Correlation between immune-related adverse events and long-terms outcome in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: a retrospective study

doi:10.21203/rs.3.rs-2222674/v1

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Correlation between immune-related adverse events and long-terms outcome in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: a retrospective study

https://doi.org/10.21203/rs.3.rs-2222674/v1

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Background

Although immune checkpoint inhibitors (ICIs) therapy has improved the prognosis of unresectable hepatocellular carcinoma (HCC), it has also resulted in the unique immune-related adverse events (irAE). The relationship between irAE and treatment outcomes in ICIs-treated advanced HCC patients remains unknown.

Methods

From March 2019 to February 2021, a total of 190 unresectable HCC (BCLC C) patients receiving Pembrolizumab treatment were retrospectively reviewed. Overall survival (OS) was the primary endpoint. objective response rate (ORR), disease control rate (DCR) and time to progression (TTP) were secondary evaluation indexes. We assessed demographics, irAE and outcomes by retrospective review.

Results

One hundred and forty-three male and 47 female were included in the study. The ORR and DCR were 12.1% (23/190) and 52.1% (99/190) respectively. The median OS was 376 days (95% CI 340 -411 days) and the median TTP was 98 days (95% CI 75 -124 days). The overall incidence of treatment-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Child-Pugh B class, PVTT, extrahepatic metastasis, and hypothyroidism were the independent risk factors of survival. Patients with hypothyroidism were observed a longer OS than those without irAE (517 days [95% CI 423-562] vs. 431 days, [95% CI 412-485], P=0.011) and a longer TTP (125 [95% CI 89-154] vs. 87 days [95% CI 61-98], P=0.004).

Conclusion

Unresectable HCC patients experienced hypothyroidism indicated a bettertherapeutic effect.Hypothyroidism, an immune-related adverse event may be used as a clinical evaluation parameter of HCC response to ICIs.

hepatocellular carcinoma

immune checkpoint inhibitors

immune-related adverse events

overall survival

retrospective study

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death globally^[1]. Because early-stage of HCC is insidious and tumor has a tendency to invade intrahepatic vessels and distant metastasis, 80% of patients are already in the advanced stage and lose the opportunity of hepatectomy. In addition, 70% patients who received radical liver resection will experience tumor recurrence^[2]. Therefore, a large number of patients with unresectable HCC need comprehensive treatment. Locoregional therapy including radiofrequency ablation (RFA), transarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) has been proven to prolong median survival of advanced HCC^[3]. Since sorafenib has been shown to improve the prognosis of advanced HCC^[4], tyrosine kinase inhibitors (TKIs) have become the first-line treatment for advanced HCC. However, the objective response rate (ORR) of TKIs was unsatisfactory, ranging from 6.5–18.8%, and the prognosis improvement was not significant, with an average prolonged survival time of 2.8 to 5.8 months^{[5, 6]}. Recent studies have shown that immune checkpoint inhibitors (ICI) represented by pembrolizumab have become second-line treatment for advanced HCC due to their safety and long duration of response. KEYNOTE-224, a non-randomized, multi-center, open-label, phase 2 trial have proven that pembrolizumab was effective and tolerable in patients with advanced HCC who had previously been treated with sorafenib^[7].

However, the response rate of both TKIs and ICIs was less than 30%. Moreover, adverse effects of the drugs, may interfere with the judgment of curative effect and decrease the compliance to the best treatment available. Therefore, determining patients who are mostly likely to benefit from TKIs or ICIs is very important. People have been trying to find biomarkers that predict patient survival or response to drugs^[8]. Previous studies have reported that advanced HCC patients who developed hand-foot skin reaction (HFS) possessed a prolonged time to progression and better disease-control rate (DCR)^[9]. Studies have suggested that vascular endothelial growth factor (VEGF) inhibition may rely on a stronger recruitment of inflammatory cells to take a more pronounced antitumor effect that accompanied with a stronger treatment-related adverse events^[10]. Whether similar adverse events can be found to evaluate response of tumor to ICIs. irAEs has been reported to include polymyalgia, colitis, skin lesions (rash, pruritus, and vitiligo), hypophysitis, hepatitis, thyroiditis, uveitis, Guillain-Barré syndrome and immune-mediated cytopenia. It was reported that the overall incidence of all-grade irAEs was 60–80% and the incidence of high-grade irAEs was 20–30%^{[11, 12]}. Several studies have suggested that accompanying with antitumor effects, autoimmunelike toxic effects are thought to represent bystander effects from activated T-cells and are consistent with the mechanism of action of ICIs^{[13, 14]}. Herein, we retrospectively studied whether immune-related toxic effects correlated with prognosis in patients with advanced HCC treated with Pembrolizumab.

