Published online Sep 5, 2026. doi: 10.4292/wjgpt.120377
Revised: April 30, 2026
Accepted: May 22, 2026
Published online: September 5, 2026
Processing time: 188 Days and 15.2 Hours
The therapeutic landscape for unresectable hepatocellular carcinoma (HCC) has evolved with the advent of combinations of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). However, the absence of direct comparisons in clinical trials makes it challenging to determine their relative efficacy.
To explore the comparison between ICI and TKI in combination therapy and determine the relative efficacy.
We conducted a PubMed database search from inception to January 2026, selecting all first-line regimens sup
Based on our PubMed search, eight RCTs were included. Most combinations compared with sorafenib significantly improved OS, with camrelizumab plus rivoceranib showing the most favourable HR. This was followed by atezolizumab plus bevacizumab, tremelimumab plus durvalumab, toripalimab plus bevacizumab and anlotinib plus penpulimab. Cabozantinib plus atezolizumab did not demonstrate a clear benefit. Camrelizumab plus rivoceranib was superior to tremelimumab plus durvalumab (HR = 0.78; 95%CI: 0.61-0.99) and anlotinib plus penpulimab (HR = 0.73; 95%CI: 0.57-0.93). Compared with lenvatinib, nivolumab plus ipilimumab and pembrolizumab plus lenva
Our study compared the efficacy of the main first-line treatments recommended for unresectable HCC. While we were able to rank the magnitude of efficacy across these treatments, the intrinsic limitations of our methods (pri
Core Tip: In the absence of head-to-head trials for first-line unresectable hepatocellular carcinoma, we reconstructed indi
- Citation: Damuzzo V, Vecchia S, Gasperoni L, Del Bono L, Ossato A, Orlandi E, Messori A. Survival in unresectable hepatocellular carcinoma: Comparison of four treatments based on patients reconstructed from Kaplan–Meier curves of randomized trials. World J Gastrointest Pharmacol Ther 2026; 17(3): 120377
- URL: https://www.wjgnet.com/2150-5349/full/v17/i3/120377.htm
- DOI: https://dx.doi.org/10.4292/wjgpt.120377
Sorafenib has long been the standard of care for patients with unresectable hepatocellular carcinoma (HCC)[1]. However, the therapeutic armamentarium for HCC has substantially expanded because of the development of immune checkpoint inhibitors (ICIs) and multitarget tyrosine kinase inhibitors (TKIs), which are often used in combination regimens[2-10]. The first therapeutic advantage was demonstrated for lenvatinib, which demonstrated noninferiority to sorafenib in terms of overall survival (OS) and showed advantages in progression-free survival (PFS) and objective response rate[2]. The IMbrave150 trial established atezolizumab + bevacizumab as a new reference standard superseding sorafenib and demonstrating superior OS and PFS together with a favorable toxicity profile[3]. The HIMALAYA[4] and CheckMate 9DW[5] trials evaluated dual immune checkpoint blockade with tremelimumab + durvalumab administered according to the STRIDE regimen and ipilimumab + nivolumab, respectively. These combinations showed promising OS outcomes and notably prolonged response durations. Additional phase III trials have explored combinations of TKIs/antibodies targeting VEGF or multiple growth factors involved in angiogenesis with anti–PD-1/PD-L1 antibodies, with notable examples including cabozantinib + atezolizumab in COSMIC-312, camrelizumab + rivoceranib in CARES-310, toripali
In this rapidly evolving therapeutic landscape, sorafenib has been progressively superseded by several therapeutic options as the first-line standard of care. This development has triggered the evolution of treatment standards and the choice of control arms in pivotal clinical trials, with agents such as lenvatinib being increasingly used as reference comparators[1]. The abovementioned studies underscore the central role of ICI and TKI combinations in first-line HCC treatment and highlight the absence of direct head-to-head comparisons among the leading regimens and the consequent uncertainty regarding their relative therapeutic value.
