Changes in serum tumor marker levels are efficient predictors of complete response in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab

doi:10.21203/rs.3.rs-3931374/v1

Background and aims:

Atezolizumab plus bevacizumab therapy is recommended as first-line regimen for unresectable hepatocellular carcinoma (uHCC). Complete response (CR) is now being experienced at a consistent rate. This study aimed to identify predictive factors for CR.

Methods

A retrospective analysis of 319 patients with uHCC in whom atezolizumab plus bevacizumab therapy was introduced at our and joint research institutions from October 2020 to August 2023.

Results

Nineteen patients (6.0%) achieved CR. Multivariate analysis identified a Child–Pugh score 5 and decrease in alpha fetoprotein (AFP) levels of more than 20% at 3 weeks as significant and independent determinants of achieving CR. Sixteen of the 19 patients (84.2%) maintained a cancer-free status. Cancer-free patients had a significantly higher proportion of lower levels of Lens culinaris agglutinin-reactive AFP isoform (AFP-L3) at CR. Patients with AFL-L3 values of 15% or higher at CR had a significantly lower duration of response (log-rank test, P = 0.032).

Conclusions

Changes in AFP levels are important predictors of CR achievement in atezolizumab plus bevacizumab therapy. AFP-L3 levels are important for predicting maintenance of the therapeutic response.

systemic chemotherapy

immunocomplex therapy

unresectable hepatocellular carcinoma

therapeutic effect

sustained complete response

duration of response

alpha fetoprotein

lens culinaris agglutinin-reactive AFP isoform

real-world practice

multicenter joint research

Recently, the development of drugs used in systemic chemotherapy for unresectable hepatocellular carcinoma (uHCC) has changed dramatically. Currently, the first recommended systemic chemotherapy regimen for uHCC is immunocomplex therapy, which includes immune checkpoint inhibitors. Atezolizumab plus bevacizumab, an immunocomplex therapy, has been widely used in patients with uHCC since its worldwide approval in 2020 following the positive results of the phase 3 IMbrave150 trial.¹

Atezolizumab plus bevacizumab therapy is characterized by high response rate. The IMbrave150 trial, in which response to treatment was determined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), showed a higher response rate than sorafenib therapy (30% vs 11%).^1,2 It should be noted, moreover, that complete response (CR) was achieved in some patients who received atezolizumab plus bevacizumab. Although CR rate is not high (5.5%), this therapy is a hopeful treatment method for patients with uHCC, as it was 0% with sorafenib treatment.¹

Atezolizumab selectively targets programmed cell death ligand 1 and prevents programmed death receptor-1 and B7-1 receptor interactions associated with T-cell suppression.³ The mechanism of action, which is different from that of conventional molecular-targeted agents, is thought to contribute to the high response rate, including CR. In contrast, many patients do not respond to atezolizumab plus bevacizumab therapy, necessitating the identification of factors that predict response to determine whether this can become the first treatment choice. Currently, tumor markers, neutrophil to lymphocyte ratio, biomarkers, and imaging findings are reported as factors that may predict overall responses.^4-11 However, predicting factors specific to CR remains unclear.

In this study, we determined factors predicting CR in patients with uHCC who received atezolizumab plus bevacizumab therapy.

Patients

This multicenter, retrospective observational study was conducted in 11 hospitals across five prefectures in western Japan. We enrolled 319 patients with histologically or clinically confirmed uHCC who received atezolizumab plus bevacizumab as first-line chemotherapy between October 2020 and August 2023. Liver function was classified using the Child–Pugh (C–P) and the albumin–bilirubin (ALBI) scores. Patients with HCC were staged according to the Barcelona Clinical Liver Cancer (BCLC) classification.

Atezolizumab plus bevacizumab therapy regimen

The patients received 1200 mg atezolizumab plus 15 mg/kg bevacizumab intravenously once every 3 weeks. The physician decided to discontinue treatment in the following situations: disease progression, drop in performance status to 2 or higher, unacceptable toxicity, achievement of CR, or transfer to best supportive care. The duration of continuation of atezolizumab plus bevacizumab therapy after achieving CR was not specified and was determined by the physician based on the course of treatment.

