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Nivolumab in advanced hepatocellular carcinoma: Sorafenib-experienced Asian cohort analysis

Open AccessPublished:June 06, 2019DOI:https://doi.org/10.1016/j.jhep.2019.05.014

      Highlights

      • Objective responses and survival were comparable between intent-to-treat (ITT) overall population and Asian cohort.
      • Median overall survival in Asian patients was similar across HCC aetiologies.
      • Nivolumab had a manageable safety profile in both the ITT overall population and Asian cohort.

      Background & Aims

      Nivolumab, an immune checkpoint inhibitor, is approved in several countries to treat sorafenib-experienced patients with HCC, based on results from the CheckMate 040 study (NCT01658878). Marked differences exist in HCC clinical presentation, aetiology, treatment patterns and outcomes across regions. This analysis assessed the safety and efficacy of nivolumab in the Asian cohort of CheckMate 040.

      Methods

      CheckMate 040 is an international, multicentre, open-label, phase I/II study of nivolumab in adults with advanced HCC, regardless of aetiology, not amenable to curative resection or local treatment and with/without previous sorafenib treatment. This analysis included all sorafenib-experienced patients in the intent-to-treat (ITT) overall population and Asian cohort. The analysis cut-off date was March 2018.

      Results

      There were 182 and 85 patients in the ITT population and Asian cohort, respectively. In both populations, most patients were older than 60 years, had BCLC (Barcelona Clinic Liver Cancer) Stage C disease, and had received previous systemic therapy. A higher percentage of Asian patients had HBV infections, extrahepatic metastases and prior therapies. Median follow-up was 31.6 and 31.3 months for the ITT and Asian patients, respectively. Objective response rates were 14% and 15% in the ITT population and Asian cohort, respectively. In the Asian cohort, patients with HBV, HCV or those who were uninfected had objective response rates of 13%, 14% and 21%, respectively. The median duration of response was longer in the ITT (19.4 months) vs. Asian patients (9.7 months). Median overall survival was similar between the ITT (15.1 months) and Asian patients (14.9 months), and unaffected by aetiology in Asian patients. The nivolumab safety profile was similar and manageable across both populations.

      Conclusion

      Nivolumab safety and efficacy are comparable between sorafenib-experienced ITT and Asian patients.

      Lay summary

      The CheckMate 040 study evaluated the safety and efficacy of nivolumab in patients with advanced hepatocellular carcinoma who were refractory to previous sorafenib treatment or chemotherapy. This subanalysis of the data showed that treatment responses and safety in patients in Asia were similar to those of the overall treatment population, providing support for nivolumab as a treatment option for these patients.
      Clinical trial number: NCT01658878.

      Graphical abstract

      Keywords

      Linked Article

      Introduction

      Worldwide, liver cancer is predicted to be the fourth most common cause of cancer-related mortality, accounting for an estimated 782,000 deaths in 2018, with most liver cancers HCC.
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      The phase I/II CheckMate 040 study (NCT01658878; CA209-040) investigated nivolumab treatment in patients with advanced HCC. In the dose-expansion phase of this study, patients received nivolumab 3 mg/kg, and the objective response rate (ORR) was 20%, with a median duration of response (DOR) of 9.9 months and a 9-month OS rate of 74%.
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      The nivolumab safety profile was consistent with that observed in other tumour types and no new safety signals were observed. Nivolumab is approved in various countries, including the USA, Canada, Taiwan, Hong Kong and Australia, for patients with advanced HCC who were previously treated with sorafenib. Similarly, the phase II pembrolizumab trial also confirmed promising efficacy with good tolerability for checkpoint inhibitor therapy in patients with advanced HCC. Interestingly, the pembrolizumab trial demonstrated a trend in ORR in patients in the USA vs. those elsewhere (26% vs. 15%, respectively), again suggesting regional variation in treatment outcomes.
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      Given the observed differences in treatment outcome with various systemic therapies, particularly with targeted agents, and the trend towards varying regional ORRs in patients with advanced HCC treated with pembrolizumab, it is important to understand possible differences in nivolumab treatment outcomes in non-Asian vs. Asian populations. Thus, this analysis assesses the safety and efficacy profile of nivolumab in patients recruited from Asia vs. those of the broader intent-to-treat (ITT) patient population in the CheckMate 040 study.

      Patients and methods

      Study design

      The multicentre, open-label, phase I/II CheckMate 040 study included dose-escalation and -expansion cohorts to evaluate nivolumab efficacy and safety in patients with advanced HCC with or without chronic viral hepatitis (patients with HBV had detectable HBsAg, HBeAg, or HBV DNA; patients with HCV had detectable HCV RNA). Patients aged 18 years or older with histologically confirmed HCC, previously treated with sorafenib or naïve and/or intolerant to sorafenib, and not amenable to curative resection or local treatment, were eligible for the study. Study design details have been previously published.
      • El-Khoueiry A.B.
      • Sangro B.
      • Yau T.
      • Crocenzi T.S.
      • Kudo M.
      • Hsu C.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
      This analysis includes patients from both the dose-escalation and -expansion phases of the study. The ITT population included sorafenib-experienced patients from the global ITT population, and the Asian cohort included all such patients from the ITT population who were recruited in Asian countries (Fig. S1). Most patients received nivolumab 3 mg/kg (ITT, n = 154; Asian, n = 76). Fewer patients received either lower doses of 0.1 mg/kg (ITT, n = 5; Asian, n = 3), 0.3 mg/kg (ITT, n = 7; Asian, n = 3), or 1.0 mg/kg (ITT, n = 6; Asian, n = 2), or a higher dose of 10 mg/kg (ITT, n = 10; Asian, n = 1).

