Analysis of hyperprogressive disease due to atezolizumab combined with bevacizumab treatment in patients with advanced hepatocellular carcinoma

doi:10.21203/rs.3.rs-1761220/v1

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Analysis of hyperprogressive disease due to atezolizumab combined with bevacizumab treatment in patients with advanced hepatocellular carcinoma

https://doi.org/10.21203/rs.3.rs-1761220/v1

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Aim: To clarify the reality of hyperprogressive disease (HPD), a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy, in patients with advanced hepatocellular carcinoma (HCC) who were treated with atezolizumab plus bevacizumab (Atez/Bev) using tumor dynamics.

Methods: Medical records of consecutive patients with advanced HCC who were treated with Atez/Bev were retrospectively reviewed. HPD was defined as a more than two- or fourfold increase in tumor growth rate (TGR) or tumor growth kinetics rate (TGK_R) pre- and post-treatment. Overall survival (OS) and baseline characteristics with or without HPD were analyzed.

Results: A total of 85 patients were included in the analysis. At the first imaging, complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were observed in 1 (1.2%), 4 (4.7%), 61 (71.8%), and 19 (22.4%) patients. When HPD was defined as a twofold of TGR or TGK_R, 8 patients (9.4%, 8/85) had HPD and 11 had PD without HPD. A total of 5 patients (5.9%, 5/85) were diagnosed with HPD and 14 with PD without HPD when HPD was defined as a fourfold of TGR or TGK_R. No significant difference was observed in the baseline characteristics and OS between HPD and non-HPD.

Conclusion: The prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than those treated with nivolumab monotherapy. The HPD mechanism in immune checkpoint inhibitor (ICI) combined with anti-VEGF antibody remains to be elucidated.

hyperprogressive disease

atezolizumab and bevacizumab

hepatocellular carcinoma

immunotherapy

Hepatocellular carcinoma (HCC) is ranked as the 7th most common neoplasm and the second leading cause of cancer-related death worldwide [1]. Although majority of worldwide guidelines have suggested screening of high-risk population with viral hepatitis carriers or/and cirrhosis [2], many patients are still diagnosed after reaching advanced HCC. Therefore, systemic therapies are critical to improve the prognosis of patients with HCC [3]. Immunotherapy for advanced HCC started to occur somewhat later than that for other carcinomas. Although anti-progressive disease (PD)-1 antibody monotherapies (nivolumab and pembrolizumab) demonstrated antitumor activities in phase II and randomized III trials [4–7], none of them could show survival benefits in the randomized phase III trial. At the end of the 2010s, the combination of atezolizumab (antibodies targeting programmed cell death ligand 1 [PD-L1]) plus bevacizumab (antibodies targeting vascular endothelial growth factor [VEGF]) (Atez/Bev) was shown in global phase 3 trial (IMbrave 150) to significantly prolong overall survival (OS) compared to sorafenib alone in the treatment of patients with advanced HCC who did not have any previous history of systemic therapy. Based on this result, the combination immunotherapy has been the standard first-line systemic therapy for advanced HCC [8]. This change has made immunotherapy the mainstay of systemic therapy in advanced HCC as well as other carcinomas [9–12].

Immune checkpoint inhibitor (ICI) therapy has revealed and noted a unique tumor progression called hyperprogressive disease (HPD) when used for the management of various malignancies in clinical practice. HPD is a phenomenon with greatly accelerated tumor growth and clinical deterioration rates compared to pre-therapy [13, 14], has reported an incidence of 9–29% in various cancer types (mixed solid tumors, non-small cell lung cancers, advanced gastric cancer, and head and neck cancers) [15–17]. Several reports demonstrated that HPD was a poor prognostic factor due to extremely rapid tumor growth. However, HPD has various definitions in previous reports. In other words, there is no fixed definition of HPD at this time, and thus, its definition should be unified to evaluate HPD and to clarify the reality of HPD.

