Predictive factors for transition to conversion therapy in hepatocellular carcinoma using atezolizumab plus bevacizumab

To identify predictive factors associated with successful transition to conversion therapy following combination therapy with atezolizumab and bevacizumab in the treatment of unresectable hepatocellular carcinoma (HCC).


| INTRODUC TI ON
Systemic chemotherapy has been actively implemented to treat unresectable hepatocellular carcinoma (HCC).Following the reported favourable therapeutic effects of sorafenib and lenvatinib in intermediate-compared with advanced-stage HCC, 1,2 multimolecular targeted agents (MTA) have been recommended as a treatment option for this stage of HCC in the latest Barcelona Clinic Liver Cancer (BCLC) strategy.4][5][6][7] Treatments that enhance the curability of HCC are anticipated to be developed.
Atezolizumab plus bevacizumab combination therapy was approved worldwide in 2020, following positive results of the phase 3 IMbrave150 trial. 8This therapy has been reported to have high therapeutic effects in patients with advanced unresectable HCC (overall response rate [ORR] 30% [95% confidence interval (CI): 25-35]) assessed according to the Response Evaluation Criteria in Solid Tumours (RECIST) guidelines, version 1.1. 9Furthermore, atezolizumab plus bevacizumab curative (ABC) conversion is reported as a new treatment strategy. 10,11The results of a multicentre study investigating ABC conversion also demonstrated a high drug-free rate (35%) in achieving a cancer-free status. 12wever, not all patients with HCC who received atezolizumab plus bevacizumab combination therapy are necessarily suitable candidates for conversion therapy.Excessive chemotherapy may decrease liver function and worsen prognosis; therefore, it is important to identify factors that can predict and accurately determine which patients are most suitable for conversion therapy.In the present study, we aimed to investigate the actual conditions of conversion therapy using real-world data by surveying patients with HCC who received atezolizumab plus bevacizumab combination therapy, with the purpose of revealing predictive factors for successful transition to conversion therapy and the characteristics of those who achieved cancer-free status.

| Patients
This multicentre, retrospective, observational study was conducted in 11 hospitals across five prefectures in western Japan.A total of 272 patients with histologically or clinically confirmed unresectable HCC, who underwent atezolizumab plus bevacizumab combination therapy between 1 October 2020 and 30 September 2022, were enrolled.In total, 193 patients underwent atezolizumab plus bevacizumab combination therapy as first-line chemotherapy; however, five patients who achieved complete response (CR) with systemic chemotherapy alone were excluded from the analysis.
Ultimately, therefore, 188 patients were included in the analysis (Figure 1).Liver function was classified according to Child-Pugh and have lower Child-Pugh scores and alpha-fetoprotein levels.Multivariate analysis revealed that BCLC stage was a predictive factor for the implementation of conversion therapy (A or B; odds ratio 3.7 [95% CI: 1.1-13]; p = .04).Furthermore, 10 (66.7%) patients achieved cancer-free status and exhibited a smaller number of intrahepatic lesions at the start of treatment (3.5 vs. 7; p < .01),and a shorter interval between systemic chemotherapy induction and conversion therapy (131 vs. 404 days; p < .01).
In addition, the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03).

Conclusion:
BCLC stage was the sole predictive factor for successful transition to conversion therapy when using combination therapy with atezolizumab and bevacizumab to treat HCC.Furthermore, a small number of intrahepatic lesions and early transition to conversion therapy were associated with the achievement of cancer-free status.

K E Y W O R D S
alfa-fetoprotein, atezolizumab, Barcelona clinic liver cancer stage, bevacizumab, cancer-free, child-Pugh score, conversion therapy, hepatocellular carcinoma, real-world practice, tumour response

Key points
Barcelona Clinic Liver Cancer stage A or B was associated with a favourable transition to conversion therapy when a combination therapy of atezolizumab and bevacizumab was used to treat unresectable hepatocellular carcinoma.Subsequent cancer-free status was likely to be achieved, especially when the number of intrahepatic lesions was limited and an early tumour response to chemotherapy was observed.albumin-bilirubin (ALBI) scores.HCC was staged in accordance with the Barcelona Clinical Liver Cancer (BCLC) classification system.

| Atezolizumab plus bevacizumab combination therapy regimens
Patients received 1200 mg of atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks until disease progression was confirmed, a drop in performance status to ≥2 or unacceptable toxicity.When physicians decided to discontinue treatment for these reasons, patients would undergo other chemotherapies or were transitioned to the best supportive care.

| Definition of conversion therapy and cancer-free status
In this study, conversion therapy was defined as treatment in which tumour shrinkage was observed with chemotherapy and all remaining lesions could be treated with additional locoregional therapy.Surgical resection, ablation therapy, transcatheter arterial chemoembolization (TACE) and radiation therapy were administered.
Conversion therapy was implemented at the discretion of the physician, when they determine that curative treatment by additional locoregional therapies, such as surgical resection, is feasible.All conversion therapies were performed within 1-3 months of the best treatment effect determination time.
Cancer-free status was defined as HCC-free on imaging for at least 6 months during the observation period after conversion therapy.