      Endpoints and assessments

      The primary endpoints in CheckMate 040 were safety and tolerability for the dose-escalation phase and ORR by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 for the dose-expansion phase.
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      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
      Key secondary endpoints included ORR for the dose-escalation phase, complete response (CR) rate, disease control rate (DCR; the proportion of patients whose best overall response was CR, partial response [PR], or stable disease [SD; where predefined SD criteria must have been met at least once within ∼6 weeks of the first nivolumab dose]), DOR, OS and response stratified by tumour programmed death-ligand 1 (PD-L1) expression. Disease assessments were performed by BICR per RECIST v.1.1
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      using computed tomography (CT) or magnetic resonance imaging (MRI). Tumour assessment by modified RECIST (mRECIST; by BICR) was an exploratory endpoint.
      Tumour biopsies collected at baseline, either fresh or archival, were used retrospectively for the analysis of tumour PD-L1 expression by immunohistochemistry using the PD-L1 IHC 28-8 pharmDx assay (Dako, an Agilent Technologies Inc. company, Santa Clara, CA, USA; for further details regarding the materials used, please refer to the CTAT table and Supplementary information). Additional details on measurement of tumour PD-L1 expression are described in the appendix of the primary paper for this study.
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      • Crocenzi T.S.
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      • Hsu C.
      • et al.
      Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial.
      Safety was assessed continuously during treatment and for up to 30 days after the last dose or until all treatment-related adverse events (TRAEs) were resolved to baseline levels or deemed irreversible by the investigator.
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      Select adverse events (AEs) were defined as events with a potential inflammatory mechanism requiring more frequent monitoring and/or unique intervention, such as immunosuppressants and/or endocrine replacement therapy. These included gastrointestinal AEs, pulmonary AEs, renal AEs, hepatic AEs, skin AEs, hypersensitivity AEs and endocrinopathies. Patients received a survival follow-up assessment every 3 months.

      Study oversight

      The CheckMate 040 study was approved by the institutional review board or independent ethics committee at each site and was conducted in accordance with Good Clinical Practice guidelines defined by the International Council on Harmonisation. All patients provided written informed consent to participate based on the principles of the Declaration of Helsinki.

      Statistical analyses

      Two-sided 95% confidence intervals (CIs) were estimated using the Clopper–Pearson method for ORR, CR rate and DCR. Kaplan–Meier methodology was used to determine medians and 95% CIs for DOR, OS and OS rate.

      Results

      Patients

      The cut-off date for this analysis was March 2018. There were 182 patients in the ITT population and 85 patients in the Asian cohort. Asian patients were recruited from Japan (n = 26), Hong Kong (n = 24), Taiwan (n = 17), South Korea (n = 13), and Singapore (n = 5).
      Table 1 shows the baseline patient characteristics. Patients in the ITT population and Asian cohort were comparable in terms of median age, sex distribution and liver function status by Child–Pugh scoring. The dominant aetiology was HBV in the Asian cohort (55%) and uninfected (non-hepatitis virus related) in the ITT population (49%). Of interest, 28% of the patients in the Asian cohort had non-viral HCC and 32% of the ITT population had HBV-related HCC.
      Table 1Baseline patient characteristics.
      Patient characteristicITT population (n = 182)Asian cohort (n = 85)
      Median age (range), years63 (19–81)62 (22–81)
      Male, n (%)139 (76)65 (76)
      Race, n (%)
      Asian91 (50)85 (100)
      Chinese49 (27)45 (53)
      Japanese25 (14)25 (29)
      Korean13 (7)13 (15)
      Other Asian3 (2)1 (1)
      Asian Indian1 (1)1 (1)
      White87 (48)0
      Black4 (2)0
      HCC aetiology, n (%)
       HCV infected35 (19)14 (16)
       HBV infected58 (32)47 (55)
       Uninfected89 (49)24 (28)
      BCLC stage all patients, n (%)
       B17 (9)5 (6)
       C162 (89)80 (94)
      BCLC stage HBV, n (%)
       B2 (3)1 (2)
       C56 (97)46 (98)
      BCLC stage HCV, n (%)
       B6 (17)4 (29)
       C26 (74)10 (71)
      BCLC stage uninfected, n (%)
       B9 (10)0 (0)
       C80 (90)24 (100)
      Extrahepatic metastases, n (%)129 (71)70 (82)
      Vascular invasion, n (%)55 (30)24 (28)
      Child–Pugh score of 5–6, n (%)180 (99)84 (99)
      AFP ≥400 µg/L, n (%)
      AFP data were not available in five ITT patients and in one Asian patient.
      67 (37)37 (44)
      Prior therapy, n (%)
       Surgical resection122 (67)66 (78)
       Radiotherapy45 (25)23 (27)
       Local treatment for HCC104 (57)64 (75)
       Sorafenib182 (100)85 (100)
      Reason for sorafenib discontinuation
      Some patients had more than one reason for sorafenib discontinuation.
       Disease progression135 (74)66 (78)
       Toxicity39 (21)16 (19)
       Other10 (5)4 (5)
      Number of prior therapies, n (%)
       1141 (77)55 (65)
       220 (11)14 (16)
       ≥321 (12)16 (19)
      AFP, alpha-fetoprotein; BCLC, Barcelona Clinic Liver Cancer; ITT, intent-to-treat.
      * AFP data were not available in five ITT patients and in one Asian patient.
      Some patients had more than one reason for sorafenib discontinuation.
      Overall, most patients were staged as Barcelona Clinic Liver Cancer (BCLC) C in both the Asian cohort and ITT population. Most patients with HBV-related HCC and non-viral HCC were also staged as BCLC C in both populations. For HCV-related HCC, a larger proportion of patients were staged as BCLC B in the Asian cohort (29%) compared with the ITT population (17%).
      The Asian cohort had a slightly higher percentage of patients with extrahepatic metastases compared with the ITT population (82% vs. 71%, respectively). The presence of vascular invasion and an alpha-fetoprotein (AFP) score 400 µg/L at baseline was comparable between the two populations. The Asian cohort had a slightly higher frequency of surgical resection (78% vs. 67%, respectively) and a higher frequency of locoregional therapy (75% vs. 57%, respectively) compared with the ITT population. Most patients had progressed on sorafenib: 74% in the ITT population and 78% in the Asian cohort. A higher percentage of patients in the Asian cohort (35%) had received two or more prior therapies compared with the ITT population (23%). When baseline characteristics of the Asian cohort were compared directly to the non-Asian cohort (i.e. all patients recruited outside of Asia), there was a similar trend toward more extrahepatic metastases and a greater number of prior systemic therapies in the Asian cohort (Table S1).

