Abstract
Introduction
In the preplanned interim analysis of the phase 3 CheckMate 9DW trial, first-line nivolumab plus ipilimumab demonstrated significant overall survival (OS) benefit versus lenvatinib or sorafenib (hazard ratio [HR] = 0.79; 95% confidence interval [CI]: 0.65–0.96; p = 0.018) in patients with unresectable hepatocellular carcinoma (HCC). We present outcomes in Japanese patients from this trial.
Methods
Patients with unresectable HCC without prior systemic therapy were randomized 1:1 to receive nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks (up to 4 doses, then nivolumab 480 mg every 4 weeks) or investigator’s choice of lenvatinib or sorafenib. The primary endpoint was OS. Secondary endpoints included objective response rate (ORR) and duration of response (DOR) per blinded independent central review (BICR); safety was an exploratory endpoint.
Results
Fifty-six Japanese patients were randomized to nivolumab plus ipilimumab (n = 25) and lenvatinib or sorafenib (n = 31). After a median follow-up of 35.8 months (range: 28.2–45.3), median OS was not reached (NR) (95% CI: 16.9 months to not estimable [NE]) with nivolumab plus ipilimumab and 32.0 months (95% CI: 20.9–NE) with lenvatinib or sorafenib (HR = 0.64 [95% CI: 0.27–1.50]); 24- and 36-month OS rates were 70% versus 63% and 64% versus 40%, respectively. ORR per BICR with nivolumab plus ipilimumab was 56% (95% CI: 35–76) versus 16% (95% CI: 6–34) with lenvatinib or sorafenib. Median DOR was NR (95% CI: NE) and 11.1 months (95% CI: 6.4–NE), respectively. Grade 3/4 treatment-related adverse events occurred in 50% versus 65% of patients, respectively. There were no treatment-related deaths among Japanese patients.
Conclusion
Consistent with the global population, first-line nivolumab plus ipilimumab showed clinically meaningful improvement in OS and ORR versus lenvatinib or sorafenib in Japanese patients with unresectable HCC, along with manageable safety. These results support nivolumab plus ipilimumab as a potential new first-line treatment for unresectable HCC in Japan.
Keywords: Hepatocellular carcinoma, Immunotherapy, Nivolumab, Ipilimumab
Introduction
Liver cancer is one of the most common causes of cancer-related deaths, ranking third globally and fifth in Japan [1, 2]. Japan has one of the highest rates of liver cancer in industrialized countries with a very high human development index, although the incidence has been decreasing in Japan since 2004 [2, 3]. Hepatocellular carcinoma (HCC) is the most common type of liver cancer, accounting for 75%–85% of liver cancer cases worldwide and over 90% in Japan; patients with unresectable or advanced disease have a poor prognosis [1, 4]. For over a decade, first-line treatment options for unresectable HCC have been limited to multi-kinase inhibitors including lenvatinib and sorafenib; however, these treatments are associated with modest improvements in overall survival (OS) and unsatisfactory safety outcomes [5, 6]. More recently, programmed death ligand 1 (PD-L1) inhibitor-based regimens have become the standard of care for first-line treatment of HCC based on data from the IMbrave150 and HIMALAYA clinical trials, demonstrating median OS ranging from 16 to 19 months [7–10]. Despite these advances, the long-term prognosis for patients with unresectable HCC remains poor, leading to an unmet need in this setting [11].
Nivolumab, a programmed death 1 (PD-1) inhibitor, in combination with ipilimumab, a cytotoxic T-lymphocyte antigen 4 inhibitor, has demonstrated favorable clinical benefit with manageable safety profiles across multiple tumor types [12–17]. Nivolumab plus ipilimumab demonstrated clinically meaningful efficacy and manageable safety in patients with advanced HCC previously treated with sorafenib in the CheckMate 040 trial [15, 16]. In the global phase 3 CheckMate 9DW trial, nivolumab plus ipilimumab demonstrated statistically significant and clinically meaningful OS benefit versus lenvatinib or sorafenib in patients with unresectable HCC in the first-line setting [18]. With a median follow-up of 35.2 months, median OS was 23.7 months (95% confidence interval [CI]: 18.8–29.4) with nivolumab plus ipilimumab versus 20.6 months (95% CI: 17.5–22.5) with lenvatinib or sorafenib (hazard ratio [HR] = 0.79 [95% CI: 0.65–0.96]; p = 0.018); 24- and 36-month OS rates were 49% versus 39% and 38% versus 24%, respectively. Additionally, first-line nivolumab plus ipilimumab demonstrated statistically significant and clinically meaningful objective response rate (ORR) benefit (36% vs. 13%; p < 0.0001) with numerically longer median duration of response (DOR; 30.4 vs. 12.9 months) compared with lenvatinib or sorafenib and manageable safety.