To close this evidence gap, we herein apply the IPDfromKM algorithm, an artificial intelligence-assisted method that reconstructs individual patient data (IPD) from published Kaplan-Meier (KM) curves, extracting information from time-to-event curves to create a database representing individual patients (including follow-up time and event status) and thereby enabling indirect comparisons in the absence of head-to-head trials[11]. By combining this reconstruction strategy with the careful assessment of between-trial heterogeneity and consistency assumptions, our analysis aims to position the main combinatorial regimens for first-line HCC treatment within a coherent comparative framework and generate cli
We systematically searched PubMed to identify randomized controlled trials (RCTs) pertinent to this analysis, with the final search conducted on January 28, 2026. The search strategy was based on the following combination of terms: [(“hepatocellular carcinoma” OR HCC OR “hepatocellular cancer”) AND (“first line” OR “first-line” OR unresectable OR advanced) AND (lenvatinib OR sorafenib)]. Study selection followed PRISMA recommendations (Figure 1)[12].
Each eligible RCT was phase III, was performed in patients with previously untreated unresectable HCC, reported OS, and presented outcomes with KM survival curves. When multiple reports from the same study were identified, the most up-to-date and comprehensive publication was included to prevent data duplication.
Eight trials providing evidence for first-line combination regimens included in indirect comparisons were identified (Table 1 and Supplementary Table 1)[3-10]. As these trials were based on long-term follow-ups, OS data were analyzed using a validated approach based on the abovementioned IPDfromKM method[11], which enables the simulation of comparative treatment analyses even when original patient-level data are unavailable. Herein, these comparative ana
| Ref. | Treatments under comparison | Regions | Patient number | Number of events OS | HR (reported in the original trial) | Geographical region (Asia) | Etiology (HBV-HCV positivity) |
| Cheng et al[3], 2022, IMbrave150 | Atezolizumab + bevacizumab vs sorafenib | 17 countries and regions | 336; 165 | 179; 99 | 0.66 (95%CI: 0.52-0.85) | 133 (57); 68 (41) | 236 (70); 112 (68) |
| Sangro et al[4], 2024, HIMALAYA | Tremelimumab + durvalumab vs sorafenib | Asia (except Japan), 83% | 393; 389 | 291; 316 | 0.78 (95%CI: 0.67-0.92) | 41 (39.8); 23 (35.9) | 63 (61.1); 42 (65.6) |
| Yau et al[6], 2024, COSMIC-312 | Cabozantinib + atezolizumab vs sorafenib | Asia, 29%; other, 71% | 432; 217 | 262; 121 | 0.98 (95%CI: 0.78-1.24) | 127 (29); 63 (29) | 263 (60); 131 (60) |
| Qin et al[7], 2025, CARES-310 | Camrelizumab + rivoceranib vs sorafenib | Asia, 83% | 272; 271 | 111; 151 | 0.64 (95%CI: 0.49-0.80) | 225 (83); 224 (83) | 230 (84); 226 (84) |
| Shi et al[8], 2025, HEPATORCH | Toripalimab + bevacizumab vs sorafenib | China, 96% | 162; 164 | 104; 126 | 0.76 (95%CI: 0.58-0.99) | NR | 293 (90); 15 (5) |
| Zhou et al[10], 2025, APOLLO | Anlotinib + penpulimab vs sorafenib | China, 100% | 433; 216 | 217; 122 | 0.69 (95%CI: 0.55-0.87) | 433 (100); 216 (100) | 381 (88); 188 (87) |
| Llovet et al[9], 2023, LEAP-002 | Lenvatinib + pembrolizumab vs lenvatinib | Asia (excluding Japan), 31%; Japan and Western regions, 69% | 395; 399 | 252; 282 | 0.84 (95%CI: 0.71-1.00) | 172 (44); 173 (43) | 247 (63); 237 (59) |
| Yau et al[5], 2025, CheckMate 9DW1 | Nivolumab + ipilimumab vs sorafenib/lenvatinib | Europe or North America, 43%; Asia, 42% | 335; 333 | 194; 228 | 0.79 (95%CI: 0.65-0.96) | 140 (42); 152 (46) | 211 (63); 214 (65) |
In brief, IPD were derived from KM survival curves presented in both the experimental and control groups of the included RCTs. Curve digitization was accomplished through WebPlotDigitizer (version 4.7, retrieved January 29, 2026; distance = 20, Δx = Δy = 15). The resulting coordinate pairs, combined with participant enrolment figures and event counts, were processed using the IPDfromKM software package (version 1.2.3.0; most recent update March 22, 2022; retrieved January 29, 2026). This process produced a synthetic dataset containing time-to-event information (measured from study entry to the final observation point) and patient status classifications (surviving/censored or deceased/progressed). The above procedure was used to generate synthetic individual-level data for each trial arm. Digitization and data reconstruction were independently executed by two separate investigators, and the findings were subsequently cross-verified to reduce human errors.
