Abstract
Background
The PRISM study is a nationwide, multicenter, prospective observational study in Japan evaluating the real-world efficacy and safety of systemic therapies for unresectable hepatocellular carcinoma (HCC). HCC patients starting systemic therapy are prospectively enrolled, enabling assessment of outcomes and tolerability across treatment lines. By capturing all patients treated in routine practice, the study is expected to provide a clear picture of the actual treatment outcomes in Japan.
Methods
We analyzed the first 1,000 patients enrolled between July 2020 and July 2022, focusing on outcomes of first-line therapy and subsequent patterns. Data on demographics, tumor stage, liver function, regimens, survival, and adverse events (AEs) were prospectively collected and centrally monitored. Survival was estimated by Kaplan-Meier method, and tumor responses were assessed per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST (mRECIST).
Results
Of 935 evaluable patients, 82.8% received atezolizumab + bevacizumab (Atezo+Bev) and 15.2% lenvatinib as first-line therapy. Median overall survival and progression-free survival were 21.8 and 7.7 months for Atezo+Bev, respectively, and 20.8 and 6.7 months for lenvatinib, with overall survival numerically longer than that reported in pivotal clinical trials, while progression-free survival remained comparable. Objective response rates were 29.6% (RECIST) and 35.0% (mRECIST) for Atezo+Bev, 24.6% and 35.2% for lenvatinib, and 0% and 6.3% for sorafenib by RECIST and mRECIST, respectively. Grade ≥3 treatment-related AEs occurred in 21.6% and 22.9%, with safety profiles consistent with prior reports. Approximately 50% of patients received second-line therapy, most often lenvatinib after Atezo+Bev and vice versa, with a median progression-free survival of ∼4 months; later-line regimens yielded even shorter benefit.
Conclusion
The PRISM study confirms the real-world reproducibility of Atezo+Bev and lenvatinib in Japan, demonstrating their feasibility across diverse patient populations. Ongoing follow-up and subgroup analyses, particularly in special populations, are expected to help optimize long-term outcomes.
Keywords: Hepatocellular carcinoma, Atezolizumab + bevacizumab, Lenvatinib, Systemic therapy, Prospective study
Background
Hepatocellular carcinoma (HCC) is a major global malignancy, with Japan being among the regions with a high incidence and ranking fifth in cancer-related mortality. While the majority of cases have historically arisen in cases with underlying chronic hepatitis or cirrhosis caused by hepatitis B or C virus infection, the proportion of cases associated with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) has been steadily increasing, reflecting a shift in the epidemiologic trends [1]. In the era that was dominated by viral hepatitis and cirrhosis, effective surveillance programs often enabled early detection, allowing for curative resection or local therapies. However, HCC associated with MASLD or MASH is frequently asymptomatic and tends to be diagnosed at more advanced stages, when curative interventions are no longer feasible [2]. The HCC patient population in Japan is also aging, with more than half of the patients aged 75 years or older, adding to the complexity of treatment decisions [3]. Against these backgrounds, therapeutic options for advanced HCC have also expanded rapidly with the introduction of multiple molecular-targeted agents and immune checkpoint inhibitors, making the development of optimal treatment strategies an urgent clinical priority.
In Japan, systemic therapy for HCC has expanded rapidly since the approval of sorafenib in 2009 [4, 5], with multiple agents, including regorafenib [6], lenvatinib [7], ramucirumab [8], cabozantinib [9], and the combination of atezolizumab + bevacizumab (Atezo+Bev) [10], introduced by 2020, followed by durvalumab + tremelimumab (Durva+Treme) and durvalumab alone [11] approved in 2022, and nivolumab + ipilimumab (Nivo+Ipi) [12] approved in 2025. Nine systemic therapy options are now available, with a shift from the use of mainly molecular-targeted agents to mainly immune checkpoint inhibitors. Under the Japanese national insurance system, agents covered for first-line treatment are also covered for later-line treatments, but optimal sequencing and drug selection remain unclear. While the efficacy of each agent has been demonstrated in global phase III clinical trials, the results are often based on highly selected patient populations meeting strict eligibility criteria. In actual clinical practice, patients with HCC excluded from clinical trials, such as the elderly, those with comorbidities, or those with impaired liver function, also have to receive treatment. Therefore, establishment of real-world evidence reflecting the efficacy and safety of the treatments in routine clinical practice is also essential.
Therefore, we initiated a nationwide multicenter, prospective observational study, PRISM, in Japan in July 2020. We continue to enroll patients with systemic therapy-naïve HCC in the study, with a target sample size of 2,000 patients. Our objective is to evaluate not only the efficacy/safety of first-line therapy but also that of subsequent lines of treatment. In this report, we present the study design of the PRISM study and the baseline characteristics and treatment patterns/outcomes of the first 1,000 patients enrolled in the study for whom 2 years of follow-up have been completed. This analysis was preplanned in the study protocol, and these patients represent the initial subset of the total of 1,730 patients already enrolled in the trial as of August 2025. We expect that these findings would contribute to the development of optimal treatment strategies for unresectable HCC in future and serve as important evidence to guide future clinical decision-making.
Patients and Methods
Study Design and Objectives
The PRISM is a nationwide, multicenter, prospective observational study of the efficacy/safety of systemic therapy for HCC being conducted with the participation of 54 major hospitals in Japan (online suppl. Fig. 1; for all online suppl. material, see https://doi.org/10.1159/000552686). The objective of this study is to evaluate the efficacy and safety of each treatment regimen at each line of therapy in patients with unresectable HCC who received systemic therapy. The primary endpoint is overall survival (OS) with first-line treatment. The secondary endpoints are progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), time to treatment failure (TTF), incidence/nature of grade ≥3 adverse events (AEs), and proportion of patients who can be transitioned to subsequent-line therapy in each treatment line. The study protocol was approved by the institutional review board (IRB) of each of the participating hospitals. Written informed consent is obtained from each of the patients prior to his/her enrollment. The study is being conducted in accordance with the principles enshrined in the Declaration of Helsinki and the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” in Japan.