Terminology

Overall survival (OS) was defined as the time from start of ICIs until death or until last follow-up. ORR was defined as the proportion of patients achieving to complete response (CR) and partial response (PR). DCR as defined as the proportion of patients achieving to complete response (CR), partial response (PR) and stable disease (SD). Time to progression (TTP) as defined as the time from start of ICIs to the radiological confirmation of tumor progression. Tumor burden score (TBS) = \(\sqrt{{\text{a}}^{2}+{\text{b}}^{2}}\)(a = maximum tumor diameter (cm); measuring the area of arterial enhancement and excluding the area of internal necrosis^[15], b = tumor number; the lesion is least 1cm)^[16].

Patients

Between March 2019 and February 2021, a total of 190 patients who received ICIs treatment was included in the retrospective study at Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. All patients included in the study met these criteria: 1) Child-Pugh A/B; 2) advanced HCC (BCLC C); 3) not receiving previous antitumor therapy. HCC was diagnosed by the European Association for the Study of Liver criteria and American Association for the Study of Liver Disease guideline^{[17, 18]}. The history including age, sex, etc, laboratory examination including levels of alanine transaminase (ALT), aspartate aminotransferase (AST), alpha fetoprotein (AFP), etc, imageological examination and survival status were reviewed retrospectively. The study was approved by the Ethical Committee of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. All procedures performed in this study abided with the Declaration of Helsinki.

Usage of ICIs

All the patients received treatment with Pembrolizumab [KEYTRUDA, Merck Sharp & Dohme Co., Inc.], 200 mg/ time, every 3 weeks, intravenous infusion ^[7] according to the guidelines or expert consensus, with dose modification according to toxic effects as needed.

Follow-up and irAE assessment

Follow-up was terminated on April 24, 2022. The survival status was confirmed by governmental death registration or telephone. An experienced radiologist who blinded to patients’ information assessed the tumor response according to modified response evaluation criteria in solid tumors criteria (mRECIST) every 3–6 weeks by contrast-enhanced CT or MRI examination. Common Terminology Criteria for Adverse Events (CTCAE) was referred to assess independently irAEs by two experienced hepatologists. Corresponding examination or imageological examination were performed to diagnose irAEs and assess the grades according to CTCAE. The flow diagram was displayed in Fig. 1.

Statistics analysis

Continuous variables were presented as the median and interquartile range (IQR) and categorical data as number and percentage. Survival analysis was carried out using Kaplan-Meier method and a log-rank test. Univariate and multivariate Cox proportional regression analysis were used to evaluate risk factors for OS or TTP. A two-sided P < 0.05 was considered statistically significant. Statistical analyses were performed using SPSS version 19.0 for Windows (SPSS, Chicago, Illinois, USA). GraphPad Prism 7 software was used for all graphics drawing.

Demographics

The baseline characteristics of 190 advanced HCC (BCLC C) patients receiving Pembrolizumab as an initial treatment were summarized in the Table 1. One hundred and fifty-four (81.1%) of the patients were male, and the primary cause of disease was chronic hepatitis B virus infection (75.8%). One hundred forty-six (76.8%) of the patients were Child-Pugh class A and 44 (23.2%) were Child-Pugh class B. All the patients were at Barcelona Clinic Liver Cancer (BCLC) stage C.

Table 1

Clinical Characteristics of 190 patients
Clinical characteristics	No. of patients
Patients, N (%)	190 (100)
Age (y) Median (IQR)	51 (42–58)
Sex
Male, N (%)	154 (81.1)
Etiology
Hepatitis B	144 (75.8)
Hepatitis C	4 (2.1)
Hepatitis B & C	2 (1.1)
Non-B, Non-C	40 (21.0)
ALT (U/L) Median IQR)	75 (51–254)
AST (U/L) Median (IQR)	57 (47–302)
TBiL(µmol/L) Median (IQR)	20.1 (11.2–31.2)
AFP (ng/mL) Median (IQR)	205 (19.2–4692)
Child-Pugh
A	146 (76.8)
B	44 (23.2)
Portal vein tumor thrombosis	131 (68.9)
Extrahepatic metastasis
Lung	64 (33.7)
Bone	31 (16.3)
Peritoneum	25 (13.1)
Multiple locations	15 (7.9)
BCLC stage
C	190 (100)
Anti-PD-1 antibody
Camrelizumab	37 (19.5)
Pembrolizumab	120 (63.2)
Tislelizumab	33 (17.3)
Tumor response
Complete response (CR)	0 (0)
Partial response (PR)	23 (12.1)
Stable disease (SD)	76 (40.0)
Progressive disease (PD)	91 (47.9)
Follow-up time, Median (Range)	748 (438–1146) days
TTP, Median (95%CI)	98 (75–124) days
OS, Median (95%CI)	376 (340–411) days
IQR: range interquartile; ALT: alanine transaminase; AST: aspartate aminotransferase; TBiL: total bilirubin; AFP: alpha fetal protein; TTP: time to progression; OS: overall survival; BCLC: Barcelona Clinic Liver Cancer

