu University School of Medicine, Hepatology Division,
  Department of Internal Medicine II, Shizuoka, Japan
\item
  Kansai Medical University, Department of Surgery, Osaka, Japan
\item
  Iwate Medical University, Division of Hepatology, Department of
  Internal Medicine, School of Medicine, Iwate, Japan
\item
  St. Mary's Hospital, Department of Hepatology, Hyogo, Japan
\item
  Hanwa Memorial Hospital, Department of Gastroenterology, Osaka, Japan
\item
  Japanese Red Cross Matsuyama Hospital, Hepato-biliary Center, Ehime,
  Japan
\item
  Osaka Medical and Pharmaceutical University, Department of
  Gastroenterology,Osaka, Japan
\item
  Gifu Kyoritsu University, Department of Nursing, Gifu, Japan
\end{enumerate}

Running head: new prognostic predictive score for Atez/Bev

+ {[}Corresponding author{]}

Atsushi Hiraoka, MD, PhD

Ehime Prefectural Central Hospital, Gastroenterology Center,

83 Kasuga-cho, Matsuyama, Ehime, 790-0024, Japan

Email:\emph{hirage@m.ehime-u.ac.jp}Tel +81-89-947-1111. Fax
+81-89-943-4136.

Text 28 pages. Tables 2. Figures 3. Supplemental Tables 1. Supplemental
Figures 2. References 37. Manuscript 3872 words.

Abstract

Background/Aim: The present study aimed to develop detailed parameters
for prediction of prognosis for patients with unresectable
hepatocellular carcinoma (uHCC) receiving Atezolizumab plus Bevacizumab
(Atez/Bev).

Methods: Between September 2020 and January 2023, the patients treated
with Atez/Bev were enrolled (n=719, males 577, median age 74 years).
Factors involved in overall survival (OS) were extracted and a
prognostic scoring system based on hazard ratio (HR) was created. OS and
progression-free survival (PFS) were examined retrospectively, and the
prognostic ability of the newly system was compared to CRAFITY score
using concordance index (c-index) and Akaike Information Criterion (AIC)
results.

Results: Cox-hazards multivariate analysis showed BCLC classification
C/D (HR 1.4; 1 point), AFP [?]100 ng/mL (HR 1.4; 1 point), mALBI 2a (HR
1.7; 1 point), mALBI 2b/3 (HR 2.8; 2 points), and DCP [?]100 mAU/mL (HR
1.6; 1 point) as significant factors. The assigned points were added and
used for \emph{IM} nunotherapy with \emph{A} FP, \emph{B} CLC staging,
m\emph{AL} B\emph{I,} and \emph{D} CP \emph{e} valuation (IMABALI-De)
scoring. For IMABALI-De scores of 0/1/2/3/4/5, OS was not applicable
(NA)/NA/26.11/18.79/14.07/8.32 months (P\textless{}0.001; AIC 2788.67,
c-index 0.699), while for CRAFITY scores of 0/1/2, OS was
26.11/20.29/11.32 months (p\textless{}0.001; AIC 2864.54, c-index
0.606). PFS for those IMABALI-De scores was
21.75/12.89/9.18/8.0/5.0/3.75 months (P\textless{}0.001; AIC 5203.32,
c-index 0.623) and for the CRAFITY scores was10.32/7.68/3.57 months
(p\textless{}0.001; AIC 5246.61, c-index 0.574). IMABALI-De score had
better AIC and c-index results as compared to CRAFITY score for both OS
and PFS.

Conclusion: The proposed IMABALI-De score may have a favorable
prognostic predictive ability for uHCC patients with Atez/Bev.