HCC is a heterogenous disease with variations in incidence, etiology, genomic profiles, and prognosis between Japan and Western countries [2, 19, 20]. In Japan, HCC cases are predominantly associated with hepatitis C virus (HCV) infection with an increasing association seen with nonviral etiology, particularly metabolic dysfunction-associated steatohepatitis. However, hepatitis B virus (HBV) infection or nonviral etiology such as metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis or aflatoxin exposure are the major causes of HCC at the global level [20–23]. There are also differences in HCC surveillance, staging systems, and treatment guidelines between Japan and rest of the world [24, 25]. In Japan, the immunotherapy combinations of atezolizumab plus bevacizumab and durvalumab with or without tremelimumab are approved for first-line treatment of advanced HCC based on results from the IMbrave150 and HIMALAYA trials, respectively [26]. Lenvatinib and sorafenib remain the first-line treatment option for advanced HCC in Japanese patients not indicated for immunotherapy regimens [26, 27]. Japanese patients with advanced HCC treated with sorafenib are more likely to discontinue treatment early due to toxicities compared with patients from other countries, highlighting the need for new treatment options in this subgroup [28, 29]. Given the differences in patient demographics, HCC etiology, and treatment algorithms between Japan and other regions that could influence the course of disease and treatment outcomes, it is important to evaluate the efficacy and safety of first-line nivolumab plus ipilimumab in Japanese patients [21, 22, 24, 30]. Here, we report the efficacy and safety outcomes in Japanese patients from CheckMate 9DW.
Methods
Study Design, Participants, and Procedures
Detailed study design and methods for CheckMate 9DW (NCT04039607) have been previously described [18]. Briefly, this multicenter, randomized, open-label, phase 3 trial enrolled patients at 163 hospitals and cancer centers across 25 countries, including at 20 centers in Japan. Adult patients with histologically confirmed advanced HCC (defined as either not eligible for curative surgical and/or locoregional therapy or having progressed after surgical and/or locoregional therapy) who had not received prior systemic therapy for advanced disease and had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a Child-Pugh score of 5 or 6, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled.
Patients were randomized 1:1 to receive nivolumab 1 mg/kg and ipilimumab 3 mg/kg intravenously every 3 weeks (up to 4 doses) followed by nivolumab 480 mg every 4 weeks or investigator’s choice of lenvatinib 8 mg daily (if body weight <60 kg) or 12 mg daily (if body weight ≥60 kg) or sorafenib 400 mg twice a day orally. Patients were stratified according to etiology (HBV vs. HCV vs. uninfected), macrovascular invasion and/or extrahepatic spread (present vs. absent), and baseline alpha-fetoprotein level (<400 vs. ≥400 ng/mL). Treatment continued until disease progression (treatment beyond progression was allowed after assessment of clinical benefit by investigator), unacceptable toxicity, or withdrawal of consent (applied to both arms) or for a maximum of 2 years (applicable to nivolumab plus ipilimumab arm only).
Outcomes
The primary endpoint was OS. Secondary endpoints included ORR and DOR per blinded independent central review (BICR) using RECIST version 1.1 and time to symptom deterioration in the hepatobiliary cancer subscale (HCS) score of the Functional Assessment of Cancer Therapy Hepatobiliary Cancer (FACT-Hep). Key exploratory endpoints included time to objective response and progression-free survival (PFS) per BICR using RECIST version 1.1, and safety. This Japanese subgroup analysis includes data from primary, secondary, and key exploratory endpoints.
Statistical Analyses
Efficacy and health-related quality of life were assessed in patients who were randomized to any treatment group in the study (all randomized population); time to response and DOR were assessed in all randomized patients with a confirmed complete or partial response. Safety was assessed in all patients who received at least one dose of study medication (all treated population). For the Japanese subgroup analyses, no formal hypothesis testing was planned and performed, and only descriptive analyses were conducted. Median OS, DOR, and PFS were estimated using Kaplan-Meier methods and CIs calculated using a log-log transformation method. HRs were estimated from unstratified Cox proportional hazard models in Japanese patients. Statistical analyses were performed using SAS software version 9.4 (SAS Institute, Cary, NC, USA).
