**E**ff**ectiveness and Safety of Nivolumab in Child–Pugh B Patients with Hepatocellular Carcinoma: A Real-World Cohort Study**

**Won-Mook Choi <sup>1</sup> , Danbi Lee <sup>1</sup> , Ju Hyun Shim <sup>1</sup> , Kang Mo Kim <sup>1</sup> , Young-Suk Lim <sup>1</sup> , Han Chu Lee <sup>1</sup> , Changhoon Yoo <sup>2</sup> , Sook Ryun Park <sup>2</sup> , Min-Hee Ryu <sup>2</sup> , Baek-Yeol Ryoo <sup>2</sup> and Jonggi Choi 1,\***


Received: 31 May 2020; Accepted: 18 July 2020; Published: 20 July 2020

**Abstract:** Nivolumab has shown durable response and safety in patients with hepatocellular carcinoma (HCC) in previous trials. However, real-world data of nivolumab in HCC patients, especially those with Child–Pugh class B, are limited. To investigate the effectiveness and safety of nivolumab in a real-world cohort of patients with advanced HCC, we retrospectively evaluated 203 patients with HCC who were treated with nivolumab between July 2017 and February 2019. Of 203 patients, 132 patients were classified as Child–Pugh class A and 71 patients were Child–Pugh class B. Objective response rate was lower in patients with Child–Pugh class B than A (2.8% vs. 15.9%; *p* = 0.010). Child–Pugh class B was an independent negative predictor for objective response. Median overall survival was shorter in Child–Pugh B patients (11.3 vs. 42.9 weeks; adjusted hazard ratio [AHR], 2.10; *p* < 0.001). In Child–Pugh B patients, overall survival of patients with Child–Pugh score of 8 or 9 was worse than patients with Child–Pugh score of 7 (7.4 vs. 15.3 weeks; AHR, 1.93; *p* < 0.020). In conclusion, considering the unsatisfactory response in Child–Pugh B patients, nivolumab may not be used in unselected Child–Pugh B patients. Further studies are needed in this patient population.

**Keywords:** liver cancer; immune checkpoint inhibitor; effectiveness; safety

### **1. Introduction**

Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer, and the second most common cause of cancer deaths in Korea and worldwide, leading to nearly 745,000 deaths globally each year [1,2]. Many patients are newly diagnosed with advanced HCC despite regular surveillance of patients at risk, and disease recurrence or progression after initial treatment, which requires systemic therapy, is common [3,4]. Sorafenib, an oral multikinase inhibitor which improved overall survival (OS) compared to placebo in the SHARP trial [5], has been the only viable treatment for HCC over the last decade, but recent successful phase 2/3 trials of first- or second-line therapies have expanded the treatment landscape for patients with advanced HCC [6–9]. However, the majority of systemic therapies have been studied in Child–Pugh A populations. Because most trials of systemic therapies for HCC excluded patients with poor liver function (Child–Pugh B or greater hepatic dysfunction). Therefore, limited data are currently available for systemic therapies in patients with advanced liver

cirrhosis. In real-world practice, liver function of patients with advanced HCC who require systemic therapy is often poor due to the tumor itself, or it has been deteriorated by previous treatments for HCC. Thus, real-world data regarding the safety and clinical outcomes of systemic therapy in HCC patients with poor liver function are of importance to guide the use of systemic therapy in this population.

Nivolumab, an immune checkpoint inhibitor that blocks programmed cell death protein-1, showed durable responses and prolonged long-term survival in the CheckMate 040 trial [6]. Although patients with Child–Pugh class B disease were included in the CheckMate 040 study, the efficacy and safety of nivolumab have not been established in HCC patients with advanced cirrhosis. Eligibility was restricted to patients with Child–Pugh scores of 7 or 8 and patients with ascites requiring paracentesis were excluded from the study. A few retrospective cohort studies and case series have reported on the safety and effectiveness of immune checkpoint inhibitors for advanced HCC patients with poor liver function [10–12]; however, those studies were limited by small numbers of patients. Here we report real-world data on the clinical outcomes and safety of nivolumab using a large retrospective cohort of patients with advanced HCC, including a large number of Child–Pugh B patients.

