Hepatocellular carcinoma (HCC) remains a significant global health concern. A recent study reported that HCC was among the top three causes of cancer-related deaths in 46 countries and ranked within the top five in 90 countries as of 2020. Projections indicate that if current incidence and mortality rates persist, the annual number of new liver cancer cases could increase by over 55% by 2040, reaching approximately 1.4 million new diagnoses and an estimated 1.3 million deaths (1).

Based on the results of the IMbrave150 trial, the combination of atezolizumab and bevacizumab demonstrated superiority over sorafenib in patients with unresectable HCC, establishing it as a standard first-line therapy for advanced HCC (2). This marked a significant shift in the treatment landscape, positioning immune checkpoint inhibitors (ICIs) as a key component of systemic therapy for this malignancy.

To optimize the clinical application of ICI-based therapies, it is important to consider their unique response kinetics. Atypical response patterns, such as pseudoprogression (3, 4) delayed responses (5), which differ from the conventional patterns observed with cytotoxic chemotherapy or molecular-targeted therapy, have been increasingly recognized. Moreover, it has been reported that ICIs may induce immune-related responses that are not adequately captured by conventional evaluation methods such as RECIST 1.1, further supporting the rationale for treatment beyond progression (4, 6). These phenomena provide a rationale for continuing treatment beyond initial disease progression (PD), even in the absence of immediate radiographic improvement. As a result, the concept of treatment beyond progression (TBP) has been incorporated into the design of some clinical trials and is gaining traction in real-world clinical decision-making for selected patients (7). Accumulating evidence from multiple studies across different tumor types, including melanoma and non-small cell lung cancer (NSCLC), suggests that continued ICI treatment beyond PD may offer clinical benefit in certain cases (8–13). In HCC, the safety of TBP has been reported in a patient cohort, including nine cases treated with atezolizumab plus bevacizumab, suggesting that TBP may represent a viable treatment option (14). However, the efficacy of TBP remains controversial. For instance, a recent study in NSCLC reported no significant clinical advantage of ICI continuation after PD (15), highlighting the importance of a cautious and personalized approach to treatment. Therefore, the clinical value of TBP should be carefully evaluated, and more refined patient stratification is essential to identify those most likely to benefit from this approach (16).

Given the current evidence and ongoing debate regarding treatment beyond progression, the present study aimed to evaluate the clinical utility of this approach in patients with hepatocellular carcinoma who received atezolizumab plus bevacizumab. By employing a multicenter cohort design, we sought to assess the real-world safety and efficacy of this strategy and contribute to the growing body of evidence on the optimal management of advanced HCC.

In this multicenter retrospective study, we demonstrated that TBP with atezolizumab plus bevacizumab was associated with significantly improved OS compared to immediate treatment discontinuation in individuals with unresectable HCC. Notably, individuals receiving TBP showed superior OS compared to those who transitioned directly to palliative care, highlighting the potential benefit of this strategy in carefully selected individuals. Additionally, OS did not significantly differ between the TBP group and those who transitioned to subsequent systemic therapy.

The combination therapy of atezolizumab and bevacizumab has demonstrated a favorable safety profile and tolerability in individuals with unresectable HCC, particularly when compared to other systemic therapies (7). In the phase III IMbrave150 trial, the incidence of treatment discontinuation due to adverse events was relatively low in the atezolizumab plus bevacizumab group compared with the sorafenib group. Furthermore, patient-reported outcomes from the same trial indicated that the combination therapy was associated with a longer median time to deterioration in quality of life (11.2 months vs. 3.6 months), suggesting better tolerability from the individual’s perspective (2). Specifically, patient-reported outcomes from the IMbrave150 trial demonstrated clinically meaningful benefits in quality of life, functioning, and symptom relief with atezolizumab plus bevacizumab compared to sorafenib, including significantly reduced risks of deterioration in appetite loss, diarrhea, fatigue, and pain. These improvements further underscore the potential for atezolizumab and bevacizumab to positively impact individuals’ overall quality of life and daily functioning during treatment (19).