Eligibility Criteria
Eligible patients are patients who have been histologically or clinically diagnosed as having HCC and are scheduled to receive first-line systemic therapy for unresectable HCC, which is defined based on the clinical judgment of the treating physicians at each participating institution, considering tumor burden, liver function, and overall patient condition. Concomitant treatment with other modalities, such as transarterial chemoembolization, at the initiation of systemic therapy is not permitted in the study subjects. Additional eligibility criteria include age ≥20 years at the time of provision of written informed consent prior to enrollment. Patients are excluded if they have received prior systemic therapy for HCC, including cytotoxic chemotherapy, molecular-targeted therapy, or investigational drugs; however, previous hepatic resection, local ablative therapy, transarterial chemoembolization, or radiotherapy are not considered as exclusion criteria. Other exclusion criteria include ongoing participation in other interventional clinical trials at the time of registration or any condition judged by the investigator or treating physician as rendering the patient unsuitable for participation in the study.
Planned Sample Size, Enrollment Period, and Follow-Up
The planned sample size is 2,000 patients. Enrollment was started on July 1, 2020, and was scheduled to continue until May 31, 2026. The follow-up period is set at 2 years after completion of enrollment, with observations therefore scheduled to continue until May 31, 2028. The total study period, including final analysis and report preparation, will end on September 30, 2028. As a descriptive observational study without hypothesis testing, no formal sample size calculation was performed; however, a cohort of 2,000 patients is expected to allow an estimation of the 2-year OS following treatment with key first-line regimens with a 95% confidence interval (CI) width of approximately ±4%, providing sufficient precision for real-world outcome assessment. For the present analysis of the initial cohort of 1,000 patients, the data cutoff date was July 21, 2024.
Treatment
Therapeutic regimens and dosing are not specified and are determined at the discretion of the treating physician in routine clinical practice. Approved systemic therapies available in Japan, including sorafenib, regorafenib, lenvatinib, ramucirumab, cabozantinib, Atezo+Bev, Durva+Treme, durvalumab monotherapy, and Nivo+Ipi are permitted. Treatment dosing, including the initial dose and any dose modifications, was determined at the discretion of the treating physicians in routine clinical practice.
Data Collection and Monitoring
Data collected include the patient demographics, tumor characteristics, liver function (Child-Pugh classification, albumin-bilirubin [ALBI] grade), treatment details, AEs (graded as per CTCAE v5.0), and imaging results at the baseline, during treatment, at treatment discontinuation, and at the final follow-up. Continuous variables are presented as median (IQR, range). The ALBI score was calculated using the following formula: (log10 bilirubin [μmol/L] × 0.66) + (albumin [g/L] × −0.085). ALBI grades were defined as follows: grade 1, ≤ −2.60; grade 2, > −2.60 to ≤ −1.39; and grade 3, > −1.39. The study protocol recommended that radiological evaluations be conducted at intervals of approximately 1–3 months. However, imaging assessments were performed according to routine clinical practice at each participating institution, and the timing and methods were ultimately determined at the discretion of the treating physicians. Data are entered into an electronic data capture system and monitored periodically by independent monitors for progress tracking and eligibility verification. All serious AEs (SAEs) are reported promptly to the PRISM Data Center and, when necessary, to the relevant regulatory or corporate pharmaceutical companies.
Statistical Analysis
OS was measured from the date of initial treatment to the date of death or the date of the last follow-up examination. PFS was defined as the time from the date of initial treatment to the first documentation of disease progression or death from any cause, and TTF was defined as the actual period of treatment administration from initiation to discontinuation, irrespective of disease progression status. Survival curves are estimated using the Kaplan-Meier method. ORR was defined as the proportion of patients achieving complete or partial response, and DCR was defined as the proportion of patients achieving complete response, partial response, or stable disease. Tumor responses are assessed in accordance with modified Response Evaluation Criteria in Solid Tumors (mRECIST) and Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. ORR and DCR are presented as point estimates with 95% CI. No formal statistical comparisons between treatment groups were performed, and all analyses were descriptive in nature. Analyses are conducted on the Full Analysis Set for both efficacy and safety.
Results
Patient Enrollment and Analysis Set
Between July 2020 and July 21, 2022, a total of 1,000 patients were enrolled in the study from 42 institutions across Japan. Of the 65 excluded patients, 58 patients were excluded due to ineligibility and 7 patients due to the absence of treatment, and data of the remaining 935 patients were included in the analyses (Fig. 1). The major reasons for discontinuation of the PRISM study were patient death (58.9%), hospital transfer (12.8%), transition to best supportive care (1.0%), and missing patients (1.6%). At the data cutoff (July 21, 2024), systemic treatment was ongoing in 25.6% of the patients. The median follow-up duration from treatment initiation was 17.2 months (range, 0.3–48.7 months).
Fig. 1.
Flow diagram of participant inclusion.
Patient Characteristics
The patient characteristics of the 935 patients are summarized in Table 1. The median age was 73 years (range: 30–93 years), with 45.5% of the patients aged ≥75 years. According to the Child-Pugh classification, 82.5% were graded as class A and 17.0% as class B; the ALBI grade was grade 1 in 32.2%, grade 2 in 65.0%, and grade 3 in 2.8% of patients. No patients had severe hepatic encephalopathy at baseline. Ascites was observed in 11.9% of patients, and no patients had massive ascites. The Barcelona clinic liver cancer (BCLC) stage was B in 37.3% and C in 56.7% of patients. Macrovascular invasion was present in 32.4%, and extrahepatic spread in 27% of patients. First-line therapy consisted of Atezo+Bev in 774 patients (82.8%), lenvatinib in 142 patients (15.2%), sorafenib in 16 patients (1.7%), and other regimens in 3 patients (0.3%).