#### **2. Results**

#### *2.1. Baseline Characteristics of the Study Cohort*

A total of 203 patients were included in the study. Information on patient demographics, liver function characteristics, and cancer staging is presented in Table 1. Of the included patients, 132 patients had Child–Pugh class A disease and 71 patients had Child–Pugh class B disease. Most of the baseline characteristics between Child–Pugh A and B patients were significantly different. The Eastern Cooperative Oncology Group (ECOG) performance status was higher in Child–Pugh B patients than in Child–Pugh A patients. Moreover, Child–Pugh B patients had more aggressive tumor characteristics at baseline than Child–Pugh A patients, including higher levels of α-fetoprotein and protein induced by vitamin K absence or antagonist-II, and Child–Pugh B patients had more patients with portal vein invasion (Table 1).

#### *2.2. Treatment Outcomes of Patients Receiving Nivolumab*

Over a maximum follow-up period of 37.0 months with a median follow-up duration of 5.6 months (interquartile range [IQR], 2.3–11.4), 146 patients died, and 150 patients experienced disease progression after nivolumab treatment. The treatment overview of the study population is summarized in Table 2. The median duration of nivolumab treatment was 1.6 (IQR, 0.9–5.0) and 0.9 (IQR, 0.5–1.9) months with a median of four (ranged 1–57) and three (ranged 1–34) cycles; 17 (12.9%) and eight (11.3%) patients remained on treatment at the time of the last follow-up in Child–Pugh A and B groups, respectively. One hundred and fifteen (87.1%) and 63 (88.7%) patients discontinued treatment in Child–Pugh A and B groups, respectively; the reasons for treatment discontinuation were disease progression in 103 (78.0%) and 46 (64.8%) patients, death in seven (5.3%) and 16 (22.5%) patients, and adverse events (AEs) in five (3.8%) and one (1.4%) patients in Child–Pugh A and B groups, respectively. During treatment, one patient (0.5%) achieved a complete response, while 22 (10.8%) patients achieved a partial response, and 49 (24.1%) patients had stable disease, with an 11.3% objective response rate (ORR) in the total study population.


**Table 1.** Baseline characteristics of the study population.

Abbreviations: ALBI, albumin-bilirubin; BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus; IQR, interquartile range; PIVKA, protein induced by vitamin K absence or antagonist-II; SD, standard deviation.


**Table 2.** Treatment summary of the study population.

Abbreviations: IQR, interquartile range; SD, standard deviation.

#### *2.3. Treatment Outcomes Stratified by Child–Pugh Class*

When stratified by Child–Pugh class, ORR was significantly lower in the Child–Pugh B group than in the Child–Pugh A group (2.8% vs. 15.9%; *p* = 0.010) (Table 3). Two Child–Pugh B patients (2.8%) achieved partial response, with response ongoing for over six months at the time of last follow-up. Disease control rate (DCR) in the total study population was 35.5%. DCR was lower in the Child–Pugh B group than in the Child–Pugh A group (22.5% vs. 42.4%; *p* = 0.008) (Table 3).

**Table 3.** Tumor responses in the study population according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria.


<sup>a</sup> By χ 2 test or Fisher exact test, as appropriate, for radiologic response. <sup>b</sup> Due to death without radiologic disease progression or early drug discontinuation due to a severe adverse drug reaction. <sup>c</sup> Objective response rate, defined as the proportion of patients who had complete response or partial response. <sup>d</sup> Disease control rate, defined as the proportion of patients who had complete response, partial response, or stable disease.

OS was longer in the Child–Pugh A group than in the Child–Pugh B group (42.9 vs. 11.3 weeks; hazard ratio [HR], 3.02; 95% confidence interval [CI], 2.15–4.24; *p* < 0.001; Figure 1A); consistent results were also seen in the multivariable analyses (adjusted hazard ratio [AHR], 2.10; 95% CI, 1.38–3.19; *p* < 0.001) (Table 4). In addition to Child–Pugh class, ECOG performance status, albumin-bilirubin grade of 3, and α-fetoprotein were other independent prognostic factors for OS of the study population in the multivariable analysis (Table S1). Median progression-free survival (PFS) was longer in the Child–Pugh A group than in the Child–Pugh B group in the univariate analysis (7.4 vs. 6.0 weeks; HR, 1.67; 95% CI, 1.22–2.29; *p* = 0.014; Figure 1B); however, this difference was not statistically significant after multivariable adjustment (AHR, 1.17; 95% CI, 0.79–1.72; *p* = 0.430) (Table 4). ECOG performance