Very recently, HPD in patients with advanced HCC who received ICI is gradually clarified. Kim GG et al. reported the incidence of HPD in patients with advanced HCC treated with nivolumab (anti-PD-1 antibody) monotherapy was 12.7% [18]. In this cohort, all patients received nivolumab as a second-line agent after sorafenib. Another report from Japan initially demonstrated the occurrence rate of HPD in patients with advanced HCC who were treated Atez/Bev in either the front or later lines [19]. Although both reports identified patients with HPD with tumor growth dynamics such as tumor growth rate (TGR) and tumor growth kinetics ratio (TGK_R), the definition for increasing rate differed in each report. Namely, at present, whether HPD differs between ICI monotherapy and combination immunotherapy in patients with advanced HCC remains unclear. Therefore, this study aimed to clarify the prevalence of HPD in patients treated with Atez/Bev based on several examinations using tumor dynamics.

Patients

We retrospectively collected data of patients with advanced HCC who received Atez/Bev in six institutions in Japan between October 2020 and July 2021. In this analysis, the observation period lasted until the end of October 2021. Patients who did not undergo appropriate radiological assessments that can be evaluated as described in radiological evaluation were excluded. Those with pseudoprogression were also excluded based on the definition that was evaluated as initial progression followed by complete response (CR) or partial response (PR) or stable disease (SD) lasting > 6 months by RECIST v1.1 [20, 21].

Following data were obtained at the first dose of Atez/Bev: gender, age, HBV positive, HCV positive, Child–Pugh score, AFP value, BCLC stage, macrovascular invasion, extrahepatic spread, treatment line of Atez/Bev, ECOG performance status, and neutrophil-to-lymphocyte ratio (NLR). This study was approved by the Research Ethics Committee of the Graduate School of Medicine, Chiba University (No. 3091).

Radiological evaluation

Patients who underwent three successive computed tomography (CT) or magnetic resonance imaging (MRI) scans available for a RECIST 1.1 assessment: a baseline scan before the first administration of Atez/Bev, a first response assessment (experimental) scan within 12 weeks, and a reference scan within 2 weeks to 3 months before the baseline scan. The reference period was defined as the time between reference and baseline scans, whereas the experimental period was defined as the time between the baseline and experimental scans.

Definitions of tumor growth dynamics and HPD

Tumor growth dynamics were evaluated based on both TGR and TGK_R, based on the definitions of previous studies [13, 17, 22]. Target lesions included all measurable lesions up to a maximum of two lesions per organ and a total of five lesions selected from the largest lesions according to RECIST v1.1. HPD was evaluated for both more than two- or fourfold increase in TGR or TGK_R of the experimental period compared with that of the reference period in patients with PD by RECIST v1.1 at the first response evaluation after Atez/Bev administration, respectively.

Statistical analysis

The Pearson’s χ² test was used to compare clinical characteristics. OS was defined as the time of the first dose of Atez/Bev until death or date of last follow-up. Kaplan–Meier plots of medians with 95% confidence intervals (CIs) were used to estimate OS. Univariate and multivariate logistic regression analyses were performed to identify predictive factors associated with HPD. All P-values < 0.05 were considered statistically significant. All statistical analyses were performed using Statistical Package for the Social Sciences statistical software version 25 (IBM, Chicago, IL, USA).

Patient characteristics

During the study period, 147 patients with advanced HCC received Atez/Bev at six Japanese institutions. Among these 147 patients, 59 who did not undergo appropriate radiological examinations (CT or MRI) at pre- or post-treatment and 3 who were diagnosed with pseudoprogression were excluded. Finally, a total of 85 patients were included in the analysis.

The baseline characteristics of these 85 patients are summarized in Table I. The majority of patients (73/85, 85.9%) were men, and the median age was 74 (range, 48–88) years. During the Atez/Bev administration, most of the patients were classified as Child–Pugh scores of 5 or 6 (79/85, 92.9%) and ECOG-PS of 0 or 1 (85/85, 100%). The median observation period was 6.2 (range, 1.1–12.2) months in the present cohort.