Table 1.
Patient characteristics (n = 935)
| Variables | Evaluable population | Patients, n (%) | |
|---|---|---|---|
| Gender | Male | 935 | 748 (80.0) |
| Age, years | Median (range) | 935 | 73 (30–93) |
| IQR | 68–79 | ||
| Hepatitis virus | Absent | 935 | 462 (49.4) |
| Hepatitis B | 935 | 191 (20.4) | |
| Hepatitis C | 935 | 296 (31.7) | |
| ALD | Present | 935 | 254 (27.2) |
| MASLD | Present | 935 | 136 (14.6) |
| Prior treatment | Absent | 935 | 301 (32.2) |
| Present | 935 | 634 (67.8) | |
| Resection | 232 (24.8) | ||
| Radiation | 21 (2.2) | ||
| Ablation therapy | 142 (15.2) | ||
| TACE/TAE | 203 (21.7) | ||
| HAIC | 23 (2.5) | ||
| Others | 13 (1.4) | ||
| Reasons for initiating systemic therapy | TACE – refractory | 935 | 207 (22.1) |
| TACE – failure | 935 | 36 (3.9) | |
| TACE – unsuitability | 935 | 357 (38.2) | |
| HAIC – refractory | 935 | 15 (1.6) | |
| Macrovascular invasion | 935 | 185 (19.8) | |
| Extrahepatic lesion | 935 | 199 (21.3) | |
| Others | 935 | 62 (6.6) | |
| ECOG Performance Status | 0 | 868 | 704 (81.1) |
| 1 | 868 | 143 (16.5) | |
| 2 | 868 | 19 (2.2) | |
| 3 | 868 | 2 (0.2) | |
| Encephalopathy | Mild | 935 | 13 (1.4) |
| Ascites | Present | 935 | 111 (11.9) |
| Child-Pugh classification | A | 930 | 767 (82.5) |
| B | 930 | 158 (17.0) | |
| C | 930 | 5 (0.5) | |
| ALBI grade | Grade 1 | 934 | 301 (32.2) |
| Grade 2 | 934 | 607 (65.0) | |
| Grade 3 | 934 | 26 (2.8) | |
| BCLC stage | Stage 0 | 935 | 5 (0.5) |
| Stage A | 935 | 46 (4.9) | |
| Stage B | 935 | 349 (37.3) | |
| Stage C | 935 | 530 (56.7) | |
| Stage D | 935 | 5 (0.5) | |
| Up-to-7 criteria | OUT | 934 | 624 (66.8) |
| TNM Classification (UICC 8th Edition) | IA | 935 | 8 (0.9) |
| IB | 935 | 39 (4.2) | |
| II | 935 | 326 (34.9) | |
| IIIA | 935 | 128 (13.7) | |
| IIIB | 935 | 135 (14.5) | |
| IVA | 935 | 45 (4.8) | |
| IVB | 935 | 252 (27.0) | |
| Maximum tumor size, cm | Median (range) | 934 | 3.6 (0.0–26.0) |
| IQR | 2.0–7.4 | ||
| Intrahepatic lesion | Absent | 935 | 72 (7.7) |
| 1-3 lesions | 935 | 338 (36.1) | |
| 4-7 lesions | 935 | 134 (14.3) | |
| ≥8 lesions | 935 | 391 (45.3) | |
| Location of intrahepatic lesion | Unilobar | 863 | 388 (45.0) |
| Bilobar | 863 | 475 (55.0) | |
| Portal vein invasion | Present | 935 | 260 (27.8) |
| Hepatic vein invasion | Present | 935 | 84 (9.0) |
| Bile duct invasion | Present | 935 | 56 (6.0) |
| Regional lymph node metastasis | Present | 935 | 104 (11.1) |
| Extrahepatic spread | Present | 935 | 252 (27.0) |
| Esophageal or gastric varices | Present | 913 | 254 (27.8) |
| AFP, ng/mL | Median (range) | 916 | 31.5 (0.9–1,020,790) |
| IQR | 5.8–510.5 | ||
| AFP-L3 (%) | Median (range) | 668 | 14.0 (0–99.7) |
| IQR | 0.6–52.3 | ||
| PIVKA II, mAU/mL | Median (range) | 918 | 318.5 (8.7–3,637,900) |
| IQR | 62.0–3,743.0 | ||
TACE – refractory/failure, TACE – unsuitability, HAIC – refractory, and macrovascular invasion were defined according to clinical judgment at each participating institution in routine practice.
ALD, alcoholic liver disease; MASLD, metabolic dysfunction-associated steatotic liver disease; TACE, transarterial chemoembolization; HAIC, hepatic arterial infusion chemotherapy; ECOG, Eastern Cooperative Oncology Group; ALBI, albumin-bilirubin; BCLC, Barcelona clinic liver cancer; AFP, alpha-fetoprotein; PIVKA II, protein induced by vitamin K absence or antagonist II.
Outcomes of First-Line Treatment
The results of first-line treatment with three key regimens, namely, Atezo+Bev, lenvatinib, and sorafenib, are summarized in Table 2. The main reasons for discontinuation of first-line therapy were disease progression (Atezo+Bev group, 58%; lenvatinib group, 54%; and sorafenib group, 69%), emergence of AEs (Atezo+Bev group, 18%; lenvatinib group, 22%; and sorafenib group, 19%), and patients’ wishes (Atezo+Bev group, 6%; lenvatinib group, 5%; and sorafenib group, 0%). At data cutoff, treatment was ongoing in 18% of patients in the Atezo+Bev group, 16% of patients in the lenvatinib group, and 6% of patients in the sorafenib group.