      Efficacy

      Treatment responses to nivolumab are shown in Table 2. The ORRs were comparable between the Asian cohort (15%) and ITT population (14%). There was a slightly higher percentage of patients with progressive disease (PD) in the Asian cohort (47%) compared with the ITT population (39%). Comparable DCRs were observed between the Asian cohort (49%) and ITT population (55%). Notably, the median DOR (95% CI) was shorter for the Asian cohort (9.7 months [5.6–not evaluable]) than for the ITT population (19.4 months [9.7–not evaluable]). The median time to response in the Asian cohort (2.8 months) was comparable with that of the ITT population (2.7 months) (Fig. 1). Ongoing responses were seen in one of 13 responders in the Asian cohort and in seven of 26 responders in the ITT population. When tumour responses in the Asian cohort were compared directly with the non-Asian cohort, ORRs of 15% and 13% were reported in the Asian and non-Asian patients, respectively; the median DOR was not evaluable in the non-Asian cohort because less than half of the responders had progressed (Table S2). The ORR was also analysed using mRECIST by BICR; under these criteria, the ORR was 24% in the Asian cohort, 13% in the non-Asian cohort and 18% in the ITT population (Table S2).
      Table 2Antitumour activity.
      ActivityITT population (n = 182)
      Tumour responses were not evaluable in 12 ITT patients and in three Asian patients.
      Asian cohort (n = 85)
      Tumour responses were not evaluable in 12 ITT patients and in three Asian patients.
      Uninfected (n = 89)HBV (n = 58)HCV (n = 35)All (n = 182)Uninfected (n = 24)HBV (n = 47)HCV (n = 14)All (n = 85)
      ORR, n (%)
      Reported by BICR using RECIST v1.1.
      ,
      Defined as CR + PR.
      12 (13)7 (12)7 (20)26 (14)5 (21)6 (13)2 (14)13 (15)
       CR1 (1)3 (5)1 (3)5 (3)02 (4)1 (7)3 (4)
       PR11 (12)4 (7)6 (17)21 (12)5 (21)4 (9)1 (7)10 (12)
      SD, n (%)
      Reported by BICR using RECIST v1.1.
      ,
      Stable disease was reported as non-CR/non-PD in two patients in the ITT population.
      43 (48)18 (31)11 (31)72 (40)9 (38)15 (32)5 (36)29 (34)
      PD, n (%)
      Reported by BICR using RECIST v1.1.
      28 (32)29 (50)13 (37)70 (39)9 (38)25 (53)6 (43)40 (47)
      DCR, n (%)
      Reported by BICR using RECIST v1.1.
      ,
      DCR defined as CR + PR + SD.
      56 (63)26 (45)18 (51)100 (55)14 (58)21 (45)7 (50)42 (49)
      KM Median DOR (95% CI), months
      Reported by BICR using RECIST v1.1.
      11.3 (8.3–NE)NE (2.8–NE)NE (3.2–NE)19.4 (9.7–NE)9.4 (5.6–11.2)NE (2.8–NE)6.4 (3.2–9.7)9.7 (5.6–NE)
      PD-L1 expression ≥1%, n (%)
      Tumour cell PD-L1 expression was not evaluable in 20 ITT patients and in two Asian patients.
      12 (14)13 (22)9 (26)34 (19)3 (13)10 (21)3 (21)16 (19)
       ORR, n/N (%; 95% CI)
      ORR by investigator assessment using RECIST v1.1.
      5/12 (42; 15.2–72.3)2/13 (15; 1.9–45.4)3/9 (33; 7.5–70.1)10/34 (29; 15.1–47.5)1/3 (33; 0.8–90.6)0/10 (0; 0.0–30.8)1/3 (33; 0.8–90.6)2/16 (13; 1.6–38.3)
      PD-L1 expression <1%, n (%)
      Tumour cell PD-L1 expression was not evaluable in 20 ITT patients and in two Asian patients.
      60 (67)43 (74)25 (71)128 (70)20 (83)36 (77)11 (79)67 (79)
       ORR, n/N (%; 95% CI)
      ORR by investigator assessment using RECIST v1.1.
      13/60 (22; 12.1–34.2)5/43 (12; 3.9–25.1)7/25 (28; 12.1–49.4)25/128 (20; 13.1–27.5)7/20 (35; 15.4–59.2)5/36 (14; 4.7–29.5)3/11 (27; 6.0–61.0)15/67 (22; 13.1–34.2)
      BICR, blinded independent central review; CR, complete response; DCR, disease control rate; DOR, duration of response; ITT, intent-to-treat; KM, Kaplan-Meier; NE, not estimable; ORR, objective response rate; PD, progressive disease; PD-L1, programmed death-ligand 1; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.
      * Tumour responses were not evaluable in 12 ITT patients and in three Asian patients.
      ** Tumour cell PD-L1 expression was not evaluable in 20 ITT patients and in two Asian patients.
      Reported by BICR using RECIST v1.1.
      Defined as CR + PR.
      § Stable disease was reported as non-CR/non-PD in two patients in the ITT population.
      DCR defined as CR + PR + SD.
      †† ORR by investigator assessment using RECIST v1.1.
      Figure thumbnail gr1
      Fig. 1Characterisation of response. (A) ITT population (n = 26 responses). (B) Asian cohort (n = 13 responses). Tumour response assessed by BICR using RECIST v1.1; bars represent time to progression (in months). Abbreviations: BICR, blinded independent central review; ITT, intent-to-treat; NE, not estimable; RECIST, Response Evaluation Criteria in Solid Tumours.
      Reductions from baseline in tumour burden were seen in both the Asian cohort and ITT population irrespective of HCC aetiology (Fig. 2). In both populations, no marked differences in outcomes were observed relative to tumour PD-L1 expression (Table 2). Objective responses occurred regardless of PD-L1 tumour expression across all aetiologies. Responses in both populations were also not affected by age categorisation (<65 years vs. ≥65 years; Table S3).
      Figure thumbnail gr2
      Fig. 2Waterfall plots depicting the best reduction in target lesions by aetiology. (A) ITT population. (B) Asian cohort. Dashed line indicates a 30% reduction, consistent with a response per RECIST v1.1. The asterisk represents responders; the square symbol represents percentage change truncated to 100%. Abbreviations: ITT, intent-to-treat; RECIST, Response Evaluation Criteria in Solid Tumours.
      Median OS (95% CI) was comparable between the Asian cohort (14.9 [11.6–18.9] months) and ITT population (15.1 [13.2–18.2] months) (Fig. 3A). OS rates at 12, 18, and 24 months were similarly comparable. Median OS (95% CI) for the non-Asian cohort was similar to that noted earlier, at 15.6 (11.3–20.2) months (Fig. 3B). Survival in both populations was also similar across HCC aetiology (Fig. 4) and when categorised by age (<65 years vs. ≥65 years; Fig. S2). In both the Asian cohort and ITT population, 100% of patients achieving a CR survived up to 24 months from the date of randomisation (Fig. S3).
      Figure thumbnail gr3
      Fig. 3Kaplan–Meier analysis of overall survival. (A) ITT population and Asian cohort. (B) Asian and non-Asian cohorts. Abbreviations: ITT, intent-to-treat; OS, overall survival.
      Figure thumbnail gr4
      Fig. 4Kaplan–Meier analysis of overall survival stratified by aetiology. (A) ITT population. (B) Asian cohort. Abbreviations: ITT, intent-to-treat; NE, not estimable; OS, overall survival.