| Follow-up
Tumours were assessed using contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) every 9-12 weeks during the screening period.Responses were graded as CR, PR, stable disease (SD) and progressive disease (PD) in accordance with the RECIST guidelines (version 1.1).Furthermore, tumour marker levels of alpha-fetoprotein (AFP), Lens culinaris agglutinin (LCA)-reactive AFP isoform (AFP-L3) and des-gamma-carboxy prothrombin (DCP) were analysed at baseline and during treatment.

| Statistical analyses
Demographic data, underlying liver diseases, laboratory data and previous treatments were retrospectively assessed and compared.Baseline characteristics are expressed as median and range.
Continuous variables were compared using the Wilcoxon rank-sum test, and categorical data were analysed using the chi-squared test.
Multivariate logistic regression analysis was performed to identify factors associated with conversion therapy.Factors used in the multivariate analysis included items that were p < .10 in univariate analysis and were significantly different in the chi-squared test.Overall survival (OS) was estimated using the Kaplan-Meier method and compared among patient groups using the log-rank test.All statistical tests were two-sided, and differences with p < .05were considered to be statistically significant.All analyses were performed using JMP version 16.0 (SAS Institute Japan Ltd., Tokyo, Japan).

| Patient characteristics
The characteristics and clinical results of 188 patients who received treatment with atezolizumab plus bevacizumab as first-line therapy, excluding those who achieved CR with systemic chemotherapy alone, are summarized in Table 1.The median age was 76 years, and 139 (73.9%) patients were male.Of these, 113 (60.1%) patients had a Child-Pugh score of 5, and the median ALBI score was −2.4; these included 98 (52.4%) patients with BCLC stage C HCC. Based on the best response to chemotherapy during the treatment period, the proportions of patients who achieved CR, PR, SD and PD were 2.6%, 33.2%, 40.9% and 23.3%, respectively.The overall response rate (ORR [i.e., CR + PR]) was 35.8%, and the disease control rate (DCR [i.e., CR + PR + SD]) was 76.7% (Table 2).

| BCLC stage was the predictive factor for conversion therapy
Among the 64 patients who achieved PR with systemic chemotherapy, 15 (23.4%) underwent conversion therapy.In the conversion group, there was a significantly higher proportion of patients with BCLC stage A or B (73.3%; p < .05).These patients had significantly lower Child-Pugh scores and serum AFP levels (Table 1).Among them, BCLC stage was the sole predictive factor for the implementation of curative conversion therapy (A or B; OR 3.7 [95% CI: 1.1-13]; p = .04)according to multivariate analysis (Table 3).

| Clinical features of patients achieving cancer-free status after conversion therapy
Among the 15 patients who underwent conversion therapy, 10 (66.7%) achieved radiological cancer-free status for at least 6 months (Table 4).There was no significant difference in BCLC stage between the two groups.Patients who were cancer-free exhibited a significantly lower number of intrahepatic lesions than other patients (3.5 vs. 7, respectively; p < .01),and it was confirmed that the rate of achieving cancer-free status by undergoing surgical resection or ablation therapy was significantly higher (p = .03).
Additionally, the interval between systemic chemotherapy induction and conversion therapy in cancer-free patients was significantly shorter than that in other patients (131 vs. 404 days; p < .05).
Details of all patients who underwent conversion therapy are summarized in Table S1.Among them, there was no predictive factor for the implementation of cancer-free status by multivariate analysis.

| Prognosis of patients who underwent conversion therapy
The OS rates of patients who underwent conversion therapy versus those who did not are presented in  the other patients (p < .01).Furthermore, patients who underwent conversion therapy exhibited significantly better survival rates than those who did not.