Table 2.
First-line treatment outcomes for Atezo+Bev, lenvatinib, and sorafenib
| Regimen | Atezo+Bev | Lenvatinib | Sorafenib |
|---|---|---|---|
| Patients, n | 773 | 142 | 16 |
| OS (median), months | 21.8 (19.4–24.3) | 20.8 (15.3–24.5) | 13.5 (6.9–25.0) |
| 1-year OS, % | 71.3 (67.9–74.4) | 64.4 (55.7–71.9) | 53.7 (26.3–74.9) |
| 2-year OS, % | 46.4 (42.6–50.1) | 42.5 (33.9–50.9) | 26.8 (6.9–52.3) |
| 3-year OS, % | 32.9 (28.9–36.9) | 35.7 (27.1–44.3) | 8.9 (0.6–32.6) |
| PFS (median), months | 7.7 (6.9–9.0) | 6.7 (4.9–9.2) | 3 (1.6–4.0) |
| ORR – RECIST v1.1, % | 29.6 (26.3–32.9) | 24.6 (17.8–32.6) | 0 (0–20.6) |
| ORR – mRECIST, % | 35.0 (31.7–38.5) | 35.2 (27.4–43.7) | 6.3 (0.2–30.2) |
| DCR – RECIST v1.1, % | 77.7 (74.6–80.6) | 71.1 (62.9–78.4) | 56.3 (29.9–80.2) |
| DCR – mRECIST, % | 76.8 (73.7–79.8) | 72.5 (64.4–79.7) | 56.3 (29.9–80.2) |
| TTF (median), months | 11.2 (9.9–12.2) | 9.1 (6.1–14.7) | 3.0 (1.5–9.2) |
| Proportion of grade ≥3 AEs | 21.6% | 22.9% | 6.2% |
The values in parentheses represent the 95% CI.
Atezo+Bev, atezolizumab + bevacizumab; OS, overall survival; PFS, progression-free survival; ORR, objective response rate; DCR, disease control rate; RECIST, Response Evaluation Criteria in Solid Tumors; mRECIST, modified RECIST; TTF, time to treatment failure; AE, adverse event; CI, confidence interval.
The median OS duration (95% CI) by regimen was 21.8 (19.4–24.3) months in the Atezo+Bev group, 20.8 (15.3–24.5) months in the lenvatinib group, and 13.5 (6.9–25.0) months in the sorafenib group (Fig. 2a). The 1-, 2-, and 3-year OS rates were 71.3%, 46.4%, and 32.9% in the Atezo+Bev group, 64.4%, 42.5%, and 35.7% in the lenvatinib group, and 53.7%, 26.8%, and 8.9% in the sorafenib group, respectively. The median PFS (95% CI) was 7.7 (6.9–9.0) months in the Atezo+Bev group, 6.7 (4.9–9.2) months in the lenvatinib group, and 3.0 (1.6–4.0) months in the sorafenib group (Fig. 2b). Assessment according to RECIST v1.1 revealed an ORR (95% CI) of 29.6% (26.3–32.9) in the Atezo+Bev group, 24.6% (17.8–32.6) in the lenvatinib group, and 0.0% (0–20.6) in the sorafenib group. Assessment according to mRECIST revealed corresponding ORRs of 35.0% (31.7–38.5), 35.2% (27.4–43.7), and 6.3% (0.2–30.2), respectively. The DCR as assessed according to RECIST v1.1 was 77.7% (74.6–80.6) in the Atezo+Bev group, 71.1% (62.9–78.4) in the lenvatinib group, and 56.3% (29.9–80.2) in the sorafenib group. The median TTF (95% CI) was 11.2 (9.9–12.2) months in the Atezo+Bev group, 9.1 (6.1–14.7) months in the lenvatinib group, and 3.0 (1.5–9.2) months in the sorafenib group. The TTF was slightly shorter than the PFS in the Atezo+Bev and lenvatinib groups, reflecting treatment discontinuations in these groups due to AEs or other reasons.
Fig. 2.
OS and PFS for each first-line regimen. a OS for first-line atezolizumab + bevacizumab, lenvatinib, and sorafenib. b PFS for first-line atezolizumab + bevacizumab, lenvatinib, and sorafenib.
In terms of AEs, grade ≥3 treatment-related AEs occurred in 21.6% of patients in the Atezo+Bev group, 22.9% of patients in the lenvatinib group, and 6.2% of patients in the sorafenib group. The most frequent events were hypertension (14%), proteinuria (8%), and hepatic dysfunction (7%) in the Atezo+Bev group, with gastrointestinal bleeding observed in 2% of patients overall; hypertension (18%), hand-foot skin reaction (12%), and proteinuria (9%) in the lenvatinib group; and prominent hand-foot skin reaction (25%) in the sorafenib group. SAEs occurred in 5% of patients in the Atezo+Bev group, 7% in the lenvatinib group, and 6% of patients in the sorafenib group, most of which improved with supportive care or treatment discontinuation. There were three treatment-related deaths in the Atezo+Bev group: two due to interstitial pneumonitis and one due to liver failure.
Subsequent Treatments
The progress to subsequent treatments is shown in Figure 3. The treatment outcomes of later-line treatments for cohorts of 10 or more patients are summarized in Table 3. Analyses of second- and later-line therapies were limited to cohorts with at least 10 patients. Overall, 464 of the 893 patients (52%) who discontinued first-line therapy transitioned to second-line treatment. The most commonly used second- and later-line treatments in the Atezo+Bev group were lenvatinib (35.3%), cabozantinib (8.1%), and Durva+Treme (4.4%), those in the lenvatinib group were Atezo+Bev (21.8%), cabozantinib (4.9%), and ramucirumab (4.2%), and those in the sorafenib group were lenvatinib (25%) and cabozantinib (12.5%).