Results
Between April 23, 2020, and September 27, 2021, 56 Japanese patients were randomly assigned to receive nivolumab plus ipilimumab (n = 25) or lenvatinib or sorafenib (n = 31; Fig. 1). Of these, 55 patients were treated (nivolumab plus ipilimumab, n = 24; lenvatinib or sorafenib, n = 31); among the 31 patients treated with lenvatinib or sorafenib, 29 patients (94%) received lenvatinib and 2 patients (6%) received sorafenib. While the demographic (age, sex) and some baseline characteristics (Eastern Cooperative Oncology Group performance status, prior local nonsystemic therapy) of Japanese patients were generally balanced between treatment arms, some imbalances were observed. For example, numerically greater number of patients with Barcelona Clinic Liver Cancer stage C, macrovascular invasion and/or extrahepatic spread, and alpha-fetoprotein ≥400 ng/mL were observed in the nivolumab plus ipilimumab group compared with the lenvatinib or sorafenib group (Table 1). An imbalance was also noted in the proportion of patients with HBV infection (Table 1). At clinical data cutoff (January 31, 2024), all 55 (100%) treated patients had discontinued treatment. The most common reasons for discontinuing treatment were disease progression (n = 9) and an adverse event related to treatment (n = 9) in the nivolumab plus ipilimumab group and disease progression (n = 27) in the lenvatinib or sorafenib group (Fig. 1).
Fig. 1.
CONSORT diagram.
Table 1.
Baseline demographics and disease characteristics in all randomized Japanese patients
| Characteristic | Nivolumab plus ipilimumab (n = 25) | Lenvatinib or sorafenib (n = 31) |
|---|---|---|
| Median age (range), years | 71 (48–85) | 71 (47–89) |
| ≥65 years | 18 (72) | 22 (71) |
| Sex, male | 21 (84) | 26 (84) |
| Etiologya,b | ||
| HBV | 4 (16) | 9 (29) |
| HCV | 10 (40) | 13 (42) |
| Uninfected | 9 (36) | 9 (29) |
| Child-Pugh score | ||
| 5 | 20 (80) | 27 (87) |
| 6 | 5 (20) | 4 (13) |
| ECOG performance status | ||
| 0 | 24 (96) | 30 (97) |
| 1 | 1 (4) | 1 (3) |
| BCLC stage | ||
| 0/A | 4 (16) | 4 (13) |
| B | 6 (24) | 15 (48) |
| C | 15 (60) | 12 (39) |
| Macrovascular invasion/extrahepatic spreada | ||
| Macrovascular invasion | 5 (20) | 2 (6) |
| Extrahepatic spread | 12 (48) | 9 (29) |
| Macrovascular invasion/extrahepatic spread | 15 (60) | 11 (35) |
| Alpha-fetoprotein | ||
| <400 ng/mL | 16 (64) | 25 (81) |
| ≥400 ng/mL | 9 (36) | 6 (19) |
| Prior local non-systemic therapy | 16 (64) | 20 (65) |
Data are n (%), unless otherwise stated.
BCLC, Barcelona Clinic Liver Cancer; ECOG, Eastern Cooperative Oncology Group; HBV, hepatitis B virus; HCV, hepatitis C virus.
aPer case report form.
bTwo patients in the nivolumab plus ipilimumab group were reported as having both HBV and HCV as risk factors for hepatocellular carcinoma; these patients did not have active coinfection with HBV and HCV.
Efficacy
With a median follow-up of 35.8 months (range: 28.2–45.3), median OS was not reached (NR; 95% CI: 16.9 months to not estimable [NE]) with nivolumab plus ipilimumab versus 32.0 months (95% CI: 20.9–NE) with lenvatinib or sorafenib (HR = 0.64 [95% CI: 0.27–1.50]); 24- and 36-month OS rates were 70% (95% CI: 47–85) versus 63% (95% CI: 43–78) and 64% (95% CI: 41–81) versus 40% (95% CI: 21–59), respectively (Fig. 2).
Fig. 2.
Kaplan-Meier estimate of OS in all randomized Japanese patients. HR from an unstratified Cox proportional hazard model for nivolumab plus ipilimumab over lenvatinib or sorafenib. Tick marks indicate censored data. CI, confidence interval; HR, hazard ratio; IPI, ipilimumab; LEN, lenvatinib; mo, months; NE, not evaluable; NIVO, nivolumab; NR, not reached; OS, overall survival; SOR, sorafenib.