      Safety

      The frequency of any grade TRAEs was comparable between the Asian cohort and ITT population (74% and 79%, respectively; Table 3). The frequency of Grade 3/4 TRAEs was similarly comparable between the Asian cohort (16%) and ITT population (19%). The most common TRAEs of any grade in both populations were pruritus, rash and fatigue. TRAEs of laboratory measures were infrequent in both populations, with <10% of patients experiencing TRAEs of any grade and ≤5% of patients experiencing Grade 3/4 TRAEs for each laboratory parameter assessed. Of note, increases in aminotransferases were infrequent in both populations. In the Asian cohort, no TRAEs of ascites or encephalopathy were reported; in the ITT population, any grade treatment-related ascites was only reported in one patient (0.5%) and no patients had encephalopathy. In the Asian cohort, 11% (5/47) of patients with HBV had >1 log increase in HBV DNA and 21% (3/14) of patients with HCV had >1 log decrease in HCV RNA from baseline. In the ITT population, 9% (5/58) of patients with HBV and 26% (9/35) of patients with HCV had >1 log increase in HBV DNA and >1 log decrease in HCV RNA from baseline, respectively. Changes in viral kinetics were not associated with nivolumab-related significant hepatic AEs.
      Table 3Treatment-related adverse events.
      Includes events reported between first dose and 30 days after last dose of study therapy. Event terms were reported by investigators and were not predefined.
      Adverse eventsITT population (n = 182)Asian cohort (n = 85)
      Any gradeGrade 3/4Any gradeGrade 3/4
      TRAEs
      Any TRAE, n (%)143 (79)34 (19)63 (74)14 (16)
      TRAEs (≥10%)
      Reported in ≥10% or ≥5% of all patients in any population, any grade.
      , n (%)
       Pruritus37 (20)1 (1)22 (26)0
       Rash33 (18)1 (1)15 (18)0
       Fatigue42 (23)4 (2)12 (14)0
       Decreased appetite15 (8)1 (1)9 (11)0
       Diarrhoea27 (15)2 (1)8 (9)1 (1)
      Laboratory TRAEs (≥5%)
      Reported in ≥10% or ≥5% of all patients in any population, any grade.
      , n (%)
       Platelet count decreased9 (5)4 (2)8 (9)3 (4)
       Lipase increased12 (7)8 (4)4 (5)4 (5)
       ALT increase16 (9)5 (3)4 (5)0
       AST increased16 (9)7 (4)3 (4)1 (1)
       Amylase increased11 (6)2 (1)2 (2)1 (1)
       Blood bilirubin increased
      Blood bilirubin increases were reported in <5% of all patients.
      4 (2)01 (1)0
      sTRAEs
      sTRAEs, n (%)
       Skin
      Includes pruritus; rash; rash maculopapular; pruritus generalised; pemphigoid; rash pruritic; skin exfoliation; eczema; erythema; palmar-plantar erythrodysaesthesia syndrome; rash papular.
      61 (34)3 (2)32 (38)1 (1)
       GI
      Includes diarrhoea; colitis; enteritis; frequent bowel movements.
      29 (16)2 (1)9 (11)1 (1)
       Hypothyroidism7 (4)06 (7)0
       Hepatic
      Includes increases in ALT, AST, blood alkaline phosphatase, blood bilirubin and aminotransferases; hyperbilirubinemia; hepatitis; liver disorder.
      22 (12)8 (4)5 (6)1 (1)
       Adrenal insufficiency2 (1)1 (1)2 (2)1 (1)
       Hyperthyroidism1 (1)01 (1)0
       Thyroiditis1 (1)01 (1)0
       Pneumonitis2 (1)1 (1)1 (1)0
       Renal2 (1)01 (1)0
       Hypersensitivity/infusion-related reaction7 (4)01 (1)0
      Requiring immune-modulating therapy, n (%)
       Skin
      Includes pruritus; rash; rash maculopapular; pemphigoid; rash pruritic.
      26 (14)3 (2)18 (21)1 (1)
       GI
      Includes diarrhoea; colitis.
      6 (3)2 (1)2 (2)1 (1)
       Adrenal insufficiency2 (1)02 (2)0
       Hypersensitivity/infusion-related reaction3 (2)01 (1)0
       Pneumonitis2 (1)1 (1)1 (1)0
       Thyroiditis1 (1)01 (1)0
       ALT increase2 (1)2 (1)00
       AST increase1 (1)1 (1)00
      Hepatitis1 (1)1 (1)00
      ALT, alanine aminotransferase; AST, aspartate aminotransferase; ITT, intent-to-treat; sTRAE, select TRAE; TRAE, treatment-related adverse event.
      * Includes events reported between first dose and 30 days after last dose of study therapy. Event terms were reported by investigators and were not predefined.
      ** Includes increases in ALT, AST, blood alkaline phosphatase, blood bilirubin and aminotransferases; hyperbilirubinemia; hepatitis; liver disorder.
      Reported in ≥10% or ≥5% of all patients in any population, any grade.
      Blood bilirubin increases were reported in <5% of all patients.
      § Includes pruritus; rash; rash maculopapular; pruritus generalised; pemphigoid; rash pruritic; skin exfoliation; eczema; erythema; palmar-plantar erythrodysaesthesia syndrome; rash papular.
      Includes diarrhoea; colitis; enteritis; frequent bowel movements.
      †† Includes pruritus; rash; rash maculopapular; pemphigoid; rash pruritic.
      ‡‡ Includes diarrhoea; colitis.
      In both populations, the most common select TRAEs (sTRAEs) of any grade were skin and gastrointestinal events (Table 3 and Table S4). Grade 3/4 sTRAEs were infrequent in both populations, each occurring in <5% of patients. In the Asian cohort, Grade 3/4 gastrointestinal, hepatic, skin and adrenal insufficiency sTRAEs each occurred in ∼1% (1/85) of patients.
      Most sTRAEs were Grade 1/2 in severity, and few required immune-modulating therapy (Table 3). In both populations, the most common sTRAE category for which patients received immune-modulating therapy was skin, with 33% and 23% in the Asian cohort and ITT population, respectively, receiving topical corticosteroids. Systemic corticosteroid use was reported for any grade AEs in 15% and 17% of Asian and ITT patients, respectively.
      In the Asian cohort, there was a total of 29 events in which patients were rechallenged with nivolumab after experiencing an immune-mediated AE, three of which were Grade 3/4 events. Of the 11 events in which the rechallenge outcome was recorded by the investigator, 10 patients did not experience a recurrence of the AE after rechallenge and one patient experienced a recurrence of rash.
      A total of 60 Asian and 130 ITT patients died during the study. The most common cause of death in both populations was disease progression (Asian, n = 56, 66%; ITT, n = 119, 65%). One Asian patient died of a serious TRAE (Grade 5 pneumonitis) that occurred >100 days after nivolumab discontinuation because of disease progression and after subsequent sorafenib treatment. This event was considered by investigators to be related to both nivolumab and sorafenib treatment. In the other cases in the Asian cohort, causes of death were unrelated to study drug, and listed as intracranial haemorrhage (n = 1), suspected infection (n = 1), and indeterminable (n = 1).