Fig. 3.
Treatment sequence of systemic therapy.
Table 3.
Subsequent treatment outcomes in cohorts with 10 or more patients
| Second-line regimen | Lenvatinib | Atezo+Bev | Sorafenib | Durva+Treme | Ramucirumab | Regorafenib | Cabozantinib |
|---|---|---|---|---|---|---|---|
| Patients, n | 257 | 36 | 30 | 29 | 25 | 15 | 14 |
| PFS, median (95%CI), months | 3.9 (2.2–7.7) | 4.6 (4.1–5.6) | 2.0 (1.5–3.3) | 6.4 (2.3–13.0) | 2.8 (1.8–4.3) | 2.7 (2.5–6.4) | 6.3 (2.0–8.7) |
| ORR – RECIST v1.1 (95% CI), % | 14.0 (10.1–18.8) | 16.2 (6.2–32.0) | 0 (0–11.2) | 20.7 (8.0–39.7) | 15.4 (4.4–34.9) | 0 (0–21.8) | 20.0 (4.3–48.1) |
| ORR – mRECIST (95% CI), % | 18.5 (14.1–23.9) | 16.2 (6.2–32.0) | 0 (0–11.2) | 20.7 (8.0–39.7) | 23.1 (9.0–43.6) | 0 (0–21.8) | 26.7 (7.8–55.1) |
| DCR – RECIST v1.1 (95% CI), % | 62.9 (56.7–68.7) | 64.9 (47.5–79.8) | 35.5 (19.2–54.6) | 65.5 (45.7–82.1) | 50.0 (29.9–70.1) | 80.0 (51.9–95.7) | 66.7 (38.4–88.2) |
| DCR – mRECIST (95% CI), % | 60.6 (54.4–66.5) | 64.9 (47.5–79.8) | 29.0 (14.2–48.0) | 62.1 (42.3–79.3) | 50.0 (29.9–70.1) | 80.0 (51.9–95.7) | 66.7 (38.4–88.2) |
| TTF, median (95% CI), months | 5.9 (4.5–6.8) | 6.5 (2.7–15.6) | 2.0 (1.5–3.7) | 8.7 (3.0–NA) | 5.4 (2.2–NA) | 4.9 (2.6–9.5) | 7.3 (4.0–8.8) |
| Proportion of grade ≥3 AEs | 35.3% | 21.6% | 29.0% | 26.7% | 12.0% | 33.3% | 20.0% |
| Third-line regimen | Atezo+Bev | Sorafenib | Cabozantinib | Ramucirumab | Lenvatinib | Durva+Treme | |
|---|---|---|---|---|---|---|---|
| Patients, n | 32 | 31 | 28 | 26 | 24 | 21 | |
| PFS, median (95% CI), months | 6.2 (3.4–9.5) | 2.8 (1.4–3.9) | 1.8 (1.4–3.0) | 1.6 (1.0–2.5) | 4.9 (1.9–9.6) | 1.9 (1.2–4.0) | |
| ORR – RECIST v1.1 (95% CI), % | 12.1 (5.1–31.9) | 3.2 (0–16.7) | 0 (0–12.3) | 3.8 (0.1–19.6) | 8.3 (1.0–27.0) | 4.5 (0.1–22.8) | |
| ORR – mRECIST (95% CI), % | 15.2 (5.1–31.9) | 0 (0–11.2) | 0 (0–12.3) | 7.7 (0.9–25.1) | 16.7 (4.7–37.4) | 0 (0–15.4) | |
| DCR – RECIST v1.1 (95% CI), % | 60.6 (42.1–77.1) | 38.7 (21.8–57.8) | 42.9 (24.5–62.8) | 26.9 (11.6–47.8) | 62.5 (40.6–81.2) | 22.7 (7.8–45.4) | |
| DCR – mRECIST (95% CI), % | 60.6 (42.1–77.1) | 32.3 (16.7–51.4) | 39.3 (21.5–59.4) | 26.9 (11.6–47.8) | 62.5 (40.6–81.2) | 13.6 (2.9–34.9) | |
| TTF, median (95% CI), months | 6.6 (4.9–13.5) | 3.0 (1.7–4.4) | 2.0 (1.7–3.9) | 1.8 (1.3–4.2) | 6.7 (1.9–9.6) | 4.0 (1.2–9.4) | |
| Proportion of grade ≥3 AEs | 23.5% | 29.0% | 24.1% | 38.5% | 15.4% | 37.5% | |
| Fourth-line regimen | Cabozantinib | Lenvatinib | Durva+Treme | Atezo+Bev | | | |
|---|---|---|---|---|---|---|---|
| Patients, n | 17 | 16 | 15 | 10 | | | |
| PFS, median (95% CI), months | 2.7 (1.1-NA) | 3.0 (1.1–4.4) | 1.8 (0.6–2.3) | 5.3 (2.1–16.3) | | | |
| ORR – RECIST v1.1 (95% CI), % | 5.9 (0.1–28.7) | 12.5 (1.6–38.3) | 0 (0–20.6) | 10.0 (0.3–44.5) | | | |
| ORR – mRECIST (95% CI), % | 5.9 (0.1–28.7) | 12.5 (1.6–38.3) | 6.3 (0.2–30.2) | 10.0 (0.3–44.5) | | | |
| DCR – RECIST v1.1 (95% CI), % | 52.9 (27.8–77.0) | 25.0 (7.3–52.4) | 37.5 (15.2–64.6) | 40.0 (12.2–73.8) | | | |
| DCR – mRECIST (95% CI), % | 52.9 (27.8–77.0) | 25.0 (7.3–52.4) | 37.5 (15.2–64.6) | 40.0 (12.2–73.8) | | | |
| TTF, median (95% CI), months | 2.7 (1.1–5.0) | 3.8 (1.1–NA) | 2.0 (1.4–9.0) | 5.3 (2.1–16.3) | | | |
| Proportion of grade ≥3 AEs | 33.3% | 29.4% | 57.9% | 20.0% | | | |
| Fifth-line regimen | Cabozantinib | | | | | | |
|---|---|---|---|---|---|---|---|
| Patients, n | 12 | | | | | | |
| PFS, median (95% CI), months | 2.1 (1.0–4.4) | | | | | | |
| ORR – RECIST v1.1 (95% CI), % | 0 (0–26.5) | | | | | | |
| ORR – mRECIST (95% CI), % | 16.7 (2.0–48.4) | | | | | | |
| DCR – RECIST v1.1 (95% CI), % | 41.7 (15.2–72.3) | | | | | | |
| DCR – mRECIST (95% CI), % | 33.3 (9.9–65.1) | | | | | | |
| TTF, median (95% CI), months | 2.1 (1.0–4.1) | | | | | | |
| Proportion of grade ≥3 AEs | 57.9% | | | | | | |
Treatment outcomes were analyzed only for regimens with at least 10 patients.