The favorable safety profile is particularly important when considering treatment beyond progression, as prolonged therapy requires sustained tolerability. Moreover, the absence of a survival difference between the TBP group and those who transitioned to subsequent therapy is an important observation. Although the favorable safety profile of atezolizumab plus bevacizumab may have contributed to improved OS—particularly by reducing treatment-related interruptions or complications and thus potentially confounding the interpretation of the effects of continued treatment—these findings suggest that when OS is comparable, continuing atezolizumab plus bevacizumab may be a valuable strategy for preserving or improving quality of life (QOL). This approach may help individuals avoid the potential QOL decline associated with switching to other systemic therapies, further supporting the clinical rationale for TBP in appropriate individuals.

The comparable frequency of severe adverse events across groups suggests that the improved survival observed in the TBP group cannot simply be attributed to preferential inclusion of patients with lower toxicity profiles. Furthermore, the observation that a subset of patients in the TBP group (six initially classified as PD later reclassified as SD, and one as PR) experienced subsequent tumor control is consistent with pseudoprogression or delayed immune responses, phenomena characteristic of immunotherapy. These findings provide internal evidence supporting the biological plausibility of TBP as a valid treatment strategy in carefully selected cases.

The concept of TBP is increasingly recognized in oncology practice, particularly with ICIs, given their distinct response patterns, including pseudoprogression and delayed tumor responses. Previous studies in melanoma and NSCLC have also shown potential clinical benefits of continued ICI treatment beyond radiologic progression in selected cases (8–13). Our findings extend this observation to the treatment of advanced HCC, underscoring the importance of individual selection and careful clinical decision-making in managing treatment after radiologic progression.

Importantly, in our cohort, MVI was identified as a significant negative prognostic factor for OS in individuals undergoing TBP. This finding is consistent with previous studies that have repeatedly identified MVI as a marker of aggressive tumor behavior and a predictor of poor prognosis in advanced hepatocellular carcinoma (20, 21). Our multivariate analysis supported this observation by demonstrating that MVI independently predicted worse OS outcomes, even after adjusting for early treatment response as measured by the AFP ratio (AFP at progression diagnosis divided by AFP at baseline). Furthermore, subgroup analyses revealed differential treatment benefits based on the presence or absence of MVI. This may reflect the fact that individuals with MVI experience rapid disease progression and may not have sufficient time to benefit from the delayed therapeutic effects that TBP often requires, such as immune-mediated responses.

Furthermore, subgroup analyses revealed differential treatment benefits based on the presence or absence of MVI. Specifically, among individuals without MVI, TBP was associated with significantly improved survival compared to palliative therapy, whereas this benefit was not observed in individuals with MVI. In contrast, switching to subsequent chemotherapy maintained survival advantages over palliative care, even in MVI-positive individuals. These findings suggest that subsequent chemotherapy rather than TBP may be a more appropriate strategy for individuals with aggressive tumor features such as MVI, underscoring the necessity of individualized treatment strategies based on tumor biology and individual condition. Individuals with MVI generally have significantly poorer prognoses due to rapid disease progression and limited treatment responsiveness.

The lack of OS benefit from TBP in this subgroup may be attributed to their inability to wait for delayed treatment effects that TBP might require. Therefore, TBP should not be recommended for individuals with MVI, as the timeframe for realizing clinical benefit may be insufficient in this population. Because TBP often requires time to exert its therapeutic effects, particularly in cases where immune-related mechanisms are involved, individuals with MVI may not survive long enough to realize those benefits. Recent expert consensus has emphasized a shift away from rigid staging-based treatment algorithms toward more personalized treatment allocation strategies (22, 23) Moreover, there is emerging recognition that even in cases of slow progressive disease (slow PD), where tumors increase gradually without rapid clinical deterioration, continued therapy may still confer clinical benefit (24, 25). Our findings, particularly the utility of TBP in non-MVI individuals, support these personalized frameworks and call for treatment strategies that flexibly integrate individual and tumor characteristics into decision-making.

In conclusion, our study suggests that continuation of atezolizumab plus bevacizumab beyond radiologic progression may offer survival benefits for selected individuals with unresectable HCC, particularly those without major vessel involvement. In the absence of OS differences with subsequent therapy, TBP may provide added value by helping maintain or improve QOL. While this study focused on ICI therapy combined with VEGF inhibition, future investigations of pure ICI regimens—which represent one of the mainstays of HCC treatment—may offer an effective strategy for VEGF-intolerant patients. Importantly, this study highlights the potential of TBP as a treatment strategy in selected patients with advanced HCC. In the coming years, prospective trials and real-world data will be essential to determine whether TBP can be incorporated into treatment algorithms.