Keywords: hepatocellular carcinoma, Atezolizumab plus Bevacizumab,
prognosis, modified albumin-bilirubin grade, IMABALI-De score, IMABALI
score, CRAFITY score

Introduction

Studies have revealed that hepatocellular carcinoma (HCC) ranks as the
sixth most prevalent cancer type globally and stands as the third to
fourth leading cause of cancer-related deaths
worldwide(1)\textsuperscript{,}(2). Recently, atezolizumab and
bevacizumab (Atez/Bev), a recently developed immunotherapy, received
approval for unresectable HCC (uHCC) and has shown favorable therapeutic
outcomes in real-world clinical practice (3). When possible, it is
considered that HCC patients in Barcelona Clinic Liver Cancer stage
(BCLC) -C should be treated with Atez/Bev, while it has also been
proposed as systemic treatment for earlier stage HCC (BCLC-B) patients,
who show transcatheter arterial chemoembolization (TACE) refractoriness
status (4) (5). As a result, an assessment tool for detailed prediction
of prognosis is needed to provide clinical information regarding
prognosis after introducing Atez/Bev for treatment decision making. In
past reports, c-reactive protein (CRP) and alpha-fetoprotein (AFP) in
immunotherapy (CRAFITY) score has been shown to be a useful prognostic
scoring system for Atez/Bev cases(6) (7). Conversely, the prognosis of
HCC patients is known to be affected not only by tumor burden and
malignant potential (8), but also hepatic reserve function (9). The aim
of the present study was to develop a method for detailed prediction of
prognosis for patients treated with Atez/Bev based on clinical
parameters related to malignant potential of HCC, tumor burden, and
hepatic function.

Materials and Methods

Following exclusion of patients without CRP and/or tumor marker data
{[}AFP and/or Des-\selectlanguage{greek}γ-\selectlanguage{english}carboxy prothrombin (DCP){]} (n=36), between
September 2020 and January 2023, 719 HCC patients treated with Atez/Bev
at 25 different institutions, following written informed consent (IC).
Every enrolled patient provided written IC. The treatment strategy with
Atez/Bev was the same as previously reported and is illustrated in
Figure 1 (10). The choice to administer Atez/Bev was made by the
physician at each medical center. Patients were given intravenous
Atez/Bev, comprising Atez (1200mg) and Bev (15 mg/kg of body weight), in
accordance with the manufacturer's recommendations, every three
weeks(11). Treatment was discontinued if serious or unacceptable adverse
event (AE) occurred, or elseif there was clinical HCC progression. The
National cancer institute common terminology criteria for adverse events
(ver. 5.0)(12), was employed to assess of AEs. The attending physician
was responsible for determining the subsequent course of treatment
following the cessation of Atez/Bev.

Following official approval, the retrospective database analysis was
conducted in compliance with Japan's Ministry of Health and Welfare
Clinical Research Guidelines and the Helsinki Declaration.

Upper gastrointestinal endoscopy prior to Atez/Bev

In order to mitigate the risk of gastrointestinal bleeding as an adverse
event associated with Atez/Bev therapy, each patient had an upper
gastrointestinal endoscopy within six months of commencing Atez/Bev.
This examination aimed to monitor the presence of esophago-gastric
varices (EGV), which were categorized into 3 types; small straight (F1;
Grade 1), enlarged tortuous (F2; Grade 2), or large coil-shaped (F3;
Grade 3). In cases where bleeding was detected or high-risk situations
such as EGV grade 2 (F2) or higher, or if the red-color sign was
positive, variceal ligation or injection sclerotherapy were performed
before commencing Atez/Bev therapy.

Etiology of HCC

HCC due to infection of hepatitis B virus (HBV) was diagnosed based on a
positive HBV surface antigen, while the presence of positive anti-HCV
antibodies indicated HCC associated with hepatitis C virus (HCV)
infection. Nucleotide analogs , such as entecavir, tenofovir, or
tenofovir alafenamide fumarate were administered to HBV-infected
patients. For patients without HBV or HCV infection but with a history
of alcohol abuse ([?]60 g/day), the underlying liver disease was
attributed to alcohol (13, 14) . The patients with a documented
autoimmune disease history were ineligible for Atez/Bev treatment.

Assessments of hepatic reserve function

Hepatic reserve function was assessed using Child-Pugh classification
(15) and albumin-bilirubin (ALBI) score (16, 17) and modified ALBI grade
(mALBI): ALBI grade 2 divided into two subgrades (2a and 2b) with an
ALBI score of -2.27 as the cut-off value(9).

Diagnosis and evaluation of HCC stage

The diagnosis of the HCC relied on the consensus statement of the Japan
society of Hepatology (JSH) (18) and tumor staging was based on BCLC
stage (19).The diagnosis specifically considered increased
alpha-fetoprotein (AFP), contrast-enhanced ultrasonography with
perflubutane (20), dynamic-CT (21), magnetic resonance imaging (MRI)
(22, 23), and/or pathological findings during the clinical course.