The proportion of patients with a confirmed objective response per BICR was 56% (95% CI: 35–76) with nivolumab plus ipilimumab versus 16% (95% CI: 6–34) with lenvatinib or sorafenib; complete responses were observed in 4 (16%) versus 0 patients, respectively (Table 2). Median time to response was 2.9 months (range: 1.4–5.7) with nivolumab plus ipilimumab versus 2.3 months (range, 2.1–5.6) with lenvatinib or sorafenib (Table 2). Median DOR was NR (95% CI: NE) with nivolumab plus ipilimumab versus 11.1 months (95% CI: 6.4–NE) with lenvatinib or sorafenib (Table 2; Fig. 3). No events of progression or death were observed at this data cutoff among the responders treated with nivolumab plus ipilimumab. Median PFS assessed by BICR was NR (95% CI: 22.1 months to NE) with nivolumab plus ipilimumab versus 11.1 months (95% CI: 7.5–16.7) with lenvatinib or sorafenib (HR = 0.33 [95% CI: 0.12–0.88]); 18-month PFS rates were 77% (95% CI: 52–90) versus 21% (95% CI: 6–43) and 24-month rates were 69% (95% CI: 42–85) versus 21% (95% CI: 6–43), respectively (Fig. 4).
Table 2.
Response outcomes in all randomized Japanese patients assessed by BICR
| | Nivolumab plus ipilimumab (n = 25) | Lenvatinib or sorafenib (n = 31) |
|---|---|---|
| Objective response rate, n (%) | 14 (56) | 5 (16) |
| 95% CI | 35–76 | 6–34 |
| Best overall response, n (%) | ||
| Complete response | 4 (16) | 0 |
| Partial response | 10 (40) | 5 (16) |
| Stable diseasea | 7 (28) | 22 (71) |
| Progressive disease | 3 (12) | 3 (10) |
| Not evaluable | 1 (4) | 1 (3) |
| Time to response, median (range), monthsb | 2.9 (1.4–5.7) | 2.3 (2.1–5.6) |
| Duration of response, median (95% CI), monthsb,c | NR (NE) | 11.1 (6.4–NE) |
Per Response Evaluation Criteria in Solid Tumors, version 1.1.
BICR, blinded independent central review; CI, confidence interval; NE, not evaluable; NR, not reached.
aIncludes non-complete response/non-progressive disease: nivolumab plus ipilimumab, n = 1 (4%), which refers to patients with persistence of one or more nontarget lesion(s).
bEvaluated in patients who had a confirmed objective response.
cBased on Kaplan-Meier estimates of duration of response.
Fig. 3.
Kaplan-Meier estimate of DOR in all randomized Japanese patients with a confirmed objective response. Kaplan-Meier estimate based on all patients with a confirmed complete or partial response per BICR using Response Evaluation Criteria in Solid Tumors, version 1.1 (n = 14 in the nivolumab plus ipilimumab group; n = 5 in the lenvatinib or sorafenib group). Tick marks indicate censored data. BICR, blinded independent central review; CI, confidence interval; DOR, duration of response; HR, hazard ratio; IPI, ipilimumab; LEN, lenvatinib; mo, months; NE, not evaluable; NIVO, nivolumab; NR, not reached; SOR, sorafenib.
Fig. 4.
Kaplan-Meier estimate of PFS in all randomized Japanese patients. PFS assessed by BICR per Response Evaluation Criteria in Solid Tumors, version 1.1. HR from an unstratified Cox proportional hazard model for nivolumab plus ipilimumab over lenvatinib or sorafenib. Tick marks indicate censored data. BICR, blinded independent central review; CI, confidence interval; HR, hazard ratio; IPI, ipilimumab; LEN, lenvatinib; mo, months; NE, not evaluable; NIVO, nivolumab; NR, not reached; PFS, progression-free survival; SOR, sorafenib.
Subsequent therapies were received by 14 (56%) patients in the nivolumab plus ipilimumab group versus 25 (81%) patients in the lenvatinib or sorafenib group (Table 3). Subsequent systemic therapies were received by nine (36%) patients versus 23 (74%) patients, respectively (Table 3). Seven (28%) patients in the nivolumab plus ipilimumab group and 22 (71%) patients in the lenvatinib or sorafenib group received subsequent immunotherapies (Table 3).
Table 3.
Subsequent therapy in all randomized Japanese patients
| Subsequent therapy, n (%)a | Nivolumab plus ipilimumab (n = 25) | Lenvatinib or sorafenib (n = 31) |
|---|---|---|
| Any subsequent therapy | 14 (56) | 25 (81) |
| Subsequent radiotherapy | 2 (8) | 8 (26) |
| Subsequent surgery | 1 (4) | 0 |
| Subsequent locoregional therapy | 7 (28) | 9 (29) |
| Subsequent systemic therapy | 9 (36) | 23 (74) |
| Any immunotherapy | 7 (28) | 22 (71) |
| Any immunotherapy monotherapy | 0 | 5 (16) |
| Any immunotherapy-containing combination regimenb | 7 (28) | 21 (68) |
| Anti-VEGF agents | 4 (16) | 15 (48) |
| Investigational antineoplastic agent | 0 | 1 (3) |
Subsequent therapy was defined as therapy started on or after first dosing date (randomization date if patient never treated).