Tumor response

Follow-up was terminated on April 24, 2022. The mean follow-up time was 814 days (median, 748 days; range, 438–1146 days). No patients achieved CR. Twelve percent (23/190) patients were PR and 40% (76/190) patients were SD. The DCR was 52.1% (99/190) and the PD was 47.9% (91/190). All patients who experienced disease progression permanently discontinued ICIs treatment. None of the patients discontinued ICIs because of adverse effects. At the end of follow-up, 130 patients (68.4%) died. The median OS was 376 days (95% CI 340–411 days) and the median TTP was 98 days (95% CI 75–124 days) (Fig. 2).

The incidence of irAE

The overall incidence of immune-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Table 2 summarized the observed representative irAE. Elevated transaminase (> 3*upper limit of normal) was the most common adverse event to ICIs seen in 69 (36.3%) patients, followed by diarrhea in 40 (21.1%) patients, cutaneous toxic effects in 37 (19.5%) patients, hypothyroidism in 25 (13.2%) patients and proteinuria in 24 (12.6%) patients respectively. Relatively rare adverse events were myocarditis in 3 (1.6%) patients and hypoadrenocorticism in 5 (2.6%) patients. The elevated transaminase was the earliest irAE and median (IQR) was 4.8 weeks (3.5–7.2), followed by cutaneous toxic effects with 5.9 weeks (3.8–7.9), proteinuria with 6.8 weeks with (4.3–8.1), diarrhea with 7.1 weeks (5.2–8.9), hypoadrenocorticism with 7.9 weeks (6.7–9.5), hypothyroidism with 8.7 weeks (6.9–10.9) and myocarditis with 10.2 weeks (8.6–11.9) respectively. Figure 3 had showed that the percentage of TBS change from baseline by treatment of 99 patients who achieved DCR status. We found that those patients who developed myocarditis or hypothyroidism tended to achieve PR and have a more significant decrease in tumor burden. Figure 4 displayed a spider plot which depicted the percentage change in TBS of 25 hypothyroidism patients from baseline by treatment over time. We observed substantial reductions in tumor burden and several responders exhibited deep responses.

Table 2

Incidence of treatment-related adverse events
Adverse events	Any grade	Grade 3	Grade 4
Cutaneous toxic effects	37 (19.5)	3 (1.6)	2 (1.1)
Mucositis	14 (7.4)	2 (1.1)	1 (< 1)
Rash	16 (8.4)	1 (< 1)	1 (< 1)
Pruritus	7 (3.7)	2 (1.1)	0 (0)
Diarrhea	40 (21.1)	4 (2.1)	1 (< 1)
Elevated transaminases	69 (36.3)	10 (5.3)	2 (1.1)
Hypothyroidism	25 (13.2)	4 (2.1)	2 (1.1)
Myocarditis	3 (1.6)	1 (< 1)	2 (1.1)
Hypoadrenocorticism	5 (2.6)	1 (< 1)	0 (0)
Proteinuria	24 (12.6)	5 (2.6)	0 (0)
Overall incidence	138 (72.6)	12 (6.3)	7 (3.7)

Immune-related adverse events and prognosis

In order to determine independent risk factors effecting overall survival, the clinical parameters including demographics, laboratory results and adverse events were included in the univariate and multivariate Cox proportional regression analysis. We found that Child-Pugh B class (HR, 1.321; 95%CI, 1.112–1.711), PVTT (HR, 3.125; 95%CI, 3.021–3.568), extrahepatic metastasis (HR, 2.871; 95%CI, 2.579–3.052) and hypothyroidism (HR,0.641; 95%CI, 0.489–0.901) were the independent risk factors of survival. Similarly, AFP > 400ng/mL (HR, 1.872; 95%CI, 1.357–2.135), PVTT (HR, 2.472; 95%CI, 2.243–2.891), extrahepatic metastasis (HR,1.489; 95%CI, 1.246–1.574), and irAE of hypothyroidism (HR,0.613; 95%CI, 0.362–0.886) were the independent risk factors of TTP (Table 3). The OS and TTP of patients who developed hypothyroidism (n = 25) were compared with those patients without irAE respectively by Kaplan-Meier method and a log-rank test. We found that the median OS was 517 days (95% CI 423–562) in patients with hypothyroidism and longer than those without irAE with 431 days (431 days, [95% CI 412–485], P = 0.011) (Fig. 5A). Similarly, the median TTP was 125 days (95% CI 89–154) in patients with hypothyroidism and longer than those without irAE with 87 days (95% CI 61–98, P = 0.004) (Fig. 5B).

