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Multicenter Study
. 2025 Jun;60(6):738-753.
doi: 10.1007/s00535-025-02233-z. Epub 2025 Mar 7.

Proposal of discontinuation criteria of atezolizumab plus bevacizumab after curative conversion therapy for unresectable early-to-intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study

Tomoko Aoki  1 , Masatoshi Kudo  2 , Naoshi Nishida  1 , Kazuomi Ueshima  1 , Kaoru Tsuchiya  3 , Toshifumi Tada  4 , Masahiro Morita  1 , Hirokazu Chishina  1 , Masahiro Takita  1 , Satoru Hagiwara  1 , Hiroshi Ida  1 , Yasunori Minami  1 , Hidekatsu Kuroda  5 , Noriaki Nakamura  6 , Atsushi Hiraoka  7 , Tetsu Tomonari  8 , Joji Tani  9 , Atsushi Naganuma  10 , Satoru Kakizaki  11 , Chikara Ogawa  12 , Takeshi Hatanaka  13 , Toru Ishikawa  14 , Kazuhito Kawata  15 , Atsushi Takebe  16 , Ippei Matsumoto  16 , Masaaki Hidaka  17 , Masayuki Kurosaki  3 , Takashi Kumada  18 , Namiki Izumi  3
Affiliations
Multicenter Study

Proposal of discontinuation criteria of atezolizumab plus bevacizumab after curative conversion therapy for unresectable early-to-intermediate-stage hepatocellular carcinoma: a multicenter proof-of-concept study

Tomoko Aoki et al. J Gastroenterol. 2025 Jun.

Abstract

Background: Achieving complete response (CR) is a desirable goal in early-to-intermediate-stage hepatocellular carcinoma (HCC). While systemic and locoregional therapies show promise, optimal drug discontinuation criteria remain unclear. This study aims to investigate drug-off criteria for atezolizumab plus bevacizumab as a proof-of-concept study.

Methods: This retrospective multicenter study included child-pugh class A patients with unresectable HCC without extrahepatic spread or macrovascular invasion who received atezolizumab plus bevacizumab as first-line therapy. Modified clinical CR (mCCR) was defined as CR per mRECIST with sustained normal alpha-fetoprotein (AFP) levels (< 10.0 ng/dl). Recurrence-free survival (RFS) and overall survival (OS) were analyzed based on the "drug-off" criteria defined by following: (1) mRECIST CR with locoregional therapies, (2) sustained normalization of AFP/AFP-L3/ des-gamma-carboxy prothrombin (DCP) for 12-24 weeks, and (3) complete tumor vascularity disappearance by contrast-enhanced ultrasonography (CEUS) or pathological curative resection.

Results: The median follow-up was 16.5 months (95% CI 15.2-17.8). Among 51 patients achieving mCCR, 11 underwent surgery, with pathological CR in three cases. In contrast, viable lesions were observed in 7 of 40 cases assessed using CEUS. All patients meeting the drug-off criteria (n = 9) showed no recurrence and none of them experienced mortality, while 45.2% (19/42) of those not meeting the criteria experienced recurrence (median RFS: 12.8 months, p = 0.007). The median OS was not reached in dug-off criteria met patients (n = 9), 37.7 months (95% CI: NA) in non-criteria met patients (n = 42), and 27.1 months (95% CI 16.7-37.6) in non-mCCR patients (n = 184) (p < 0.001).

Conclusion: In patients with unresectable and TACE-unsuitable early-to-intermediate-stage HCC who met the drug-off criteria, significantly improved RFS and OS were observed compared those who did not meet the criteria. However, further validation studies are required to confirm the utility of the criteria.

Keywords: Carcinoma, Hepatocellular [MH]; Conversion therapy; Drug-off; Immune checkpoint inhibitors [MH]; Treatment outcome [MH].

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Conflict of interest statement