Evaluation of therapeutic efficacy of Atez/Bev treatment

To evaluate the therapeutic response, the response evaluation criteria
in solid tumors (RECIST), ver. 1.1 (24),or modified RECIST (mRECIST)(25)
were employed. Progression-free survival (PFS) was determined using
RECIST results. The response categories were progressive disease: PD,
stable disease: SD, partial response: PR, or complete response: CR. The
initial evaluation took place around six weeks after commencing Atez/Bev
treatment, utilizing dynamic CT scans. Additional dynamic CT scans were
carried out when necessary, and in certain cases, even before the
six-week mark, depending on the patient's condition. Subsequent dynamic
CT scans were scheduled every six weeks following the initial
assessment, with extended intervals of nine to twelve weeks after the
first six months (10).

Scoring for assessment of prognosis of uHCC patients treated with
Atez/Bev

CRAFITY score (6) (7) and the newly developed \emph{IM} nunotherapy
with\emph{A} FP, \emph{B} CLC staging, m\emph{AL} B\emph{I} and \emph{D}
CP\emph{e} valuation (IMABALI-De) score, the details of which are
presented following, were used to assess the prognosis of patients with
Atez/Bev. Because DCP is not available for clinical use in many regions
other than Japan, we also proposed IMABALI score without DCP as a
sub-score for such region.

Statistical analysis

For statistical analyses, Cox-hazard analysis, Kaplan-Meier method, and
log-rank test results were utilized. The log-rank test and Kaplan-Meier
method were used to assess overall survival (OS) and PFS following the
introduction of Atez/Bev. When median values were provided, the
interquartile range (IQR) was also reported. Statistical significance
was determined for P values less than 0.05. AIC and c-index results were
used for comparisons between both prognostic predictive scores. A
graphical user interface for R (The R Foundation for Statistical
Computing, Vienna, Austria), Easy-R (EZR), version 1.61 (Saitama Medical
Center, Jichi Medical University, Saitama, Japan)(26),was used to
perform all of the statistical analyses.

Results

Clinical features of present cohort

Table 1 displays the fundamental patient characteristics. Of all
patients, the median age was 74 (IQR: 69-80) years old and 577 were male
(80.3\%). The etiology of HCC was HBV in 117 (16.3\%), HCV in 239
(33.2\%), HBV/HCV co-infection in 1 (0.1\%), alcohol in 159 (22.1\%),
and non-HBV-non-HCV-non-alcohol in 203 (28.2\%). The median ALBI score
was -2.40 (mALBI grade1: 2a: 2b: 3 = 257: 178: 274: 10), while median
AFP was 31 (IQR: 5.45-460.50) and median DCP was 280 (IQR: 43.5-2996.0).
A Child-Pugh score of 5/ 6/ 7/ 8/ 9/ 10 was noted in 417 (58.0\%)/ 224
(31.2\%)/ 57 (7.9\%)/ 16 (2.2\%)/ 4 (0.6\%)/ 1 (0.1\%), respectively of
the patients, a CRAFITY score of 0/ 1/ 2 was noted in 367 (51.0\%)/ 274
(38.1\%)/ 78 (10.8\%), respectively, and BCLC stage 0/ A/ B/ C/ D was
noted in 11 (1.5\%)/ 44 (6.1\%)/ 257 (35.7\%)/ 390 (54.2\%)/ 17 (2.4\%),
respectively. The duration of the median follow-up was 10.34 months
(IQR: 5.38-16.17).