Atezo+Bev, atezolizumab + bevacizumab; Durva+Treme, durvalumab + tremelimumab; PFS, progression-free survival; ORR, objective response rate; DCR, disease control rate; TTF, time to treatment failure; NA, not assessed; RECIST, Response Evaluation Criteria in Solid Tumors; mRECIST, modified RECIST; AE, adverse event; CI, confidence interval.
In patients who received second-line treatment with lenvatinib (online suppl. Fig. 2a), the median PFS was 3.9 months, the ORR (mRECIST) was 18.5%, and the DCR was 60.6%. In those who received second-line Atezo+Bev (online suppl. Fig. 2b), the median PFS was 4.6 months, the ORR was 16.2%, and the DCR was 64.9%. The median PFS after later-line agents such as cabozantinib and ramucirumab was in the range of approximately 2.5–3.5 months (online suppl. Fig. 2c–g).
Of those who received second-line therapy, 32% of patients were transitioned to third-line treatment, most commonly with cabozantinib, ramucirumab, or the re-introduction of lenvatinib. The median PFS following third-line therapy was approximately 3.0 months overall (online suppl. Fig. 2h–m). Fewer than 5% of patients received fourth- or later-line therapy (online suppl. Fig. 2n–r), with a median PFS of under 2 months.
Discussion
The PRISM study is a nationwide, multicenter, prospective observational study with consecutive patient enrollment, providing a unique real-world dataset compared with previously reported retrospective or single-center studies. The present report represents the first analysis of this cohort and serves as a foundation for subsequent planned analyses focusing on clinically relevant subgroups and treatment sequencing. In this paper, we report the results of analysis of the data of the first 1,000 patients enrolled in the PRISM study, a nationwide, multicenter, prospective observational study of the efficacy/safety of systemic therapy for unresectable HCC in Japan. The PRISM study represents one of the largest prospective observational studies worldwide in this setting, with written informed consent obtained from all of the participants prior to their enrollment in the study. The third-party monitoring framework ensured the reliability of patient enrollment and data collection, positioning PRISM as a high-quality observational study [13]. To date (August 2025), 1,730 patients have been enrolled in the study, and this report focuses on the treatment outcomes of the initial 1,000 patients.
The median age of the study cohort was 73 years, with nearly 45.5% of the patients aged ≥75 years, reflecting the aging population in Japan. The underlying etiologies of HCC were diverse, including viral hepatitis, alcohol-related liver disease, and MASH/MASLD, with the proportion of MASH/MASLD cases increasing in recent years. The cohort also included patients with Child-Pugh class B disease, Barcelona clinic liver cancer (BCLC) stages A and D, and tumor thrombosis in the main portal vein, which are groups often excluded from clinical trials; therefore, the data closely reflect the treatment outcomes observed in real-world practice in Japan [13].
Atezo+Bev was the most commonly administered first-line regimen (82.8%), followed by lenvatinib (15.2%). In patients treated with Atezo+Bev, the median OS was 21.8 months, appearing slightly longer than that reported in pivotal trials. In contrast, the median OS with lenvatinib was 20.8 months, which was numerically longer than that reported in the REFLECT trial. The median PFS was 7.7 months in the Atezo+Bev group and 6.7 months in the lenvatinib group, and both the ORR and DCR were comparable to previous reports, suggesting reproducible efficacy of both combined immunotherapy and tyrosine kinase inhibitor monotherapy in appropriately selected patients. This apparent discrepancy between OS and PFS suggests that the favorable OS observed in this cohort may be partly attributable to post-progression survival rather than enhanced intrinsic efficacy of first-line therapy. The availability of subsequent systemic therapies may have contributed to improved survival outcomes. Therefore, the observed OS should be interpreted in the context of the entire treatment course, rather than being attributed solely to the effect of first-line therapy. Sorafenib use was limited (1.7%) and was associated with a shorter OS (13.5 months) and PFS (3.0 months), reflecting current treatment preferences.
The safety profiles were consistent with previous reports: grade ≥3 treatment-related AEs were reported in 21.6% of patients in the Atezo+Bev group and 22.9% of patients in the lenvatinib group, with hypertension, proteinuria, and hepatic dysfunction being the most frequently reported for Atezo+Bev, and hypertension, hand-foot skin reaction, and proteinuria being the most frequently reported for lenvatinib. SAEs were infrequent (5%–7%), with only three treatment-related deaths reported. The requirement for SAE reporting and independent monitoring ensured completeness of the safety data.