Follow-up

Tumors were assessed using contrast-enhanced computed tomography or magnetic resonance imaging every 9–12 weeks during the screening period. Responses were graded as CR, partial response (PR), stable disease (SD), or progressive disease (PD) using RECIST 1.1. CR was defined as follows: disappearance of all target lesions and reduction in the short axis of any pathological lymph nodes (whether target or non-target) to <10 mm. Furthermore, the levels of tumor markers such as alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive AFP isoform (AFP-L3), and des-gamma-carboxy prothrombin (DCP) were analyzed at baseline and during treatment.

Statistical analyses

Demographic data, underlying liver disease, and laboratory data were retrospectively assessed and compared. The baseline characteristics are presented as medians and interquartile ranges. The continuous variables were compared using the Wilcoxon rank-sum test, and categorical values were analyzed using the chi-square test. Multivariate logistic regression analysis was performed to identify the factors associated with conversion therapy. The duration of response was estimated using the Kaplan–Meier method and compared among the patient groups using the log-rank test. The cutoff value for each marker in the analysis was set based on the median value. All significance tests were two-sided; P-values <0.05 were considered to indicate statistical significance. All analyses were performed using the JMP software (version 16.0; SAS Institute Japan Ltd., Tokyo, Japan).

Therapeutic effect of atezolizumab plus bevacizumab

Among the 319 patients with uHCC who received systemic chemotherapy alone, 19 (6.0%) achieved CR. The numbers of patients who achieved PR, SD, and PD were 88 (27.6%), 123 (38.5%), and 89 (27.9%), respectively. The objective response rate was 33.5% and the disease control rate was 72.1% (Table 1).

Patient characteristics

Table 2 presents the characteristics and clinical results of the 319 patients who received atezolizumab plus bevacizumab as first-line chemotherapy. The median age was 75 years and 246 patients (77.1%) were male. A hundred and fourteen patients (43.9%) had non-viral liver diseases. A hundred and ninety-eight patients (62.1%) had a C–P score of 5, and the median ALBI score was −2.18. These patients included 190 (59.6%) with BCLC C stage HCC. A hundred and sixty-eight patients (59.2%) had four or more tumors, 87 (27.2%) showed macrovascular invasion, and 77 (24.1%) had extrahepatic metastases. The median level of AFP-L3 was 11.2%.

In the CR cohort, although the background characteristics were generally similar to those of other patients, we observed a significantly higher proportion of patients with a performance status of 0, C–P score of 5, and three or fewer tumors (P =0.066, 0.040, and 0.039, respectively) (Table 2).

Decrease in AFP levels is the predictive factor for CR

Univariate analysis identified a C–P score of 5 (odds ratio [OR] =3.5, 95% confidence interval [CI] =0.99–12, P =0.053), three or fewer tumors (OR =2.8, 95% CI =1.1–7.9, P =0.047), and a decrease in AFP levels of more than 20% at 3 weeks (OR =3.3, 95% CI =1.1–11, P =0.042) as significant determinants of achieving CR. Multivariate analysis identified a C–P score of 5 (OR =9.9, 95% CI =1.2–80, P =0.032), and a decrease in AFP levels of more than 20% at 3 weeks (OR =4.3, 95% CI =1.1–17, P =0.039) as significant and independent determinants of achieving CR (Table 3).

Clinical features of patients who were maintained cancer-free

Among the 19 patients who achieved CR, 16 (84.2%) maintained the cancer-free status. The median observation period since CR determination was 589 days (range: 437–764). The Kaplan–Meier curve for the duration of response (DOR) after CR is shown in Figure 1 (median not reached). The cancer-free patients featured a significantly higher proportion of viral liver disease, three or fewer tumors, absence of extrahepatic metastases, and lower AFP-L3 values at CR than the other patients (P =0.037, 0.042, 0.035, and <0.01, respectively) (Table 4).