Factor detection and construction of IMABALI-De score

In univariate Cox-hazard analysis findings, CRP[?]1.0 mg/dL {[}1.884: 95\%
confidence interval (CI) 1.426-2.488, P\textless{}0.001{]} , AFP [?]100
ng/mL (HR 1.706: 95\% CI 1.327-2.194, P\textless{}0.001), and DCP [?]100
mAU/mL (HR 2.109: 95\% CI 1.573-2.828, P\textless{}0.001), as well as
BCLC-C/D (HR 1.587: 95\% CI 1.219-2.067, P\textless{}0.001), and mALBI
2a (HR 1.726: 95\% CI: 1.190-2.501, P=0.004) or 2b/3 (HR 3.233: 95\% CI
2.351-4.447, P\textless{}0.001) were prognostic indicator for death.
Furthermore, prognostic indicator for death in multivariate analysis
were AFP ([?]100 ng/mL) (HR 1.392: 95\% CI 1.072-1.808, P=0.013) and DCP
([?]100 mAU/mL) (HR 1.619: 95\% CI 1.191-2.20, P=0.002), as well as BCLC
C/D (HR 1.352: 95\% CI 1.029-1.776, P=0.030), and mALBI 2a (HR 1.749:
95\% CI: 1.206-2.536, P=0.003) or 2b/3 (HR 2.848: 95\% CI 2.053-3.950,
P\textless{}0.001) (Table 2). According to the results of multivariate
Cox-hazard analysis, BCLC C/D, DCP [?]100 mAU/mL, AFP [?]100 ng/mL, and
mALBI 2a were each assigned 1 point, while mALBI 2b/3 was given 2
points, with the sum of those point values used as IMABALI-De score.
When same analysis was performed without DCP, results was not different
(Supplemental table 1). Of the 719 enrolled patients, an IMABALI-De
score of 0 was noted in 51, a score of 1 in 115, a score of 2 in 177, a
score of 3 in 169, a score of 4 in 132, and a score of 5 in 75. The
cut-off values for CRP ([?]1.0 mg/dL) (6), AFP [?]100 ng/mL (27) and DCP
[?]100 mAU/mL (27) were set based on previous reports.

Therapeutic response to Atez/Bev treatment according to IMABALI-De score

Best therapeutic response was evaluated in 664 patients (IMABALI-De
score 0:1:2:3:4:5 = 48:108:162:160:119:67). Objective response rate
(ORR) was 28.3\%, and disease control rate (DCR) was 78.6\%,
respectively. CR:PR:SD:PD for patients with an IMABALI-De score of 0 was
3:14:26:5 (ORR/DCR=35.4\%/89.5\%), with a score of 1 was 5:27:57:18
(ORR/DCR=29.9\%/83.2\%), with a score of 2 was 5:46:81:27
(ORR/DCR=32.1\%/83.0\%), with a score of 3 was 8:34:85:32
(ORR/DCR=26.4\%/79.9\%), with a score of 4 was 4:33:53:29
(ORR/DCR=31.1\%/75.6\%), and with a score of 5 was 0:9:32:26
(ORR/DCR=13.4\%/61.2\%). There was not significantly difference
regarding therapeutic response among the patient groups divided by
IMABALI-De score (p=0.054).

Overall survival according to CRAFITY score, mALBI grade, Child-Pugh
score, and IMABALI-De score

Analysis using IMABALI-De score showed median OS (mOS) was not
applicable (NA) (95\% CI: NA-NA) for a score of 0, NA (95\% CI:21.3-NA)
for a score of 1, 26.11 months (95\% CI: 17.64-NA) for a score 2, 18.79
months (95\% CI: 15.57-NA) for a score 3, 14.07 months (95\% CI:
11.57-18.25) for a score 4, and 8.32 months (95\% CI: 6.79-12.86) for a
score 5 (P\textless{}0.001) (Figure 2a). According to CRAFITY score, mOS
was 26.11 months (95\% CI: 20.14-NA) for a score of 0, 20.29 months
(95\% CI: 16.43-NA) for a score of 1, and 11.32 months (95\% CI:
6.18-13.32) for a score of 2 (p\textless{}0.001) (Figure 2b). As for
mALBI grade, mOS was NA (95\% CI: 24.54-NA) for grade 1, 24.0 months
(95\% CI: 17.75-NA) for grade 2a, 13.43 months (95\% CI: 11.82-15.32)
for grade 2b, and 11.0 months (95\% CI: 1.11-NA) for grade 3
(p\textless{}0.001) (Figure 2c), while for Child-Pugh score, mOS was
26.14 months (95\% CI: 24.0-NA) for a score of 5, 16.18 months (95\% CI:
13.97-20.07) for a score of 6, 9.36 months (95\% CI: 6.54-16.68) for a
score of 7, 6.64 months (95\% CI: 3.07-NA) for a score of 8, 4.0 months
(95\% CI: 3.43-NA) for a score of 9, and 1.11 months for a score of 10
(p\textless{}0.001) (Figure 2d). AIC results for IMABALI-De score,
CRAFITY score, mALBI grade, and Child-Pugh score were 2788.67, 2864.54,
2816.58, and 2829.04, respectively, while C-index results for those were
0.699, 0.606, 0.653, and 0.625, respectively. Regarding OS, IMABALI-De
score had better AIC and c-index results as compared to CRAFITY score,
mALBI grade, and Child-Pugh score.