      Patient disposition

      The median follow-up was comparable for both populations at the time of this database lock: 31.3 (28.4–51.0) and 31.6 (28.3–63.8) months for the Asian cohort and ITT population, respectively. In both populations, 4% continued to receive nivolumab at the time of database lock. The primary reason for discontinuing nivolumab treatment was disease progression in both the Asian (91%) and ITT (84%) populations. After progression on nivolumab, a slightly larger percentage of patients in the Asian cohort received any subsequent therapy compared with the ITT population (62% vs. 52%, respectively). In particular, more patients in the Asian cohort received systemic therapy and local therapy compared with patients in the ITT population. Additional details on subsequent treatments are provided in Table 4.
      Table 4Subsequent therapy after nivolumab progression.
      TherapyITT population (n = 182)Asian cohort (n = 85)
      Any subsequent therapy, n (%)94 (52)53 (62)
      Radiotherapy40 (22)22 (26)
      Surgery17 (9)9 (11)
      Systemic therapy62 (34)36 (42)
       Chemotherapy45 (25)37 (43)
       Targeted therapy37 (20)20 (24)
       Immune checkpoint inhibitor9 (5)5 (6)
       Other immunotherapy5 (3)5 (6)
       Experimental therapy18 (10)9 (11)
       Other10 (5)9 (11)
      Local therapy34 (19)24 (28)
       TACE24 (13)19 (22)
       HAI chemotherapy5 (3)5 (6)
       Other10 (5)4 (5)
       Radiofrequency ablation3 (2)3 (4)
      HAI, hepatic artery infusion; ITT, intent-to-treat; TACE, transcatheter arterial chemoembolisation.