AFP-L3 values at the best response are related to prognosis after CR

As shown in Figure 2, AFP-L3 values decreased significantly from the start of the treatment to the achievement of CR (P =0.037). However, as shown in Figure 3, which indicates the AFP-L3 values of all patients from the start of treatment to CR achievement, regardless of the value at treatment start, HCC recurrence occurred in the three patients with AFP-L3 values at CR of 15% or higher. Further, patients with AFL-L3 values of 15% or higher at best response had a significantly lower DOR (log-rank test, P <0.01) (Figure 4).

We found that a decrease in serum AFP levels after treatment initiation was a significant predictor of CR achievement in atezolizumab plus bevacizumab therapy, which is widely used as first-line systemic chemotherapy for uHCC. Compared with conventional molecular-targeted therapies, combination therapy with the immune checkpoint inhibitor atezolizumab and the molecular-targeted agent bevacizumab is characterized by a certain number of patients who achieve CR.¹ Even in patients with uHCC, prognosis is reported to improve when systemic chemotherapy is successful,^12,13 and especially when CR is achieved, the prognosis is markedly prolonged. In contrast, in atezolizumab plus bevacizumab therapy, as in conventional molecular-targeted drug therapy, liver function has been reported to gradually decline with treatment,^14,15 and a high incidence of adverse events occurs.¹ Therefore, to prolong prognosis for patients with uHCC, introduction or continuation of atezolizumab plus bevacizumab therapy should be considered while predicting therapeutic efficacy. Though the usefulness of multiple treatment response prediction tools has been reported, prediction regards overall responses, including CR + PR, and no tool has yet been developed specifically for CR, which is the most prognostically relevant.

AFP is widely known as a marker molecule for hepatic progenitor and hepatocarcinoma cells during liver development¹⁶ and is strongly recommended for use in surveillance as a competent marker for the diagnosis of HCC. It has also been reported to be a useful marker of HCC disease status and a potential prognostic factor in systemic chemotherapy.¹⁷ In patients receiving atezolizumab plus bevacizumab therapy, response rates have been shown to be lower if AFP values are higher at the start of treatment, and higher if AFP values decrease after treatment.^18-21 The same tendency was confirmed in our study, suggesting that AFP is truly a useful marker for predicting treatment responses in atezolizumab plus bevacizumab therapy. In contrast, previous studies were limited in examining the association between AFP values and overall responses. The usefulness of AFP as a predictor of CR achievement, which contributes the most to improved prognosis, has not yet been clarified. Our analysis that focused specifically on patients with CR found that a 20% or greater reduction in AFP values at 3 weeks after starting atezolizumab plus bevacizumab therapy is a significant predictor of achieving CR. Based on previous reports, sufficient reduction in AFP values from the early stage of treatment indicates that a good therapeutic effect has been obtained. In addition, since AFP measurement can be easily performed in general practice, it is considered a useful criterion for immediately estimating treatment course and prognosis for patients with HCC.

This study also revealed that the duration of CR maintenance depends on AFP-L3 values at the time of CR achievement. Considering that AFP values do not correlate with AFP-L3 values, the clinical utility of AFP-L3 compared to that of AFP in the treatment of HCC is expected to be recognized mainly at low AFP values. Though AFP concentrations are known to rise and fall due to liver inflammation and other factors, AFP-L3 levels are more specific for cancer than AFP values,^22,23 and are useful in determining cancer grade and treatment efficacy. Therefore, high or elevated AFP-L3 values when AFP values decrease after HCC treatment may indicate the presence of residual cancer or a high recurrence rate. In fact, the prognosis of patients with HCC with transarterial chemoembolization, resection, small liver cancer, or liver transplantation is worse when AFP-L3 values are elevated before and after treatment.^24-30 In this study, AFP and AFP-L3 values decreased after starting atezolizumab plus bevacizumab therapy. However, despite the achievement of CR on imaging, three patients still showed AFP-L3 ≥15% at the time of CR and recurrence of HCC was confirmed after completion of chemotherapy. The background of the three patients was characterized by non-viral liver disease that was difficult to control, and treatment was initiated at a more advanced stage. Even if the sensitivity of response to treatment was high, the liver may have continued to be susceptible to HCC recurrence, or residual microscopic cancers, not visible on imaging, may have been present; evaluation of AFP-L3 levels may have been useful in predicting recurrence after CR.