The mOS according to IMABALI score was NA (95\% CI: NA-NA) for a score
0, NA (95\% CI: 21.32-NA) for a score 1, 20.39 months (95\% CI:
17.32-26.14) for a score 2, 14.61 months (95\% CI: 12.5-20.43) for a
score 3, and 9.46 months (95\% CI: 7.25-13.21) for a score 4
(P\textless{}0.001) (AIC 2799.02, c-index 0.688) (Supplemental figure
1).

Progression-free survival according to CRAFITY score, mALBI grade,
Child-Pugh score, and IMABALI-De score

According to IMABALI-De score, median PFS (mPFS) was 21.75 months (95\%
CI: 10.21-NA) for a score of 0, 12.89 months (95\% CI: 10.61-17.57) for
a score 1, 9.18 months (95\% CI: 6.68-11.79) for a score 2, 8.0 months
(95\% CI: 6.54-11.0) for a score 3, 5.0 months (95\% CI: 3.46-7.0) for a
score 4, and 3.75 months (95\% CI: 3.14-4.36) for a score 5
(P\textless{}0.001) (Figure 3a). CRAFITY score showed mPFS of 10.32
months (95\% CI: 8.11-12.25) for a score of 0, 7.68 months (95\% CI:
6.25-8.96) for a score of 1, and 3.57 months (95\% CI: 3.0-4.71) for a
score of 2 (p\textless{}0.001) (Figure 3b). As for mALBI grade, mPFS was
11.96 months (95\% CI: 8.64-15.21) for grade 1, 9.50 months (95\% CI:
6.96-11.64) for grade 2a, 6.04 months (95\% CI: 5.0-7.0) for grade 2b,
and 3.43 months (95\% CI: 0.39-NA) for grade 3 (p\textless{}0.001)
(Figure 3c). Finally, mPFS was 10.32 months (95\% CI: 8.0-11.89) for a
Child-Pugh score of 5, 6.68 months (95\% CI: 5.25-7.75) for a score of
6, 5.79 months (95\% CI: 3.96-7.04) for a score of 7, 4.18 months (95\%
CI: 1.54-NA) for a score of 8, 3.43 months (95\% CI: 3.0-NA) for a score
of 9, and 0.39 months for a score of 10 (p\textless{}0.001) (Figure 3d).
AIC values for IMABALI-De score, CRAFITY score, mALBI grade, and
Child-Pugh score were 5203.32, 5246.24, 5245.61, and 5260.62,
respectively, while C-index values were 0.623, 0.574, 0.573, 0.559,
respectively. IMABALI-De score showed better AIC and C-index results as
compared to CRAFITY score, mALBI grade, and Child-Pugh score, as well as
for PFS.

The mPFS according to IMABALI score was 16.25 months (95\% CI: 11.96-NA)
for a score of 0, 9.57 months (95\% CI: 7.0-12.79) for a score of 1,
8.75 months (95\% CI: 7.25-12.50) for a score of 2, 6.54 months (95\%
CI: 4.61-7.75) for a score of 3, and 3.75 months (95\% CI: 3.14-4.46)
for a score of 4 (P\textless{}0.001) (AIC 5217.7, c-index 0.608)
(Supplemental Figure 2).

Discussion

In the present cohort, IMABALI-De score showed a favorable
stratification of prognosis of patients with Atez/Bev. The items of the
IMABALI-De scoring system for Atez/Bev treatment for uHCC include tumor
burden (BCLC) and malignant potential (AFP, DCP), the same as CRAFITY
score, while hepatic reserve function (mALBI 1, 2a, 2b/3) is also used.
This point is considered to be the main reason for the superiority of
IMABALI-De as compared to CRAFITY score found in this study.