      Discussion

      In this analysis of the CheckMate 040 data, the efficacy and safety of nivolumab treatment in sorafenib-experienced patients with advanced HCC was compared between the Asian cohort and ITT population. After a median follow-up of ∼31 months in each population, ORR and DCR were similar, despite the slightly higher proportion of HBV-related HCC, extrahepatic metastases and heavy pretreatment in the Asian cohort. The differences in patient baseline characteristics between these populations are consistent with previous reports that Asian patients tend to have more advanced disease and receive more prior therapies than patients treated in the West.
      • Choo S.P.
      • Tan W.L.
      • Goh B.K.P.
      • Tai W.M.
      • Zhu A.X.
      Comparison of hepatocellular carcinoma in Eastern versus Western populations.
      Clinically meaningful objective responses occurred in both populations regardless of HCC aetiology, age or tumour PD-L1 expression. Of note, there was a trend toward shorter median DOR for the Asian cohort at 9.7 months compared with 19.4 months for the ITT population, with overlapping confidence intervals, although the Asian cohort had small patient numbers and the subanalysis was not powered to detect a difference in DOR. The median DOR reported here for the ITT population was substantially longer than that reported in other advanced HCC trials. For example, the RESORCE trial reported a DOR of 3.5 months with regorafenib treatment
      • Bruix J.
      • Qin S.
      • Merle P.
      • Granito A.
      • Huang Y.H.
      • Bodoky G.
      • et al.
      Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial.
      and the KEYNOTE-224 study reported a DOR of at least 9 months in 77% of patients following pembrolizumab treatment.
      • Zhu A.X.
      • Finn R.S.
      • Edeline J.
      • Cattan S.
      • Ogasawara S.
      • Palmer D.
      • et al.
      Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial.
      Therefore, even though the median DOR was numerically shorter in the Asian cohort compared with the ITT population, it was substantially longer than that reported for regorafenib and comparable to pembrolizumab, and is clinically meaningful. Additionally, a separate ad hoc analysis of other cohorts in CheckMate 040 demonstrated a DOR comparable with nivolumab in sorafenib-naïve Asian vs. ITT patients; median DOR in the Asian cohort was not evaluable, with a range from 13.8 to >29.0 months, compared with a median (range) DOR of 22.6 months (from 4.2 to >29.0 months) in the ITT population (data not shown). Despite the difference in DOR, the median OS was comparable between the two populations, with similar OS rates at various time points. Based on this similar OS, and the fact that the DOR was not evaluable for many subgroups, it is not clear that DOR was significantly different between the Asian cohort and the ITT population. However, one cannot discount that the differences in patient baseline characteristics between these populations, including a higher proportion of HBV-related HCC, extrahepatic metastases and heavy pretreatment in the Asian cohort, might affect DOR. Data from larger studies could provide greater clarity on this outcome.
      The heterogeneity of HCC is reflected in the observed regional differences in the disease, as well as its aetiology, clinical presentation and management approaches. The confluence of these differences can result in variations in drug treatment outcomes. Differences in survival outcomes have been reported in systemic HCC trials, possibly related to different etiological responses or as a result of disease-stage migration related to practice differences.
      • Choo S.P.
      • Tan W.L.
      • Goh B.K.P.
      • Tai W.M.
      • Zhu A.X.
      Comparison of hepatocellular carcinoma in Eastern versus Western populations.
      Aside from the sorafenib and regorafenib phase III trials, the ramucirumab phase III second-line trial similarly showed regional differences in outcomes for OS with HRs of 0.75, 0.83 and 0.65 in the Americas, Europe, Israel and Australia (combined); Asia (excluding Japan); and Japan, respectively. Regional differences were also observed for PFS.
      • Zhu A.X.
      • Kang Y.K.
      • Yen C.J.
      • Finn R.S.
      • Galle P.R.
      • Llovet J.M.
      • et al.
      Ramucirumab after sorafenib in patients with advanced hepatocellular carcinoma and increased alpha-fetoprotein concentrations (REACH-2): a randomised, double-blind, placebo-controlled, phase 3 trial.