One limitation of this study is that the duration of atezolizumab plus bevacizumab therapy after achieving CR was not standardized because real clinical data were used. Though no patient discontinued chemotherapy immediately after achieving CR, the duration varied from 2 to 6 months; therefore, the duration of the therapeutic response may have not been accurately assessed. Additionally, a low number of cases achieved CR. However, the usefulness of AFP and AFP-L3 as indicators of therapeutic efficacy in HCC has been widely reported, and their detection as factors contributing to achieving and sustaining CR is reasonable.

Atezolizumab plus bevacizumab therapy for patients with uHCC is expected to continue to be widely used as the first option for treatment. Worldwide, the number of patients with HCC remains high, and improving life expectancy is an urgent issue. Prediction of CR achievement based on AFP trends revealed in this study is clinically useful. We believe that an even more important finding is that AFP-L3 values after achieving CR may be a valuable factor for determining when to terminate treatment.

AFP, alpha fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive alpha-fetoprotein isoform; ALBI, albumin–bilirubin; BCLC classification, Barcelona Clinical Liver Cancer classification; CI, confidence interval; C–P, Child–Pugh; CR, complete response; DCP, des-gamma-carboxy prothrombin; DOR, duration of response; NS, not significant; OR, odds ratio; PD, progressive disease; PR, partial response; RECIST 1.1, Response Evaluation Criteria in Solid Tumors, version 1.1; SD, stable disease; uHCC, unresectable hepatocellular carcinoma

Acknowledgements

We extend our thanks to our colleagues and affiliated institutions for their contributions.

Funding information

This work was supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology, Japan (#22H02828) (to M.O.), and by the Research Program on Hepatitis from the Japan Agency for Medical Research and Development, AMED (JP23fk0210092, JP23fk0210133, and JP23fk0310506 to M.O.).

Competing interest

None declared.

Author Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Yasuto Takeuchi. The first draft of the manuscript was written by Yasuto Takeuchi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Ethics statement

Written informed consent was obtained from all patients, and the study was conducted in accordance with the Declaration of Helsinki. All protocols were approved by the ethics committees of the participating institutes (ken-2012-017).

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Table 1: Tumor responses based on RECIST 1.1

Response	All patients (n = 319)
Objective response rate	107 (33.5%)
Disease control rate	230 (72.1%)
Complete response	19 (6.0%)
Partial response	88 (27.6%)
Stable disease	123 (38.5%)
Progressive disease	89 (27.9%)

RECIST 1.1: Response Evaluation Criteria in Solid Tumors, version 1.1

Table 2: Characteristics of the patients enrolled in the present study

	Patient characteristics	All patients (n = 319)	CR (n = 19)	Non–CR (n = 319)	P value
	Age (years) ⁺	75 (69–80)	74 (68–78)	75 (69–80)	NS
	Sex male female	246 (77.1%) 73 (22.9%)	13 (68.4%) 6 (31.6%)	233 (77.7%) 67 (22.3%)	NS
	Etiology viral non-viral	140 (43.9%) 179 (56.1%)	9 (47.4%) 10 (52.6%)	131 (43.7%) 169 (56.3%)	NS
	Performance Status 0 1	248 (77.7%) 71 (22.3%)	18 (94.7%) 1 (5.3%)	230 (76.7%) 70 (23.3%)	0.066
Child–Pugh score 5 ≥6		198 (62.1%) 121 (37.9%)	16 (84.2%) 3 (15.8%)	182 (60.7%) 118 (39.3%)	0.040
	ALBI score ⁺	−2.18 (−2.49–1.82)	−2.33 (−2.73–2.08)	−2.18 (−2.49–1.82)	NS
	BCLC stage A or B C	129 (40.4%) 190 (59.6%)	7 (36.8%) 12 (63.2%)	122 (40.7%) 178 (59.3%)	NS
	Tumor size (mm)	30 (15–65)	22 (11–50)	30 (15–65)	NS
	Tumor number <4 ≥4	116 (40.8%) 168 (59.2%)	11 (64.7%) 6 (35.3%)	105 (39.3%) 162 (60.7%)	0.039
	Macrovascular invasion present absent	87 (27.2%) 232 (72.3%)	7 (36.8%) 12 (63.2%)	80 (26.7%) 220 (73.3%)	NS
	Extrahepatic metastasis present absent	77 (24.1%) 242 (75.9%)	4 (21.1%) 15 (78.9%)	73 (24.3%) 227 (75.7%)	NS
	AFP (ng/ml) ⁺	20.1 (4.6–264)	20.1 (5.1–194)	19.5 (4.6–264)	NS
	AFP-L3 (%) ⁺	11.2 (0.5–46.7)	8.7 (0.5–36.2)	11.5 (0.5–46.7)	NS
	DCP (mAU/mL) ⁺	218 (42.3–2794)	79.6 (19–2794)	225 (42.3–1534)	NS