A recent report noted that overall response rate and PFS (weighted
Pearson correlation coefficient = 0.71, 95\% Cl=0.52-0.84 and 0.62; 95\%
Cl=0.35-0.84, respectively) demonstrated a good correlation with OS
(28). However, post-progression treatments have also been reported to be
significant prognostic factors in regard to immunotherapy for HCC (29).
Rates presented for post-progression treatment after Atez/Bev failure
are comparatively favorable, ranging from 74.2\% to 88.2\% (30) (31)
(32). At the time of writing, post-progression treatment is considered
to be primarily dependent on available multi-targeting agents (MTAs);
sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib, thus
consideration regarding how to prolong prognosis with sequential
post-progression treatments is important. Terashima previously noted
that post-progression survival (PPS) had a strong relationship with OS
in patients who received sorafenib treatment for HCC (r=0.834,
P\textless{}0.001), and found that the PPS rate for those classified as
Child-Pugh A was better as compared to those as Child-Pugh B (54.8\selectlanguage{ngerman}±17.4
vs. 32.0±11.6, P=0.015)(33). Needless to say, better hepatic function at
the time of introducing an MTA is a required factor for obtaining
improved prognosis following Atez/Bev failure.

Systemic therapy for uHCC is mainly performed for Child-Pugh A patients.
In the past 30 years, a relative change in hepatic reserve function in
patients with chronic liver disease has led to an increased rate of
Child-Pugh A from 52.1\% to 84.8\% (34), thus an assessment tool with
greater detail has recently been considered necessary for clinical
practice. Philip et al. developed a new tool termed ALBI grade, the only
established tool based on a statistical process, and its clinical
efficacy has been reported (16, 17), while the prognostic importance of
ALBI grade has been elucidated for patients HCC undergoing immunotherapy
(29). However, the ALBI grade 2 covers a wide range of patients, which
is thought to be a clinical issue. We established a modified tool for
assessment of hepatic function termed mALBI, in which the middle grade
is divided into two sub-grades(2a, 2b), based on a cut-off value of
indocyanine green retention rate at 15 minutes (ICG-R15) of 30\% (9).
Several reports have noted that mALBI grade plays a great role to
predict the prognosis of patients with HCC who underwent treatment with
MTA (35) (36) (37) (38) (39). In the same way, hepatic function is
thought to be an important requirement for detailed assessment of
prognosis of HCC patients with Atez/Bev. Therefore, this score is more
focused on hepatic function, not to mention tumor burden and the
malignant potential of HCC. In addition to the CRAFITY score, which
focuses more on the malignant potential of HCC, we compared IMABALI-De
score with mALBI grade and Child-Pugh score, which are indicators of
hepatic function, and confirmed the usefulness of the IMABALI-De score.
Our research group has also reported the usefulness of nutritional
indices such as NLR (40), prognostic nutritional index (PNI) (41), and
neo-GPS (42) as prognostic predictors of Atez/Bev. Because the present
study focused on hepatic function and tumor status, prognostic scores
predicted by nutritional indicators were not included in the comparison.
A study will be conducted to determine which of these various scores and
the current score is most useful in predicting Atez/Bev prognosis after
a sufficient observation period. In addition, specific subsets such as
exhausted CD8+ T cells and regulatory T cells are preferentially
enriched and potentially clonally expanded in HCC, unlike peripheral
blood (43). Accordingly, peripheral blood fraction count alone is not
necessarily a sufficient nutritional immune-biomarker, there is a need
to establish a simple prognostic index combined with tumor burden, tumor
malignant potential and hepatic function in the future.

Based on the clinical importance of hepatic reserve function, the
present proposed scoring system is thought to be reasonable. However,
therapeutic response was not significantly different among the
IMABALI-De scores, except for a score of 5. On the other hand, PFS
grading with IMABALI-De score showed a good separation, other than
between the score of 2 and 3. Although these results suggest that
Atez/bev can serve as an effective treatment regimen for uHCC, the
response duration became shorter as IMABALI-De score increased. During
the clinical course of HCC, assessment with the present scoring system
should be considered so as to not to lose the opportunity of
introduction of Atez/Bev for improving prognosis within a short time
after BCLC-B status or greater is noted. While systemic therapy is the
only treatment for BCLC-C HCC, TACE is one of major option for BCLC-B
HCC, as well as systemic therapies. Atez/Bev has been reported to
provide clinical benefit to TACE unsuitable patients with BCLC-B HCC
beyond the up to 7 criteria (44). Therefore, clinicians should consider
switching to Atez/Bev, especially when the IMABALI-De score is as low as
possible, to obtain more therapeutic benefit with Atez/Bev. Namely, the
present IMABALI-De score might be a useful indicator to switch treatment
in BCLC-B HCC patients initiating TACE before the poor prognostic
benefit of treatment with Atez/Bev is predicted.