Table 3

Univariate and multivariate analysis of prognostic factors for predicting progression
Variables	Univariate Analysis		Multivariate Analysis
Variables	HR (95% CI)	P	HR (95% CI)	P
OS
Age, > 55y	1.365(0.423–1.574)	0.211
Sex, male	1.378(0.841–1.684)	0.517
Lg (HBV-DNA) > 2	1.123(0.944–1.254)	0.647
ALT > 40U/L	1.258(0.987–1.358)	0.268
AST > 40U/L	1.114(0.875–1.258)	0.744
Total bilirubin > 1mg/dL	1.358(0.974–1.569)	0.147
Child-Pugh, B class	1.446(1.044–1.547)	0.039	1.321(1.112–1.711)	0.021
AFP > 400ng/mL	1.651(1.351–1.782)	0.021	1.446(0.875–1.836)	0.239
PIVKA > 40mAU/mL	1.324(1.023–1.472)	0.043	1.568(0.411–1.687)	0.085
PVTT, yes	2.145(1.897–3.587)	0.003	3.125(3.015–3.568)	0.008
Extrahepatic metastasis, yes	1.784(1.254–2.571)	0.013	2.871(2.581–3.052)	0.028
Diarrhea, yes	1.428(0.874–1.587)	0.125
Cutaneous toxic effects, yes	0.741(0.654–0.968)	0.025	0.845 (0.425–1.751)	0.129
Hypothyroidism, yes	0.623(0.487–0.912)	0.034	0.641(0.489–0.901)	0.017
Proteinuria, yes	0.783(0.689–1.158)	0.139
TTP
Age, > 55y	1.218(0.423–1.174)	0.258
Sex, male	1.178(0.941–1.224)	0.547
Lg (HBV-DNA) > 2	1.148(0.914–1.258)	0.489
ALT > 40U/L	1.369(0.896–1.348)	0.147
AST > 40U/L	1.256(0.759–1.354)	0.249
Total bilirubin > 1mg/dL	1.025(0.895–1.147)	0.124
Child-Pugh, B class	1.196(0.947–1.264)	0.158
AFP > 400ng/mL	1.757(1.271–1.972)	0.023	1.872(1.357–2.135)	0.017
PIVKA > 40mAU/mL	1.141(0.971–1.242)	0.141
PVTT, yes	2.595(1.377–3.889)	0.003	2.472(2.243–2.891)	0.008
Extrahepatic metastasis, yes	1.536(1.296–1.765)	0.031	1.489(1.246–1.574)	0.012
Diarrhea, yes	0.912(0.712–1.241)	0.251
Cutaneous toxic effects, yes	0.874(0.621–0.925)	0.036	0.785(0.358–1.258)	0.157
Hypothyroidism, yes	0.741(0.514–0.870)	0.024	0.613(0.362–0.886)	0.018
Proteinuria, yes	0.849(0.716–1.121)	0.189
ALT: alanine transaminase; AST: aspartate aminotransferase; AFP: alpha fetal protein; PIVKA: protein induced by vitamin K absence or antagonist-II; OS: overall survival; TTP: time to progression; PVTT: portal vein tumor thrombus; HR: hazard rate