Data are presented as the median (interquartile range) or n (%) unless otherwise indicated. AFP, alpha-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive alpha-fetoprotein isoform; ALBI, albumin–bilirubin; BCLC, Barcelona Clinic Liver Cancer; CR, complete response; DCP, des-gamma-carboxy prothrombin; NS, not significant

Table 3: Results of logistic regression analysis of the factors associated with CR

	Univariate analysis		Multivariate analysis
Factors	Odds ratio (95% CI)	P value	Odds ratio (95% CI)	P value
Age (<75 years)	1.7 (0.63–4.5)	NS
Etiology (viral)	1.2 (0.46–2.9)	NS
Performance status (0)	5.5 (0.78–42)	NS
Child–Pugh score (5)	3.5 (0.99–12)	0.053	9.9 (1.2–80)	0.032
Tumor number (<4)	2.8 (1.1–7.9)	0.047	3.2 (0.80–12)	NS
Macrovascular invasion (absent)	1.6 (0.61–4.2)	NS
Extrahepatic metastasis (absent)	1.2 (0.39–3.7)	NS
BCLC (A or B)	1.2 (0.45–3.1)	NS
AFP (<200 ng/ml)	1.5 (0.47–4.5)	NS
AFP-L3 (<15%)	1.3 (0.44–3.6)	NS
DCP (<400 mAU/mL)	1.1 (0.42–2.8)	NS
AFP decrease at 3 weeks (≥20%)	3.3 (1.1–11)	0.042	4.3 (1.1–17)	0.039

AFP, alpha-fetoprotein; AFP-L3, Lens culinaris agglutinin-reactive alpha-fetoprotein isoform; ALBI, albumin–bilirubin; CI, confidence interval; DCP, des-gamma-carboxy prothrombin; NS, not significant

Table 4: Characteristics of the patients with maintained therapeutic effect after achieving CR

Patient characteristics

Maintained CR

(n = 16)

Recurrence

(n = 3)

P value

Etiology

viral

non-viral

9 (56.3%)

7 (43.7%)

0 (0.0%)

3 (100%)

0.037

Tumor number

<4

≥4

12 (75.0%)

4 (25.0%)

0 (0.0%)

3 (100%)

0.042

Extrahepatic metastasis

present

absent

2 (12.5%)

14 (87.5%)

2 (66.7%)

1 (33.3%)

0.035

AFP-L3 at start (%) ⁺

0.5 (0–29)

9.4 (4.7–34)

NS

AFP-L3 at CR (%) ⁺

0.5 (0.5–0.5)

17 (15–22)

<0.01

Data are presented as the median (interquartile range) or n (%) unless otherwise indicated. AFP-L3, Lens culinaris agglutinin-reactive alpha-fetoprotein isoform; CR, complete response; NS, not significant

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Changes in serum tumor marker levels are efficient predictors of complete response in patients with unresectable hepatocellular carcinoma treated with atezolizumab plus bevacizumab

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