The present study has some limitations. Firstly, while the results were
obtained from multiple institutions, they were retrospectively analyzed.
Second, because there were some patients with missing data including
number of neutrophil and lymphocyte cells, comparisons among previous
reported prognostic indicators were not performed in this study. Further
prospective studies using long-term follow-up findings are needed to
confirm the usefulness of the present IMABALI-De score and to compare it
with other prognostic indicators. In near future, it is desirable to
continue to search common clinical factors specific to this combined
immunotherapy.

In conclusion, the proposed IMABALI-De score, which consists only of
common clinical items including mALBI grade, is considered to have a
good prognostic predictive ability for uHCC patients treated with
Atez/Bev. With considerations based individual case factors,
introduction of Atez/Bev at the lowest possible IMABALI-De score is
recommended to improve prognosis.

Statements

{[}Declarations and Ethical Statements{]}

The entire research protocol received approval from Ehime Prefectural
Central Hospital Institutional ethics committee: No. 2022-46. After
receiving official authorization, this study proceeded as a
retrospective study of database records, following the Ministry of
Health and Welfare of Japan's Clinical Research Guidelines and adhering
to the principles of the Helsinki Declaration. To protect patient
confidentiality, all data were anonymized before analysis. Before
treatment, written IC was obtained from all patients. Ethical approval
was granted for employing an opt-out approach due to the minimal risk to
participants.

{[}Funding{]}

This study did not receive any external funding.

{[}Conflicts of interest{]}

Atsushi Hiraoka, MD, PhD; for lecture fees from Chugai, AstraZeneca, and
Eli Lilly. Takashi Kumada, MD, PhD; for lecture fees from Eisai.

Toshifumi Tada, MD, PhD; for lecture fees from Abbvie, Eisai.

Takeshi Hatanaka MD, PhD; for lecture fees from Eisai.

The rest of the authors do not possess any potential conflicts of
interest to disclose.

{[}Authors' contributions{]}

Conceived the study, participated in its design and coordination was
performed by Hironori Ochi, Atsushi Hiraoka, Takashi Kumada. Data
curation was performed by Atsushi Hiraoka/ Hideko Ohama/ Masashi
Hirooka/ Toshifumi Tada/ Hidenori Toyoda / Kazuya Kariyama/ Takeshi
Hatanaka/ Masanori Atsukawa/ Joji Tani/ Koichi Takaguchi/ Takashi
Nishimura/ Kazuto Tajiri/ Kunihiko Tsuji/ Hidekatsu Kuroda / Ei
Itobayashi/ Toru Ishikawa/ Satoshi Yasuda/ Chikara Ogawa/ Tomomitsu
Matono / Fujimasa Tada/ Shinya Fukunishi/ Satoru Kakizaki/ Atsushi
Naganuma/ Noritomo Shimada/ Kazuhito Kawata/ Kazuhiro Nouso/ Hisashi
Kosaka/ Yutaka Yata/ Asahiro Morishita/ Takuya Nagano/ Keisuke Yokohama/
Akemi Tsutsui/ Norio Itokawa/ Taeang Arai/ Tomomi Okubo/ Yohei Koizumi/
Hiroko Iijima/ Hiroki Nishikawa/ Michitaka Imai/ Shinichiro Nakamura/
Masaki Kaibori/ Yoichi Hiasa. Atsushi Hiraoka conducted statistical
analyses and interpretation. The manuscript text was drafted by Hideko
Ohama and Atsushi Hiraoka. All authors have reviewed and endorsed the
manuscript's final version.

{[}Data availability{]}

Given the nature of this study, it was not feasible to contact the
participants to seek their permission for public sharing of the
findings. Consequently, the supporting data, such as datasets generated
or analyzed for this study, are not accessible to the public.