Approximately 50% of patients could be transitioned to second-line therapy, most commonly lenvatinib after Atezo+Bev and Atezo+Bev after lenvatinib. The median PFS duration in the second-line setting was 3.9 months in the patients who received second-line lenvatinib and 4.6 months in those who received second-line Atezo+Bev. Later-line agents not used for first-line treatment, including regorafenib and ramucirumab, yielded even shorter PFS durations (2.7–2.8 months); however, patients treated with cabozantinib showed a longer PFS of 6.3 months, although this finding has to be interpreted with caution due to the small sample size. About 30% of patients also received third-line therapy (median PFS duration, 1.6–6.2 months), with occasional benefit from combined regimens including Atezo+Bev. These findings highlight the need to optimize sequential treatment strategies. In this context, OS should be interpreted in the context of the entire treatment course, as subsequent therapies may have influenced the observed outcomes.
Numerous real world data (RWD) on systemic therapy for unresectable HCC have been published worldwide [13–23]. Major Atezo+Bev series have reported median OS durations of 18–24 months and median PFS durations of 8–10 months [13–16], which closely match the data obtained from the initial 1,000 patients enrolled in the PRISM study. The treatment outcomes of tyrosine kinase inhibitor monotherapy, including lenvatinib therapy, in PRISM were slightly better than those reported from western RWD [17], potentially reflecting differences in liver disease management and patient selection in Japan as compared with western countries. Post-progression treatment rates in PRISM (52%) were also higher than those reported from other trials (37%–45%) [18–23], likely due to the broader availability of systemic agents for use beyond the first-line setting in Japan. Among the extensive RWD reported in the literature, PRISM stands out as the first nationwide, prospective observational study to enroll the largest cohort of patients worldwide, with written informed consent obtained from each of the participants prior to enrollment. These features enhance the precision, credibility, and international relevance of the dataset, positioning it as a high-quality evidence source to guide future clinical practice and comparative research.
The study limitations include the inherent constraints of observational research, such as variability in treatment selection and assessment intervals, missing evaluation of imaging, and the relatively short follow-up of 2 years after enrollment of the initial 1,000 patients, limiting evaluation of long-term outcomes and late toxicities. Data on newer regimens, such as Durva+Treme and Nivo+Ipi, are limited because these therapies were not yet approved at the start of patient enrollment. As this study included only Japanese patients treated within a healthcare system with broad access to systemic therapies, the generalizability of these findings to other regions may be limited. In addition, as no multivariable or propensity-based adjustments were performed, comparisons between treatment regimens should be interpreted as descriptive. Analyses of second- and later-line therapies were exploratory and limited to cohorts with at least 10 patients; therefore, the results should be interpreted with caution. In addition, as imaging assessments were performed according to routine clinical practice, some evaluations may have been missing or unevaluable, and efficacy analyses were therefore based on available data without formal imputation. Nevertheless, the robust prospective data collection, comprehensive monitoring, and large-scale representation of real-world practice ensure that our findings reliably reflect the outcomes and safety of systemic therapy in Japanese patients with HCC.
Analysis of the initial 1,000 patients enrolled in the PRISM study showed that, in Japan, first-line treatment with Atezo+Bev for unresectable HCC yielded efficacy and safety comparable to the pivotal clinical trials, demonstrating high reproducibility of the trial results in routine practice. First-line lenvatinib also exhibited favorable efficacy and safety, with patients treated with this drug showing a slightly longer OS than that reported from the pivotal trials. Both regimens were well-tolerated across a wide range of patient backgrounds and delivered consistent outcomes. In contrast, diminished efficacy of these regimens in the second-line and later settings underscores the urgent need to define optimal treatment sequential therapy after first-line treatments. Ongoing follow-up is expected to provide important evidence for refining therapeutic strategies and improving the long-term outcomes, and various secondary analyses are planned for the future.
Acknowledgments
This study was conducted with the cooperation of physicians, nurses, pharmacists, and other healthcare professionals from participating institutions across Japan involved in the PRISM study. We sincerely thank all research staff for their dedicated efforts in patient enrollment and data collection. We are deeply grateful to the patients and their families for their participation in this study and for providing valuable clinical information. We also extend our appreciation to the IIS data center, Ms. Rie Kotani, and Mr. Ken Toyoda, and data management teams, for their commitment to ensuring the quality of the data.
Statement of Ethics
All investigators involved in this study conducted the research in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. This trial is registered with the University Hospital Medical Information Network under identification number UMIN000040488. This study protocol was reviewed and approved by National Cancer Center Institutional Review Board, Approval No. [2020-127]. This clinical trial was conducted with the approval of the institutional review board of each participating institution (UMIN000040488). All patients gave their written informed consent before enrollment in this trial.