status and liver involvement of HCC were poor prognostic factors for PFS in the multivariable analysis (Table S2). Median time to progression (TTP) was 7.9 weeks (95% CI, 7.1–11.6) for the Child–Pugh A group and 6.9 weeks (95% CI, 6.0–10.1) for the Child–Pugh B group. There was no difference in TTP between the two groups in the univariate (HR, 1.35; 95% CI, 0.95–1.92; *p* = 0.093) and multivariable (AHR, 1.00; 95% CI, 0.66–1.50; *p* = 0.992) analyses (Table 4). *Cancers* **2020**, *11*, x 20 of 20 11.6) for the Child–Pugh A group and 6.9 weeks (95% CI, 6.0–10.1) for the Child–Pugh B group. There was no difference in TTP between the two groups in the univariate (HR, 1.35; 95% CI, 0.95–1.92; *p* = 0.093) and multivariable (AHR, 1.00; 95% CI, 0.66–1.50; *p* = 0.992) analyses (Table 4).

(**B**) Progression-free survival

**Figure 1.** Kaplan–Meier analyses of survival outcomes between Child–Pugh A and B patients. (**A**) overall survival and (**B**) progression-free survival. **Figure 1.** Kaplan–Meier analyses of survival outcomes between Child–Pugh A and B patients. (**A**) overall survival and (**B**) progression-free survival.

*Cancers* **2019**, *11*, x; doi: www.mdpi.com/journal/cancers


**Table 4.** Survival outcomes of the study population.

<sup>a</sup> Cox proportional hazard regression model for the Child–Pugh B group with the Child–Pugh A group as a reference. Abbreviations: AHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio.

#### *2.4. Treatment Outcomes of Child–Pugh B Patients Receiving Nivolumab*

Of 71 patients with Child–Pugh class B disease, 41 patients had a Child–Pugh score of 7 and the remaining 30 patients had Child–Pugh scores of 8 or 9. Marginally longer OS was observed in patients with a Child–Pugh score of 7 compared to patients with Child–Pugh scores of 8 or 9 in the univariate analysis (15.3 vs. 7.4 weeks; HR, 1.64; 95% CI, 0.98–2.72; *p* = 0.058; Figure 2A), and this difference became statistically significant after multivariable adjustment (AHR, 1.93; 95% CI, 1.11–3.35; *p* = 0.020) (Table 5). There were no significant differences in PFS (6.3 vs. 4.8 weeks; HR, 1.23; 95% CI, 0.74–2.04; *p* = 0.416; Figure 2B and AHR, 1.53; 95% CI, 0.86–2.58; *p* = 0.153) and TTP (6.9 vs. 6.1 weeks; HR, 1.04; 95% CI, 0.57–1.88; *p* = 0.895 and AHR, 1.30; 95% CI, 0.70–2.40; *p* = 0.408) between the two groups both in the univariate and multivariable analyses (Table 5). ECOG performance status and lung involvement of HCC were independent risk factors for poor OS and PFS in the multivariate analysis (Tables S3 and S4).


**Table 5.** Survival outcomes of Child–Pugh B patients.

<sup>a</sup> Cox proportional hazard regression model for the Child–Pugh B8/9 group with the Child–Pugh B7 group as a reference. Abbreviations: AHR, adjusted hazard ratio; CI, confidence interval; HR, hazard ratio; NA, not applicable.

#### *2.5. Predictive Factors Associated with Treatment Response*

Regarding predictive factors associated with treatment response (i.e., complete response and partial response) in patients receiving nivolumab, patients with advanced liver disease (Child–Pugh class B vs. Child–Pugh class A), high levels of tumor markers and liver involvement of HCC were poorly responsive to treatment by univariate analysis. After inclusion of predictive factors with a *p* value < 0.05 from the univariate analysis in the multivariable-adjusted model, Child–Pugh class (B vs. A; adjusted odds ratio [AOR], 0.21; 95% CI, 0.05–0.93; *p* = 0.040) and liver involvement of HCC (AOR, 0.34; 95% CI, 0.13–0.92; *p* = 0.034) remained as significant independent negative predictors for treatment response (Table 6).