Following the generation of these individual-level datasets, we conducted indirect treatment comparisons between experimental combination regimens and conventional therapy, applying statistical methodologies identical to those utilized in investigations involving actual patient populations. To validate our method, we performed heterogeneity analysis, comparing the control arms of the included RCTs with one another. Heterogeneity was assessed using the likelihood ratio and Wald’s tests, along with the corresponding p-values. The statistics on the reconstructed patients used the same tests as studies based on real patients, namely the univariate Cox model with hazard ratios (HRs) and 95%CIs. Restricted mean survival times (RMSTs) were calculated using the R-platform (version 4.3.2). KM curves were truncated at 28 months for RMST analysis, which corresponds to the minimum follow-up time available across the included RCTs.
Relevant RCTs were divided into two subgroups, namely those with sorafenib and lenvatinib as comparators. The CheckMate 9DW trial was the only exception, as both lenvatinib and sorafenib could be administered to the control group. However, as these trials generated two separate network geometries with no in-between connection, we per
Preliminary analysis aimed to assess the comparability of the included studies revealed a high degree of heterogeneity among TKI controls (likelihood ratio test statistic = 31.49 on seven degrees of freedom, P = 5 × 10−5) (Supplementary Figure 1). This difference was due to lenvatinib being superior to sorafenib (HR: 0.77, 95%CI: 0.69-0.86), i.e., an indirect comparison of all the studies planned for analysis could not be performed because of the lack of a common comparator. Consequently, we presented the results of the indirect comparison of RCT efficacy by dividing studies into two groups, namely those with (1) Sorafenib; and (2) Lenvatinib as common comparators. The CheckMate 9DW trial involved both TKIs as comparators; however, as 75% of the patients in the control group received lenvatinib, this study was included in the second group. Given these premises, the heterogeneity within the two groups remained within the specifications necessary to ensure comparability (Supplementary Figure 2). The first group included the CARES-310, HIMALAYA, IMbrave150, COSMIC-312, APOLLO, and HEPATORCH trials. Heterogeneity within this group was minimal (likelihood ratio test statistic = 8.24 on five degrees of freedom, P = 0.1). The second group included the LEAP-002 and CheckMate 9DW trials, and the heterogeneity of the control groups remained low (likelihood ratio test statistic = 0.01 on one degree of freedom, P = 0.9) despite the inclusion of patients treated with sorafenib (15% for CheckMate 9DW).
In our main analysis, the OS benefit of each of the eight combination regimens was compared with that of a standard TKI (sorafenib or lenvatinib, with all respective control groups pooled together) and, more importantly, with those of the other combination regimens.
The KM curves for OS in the first group are compared in Figure 2. Five combination regimens superior to sorafenib were identified, ranked in order of decreasing efficacy as camrelizumab + rivoceranib (HR: 0.61, 95%CI: 0.50-0.75), atezolizumab + bevacizumab (HR: 0.75, 95%CI: 0.64-0.89), tremelimumab + durvalumab (HR: 0.78, 95%CI: 0.68-0.90), toripalimab + bevacizumab (HR: 0.78, 95%CI: 0.63-0.97), and anlotinib + penpulimab (HR: 0.84, 95%CI: 0.73-0.96). However, this was not the case for atezolizumab + cabozantinib (HR: 0.90, 95%CI: 0.78-1.03). These findings are consistent with those reported in the original trials. The median survival advantage ranged from 22.2 months (95%CI: 20.4-27.2) for camrelizumab + rivoceranib to 16.3 months (95%CI: 15.5-19.8) for anlotinib + penpulimab, exceeding the median OS of sorafenib controls (14.4 months, 95%CI: 13.6-15.7).