Declarations. Conflict of interest: T.A. received lecture fees; Eisai. M.K. received grants from Taiho Pharmaceuticals, Chugai Pharmaceuticals, Otsuka, Takeda, GE Healthcare, AbbVie, Astellas Pharma, Eisai, Eli Lilly, and AstraZeneca. He has also received grants and personal fees from Eisai, Roche, Chugai, and AstraZeneca. N.N. No relevant conflicts of interest to disclose. K.U. received honoraria from Eisai, Takeda and Chugai. K.T. received lecture fees; Chugai, Eisai, AstraZeneca, Takeda. T.T.: received lecture fees; Abbvie, Chugai and Eisai. M.M. No relevant conflicts of interest to disclose. H.C. No relevant conflicts of interest to disclose. M.T. No relevant conflicts of interest to disclose. S.H. No relevant conflicts of interest to disclose. H.I. No relevant conflicts of interest to disclose. Y.M. No relevant conflicts of interest to disclose. H.K. No relevant conflicts of interest to disclose. N.N. No relevant conflicts of interest to disclose. A.H.: received lecture fees; Chugai, AstraZeneca and Eli Lilly. T.T. No relevant conflicts of interest to disclose. J.T. received lecture fees; AstraZeneca. A.N. No relevant conflicts of interest to disclose. S.K.: received lecture fees; Abbvie. C.O. received lecture fees; Chugai. T.H. received lecture fees; Eisai. T.I. No relevant conflicts of interest to disclose. K.K. No relevant conflicts of interest to disclose. A.T. No relevant conflicts of interest to disclose. I.M. No relevant conflicts of interest to disclose. M.H. No relevant conflicts of interest to disclose. M.K. received lecture fees; Eisai, Bayer, Lilly, Chugai, Takeda, AstraZeneca. T.K.: received lecture fees; Eisai. N.I. received lecture fees; Chugai, AstraZeneca, Eisai, Takeda. Ethical approval: This study was approved by the Medical Ethics Committee of Kindai University Hospital (Approval R02-258) in 2020, and written informed consent was obtained from all patients.

Figures

Fig. 1
Fig. 1
Treatment protocol of atezolizumab plus bevacizumab curative conversion therapy. Patients diagnosed with unresectable and transarterial chemoembolization (TACE)-unsuitable hepatocellular carcinoma (HCC) were treated with atezolizumab plus bevacizumab every 3 weeks. Serum tumor marker assessments were performed every 3 weeks, and imaging evaluations with contrast-enhanced computed tomography/magnetic resonance imaging were conducted every 6 weeks. Optional locoregional therapies were added after 3–4 cycles of drug administration. “Modified clinical complete response (mCCR)” was defined as maintaining alpha-fetoprotein (AFP) levels within the normal range for ≥ 6 weeks and achieving CR according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Subsequently, “drug-off criteria” were met if AFP/AFP-L3 fraction/des-gamma-carboxy prothrombin (DCP) remained within the normal range for 12–24 weeks and if pathological cure was confirmed through surgical resection or tumor vascularity disappeared on contrast-enhanced ultrasound (CEUS)
Fig. 2
Fig. 2
a Schematic of prospective cohort study design. A total of 235 patients who met the inclusion criteria were enrolled in this study. Among them, 51 achieved mCCR, and of these, 11 were confirmed to have achieved curative pathological resection. Among the remaining 40 patients, perflubutane contrast-enhanced ultrasound (CEUS) was performed in 33 patients, and subtle tumor vascularity was observed in 7 patients, leading to the achievement of curative conversion through additional locoregional therapy. Ultimately, 9 patients met the “drug-off criteria.” b Transitions in ABC conversion treatment. In patients with BCLC Stage A/B unresectable, TACE-unsuitable, or TACE-refractory HCC treated with atezolizumab plus bevacizumab, at the time of discontinuation of observation, 52 patients were still on treatment, 38 patients discontinued due to transition to other locoregional therapies, 57 patients discontinued due to adverse events (AEs), and 88 patients discontinued due to disease progression (PD). While most patients who discontinued treatment due to AEs, PD, or were continuing on the drug did not achieve mCCR, those who discontinued atezolizumab plus bevacizumab to transition to other therapies were able to achieve mCCR. Of the 51 patients who achieved mCCR, 9 met the drug-off criteria
Fig. 3
Fig. 3
Spider plots of serum tumor marker. Serum tumor markers after initiation of atezolizumab plus bevacizumab combination therapy presented as spider plots divided into three groups: a AFP levels, b AFP-L3 fraction, and c DCP levels
Fig. 4
Fig. 4
Kaplan–Meier curve for recurrence-free survival and overall survival. We investigated factors contributing to the recurrence-free survival (RFS) after achieving mCCR, and the results are presented in (a) and (b). a RFS according to mALBI grade and the response to atezolizumab plus bevacizumab based on RECIST v1.1 are shown. b RFS between patients who met the drug-off criteria and those who did not. Among the patients who met the “drug-off criteria” (n = 9), none experienced recurrence, while among those who did not meet the drug-off criteria with mCCR (n = 42), 19 patients showed recurrence. c overall survival (OS) analysis was performed on the 235 patients. Patients who did not achieve mCCR had significantly worse prognosis, whereas those who met the drug-off criteria had the most favorable prognosis
Fig. 5
Fig. 5
The achievement rates of mCCR and drug-off criteria based on the number of intrahepatic HCC nodules and tumor maximum diameter. Categories containing patients who met the drug-off criteria are indicated in green, whereas categories in which neither mCCR nor the drug-off criteria were achieved are shown in gray
See this image and copyright information in PMC

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