Treatment outcomes and identification of HPD in patients treated with Atez/Bev in the present cohort

At the initial radiological evaluation, CR, PR, SD, and PD were observed in 1 (1.2%), 4 (4.7%), 61 (71.8%), 19 (22.4%) patients, respectively. The median progression-free survival and OS of the present cohort were 5.5 months (95%CI, 4.3–6.8) and undefined, respectively.

To evaluate the HPD incidence, the tumor growth dynamics were assessed using TGR and TGK_R [13, 17, 22]. When HPD was identified using the HPD definition according to a twofold or more increase in TGR or TGK_R, 8 (9.4%, 8/85) and 11 patients were found to have HPD and PD without HPD, respectively. Conversely, 5 patients (5.9%, 5/85) were identified to have HPD and 14 patients had PD without HPD when HPD was defined as a fourfold or more increase in TGR or TGK_R. Two typical cases of HPD in patients with advanced HCC are shown in Fig.I based on the fourfold or more increase in TGR or TGK_R (left column, first-line patient; right column, second- or later-lines patient). The comparison of baseline characteristics in patients with and without HPD is summarized in Table II. No significant difference was observed in the baseline characteristics between patients with and without HPD using either definition in the present cohort.

We illustrated TGR and TGK_R distributions of all study population in Fig.II. According to the definition of twofold or more increase in TGR or TGK_R, the median increase in TGR and TGK_R in patients with HPD was 4.25 (range 2.11–7.03) and 4.07 (range 2.06–7.63), respectively. Conversely, the median increases of TGR and TGK_R in patients without HPD were − 0.02 (range − 9.21–1.84) and − 0.03 (range − 9.21–1.78), respectively. The median increases of TGR and TGK_R in patients with HPD were 5.68 (range 4.05–7.63) and 6.21 (range 4.07–7.63), respectively, based on the definition of fourfold or more increase of TGR or TGK_R. Likewise, the median increases of TGR and TGK_R in patients without HPD were − 0.00 (range − 9.21–2.87) and − 0.00 (range − 9.21–2.38), respectively. All five patients identified as HPD based on the definition of fourfold or more increase of TGR or TGK_R observed new lesions at the same time when deemed to PD.

Tumor growth dynamics using TGK_R and TGR and associations between HPD

We compared the correlation between treatment response and tumor growth dynamics using log-transformed TGR and TGK_R based on the reference and experimental periods (Fig.IIIa and b). The majority of patients achieved a deceleration in the growth speed of their tumors with Atez/Bev even if the best tumor response was PD according to RECIST version 1.1 (blue dots in Fig.IIIa and b). Conversely, the majority of accelerated tumor growth was observed in patients treated with Atez/Bev after second- or later-lines (10 of 14 patients in TGR and 11 of 15 patients in TGK_R).

Impact of HPD on survival in patients with advanced HCC who received Atez/Bev in the real-world practice

Fig.Ⅳ shows Kaplan–Meier curves of OS in patients with advanced HCC who received Atez/Bev. We compared OS between non-PD, PD without HPD, and PD with HPD groups in these analyses. In both definitions of two- and fourfold or more increase of TGR or TGK_R, no significant differences were observed between PD with and without HPD (twofold: P = 0.233, fourfold: P = 0.969). We also confirmed the impact of HPD based on both definitions of two- and fourfold or more increase of TGR or TGK_R on survival in univariate and multivariate analyses. In the preset cohort, HPD was not a significantly poor prognostic factor in both definitions (Tables SI and SII).

This study clarified the reality of HPD in patients with advanced HCC treated with Atez/Bev using two different definitions based on tumor dynamics immediately before and after Atez/Bev administration. In particular, HPD in Atez/Bev was confirmed to be lesser than ICI monotherapy in patients with advanced HCC, as evaluated based on the definition set out in the previous report [19]. Unfortunately, this study could not identify any clinical parameter that predicted HPD in patients with advanced HCC treated with Atez/Bev.