Conflict of Interest Statement
Masafumi Ikeda reports receiving grants or contracts from AstraZeneca, Bayer, Bristol Myers Squibb, Chiome Bioscience, Chugai Pharmaceutical, Eisai, Eli Lilly, Delta-Fly Pharma, Invitae, J-Pharma, Merck Biopharma, Merus N.V., MSD, Novartis, Servier, Ono, Pfizer, Takeda, and Yakult Honsha, as well as personal fees and other funding from AstraZeneca, AbbVie, Abbott Japan, Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly, EA Pharma, Fujifilm Toyama Chemical, Incyte Biosciences Japan, MSD, Servier, Nippon Kayaku, Novartis, Otsuka, Teijin, Taiho, Taisho Pharmaceutical, Takeda, and Yakult outside the submitted work. Shinji Itoh reports receiving lecture fees/honoraria from Astellas Pharma, AstraZeneca, Chugai, Eisai, Incyte Biosciences Japan, Johnson & Johnson, and MSD. Daisuke Onozuka reports receiving grants from the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant No. 26K13255 and 21K12274) and the Ministry of Health, Labour and Welfare Research (Grant No. 24KA2001). Sadahisa Ogasawara reports receiving grants from AstraZeneca, Chugai, Daiichi Sankyo; consulting fees from AstraZeneca, Chugai, Eisai, Bristol Myers Squibb, Ono, MSD; and lecture fees/honoraria from AstraZeneca, Chugai, Eisai, Bristol Myers Squibb, Ono, Takeda, Gilead Sciences, and AbbVie. Tomokazu Kawaoka reports receiving lecture fees/honoraria from Eisai, AstraZeneca, Bristol Myers Squibb, and Chugai. Taro Yamashita reports receiving grants from Eisai, Bristol Myers Squibb, Chugai, and AstraZeneca. Yasuhito Tanaka reports receiving scholarship donations from AbbVie and Otsuka Pharmaceutical; research funding from AbbVie, Fujirebio, Sysmex Corporation, GlaxoSmithKline, Gilead Sciences, and AstraZeneca; and lecture fees/honoraria from AbbVie, Gilead Sciences, Chugai, ASKA Pharmaceutical Holdings, GlaxoSmithKline, AstraZeneca, Eisai, and HU Frontier. Tomoharu Yamada reports receiving grants from Kowa; lecture fees/honoraria from Eisai, Chugai, AstraZeneca, and Bristol Myers Squibb; and advisory fees from Kaneka Corporation. Ryosuke Tateishi reports receiving lecture fees/honoraria from Bristol Myers Squibb, AstraZeneca, MSD, STARMED, AbbVie, Eisai, Canon Medical Systems, Gilead Sciences, Terumo, Novo Nordisk, Asahi Kasei, Medtronic, Ono, Chugai, Japan Lifeline, and Fujifilm, and serving on governing boards for the Japan Academy for Tumor Ablation and the Japan Liver Cancer Association. Tatsuya Yamashita reports receiving lecture fees/honoraria from Chugai, Bristol Myers Squibb, Eisai, and AstraZeneca. Takuji Okusaka reports receiving grants from AstraZeneca, Sysmex Corporation, Syneos Health, Amgen, Incyte, Linical, Chiome Bioscience, and Labcorp Genetics; consulting fees from AstraZeneca, Jazz Pharmaceuticals, Eisai, OHARA Pharmaceutical, Nihon Medi-Physics, and Amgen; and lecture fees/honoraria from MSD, Chugai, Eisai, Johnson & Johnson, Taiho, AstraZeneca, Ono, Kyowa Kirin, Daiichi Sankyo, Novartis, and Servier. Junji Furuse reports receiving lecture fees/honoraria from Eisai, AstraZeneca, Servier, MSD, Novartis, Takeda, Taiho, Teijin, Daiichi Sankyo, Ohara, Pfizer, and Incyte Biosciences, and serving on Data Safety Monitoring Boards for Ono, Chugai, and Astellas. Masatoshi Kudo reports receiving grants from Otsuka; consulting fees from Chugai, F. Hoffmann-La Roche, Eisai, and AstraZeneca; and lecture fees/honoraria from Chugai, AstraZeneca, and Eisai. Takashi Niizeki and Kazushi Numata declare no conflicts of interest. Masafumi Ikeda, Ryosuke Tateishi, Tatsuya Yamashita, and Masatoshi Kudo were members of the journal’s Editorial Board at the time of submission.
Funding Sources
This study received funding from Eisai Co., Ltd., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd. The funding sources were not involved in the collection or analysis of the data or in the preparation of the manuscript.
Author Contributions
Masafumi Ikeda conceived the original study design, discussed and modified the study protocol, helped in the collection and/or assembly of data, interpreted the data, and prepared the first manuscript draft. Shinji Itoh and Masatoshi Kudo conceived the original study design, discussed and modified the study protocol, helped in the collection and/or assembly of data, interpreted the data, and critically reviewed the manuscript drafts. Daisuke Onozuka helped conceive the study design, performed the statistical analyses, interpreted the data, and critically reviewed the manuscript drafts. Sadahisa Ogasawara, Tomokazu Kawaoka, Takashi Niizeki, Taro Yamashita, Yasuhito Tanaka, Tomoharu Yamada, and Kazushi Numata helped in the collection and/or assembly of data, interpreted the data, and critically reviewed the manuscript drafts. Ryosuke Tateishi, Tatsuya Yamashita, Takuji Okusaka, and Junji Furuse conceived the original study design, discussed and modified the study protocol, interpreted the data, and critically reviewed the manuscript drafts. All authors provided final approval of the manuscript submitted for publication consideration.
Funding Statement
This study received funding from Eisai Co., Ltd., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd. The funding sources were not involved in the collection or analysis of the data or in the preparation of the manuscript.
Data Availability Statement
The datasets generated and analyzed during the current study are not publicly available due to restrictions related to patient privacy and ethical regulations. However, the data are available from the Study Committee for Safety and Efficacy Monitoring for qualified secondary research purposes, such as meta-analyses, upon reasonable request and approval. Further inquiries regarding access to the data may be directed to the corresponding author.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The datasets generated and analyzed during the current study are not publicly available due to restrictions related to patient privacy and ethical regulations. However, the data are available from the Study Committee for Safety and Efficacy Monitoring for qualified secondary research purposes, such as meta-analyses, upon reasonable request and approval. Further inquiries regarding access to the data may be directed to the corresponding author.