In addition, we compared the efficacies of the abovementioned five combination regimens with each other, revealing that camrelizumab + rivoceranib was superior to tremelimumab + durvalumab (HR: 0.78, 95%CI: 0.61-0.99) and anlotinib + penpulimab (HR: 0.73, 95%CI: 0.57-0.93), with no significant difference observed between the other combinations.
In the second group, the approximation made because 15% of control patients in the CheckMate 9DW trial received sorafenib[5] was thought to have a negligible effect. The analysis of this second group (Figure 3) showed that pembrolizumab + lenvatinib achieved a median survival of 22.8 months with a survival advantage over lenvatinib at limits of statistical significance (HR: 0.84; 95%CI: 0.71-0.98); nivolumab + ipilimumab achieved a median survival of 25.5 months with HR of 0.79 (95%CI: 0.67-0.94). The head-to-head indirect comparison of the two treatment regimens (pembrolizumab + lenvatinib vs nivolumab + ipilimumab) showed no significant difference in efficacy (HR: 1.05, 95%CI: 0.83-1.33).
When OS was estimated using the RMST method (truncation time = 27 months), camrelizumab + rivoceranib pre
| Arm | RMST (months) | Lower 95%CI | Upper 95%CI | Difference in RMST compared to sorafenib/lenvatinib (months) | Difference in RMST compared to camrelizumab + rivoceranib (months) |
| Sorafenib (pooled) | 15.87 | 15.33 | 16.40 | 0 | -3.78 |
| Camrelizumab + rivoceranib | 19.65 | 18.42 | 20.87 | 3.78 | 0 |
| Tremelimumab + durvalumab | 17.18 | 16.17 | 18.20 | 1.32 | -2.46 |
| Atezolizumab + bevacizumab | 18.22 | 17.11 | 19.32 | 2.35 | -1.42 |
| Toripalimab + bevacizumab | 16.88 | 15.93 | 17.82 | 1.01 | -2.77 |
| Anlotinib + penpulimab | 17.94 | 16.37 | 19.51 | 2.07 | -1.71 |
| Lenvatinib (pooled) | 18.86 | 18.21 | 19.58 | 3.01 | -0.77 |
| Pembrolizumab + lenvatinib | 19.63 | 18.73 | 20.54 | 3.77 | -0.01 |
| Nivolumab + ipilimumab | 19.14 | 18.03 | 20.24 | 3.27 | -0.51 |
Our indirect comparison of first-line systemic therapies for unresectable HCC demonstrates that most ICI + TKI com
A key methodological limitation of our analysis is the lack of a single consistent comparator across all included RCTs. Although TKIs were consistently used as controls, they were not equivalent. Our preliminary heterogeneity analysis demonstrated a significant difference between the two comparators, reflecting the established survival advantage of lenvatinib over sorafenib[2]. This finding implies a violation of the fundamental assumptions underlying indirect treatment comparisons, namely the principles of transitivity and consistency, which require relative treatment effects to be estimated against a common and comparable reference (the so-called anchored comparisons). Consequently, perfor
To mitigate this limitation, we conducted analysis in two comparison networks, categorized according to the TKI comparator (sorafenib or lenvatinib) used in the original trials. This approach ensured internal consistency within each network and allowed indirect comparisons to be conducted only among studies sharing a sufficiently comparable refe
Within this framework, OS results expressed as HRs should be interpreted separately for each comparator-defined group, as the apparent magnitudes and temporal patterns of treatment effects are inherently influenced by the efficacy of the reference therapy. Conversely, OS estimation using RMST is less dependent on the treatment effect of the control arm, although cross-treatment comparisons can only be qualitative when this indicator is used.