VEGF, vascular endothelial growth factor.
aPatients may have received more than 1 type of subsequent therapy.
bIncludes regimens combining anti-programmed death 1 or anti-programmed death ligand 1 agents with anti-VEGF, anti-cytotoxic T-lymphocyte antigen 4, or anti-lymphocyte activation gene-3 agents, as well as other systemic therapies.
Exposure, Safety, and Health-Related Quality of Life
Among all 55 treated patients, median duration of treatment was 1.7 months (range: <0.1–23.7) with nivolumab plus ipilimumab and 8.7 months (range: 0.7–21.9) with lenvatinib or sorafenib (Table 4). Among 24 treated patients in the nivolumab plus ipilimumab group, the median number of doses received was 3.0 (range: 1–4) for both nivolumab and ipilimumab during the combination phase.
Table 4.
Exposure and TRAEs in all treated Japanese patients
| All treated patients | Nivolumab plus ipilimumab (n = 24) | Lenvatinib or sorafenib (n = 31) |
|---|---|---|
| Duration of treatment, median (range), months | 1.7 (<0.1–23.7) | 8.7 (0.7–21.9) |
| TRAEs | Any grade | Grade 3/4 | Any grade | Grade 3/4 |
|---|---|---|---|---|
| Any TRAE | 21 (88) | 12 (50) | 31 (100) | 20 (65) |
| TRAEs in ≥10% of patients | ||||
| AST increased | 7 (29) | 2 (8) | 1 (3) | 1 (3) |
| ALT increased | 7 (29) | 2 (8) | 1 (3) | 0 |
| Decreased appetite | 5 (21) | 1 (4) | 10 (32) | 1 (3) |
| Malaise | 5 (21) | 0 | 6 (19) | 1 (3) |
| Rash macro-papular | 4 (17) | 0 | 2 (6) | 0 |
| Rash | 4 (17) | 1 (4) | 0 | 0 |
| Pyrexia | 4 (17) | 0 | 0 | 0 |
| Lipase increased | 3 (13) | 2 (8) | 1 (3) | 0 |
| Amylase increased | 3 (13) | 0 | 0 | 0 |
| Diarrhea | 2 (8) | 0 | 11 (35) | 2 (6) |
| Weight decreased | 2 (8) | 0 | 3 (10) | 0 |
| Hypothyroidism | 1 (4) | 0 | 13 (42) | 0 |
| Stomatitis | 1 (4) | 0 | 3 (10) | 0 |
| Hypertension | 0 | 0 | 18 (58) | 6 (19) |
| Proteinuria | 0 | 0 | 16 (52) | 7 (23) |
| PPE syndrome | 0 | 0 | 14 (45) | 1 (3) |
| Dysphonia | 0 | 0 | 10 (32) | 0 |
| Edema peripheral | 0 | 0 | 6 (19) | 1 (3) |
| Fatigue | 0 | 0 | 6 (19) | 0 |
| Nausea | 0 | 0 | 5 (16) | 0 |
| Decreased platelet count | 0 | 0 | 4 (13) | 1 (3) |
| Thrombocytopenia | 0 | 0 | 3 (10) | 2 (6) |
| Hypoalbuminemia | 0 | 0 | 3 (10) | 0 |
| Serious TRAE | 8 (33) | 8 (33) | 5 (16) | 2 (6) |
| TRAE leading to discontinuation | 7 (29) | 5 (21) | 1 (3) | 1 (3) |
| Treatment-related deaths | 0 | | 0 | |
Data are n (%), unless otherwise stated. Includes patients who received at least one dose of the study treatment. All events were reported between first dose and 30 days after last dose of study therapy.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; PPE, palmar-plantar erythrodysesthesia; TRAE, treatment-related adverse event.
Any-grade treatment-related adverse events (TRAEs) were observed in 21 (88%) patients in the nivolumab plus ipilimumab group and 31 (100%) patients in the lenvatinib or sorafenib group; grade 3 or 4 TRAEs were observed in 12 (50%) and 20 (65%) patients, respectively (Table 4). The most common any-grade TRAEs were increased aspartate aminotransferase (29%), increased alanine aminotransferase (29%), decreased appetite (21%), and malaise (21%) in the nivolumab plus ipilimumab group and hypertension (58%), proteinuria (52%), and palmar-plantar erythrodysesthesia syndrome (45%) in the lenvatinib or sorafenib group. Any-grade TRAEs leading to discontinuation occurred in 7 (29%) patients in the nivolumab plus ipilimumab group and 1 (3%) patient in the lenvatinib or sorafenib group. No treatment-related deaths were reported.