In the present study, HPD was evaluated based on the definition of two- and fourfold or greater increase of TGR or TGK_R with reference on a previous study [18]. Several current studies that analyzed HPD in other malignancies adopted the definition of twofold or greater increase of TGR or TGK_R [15–17]. The majority of reports on other cancers using this definition were analyses of cohorts including ICI as the first-line treatment. Conversely, Kim et al. recently reported that the HPD frequency in ICI monotherapy as second- or later-lines treatment for advanced HCC used the definition of fourfold or greater increase of TGR or TGK_R [18]. The definition here was established based on the findings that no patient with advanced HCC had increased tumor growth dynamics using TGR and TGK_R higher than fourfold who converted from sorafenib as first-line treatment to other ICIs, such as regorafenib or best-supportive care. The presence or absence of pre-treatment should have different implications for tumor growth dynamics using TGR and TGK_R, as determined by changes in the tumor growth rate between the period immediately before and after initiating ICI treatment. This is because the tumor growth in the period immediately before ICI treatment is influenced by the previous systemic therapy in the analysis of tumor growth dynamics using TGR and TGK_R in patients who received ICI as second- or later-lines treatment. In other words, tumor growth acceleration after ICI administration as second- or later-lines treatments should be considered not only due to HPD but also due to the lack of efficacy of the previous treatment. Since this study included patients with advanced HCC who started Atez/Bev as both first- and second- or later-lines, we assessed HPD using two different definitions.

We found that the frequency of HPD in patients with advanced HCC treated with Atez/Bev was 5.9% (first-line: 5.1%; second- or later-line: 6.5%) using the same method in the current report by Kim et al. This HPD rate was lower than the 12.7% indicated in the study that observed the frequency of HPD in ICI monotherapy as second- or later-lines treatment for patients with advanced HCC. A very recent report from Japan evaluating HPD based the definition of a twofold or greater increase of TGR or TGK_R indicated the frequency of HPD as 10.2% [19], which was identical to 9.4% of our results adopting the same definition. Taken together with these results, HPD was likely reduced by anti-VEGF antibodies combined with ICI in patients with advanced HCC. ICI combined with anti-VEGF antibody is known to have synergic effects due to the action of an anti-VEGF antibody on tumor microenvironment, including enhancing T-cell priming and activation via promotion of dendritic cell maturation, increasing T-cell tumor infiltration by normalizing tumor vasculature, and establishing an immune-permissive tumor microenvironment by decreasing myeloid-derived suppressor-cell and regulatory T-cell populations [23, 24].

These effects of anti-VEGF antibody toward tumor microenvironment would most likely reduce HPD in patients with advanced HCC treated with Atez/Bev. Several reports have demonstrated the HPD mechanisms in other malignancies. However, most of them were HPD analyses with ICI monotherapy or combination therapy of two different ICIs. To the best of our knowledge, the detailed HPD mechanism during combination treatment of ICI and anti-VEGF antibody has not yet been elucidated.

In this present study, no predictive factors of HPD were identified based on clinical parameters of baseline data at the start of Atez/Bev in patients with advanced HCC. Moreover, a significant difference in OS was not observed between patients with PD with and without HPD in our cohort. Several previous reports demonstrated that NLR was helpful in identifying HPD in both patients with advanced HCC and other cancers [25, 26]. Since both previous reports and our population comprised retrospective cohorts with a limited number of patients, predictive factors that identify HPD require further investigation in large cohort studies. In the current real-world practice, clinical issues remain to distinguish between HPD and pseudoprogression in patients who receive ICI or its combination therapies for malignant tumors including advanced HCC. In the case of unclear method for predicting HPD has been established, discontinuation of ICI-based therapy should be assessed using irRECIST for patients with PD shortly after the treatment initiation.