Our analysis of OS based on reconstructed IPD yielded the following main results. Most combination regimens demonstrated an OS benefit compared with TKI monotherapy, particularly vs sorafenib. An important exception was atezolizumab + cabozantinib, which did not show any OS advantage over sorafenib in the COSMIC-312 trial[6]. This finding may reflect the discordance between PFS and OS observed in this trial, which is possibly related to its dual primary endpoint design and the early disease control effect of cabozantinib. In addition, subgroup analyses suggested heterogeneous treatment effects across patient populations, which may have diluted any OS benefit in the intention-to-treat population. Pembrolizumab + lenvatinib also failed to meet its co-primary endpoints of superiority over lenvatinib in the LEAP-002 trial. These findings are consistent with the literature, supporting an overall advantage of combination strategies over TKI monotherapy, albeit with nonuniform outcomes across different regimens. In our indirect comparison, camrelizumab + rivoceranib was associated with a greater HR advantage than tremelimumab + durvalumab and anlotinib + penpulimab and showed a numerical RMST advantage over atezolizumab + bevacizumab and toripalimab + bevacizumab.
In the qualitative comparison of the two study groups, combination regimens using sorafenib as the control arm generally showed HRs of 0.6-0.8, with OS benefits clearly separated from the corresponding control curves. As expected, in the second group with lenvatinib as a more effective comparator, the benefit was more limited, as observed in the LEAP-002 trial, or emerged later, as in the CheckMate 9DW trial-a pattern consistent with the delayed treatment effect typically observed with immunotherapy, which may contribute to the observed HR advantage over time. The main advantage of indirect comparisons using the IPDfromKM method over classic network meta-analysis is that the former leverages reconstructed IPD, thereby accounting for the follow-up duration, whereas the latter relies on simple binary comparisons derived from HR against a common comparator. Although the IPDfromKM method allows for cross-treatment comparisons when information from real patients is unavailable, it has certain limitations. In particular, multivariate analyses cannot be performed unless separate KM curves are reported in the published articles for each covariate to be evaluated. Therefore, subgroup analyses such as hepatitis B virus (HBV) vs non-HBV or Asian vs. non-Asian populations were not conducted because separate KM curves for these subgroups were not reported in the original RCTs. Finally, given the univariate (or unadjusted) nature of the HRs estimated by the IPDfromKM method, our results should be interpreted as descriptive rather than causal.
In terms of RMST, camrelizumab + rivoceranib achieved OS values comparable with those of immunotherapy combinations and lenvatinib monotherapy. As the CARES-310 trial was not as mature as other comparable RCTs, the minimum common truncation time adopted in this analysis was 27-28 months. Although RMST enables the qualitative comparisons of survival benefits within a predefined time window, the survival advantages of different approaches may be more fully realized beyond the selected time horizon. Indeed, although applying a common truncation time is methodologically necessary for temporal comparability across trials, it limits the full capture of long-term survival benefits, particularly for immunotherapy-based strategies such as the STRIDE regimen, which exhibits the late separation of OS curves and durable advantages beyond disease progression[13]. Moreover, the clinical effects of immunotherapy may persist across subsequent lines of systemic therapy, as reflected by the prolonged time to first subsequent therapy or death and pre
Several considerations regarding population heterogeneity across the included trials should be acknowledged. In particular, the CARES-310 trial enrolled a markedly Asia- and HBV-enriched population, with 83% of patients recruited in Asia and nearly three quarters presenting HBV-related HCC. In contrast, HIMALAYA is a global study with a substantially lower proportion of HBV-related disease in the overall population despite the availability of a dedicated Asian subgroup analysis. The APOLLO trial was conducted exclusively in China, reflecting a population with a distinct geographic and etiological background. However, most other pivotal trials included in this analysis are global studies with a substantial proportion of Asian patients, typically 30%-60% (e.g., IMbrave150, HIMALAYA, CheckMate 9DW, and LEAP-002). Therefore, the overall dataset reflects predominantly mixed populations rather than a clear contrast between Asian and non-Asian cohorts, although CARES-310 represents a more pronounced enrichment. These between-trial differences may represent unmeasured sources of heterogeneity and potential effect modification in indirect comparisons, particularly for long-term OS outcomes. This aspect is especially relevant when the common comparator is sorafenib, a drug that is now largely de-emphasized in first-line clinical practice and associated with a high toxicity burden. Impor
Our indirect comparison of first-line treatments for unresectable HCC suggests that most immunotherapy + TKI com
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