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Figure legends

Figure 1. Approach employed for the management of hepatocellular
carcinoma (HCC) using atezolizumab in combination with bevacizumab
(Atez/Bev).

TACE; Transarterial chemoembolization, ECOG PS; Eastern Cooperative
Oncology Group performance status, BSC: best supportive care

Figure 2. Overall survival of patients with hepatocellular carcinoma
with atezolizumab plus bevacizumab according to score.

\begin{enumerate}
\tightlist
\item
  Median overall survival (OS) was not applicable (NA) (95\% CI:
  NA-NA)/NA (95\% CI:21.3-NA)/26.11 (95\% CI: 17.64-NA)/18.79 (95\% CI:
  15.57-NA)/14.07 (95\% CI: 11.57-18.25)/8.32 (95\% CI: 6.79-12.86)
  months for IMABALI-De score 0/1/2/3/4/5 (p\textless{}0.001).
\item
  Median OS was 26.11 (95\% CI: 20.14-NA)/20.29 (95\% CI:
  16.43-NA)/11.32 (95\% CI: 6.18-13.32) months for CRAFITY score 0/1/2
  (p\textless{}0.001).
\item
  Median OS was NA (95\% CI: 24.54-NA)/24.0 (95\% CI: 17.75-NA)/13.43
  (95\% CI: 11.82-15.32)/11.0 (95\% CI: 1.11-NA) months for modified
  albumin-bilirubin (mALBI) grade 1/2a/2b/3 (p\textless{}0.001).
\item
  Median OS was 26.14 (95\% CI: 24.0-NA)/16.18 (95\% CI:
  13.97-20.07)/9.36 (95\% CI: 6.54-16.68)/6.64 (95\% CI: 3.07-NA)/4.0
  (95\% CI: 3.43-NA)/1.11 months for Child-Pugh score 5/6/7/8/9/10
  (p\textless{}0.001).
\end{enumerate}

Figure 3. Progression-free survival of patients with hepatocellular
carcinoma with atezolizumab plus bevacizumab according to IMABALI-De
score.

\begin{enumerate}
\tightlist
\item
  Median progression-free survival (PFS) was 21.75 (95\% CI:
  10.21-NA)/12.89 (95\% CI: 10.61-17.57)/9.18 (95\% CI: 6.68-11.79)/8.0
  (95\% CI: 6.54-11.0)/5.0 months (95\% CI: 3.46-7.0)/3.75 (95\% CI:
  3.14-4.36) months for IMABALI-De score 0/1/2/3/4/5
  (p\textless{}0.001).
\item
  Median PFS was 10.32 (95\% CI: 8.11-12.25)/7.68 (95\% CI:
  6.25-8.96)/3.57 (95\% CI: 3.0-4.71) months for CRAFITY score 0/1/2
  (p\textless{}0.001).
\item
  Median PFS was 11.96 (95\% CI: 8.64-15.21)/9.50 (95\% CI:
  6.96-11.64)/6.04 (95\% CI: 5.0-7.0)/3.43 (95\% CI: 0.39-NA) months for
  modified albumin-bilirubin (mALBI) grade 1/2a/2b/3
  (p\textless{}0.001).
\item
  Median PFS was 10.32 (95\% CI: 8.0-11.89)/6.68 (95\% CI:
  5.25-7.75)/5.79 (95\% CI: 3.96-7.04)/4.18 (95\% CI: 1.54-NA)/3.43
  months for Child-Pugh score 5/6/7/8/9/10 (p\textless{}0.001).
\end{enumerate}

\textbf{Hosted file}

\verb`IMABALIde score Figure 20230720.pptx`  available at \url{https://authorea.com/users/671502/articles/671000-clinical-usefulness-of-newly-developed-prognostic-predictive-score-for-atezolizumab-plus-bevacizumab-for-hepatocellular-carcinoma}

\textbf{Hosted file}

\verb`Table 20230604.docx`  available at \url{https://authorea.com/users/671502/articles/671000-clinical-usefulness-of-newly-developed-prognostic-predictive-score-for-atezolizumab-plus-bevacizumab-for-hepatocellular-carcinoma}

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\end{document}