| DISCUSS ION
Atezolizumab plus bevacizumab combination therapy has a high response rate, 8,9 and there have been an increasing number of studies reporting improved prognosis with the transition to conversion therapy. 10,11However, the number of such reports remains small, and it is unclear which patients and characteristics can transition to conversion therapy and achieve cancerfree status.In the present study, we found that the transition rate to conversion therapy after atezolizumab and bevacizumab combination therapy in clinical practice was approximately 8.0%.
Furthermore, we report, for the first time, that HCC patients with BCLC stage A or B are strong candidates for transition to conversion therapy.More than one-half (67%) of patients who underwent conversion therapy achieved radiological cancer-free status for at least 6 months.It was also revealed that patients who achieved cancer-free status after conversion therapy exhibited a smaller number of intrahepatic lesions at the time of systemic chemotherapy induction, a shorter period leading to conversion therapy, and were in a state in which surgical resection or ablation therapy could be selected as the treatment method.According to a recent study investigating conversion therapy, surgical resection or ablation therapy yielded significantly higher recurrence-free survival. 13We believe that the results of that study are consistent with our findings.
Because the period from the initiation of systemic chemotherapy to conversion therapy in patients who achieved cancer-free status is significantly short, we suggest that an early response to systemic chemotherapy may also lead to successful transition to conversion therapy.The utility of AFP levels at 6 weeks as an early predictor of treatment response to atezolizumab plus bevacizumab combination therapy has been reported. 14Although not shown, patients enrolled in this study responded well to treatment if AFP levels declined by ≥10% at 3-6 weeks after systemic chemotherapy induction.Therefore, evaluation of tumour markers and imaging studies at 6 weeks may be useful for evaluating the possibility of a transition to conversion therapy.
When the number of tumours is large at the time of systemic chemotherapy induction, the recurrence rate after conversion therapy is high, and the proportion of patients achieving cancerfree status is low.When treating patients with a large number of tumours at the start of treatment, we would often choose TACE as a conversion therapy.However, it is extremely difficult to fully suppress the local progression of multiple intrahepatic lesions using TACE.Therefore, the large number of tumours may have led to a high risk for local recurrence and a low cancer-free rate after conversion therapy.However, if the number of tumours is small at the start of treatment and decreases after systemic chemotherapy, it would be possible-even for patients with unresectable HCC-to undergo surgical resection or ablation therapy, contributing to a higher rate of achieving cancer-free status.Currently, atezolizumab plus bevacizumab combination therapy is recommended for patients with unresectable HCC at BCLC stage B. In the context of these circumstances, if the total tumour count is low, we suggest that atezolizumab plus bevacizumab combination TA B L E 3 Logistic regression analysis of parameters associated with conversion therapy.
therapy be more actively administered to patients with unresectable HCC at BCLC stage B, considering the appropriate timing of transition to conversion therapy.
On the contrary, the usefulness of combination therapy with lenvatinib and TACE for unresectable HCC in the BCLC-B stage has also been reported. 16It is not possible to define the criteria for whether lenvatinib or atezolizumab plus bevacizumab should be preceded as treatment aimed at conversion therapy, especially when the number of tumours is small.Currently, immunocomplex therapy is recommended as the first-line regimen, as advocated in BCLC staging and other guidelines; however, this is an issue for future consideration.
According to recent studies, the rate of transition to conversion therapy after atezolizumab plus bevacizumab combination therapy was 35.5%. 12Results of the present study revealed a low conversion rate (approximately 8%), which may be due to differences in background characteristics of patients.In contrast to previous studies   15 Consistent with these studies, our results also revealed a high conversion rate (12.1%) when only intermediate-stage HCC was included in the analysis.Meanwhile, when compared to other studies that included patients with advanced-stage HCC, the rate of transition to conversion therapy after atezolizumab and bevacizumab combination therapy was similar to our results. 10,13eoretically, conversion therapy plays an important role in preventing disease progression.However, it remains unclear whether it is better to transition to conversion therapy, especially when the objective assessment of tumour response to systemic chemotherapy is graded as PR because these patients were sensitive to chemotherapy and achieved CR without additional locoregional therapies.In this study, we clearly demonstrated that patients who underwent conversion therapy had a significantly higher OS rate than those who did not undergo conversion therapy, even when the tumour response was graded as PR.Therefore, conversion therapy should be actively implemented if patients respond well to systemic chemotherapy.
The present study had some limitations, the first of which were its retrospective design and the lack of radiological assessment at predefined intervals.A larger number of cases and longer observation period are required to obtain more accurate data.Furthermore, whether or not conversion therapy is performed depends, in large part, on the physician's decision.
Importantly, these results suggest that even in patients with unresectable HCC successfully transition to conversion therapy after atezolizumab plus bevacizumab combination therapy, especially when the number of intrahepatic lesions is low and an early tumour response to systemic chemotherapy is detected.Conversion therapy can improve the prognosis of patients with HCC.Because an increasing number of patients have received systemic chemotherapy in recent years, further validation through large-scale prospective studies is warranted.

F I G U R E 2
Overall survival rate was analysed by the Kaplan-Meier method.In conversion group, patients had better prognosis than non-conversion group.Patients in non-conversion group were reclassified by tumour response to chemotherapy as follows: nonconversion (PR), non-conversion (SD) and non-conversion (PD).The better tumour responses were, the longer overall survival patients had.

F I G U R E 1
Eligible patients.Study flowchart showing the identification of 193 patients with unresectable HCC who underwent atezolizumab plus bevacizumab combination therapy as first line.A total of 15 patients underwent conversion therapy.Excluded Conversion n=15 Patients with Unresectable HCC who underwent Atezolizumab plus Bevacizumab combination therapy as the 1 st line n=193 Response to chemotherapy PR: n=64 SD / PD: n=79 / 45 non-Conversion n=173 CR: n= 5

Figure 2 .
Patients who achieved PR with systemic chemotherapy had a longer survival time than TA B L E 1 Characteristics and clinical results of the patients receiving atezolizumab and bevacizumab as first-line chemotherapy.
TA B L E 4 Patient characteristics who underwent conversion therapy.that included only patients with intermediate-stage HCC, the present investigation also included those with more advanced-stage HCC.In addition, atezolizumab plus bevacizumab combination therapy has been reported to be highly effective in treating intermediatestage HCC.