Any-grade immune-mediated adverse events (IMAEs) occurred in 10 (42%) patients with nivolumab plus ipilimumab; grade 3 or 4 IMAEs were reported in 5 (21%) patients (online suppl. Table S1; for all online suppl. material, see https://doi.org/10.1159/000548300). Three (13%) patients received high-dose steroids for treatment of immune-mediated hepatitis. Hepatitis resolved in all 3 patients with a median time to resolution of 14.1 weeks; 1 patient discontinued study treatment due to the adverse event.
In health-related quality of life analyses, median time to first symptom deterioration (time from randomization until a clinically meaningful decline in the HCS score of FACT-Hep) was 3.3 months (95% CI: 1.2–NE) with nivolumab plus ipilimumab versus 1.5 months (95% CI: 0.8–6.2) with lenvatinib or sorafenib (HR = 0.64 [95% CI: 0.33–1.24]; online suppl. Fig. S1).
Discussion
In this subgroup analysis of Japanese patients from the CheckMate 9DW trial, first-line nivolumab plus ipilimumab showed clinically meaningful improvement in OS versus lenvatinib or sorafenib, along with numerically higher 2- and 3-year OS rates. Further, clinically meaningful ORR benefit, higher complete response rates, and durable responses were observed with nivolumab plus ipilimumab versus lenvatinib or sorafenib in Japanese patients. PFS rates at 18 and 24 months were numerically higher with nivolumab plus ipilimumab versus lenvatinib or sorafenib among Japanese patients. The safety profile of nivolumab plus ipilimumab in Japanese patients was manageable and consistent with the established safety profile of the regimen. Together, these results from the Japanese patients from CheckMate 9DW were consistent with those from the global study population [18].
Similar to the global study population [18], an early crossing of the Kaplan-Meier OS curves was seen in Japanese patients. Within the Japanese subgroup, 2 deaths occurred in the nivolumab plus ipilimumab arm within the first 6 months after randomization. One patient died due to adverse events unrelated to the study treatment and 1 patient died due to progressive disease. This phenomenon is likely multifactorial; the early death due to progressive disease may be partially attributed to the delayed treatment effect seen with immuno-oncology therapies compared with tyrosine kinase inhibitor regimens like lenvatinib or immuno-oncology regimens containing anti-VEGF agents, where a more immediate impact on tumor growth is often observed [31, 32]. It should be noted that the majority of Japanese patients in the comparator arm (94%) received lenvatinib, which was greater than the proportion of patients in the global population who received lenvatinib in the comparator arm (85%). These differences may have led the comparator arm to perform better in the Japanese patients compared with the global population. Despite the delayed separation of the OS curves, nivolumab plus ipilimumab showed long-term survival and ORR benefit in Japanese patients. Of note, no events of progression or death were observed among Japanese responders in the nivolumab plus ipilimumab group, although all patients had discontinued study treatment. These results suggest that therapeutic activity of nivolumab plus ipilimumab continued beyond treatment administration.
A comparison of the baseline characteristics between the Japanese patients and the global study population [18] showed a greater proportion of patients who were aged ≥65 years (71% vs. 53%) and who had intermediate stage liver disease (BCLC stage ≤B: 52% vs. 26%), better Eastern Cooperative Oncology Group performance status (score of 0: 96% vs. 71%), and HCV infection (41% vs. 28%) in the Japanese subgroup. A high frequency of HCV etiology is aligned with trends of etiologic variation in Japan, although HCV-related cases have decreased and nonviral cases increased recently [21, 22, 30, 33, 34]. In addition, a greater proportion of Japanese patients received subsequent locoregional therapy compared with the global population (29% vs. 8%). Despite a shorter median duration of nivolumab plus ipilimumab treatment in Japanese patients compared with the global population (1.7 months vs. 4.7 months), Japanese patients had a trend of longer median OS (NR vs. 23.7 months), higher ORR (56% vs. 36%) with higher complete response rates (16% vs. 7%), and longer median PFS (NR vs. 9.1 months) [18]. Indeed, the trend of longer median OS in Japanese patients compared with the global population was observed across both the nivolumab plus ipilimumab and the lenvatinib or sorafenib treatment groups [18]. Similar trends were also seen in the phase 3 LEAP-002 trial, which compared first-line lenvatinib plus pembrolizumab with lenvatinib alone in advanced HCC; however, in this study, pembrolizumab plus lenvatinib failed to demonstrate OS benefit over lenvatinib plus placebo in the global population [35]. While the reasons for these observations are unclear, they may be explained by differences in patient characteristics or disease management in Japan.