In conclusion, our study confirmed that the prevalence of HPD in patients with advanced HCC treated with Atez/Bev was lower than that of nivolumab monotherapy. Although the combination of anti-VEGF antibody in ICI suppressed to occurrence of HPD and negative clinical impact of HPD was reduced in patients with advanced HCC, elucidation of the HPD mechanism in ICI combined with anti-VEGF antibody and identification of its predictors are strongly required in patients with advanced HCC.

Fundings

The authors have no conflicts of interest to declare.

Conflict of interest

Sadahisa Ogasawara received honoraria from Bayer, Leverkusen, Germany; Eisai, Tokyo, Japan; Eli Lilly, Indianapolis, IN, USA; Chugai Pharma, Tokyo, Japan; AstraZeneca, Cambridge, UK; and Merck & Co., Inc., Kenilworth, NJ, USA, consulting or advisory fees from Bayer, Eisai, Merck & Co., Inc., Chugai Pharma, Eli Lilly, and AstraZeneca, and research grants from Bayer, AstraZeneca, and Eisai. Naoya Kato received honoraria from Bayer, Eisai, Sumitomo Dainippon Pharma, Tokyo, Japan, and Merck & Co., Inc.; consulting or advisory fees from Bayer and Eisai; and research grants from Bayer and Eisai.

Authors’ contributions
Sae Yumita, Sadahisa Ogasawara, Miyuki Nakagawa, and Naoya Kato were involved in study design and data interpretation. Sae Yumita, Sadahisa Ogasawara, Miyuki Nakagawa, Susumu Maruta, Tomomi Okubo, Norio Itokawa, Yotaro Iino, Masamichi Oobu, Yuki Haga, Atsuyoshi Seki, Tadayoshi Kogure,Takamasa Ishino, Keita Ogawa, Kisako Fujiwara, Terunao Iwanaga, Naoto Fujita, Takafumi Sakuma, Ryuta Kojima, Hiroaki Kanzaki, Keisuke Koroki, Masanori Inoue, Kazufumi Kobayashi, Soichiro Kiyono, Masato Nakamura, Naoya Kanogawa, Tomoko Saito, Takayuki Kondo, Ryo Nakagawa, Shingo Nakamoto, Ryosuke Muroyama, Tetsuhiro Chiba, Ei Itobayashi, Masanori Atsukawa, Yoshihiro Koma, Ryosaku Azemoto, Kenji Ito, Hideaki Mizumoto, Jun Kato, and Naoya Kato were involved in the data analysis. All authors critically revised the report, commented on drafts of the manuscript, and approved the final report.

Date availability

Datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

Ethical approval

This study was approved by the Research Ethics Committee of the Graduate School of Medicine, Chiba University (No. 3091).

Consent to participate

This paper has been published with the consent of patients and their families.

Consent to publish

The authors affirm that human research participants provided informed consent for publication of the images in Fig.Ia and b.

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Table I. Baseline characteristics of 85 patients with advanced hepatocellular carcinoma who received atezolizumab plus bevacizumab.

Characteristic	N = 85
Sex, male, n (%)	73 (85.9)
Age > 74, n (%)	41 (48.2)
HBV positive, n (%)	18 (21.2)
HCV positive, n (%)	25 (29.4)
Child–Pugh class A, n (%)	79 (92.9)
AFP > 400 ng/mL, n (%)	32 (37.6)
BCLC stage C, n (%)	52 (61.2)
Macrovascular invasion, n (%)	18 (21.2)
Extrahepatic spread, n (%)	35 (41.2)
Treatment line, atezolizumab plus bevacizumab,1st line, n (%)	39 (45.9)
ECOG-PS ≦ 1, n (%)	85 (100)
NLR ≧ 3.43, n (%)	35 (41.2)

Abbreviations: HBV, hepatitis B virus; HCV, hepatitis C virus; AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ECOG-PS, Eastern Cooperative Oncology Group Performance Status; NLR, neutrophil-to-lymphocyte ratio.