      The lenvatinib phase III first-line trial showed an OS HR of 0.86 in the Asia-Pacific region vs. 1.08 in the Western region and a greater trend favouring lenvatinib for PFS in Asia Pacific than in the West.
      • Kudo M.
      • Finn R.S.
      • Qin S.
      • Han K.H.
      • Ikeda K.
      • Piscaglia F.
      • et al.
      Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial.
      Conversely, the cabozantinib phase III second-line trial showed an opposite trend with an OS HR of 1.01 in Asia vs. 0.71 in other geographical regions and, when assessed by race, an OS HR of 0.86 in Asians vs. 0.75 in non-Asians. No difference in PFS were observed.
      • Abou-Alfa G.K.
      • Meyer T.
      • Cheng A.L.
      • El-Khoueiry A.B.
      • Rimassa L.
      • Ryoo B.Y.
      • et al.
      Cabozantinib in patients with advanced and progressing hepatocellular carcinoma.
      Thus, understanding the potential differences in drug treatment outcomes is important to optimise individual patient outcomes and appreciate the potential implications for clinical trial design.
      Notably, in this analysis, the median OS in uninfected patients and in patients with HBV or HCV was similar, which suggests that HCC aetiology does not have a significant impact on nivolumab survival outcomes. This differs from a meta-analysis and pooled exploratory analysis, which suggested that the impact of sorafenib treatment in patients with advanced HCC is dependent on their hepatitis status.
      • Jackson R.
      • Psarelli E.E.
      • Berhane S.
      • Khan H.
      • Johnson P.
      Impact of viral status on survival in patients receiving sorafenib for advanced hepatocellular cancer: a meta-analysis of randomized phase III trials.
      • Bruix J.
      • Cheng A.L.
      • Meinhardt G.
      • Nakajima K.
      • De Sanctis Y.
      • Llovet J.
      Prognostic factors and predictors of sorafenib benefit in patients with hepatocellular carcinoma: analysis of two phase III studies.
      In general, this analysis demonstrated that nivolumab safety in the Asian cohort was consistent with that in the ITT population, and no new safety signals were observed. Regarding hepatic parameters, there was little, if any, difference between the Asian cohort and the ITT population, despite 71% of the Asian cohort having underlying hepatitis. In both populations, the most commonly reported TRAEs were pruritus, rash and fatigue, which are typical AEs associated with immune checkpoint inhibitors.
      • Champiat S.
      • Lambotte O.
      • Barreau E.
      • Belkhir R.
      • Berdelou A.
      • Carbonnel F.
      • et al.
      Management of immune checkpoint blockade dysimmune toxicities: a collaborative position paper.
      This safety profile is consistent with nivolumab use in other tumour types, including melanoma,
      • Weber J.S.
      • D'Angelo S.P.
      • Minor D.
      • Hodi F.S.
      • Gutzmer R.
      • Neyns B.
      • et al.
      Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
      non-small cell lung cancer,
      • Borghaei H.
      • Paz-Ares L.
      • Horn L.
      • Spigel D.R.
      • Steins M.
      • Ready N.E.
      • et al.
      Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer.
      • Brahmer J.
      • Reckamp K.L.
      • Baas P.
      • Crino L.
      • Eberhardt W.E.
      • Poddubskaya E.
      • et al.
      Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer.
      renal cell carcinoma,
      • Motzer R.J.
      • Escudier B.
      • McDermott D.F.
      • George S.
      • Hammers H.J.
      • Srinivas S.
      • et al.
      Nivolumab versus everolimus in advanced renal-cell carcinoma.
      Hodgkin lymphoma
      • Ansell S.M.
      • Lesokhin A.M.
      • Borrello I.
      • Halwani A.
      • Scott E.C.
      • Gutierrez M.
      • et al.
      PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
      and squamous cell carcinoma of the head and neck.
      • Ferris R.L.
      • Blumenschein Jr., G.
      • Fayette J.
      • Guigay J.
      • Colevas A.D.
      • Licitra L.
      • et al.
      Nivolumab for recurrent squamous-cell carcinoma of the head and neck.
      Limitations of this study include that it was a post hoc analysis of a single arm, open-label, phase II trial. The sample sizes were relatively small, thus not allowing in-depth comparison of the Asian cohort with a non-Asian cohort. Therefore, comparisons between the Asian cohort and the ITT population must be interpreted with caution. Validation of the observations seen in this subanalysis will be forthcoming from the ongoing phase III CheckMate 459 trial, which will provide a larger data set for the evaluation of regional differences (ClinicalTrials.gov identifier NCT02576509).