Within the Japanese subgroup from CheckMate 9DW, we observed some differences in patient baseline characteristics between treatment arms. For instance, the proportion of patients with BCLC stage C, macrovascular invasion and/or extrahepatic spread, and alpha-fetoprotein ≥400 ng/mL was higher in the nivolumab plus ipilimumab group compared with the lenvatinib or sorafenib group (60% vs. 39%, 60% vs. 35%, and 36% vs. 19%, respectively). Despite the higher incidence of these unfavorable prognostic factors, longer median OS, higher ORR, and complete response rates were observed with nivolumab plus ipilimumab versus lenvatinib or sorafenib in Japanese patients.
Most previous phase 3 trials assessing the clinical benefit of PD-1/PD-L1 inhibitor-based regimens used sorafenib as the comparator, except the LEAP-002 trial [35]. In CheckMate 9DW, both lenvatinib and sorafenib were available in the comparator group; 94% of Japanese patients in the lenvatinib or sorafenib group received lenvatinib. Further, while favorable OS benefit of PD-L1-based regimens in Asian populations was seen in subgroup analyses from the IMbrave150 and HIMALAYA trials, the analyses did not include Japanese patients, and the predominant etiology in these subgroups was HBV [36, 37]. To our knowledge, this is the first report to show the clinical benefit of dual immunotherapy (PD-1 plus CTLA-4 inhibitors) in previously untreated Japanese patients with unresectable HCC.
The safety profile of nivolumab plus ipilimumab in Japanese patients was generally consistent with the global study population [18] as well as with previous studies of this regimen in second-line HCC and in other indications [12–16]. No new safety signals were reported in the Japanese patients. IMAEs in the nivolumab plus ipilimumab group were manageable with established algorithms, consistent with the global study population. The most common grade 3 or 4 IMAE was hepatitis, a known adverse reaction to immunotherapy, which occurred in 3 (13%) Japanese patients; all 3 patients received high-dose steroid treatment. Hepatitis resolved in all 3 patients; 1 patient discontinued study treatment due to this IMAE. In comparison, 29% of patients in the global study population received high-dose steroids for treatment of IMAEs, leading to discontinuation of study treatment in 13% of patients. The overall tolerability of nivolumab plus ipilimumab versus lenvatinib or sorafenib in Japanese patients is further supported by the reduced risk in the time to first symptom deterioration on the HCS score of the FACT-Hep (HR = 0.64 [95% CI: 0.33–1.24]).
Limitations of the CheckMate 9DW trial have been discussed previously and include the open-label nature of the study and the exclusion of patients with Vp4 portal vein thrombosis [18]. In addition, interpretation of the results from Japanese patients is limited due to the small sample size of this subgroup and the descriptive nature of this analysis. Real-world practice data might be helpful to further characterize the efficacy and safety outcomes of the nivolumab plus ipilimumab regimen in the Japanese population.
In conclusion, first-line nivolumab plus ipilimumab showed a clinically meaningful improvement in OS, ORR, and PFS versus lenvatinib or sorafenib in Japanese patients with unresectable HCC, along with manageable safety. These findings support nivolumab plus ipilimumab as a potential new first-line treatment option for unresectable HCC in Japan.
Acknowledgments
We thank the patients and their families for making this trial possible; the investigators, research staff, and clinical study team at Bristol Myers Squibb (Princeton, NJ, USA) for CheckMate 9DW trial support; Qi Wang, Gong Chen, and Nan Hu (Bristol Myers Squibb, Princeton, NJ) for contributions as statisticians for study design and data analyses; Enrico Bergonzani (Bristol Myers Squibb, Princeton, NJ) for contributions as the global trial manager; Joseph Hreiki (Bristol Myers Squibb, Princeton, NJ) for contributions as a clinical trial physician; and Caitlyn Stromko (Bristol Myers Squibb, Princeton, NJ) for contributions as a clinical scientist. Professional medical writing and editorial assistance were provided by Nitesh Sule, PhD, of Parexel.
Statement of Ethics
CheckMate 9DW was conducted in accordance with the Good Clinical Practice guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the principles of the Declaration of Helsinki. The protocol was reviewed and approved by the Institutional Review Board or Independent Ethics Committee at each participating site. The study protocol, statistical analysis plan, and full list of participating sites and ethics committees has been published previously [18]. All patients provided written informed consent. An independent data monitoring committee provided trial oversight.