Table II. Comparison of baseline characteristics in patients with advanced hepatocellular carcinoma with and without hyper-progressive disease according to two different criteria.

Characteristic	TGR ≧ 2 or TGK_R≧ 2			TGR ≧ 4 or TGK_R≧ 4
Characteristic	HPD N = 8	Non-HPD N = 77	P-value	HPD N = 5	Non-HPD N = 80	P-value
Sex, male, n (%)	7 (87.5)	66 (85.7)	1.000	5 (100)	68 (85.0)	1.000
Age > 74 years, n (%)	3 (37.5)	38 (49.4)	0.714	3 (60.0)	38 (47.5)	0.669
HBV positive, n (%)	1 (12.5)	17 (22.1)	1.000	0 (0.0)	18 (22.5)	0.579
HCV positive, n (%)	4 (50.0)	21 (27.3)	0.226	3 (60.0)	22 (27.5)	0.149
Child–Pugh class A, n (%)	7 (87.5)	72 (93.5)	0.458	5 (100)	74 (92.5)	1.000
AFP > 400 ng/mL, n (%)	3 (37.5)	29 (37.7)	1.000	2 (40.0)	30 (37.5)	1.000
BCLC stage C, n (%)	5 (62.5)	47 (61.0)	0.257	3 (60.0)	49 (61.3)	1.000
Macrovascular invasion, n (%)	1 (12.5)	17 (22.1)	1.000	0 (0.0)	18 (22.5)	0.579
Extrahepatic spread, n (%)	2 (25.0)	33 (42.9)	0.461	1 (20.0)	34 (42.5)	0.645
Treatment line, 1st line, n (%)	2 (25.0)	37 (48.1)	0.279	2 (40.0)	37 (46.3)	1.000
ECOG-PS ≦ 1, n (%)	8 (100)	77 (100)	1.000	5 (100)	80 (100)	1.000
NLR ≧ 3.43, n (%)	5 (62.5)	30 (39.0)	2.464	4 (80.0)	31 (38.8)	0.154

Competing interest reported. Sadahisa Ogasawara received honoraria from Bayer, Leverkusen, Germany; Eisai, Tokyo, Japan; Eli Lilly, Indianapolis, IN, USA; Chugai Pharma, Tokyo, Japan; AstraZeneca, Cambridge, UK; and Merck & Co., Inc., Kenilworth, NJ, USA, consulting or advisory fees from Bayer, Eisai, Merck & Co., Inc., Chugai Pharma, Eli Lilly, and AstraZeneca, and research grants from Bayer, AstraZeneca, and Eisai. Naoya Kato received honoraria from Bayer, Eisai, Sumitomo Dainippon Pharma, Tokyo, Japan, and Merck & Co., Inc.; consulting or advisory fees from Bayer and Eisai; and research grants from Bayer and Eisai.

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Analysis of hyperprogressive disease due to atezolizumab combined with bevacizumab treatment in patients with advanced hepatocellular carcinoma

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Introduction

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Patients

Radiological evaluation

Definitions of tumor growth dynamics and HPD

Statistical analysis

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Patient characteristics

Treatment outcomes and identification of HPD in patients treated with Atez/Bev in the present cohort

Tumor growth dynamics using TGK_R and TGR and associations between HPD

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Analysis of hyperprogressive disease due to atezolizumab combined with bevacizumab treatment in patients with advanced hepatocellular carcinoma

Status:

Version 1

Abstract

Figures

Introduction

Methods

Patients

Radiological evaluation

Definitions of tumor growth dynamics and HPD

Statistical analysis

Results

Patient characteristics

Treatment outcomes and identification of HPD in patients treated with Atez/Bev in the present cohort

Tumor growth dynamics using TGKR and TGR and associations between HPD

Discussion

Declarations

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1

Tumor growth dynamics using TGK_R and TGR and associations between HPD