      Conclusion

      In this analysis of sorafenib-experienced patients with advanced HCC in the CheckMate 040 study, nivolumab treatment elicited durable responses and promising long-term survival, with similar responses and survival outcomes in both Asian and ITT populations. Responses were observed across HCC aetiologies and occurred irrespective of tumour PD-L1 expression. Nivolumab was well tolerated, with similar safety profiles in both Asian and ITT populations; no new safety signals were observed. The ongoing, global, open-label, phase III CheckMate 459 study is evaluating nivolumab as a first-line therapy in patients with advanced HCC, including in Asian patients in China, Hong Kong, Japan, South Korea, Singapore, and Taiwan (ClinicalTrials.gov identifier NCT02576509).

      Financial support

      This study was supported by Bristol-Myers Squibb (Princeton, NJ, USA) and ONO Pharmaceutical Co., Ltd. (Osaka, Japan).

      Conflict of interest

      T.Y. reports receiving honoraria from Bristol-Myers Squibb (BMS) and has a consulting or advisory role at BMS. C.H. reports receiving honoraria from Bayer Schering Pharma, BMS, MSD Oncology and TTY Biopharm. S-P.C. reports receiving honoraria from BMS; has received honoraria and speaker fees from Bayer Schering Pharma and Lilly; has an advisory role and has received honoraria from Sirtex Medical, Eisai and Ipsen; has a consulting or advisory role at BMS; and received research funding from BMS. Y-K.K. reports having a consulting or advisory role at Lilly/Im Clone, Taiho Pharmaceutical, Ono Pharmaceutical Co., Roche/Genentech and Novartis and received research funding from LSK Biopharma. W.Y. reports receiving honoraria from Pfizer; and has a consulting advisory role at Lilly and Novartis. A.C. reports receiving honoraria from Bayer Schering Pharma and Janssen Oncology; has a consulting or advisory role at Astellas Pharma, AstraZeneca, Bayer Schering Pharma, Boehringer Ingelheim, Lilly, MSD Oncology and Mundipharma; has served in speakers’ bureau for BMS and Roche Molecular Diagnostics; received travel accommodations and expenses from Boehringer Ingelheim, BMS and Merck Serono; and has other relationships with BMS. M.I. reports receiving honoraria from Abbott Japan, Bayer Yakuhin, BMS Japan, Chugai Pharma, Daiichi Sankyo, Eisai, Lilly Japan, Nobelpharma, Novartis, Otsuka, Taiho Pharmaceutical and Yakult Honsha; has served as a consulting or advisory role for Bayer Yakuhin, Eisai, Kyowa Hakko Kirin, NanoCarrier, Novartis and Shire; and has received research funding from ASLAN Pharmaceuticals, AstraZeneca, Baxter, Bayer Yakuhin, BMS, Chugai Pharma, Eisai, Kowa, Kyowa Hakko Kirin, Lilly Japan, Merck Serono, NanoCarrier, Ono Pharmaceutical, Taiho Pharmaceutical, Yakult and Zeria Pharmaceutical. R.K. reports receiving research funding from BMS, Eisai, Ono Pharmaceutical, MSD, AstraZeneca, EA Pharma, Takeda and Chugai; and has received honoraria from MSD, Mitsubishi Tanabe Pharma, Shionogi & Co., GE Healthcare Japan and Daiichi Sankyo. M.M. reports receiving research funding from Bayer, Bayer (Inst), Kowa (Inst), Kyowa Hakko Kirin, Kyowa Hakko Kirin (Inst), Pfizer, Taiho Pharmaceutical and Yakult Honsha. H.Z., J.A. and C.D.C. report employment by BSM and holding stock options and other ownership interests at BSM. M.K. reports lecturing for MSD, Bayer, Eisai and Ajinomoto; has received grants from Otsuka, Taiho, AbbVie, Daiichi Sankyo, Medico’s Hirata, Astellas Pharma, Chugai, BSM, Bayer, Eisai, MSD, Ajinomoto, Takeda and Sumitomo Dainippon; and has held an advisory or consulting role at Eisai, Bayer, Kowa, MSD, BMS, Chugai, Taiho, Eli Lilly and Ono Pharmaceutical Co. T-Y.K., M-M.H., K.N. and Y. C. have nothing to disclose.

      Authors’ contributions

      J.A. and C.D.C. conceived and designed the study. T.Y., C.H., T-Y.K., S-P.C., Y-K.K., M-M.H., K.N., W.Y., A.C., M.I., R.K., M.M., Y.C. and M.K. recruited patients and collected the data. H.Z., J.A. and C.D.C. analysed the data. All authors interpreted the data and were involved in the development, review and approval of the manuscript.

      Acknowledgements

      This study was supported by Bristol-Myers Squibb and ONO Pharmaceutical Co. We thank the patients and their families, investigators and research staff at all study sites, and Dako, an Agilent Technologies Inc. company, for collaborative development of the PD-L1 IHC 28-8 pharmDx assay. Writing and editorial assistance was provided by Yvonne Yarker, Emily Bruce, Lawrence Hargett, and Christine Craig of Parexel International, and was funded by Bristol-Myers Squibb. Bristol-Myers Squibb policy on data sharing can be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.

      Supplementary data

      The following are the Supplementary data to this article:

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