It was reported that the incidence of thyroid dysfunction, such as hypothyroidism and hyperthyroidism of about 6–20%^{[19, 20]}. Typically, thyroid dysfunction caused by ICIs triggers transient hyperthyroidism, followed by permanent hypothyroidism in a median of 6–12 weeks^{[21, 22]}. Previous studies have found that the better median PFS and OS in patients with thyroid irAEs^{[23, 24]}, and it could be related to a different immunological background that exposes them to a higher risk of thyroid irAEs but at the same time that makes them more sensitive to the ICI treatment^[25]. In our study, univariate and multivariate Cox proportional regression analysis had shown that patients with hypothyroidism had a longer OS. In addition, we found that patients with hypothyroidism had a significant reduction in TBS from baseline by treatment, which was intuitive manifestation of the effectiveness of immunotherapy. However, the ICIs efficacy and thyroid irAEs are connected remains controversial. It was reported that Intrathyroidal predominance of specific T lymphocytes was associated with ICI-induced thyroiditis^[26]. Although the treatment effect related to irAE have been observed in our study, the underlying mechanisms involved in thyroid irAE and ICIs immunotherapy are not yet understood completely^[27]. It is now generally accepted that pathogenesis of ICI-induced dysthyroidism involves both immune and non-immune mechanisms^[28]. It is traditionally believed that thyroperoxidase (TPO) and thyroglobulin (Tg) antibodies may play an important role in mediating thyroiditis. Maekura et.al considered that the presence of anti-thyroid antibodies such as TPO and Tg antibodies is a positive predictive factor for developing hypothyroidism by a Japanese cohort of 64 patients with advanced non-small cell lung cancer (NSCLC) treated with nivolumab^[29]. Recent study found that the mechanism of thyroid destruction by PD-1 antibodies may be mediated by T cells, NK cells and monocytes ^[30–32]. Delivanis et al. showed that in patients treated with anti-PD-1 therapy had an increasing circulating number of CD56 + CD16 + NK cells and high HLA-DR surface expression in CD14 + CD16 + monocytes that mediate the inflammation. In addition, Das et al considered that B lymphocytes also played a role in mediating dysthyroidism. They showed that patients with advanced melanoma treated by a combined checkpoint blockade (CCB) who developed high-grade irAEs compared to those who did not, had a decreased total peripheral B lymphocyte count with increased plasmablasts and a subset of B lymphocytes^{[33, 34]}.

In a word, dysthyroidism is the most common irAEs and involves T and B-lymphocytes, multiply cytokines, and diverse factors. Further clinical and laboratory researches should be conducted to clarify the mechanism of ICIs-related dysthyroidism. Additionally, the clinical diagnosis and management of thyroid irAEs should be enhanced to avoid life-threatening complications. Besides, the long-term effects of ICIs on dysthyroidism should be further researched to better understand thyroid irAEs and autoimmune thyroid diseases.

In addition, there are some limitations in our study. First, the study is retrospective and conducted only in one center a multicenter should be evaluated in the further study. Second, the sample size was small relatively so that the sample of irAEs was small resulting in large confidence intervals and imprecise results. Third, the effect of different ICIs agents on adverse reactions and prognosis in patients was not excluded strictly in this study. Fourth, our study didn’t include these patients with autoimmune disease, thus the correlation between irAEs and prognosis in patients with autoimmune disease needs further exploration. Finally, some adverse events which tended to be ignored such as fever, weak, anorexia etc. didn’t be recorded resulting in a lower incidence of irAEs than previous studies.

Unresectable HCC patients experienced hypothyroidism indicated a better therapeutic effect. Hypothyroidism, an immune-related adverse event may be used as a clinical evaluation parameter of HCC response to ICIs.

AFP: alpha fetoprotein; ALT: alanine transaminase; AST: aspartate aminotransferase; CR: complete response; CTCAE: Common Terminology Criteria for Adverse Events; DCR: disease-control rate; HCC: hepatocellular carcinoma; HFS: hand-foot skin reaction; irAE: immune-related adverse events; ICIs: immune checkpoint inhibitors; NSCLC: non-small cell lung cancer; OS: overall survival; ORR: objective response rate; PD-1: programmed cell death protein; PVTT: portal vein tumor thrombosis; PIVKA-II: vitamin K deficiency or antagonist- II; PR: partial response; RFA: radiofrequency ablation; SIRT: selective internal radiation therapy; TBS: tumor burden score; TACE: transcatheter arterial chemoembolization; TTP: time to progression; TKIs: tyrosine kinase inhibitors; THs: thyroid hormones; VEGF: vascular endothelial growth factor

Ethics approval and consent to participate: The study was approved by the Ethical Committee of Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology. All procedures performed in this study abided with the Declaration of Helsinki.

Consent for publication: Patients consented to publication.

Availability of data and materials: The datasets [data] for this study can be found in the [figure] [https://figshare.com/s/ee63fa5271448d51104e ]. The other datasets were available on request from the corresponding author at [email protected]

Competing interests: All authors declared that they have no financial relationships to disclose.

Funding: Not applicable

Authors’ contributions: J.M.Z analyzed data and wrote the manuscript. ZWZ designed the research route. B.W modified the manuscript. All authors read and approved the final manuscript.

Acknowledgement

The authors would like to thank Chang Shu (Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology) for his assistance of statistic.

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No competing interests reported.

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Correlation between immune-related adverse events and long-terms outcome in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: a retrospective study

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Abstract

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Introduction

Materials And Methods

Terminology

Patients

Usage of ICIs

Follow-up and irAE assessment

Statistics analysis

Results

Demographics

Tumor response

The incidence of irAE

Immune-related adverse events and prognosis

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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