Conflict of Interest Statement
Masatoshi Kudo reports consulting fees from AstraZeneca, Chugai/Roche, Eisai, and Roche; honoraria from AstraZeneca, Bayer, Chugai/Roche, Eisai, Lilly Japan, and Takeda; research funding from AbbVie, Chugai/Roche, Eisai, GE Healthcare, Otsuka, and Taiho Pharmaceuticals; and is the Editor-in-Chief of Liver Cancer. Atsushi Hiraoka reports honoraria from AstraZeneca, Chugai, and Lilly. Tatsuya Yamashita reports honoraria from AstraZeneca, Chugai, and Eisai and is an Editorial Board member of Liver Cancer. Masayuki Kurosaki reports honoraria from AbbVie, AstraZeneca, Chugai, Eisai, and Gilead Sciences. Shuhei Hige reports honoraria from AbbVie and Gilead Sciences. Yoshito Itoh reports research funding from Bristol Myers Squibb. Satoshi Mochida reports honoraria from AbbVie GK, AstraZeneca KK, Aska Pharmaceutical, Eisai, Gilead Sciences, Otsuka Pharmaceutical, and Toray Industries. Tetsuya Hosaka reports honoraria from Eisai. Tomokazu Kawaoka reports honoraria from AstraZeneca and Eisai. Satoshi Kobayashi reports honoraria from AstraZeneca and Merck Sharp & Dohme. Yuting Lu reports employment at Bristol Myers Squibb. Tatsuya Ogata reports employment at Bristol Myers Squibb and stock or stock options from Bristol Myers Squibb. Maria Jesus Jimenez Exposito reports employment at Bristol Myers Squibb and stock or stock options from Bristol Myers Squibb. Masafumi Ikeda reports consulting fees from AbbVie, AstraZeneca, Bayer, Chugai, Eisai, Eli Lilly Japan, Merck Sharp & Dohme, and Ono Pharmaceutical; honoraria from Abbott, AstraZeneca, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly Japan, Merck Sharp & Dohme, and Takeda; research funding from AbbVie, AstraZeneca, Bayer, Bristol Myers Squibb, Chugai, Eisai, and Merck Sharp & Dohme; and is an Editorial Board member of Liver Cancer. Kazushi Numata, Tadashi Namisaki, Norio Akuta, Takuya Genda, and Sawako Uchida-Kobayashi have no conflicts to disclose.
Funding Sources
Bristol Myers Squibb (the sponsor of the study) provided the trial agents and collaborated with the academic authors on the trial design and on the collection, analysis, and interpretation of the data. All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The authors had access to the trial data, participated in the development or review of the manuscript, and provided final approval to submit the manuscript for publication. Medical writing support, including development of the first draft of the manuscript under the guidance of the authors, was funded by the sponsor.
Author Contributions
Conception or design of study: Masatoshi Kudo, Yuting Lu, Tatsuya Ogata, Maria Jesus Jimenez Exposito, and Masafumi Ikeda. Acquisition of data: Masatoshi Kudo, Atsushi Hiraoka, Kazushi Numata, Tatsuya Yamashita, Masayuki Kurosaki, Tadashi Namisaki, Shuhei Hige, Yoshito Itoh, Satoshi Mochida, Tetsuya Hosaka, Norio Akuta, Tomokazu Kawaoka, Takuya Genda, Satoshi Kobayashi, Sawako Uchida-Kobayashi, and Masafumi Ikeda. Data analysis: Yuting Lu, Tatsuya Ogata, and Maria Jesus Jimenez Exposito. Data interpretation: Masatoshi Kudo, Atsushi Hiraoka, Kazushi Numata, Tatsuya Yamashita, Masayuki Kurosaki, Tadashi Namisaki, Shuhei Hige, Yoshito Itoh, Satoshi Mochida, Tetsuya Hosaka, Norio Akuta, Tomokazu Kawaoka, Takuya Genda, Satoshi Kobayashi, Sawako Uchida-Kobayashi, Yuting Lu, Tatsuya Ogata, Maria Jesus Jimenez Exposito, and Masafumi Ikeda.
Funding Statement
Bristol Myers Squibb (the sponsor of the study) provided the trial agents and collaborated with the academic authors on the trial design and on the collection, analysis, and interpretation of the data. All the authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol. The authors had access to the trial data, participated in the development or review of the manuscript, and provided final approval to submit the manuscript for publication. Medical writing support, including development of the first draft of the manuscript under the guidance of the authors, was funded by the sponsor.
Data Availability Statement
The Bristol Myers Squibb data sharing policy can be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. Bristol Myers Squibb will honor legitimate requests for clinical trial data from qualified researchers. Data will be shared with external researchers whose proposed use of the data has been approved.
Supplementary Material.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The Bristol Myers Squibb data sharing policy can be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html. Bristol Myers Squibb will honor legitimate requests for clinical trial data from qualified researchers. Data will be shared with external researchers whose proposed use of the data has been approved.