Abstract
Background/Aim: To evaluate the effectiveness and safety of nivolumab plus ipilimumab for untreated metastatic renal cell carcinoma in real-world clinical practice in Japan based on 1-year follow-up results. Patients and Methods: This multicentre, retrospective study analysed 45 metastatic renal cell carcinoma patients who received nivolumab plus ipilimumab between August 2018 and January 2019 in Japan. Data were extracted from patients’ medical records. Subgroup analyses were performed based on baseline demographic data and treatment history. Results: The objective response rate was 42.5% (complete response rate: 10.0%). The 12-month overall survival rate was 81.4% and the progression-free survival rate was 56.1%. Thirty-five patients (77.8%) showed any grade treatment-related adverse events and 17 (37.8%) showed grade ≥3 treatment-related adverse events, with no significant difference in safety between subgroups. Conclusion: The effectiveness and safety of nivolumab plus ipilimumab in real-world clinical practice with 1-year follow-up were comparable with those of the CheckMate 214 trial.
Based on GLOBOCAN’s 2018 data, renal cell carcinoma (RCC) accounts for approximately 2% of global cancer diagnoses (1, 2). In Japan, the crude incidence rates of RCC in men and women were 8.2 and 3.5 per 100,000, respectively (3). Survival of patients with RCC is highly dependent on the stage at diagnosis, with a 5-year relative survival rate of 93% for stage I localised RCC, 72.5% for stage II/III regional RCC and only 12% for stage IV metastatic RCC (mRCC) (2). In the past two decades, treatments targeting vascular endothelial growth factor receptor tyrosine kinase and mammalian target of rapamycin (mTOR) pathways have clearly improved mRCC management (4). In Japan, tyrosine kinase inhibitors (TKIs) were the most common first-line treatment (72.2%) in patients with mRCC, followed by mTOR inhibitors (14.3%) and cytokines (13.5%), from 2012 to 2015 (5). However, TKIs and mTOR inhibitors are associated with inherent resistance and show limited overall survival.
Recently, the focus of mRCC treatment research has moved to immuno-oncology, and evaluations of immune checkpoint inhibitors have shifted the treatment paradigm of mRCC (4). A randomised phase III clinical trial, CheckMate 214, has demonstrated that nivolumab plus ipilimumab combination therapy was superior to a TKI, sunitinib, with respect to therapeutic effects in patients with mRCC with an intermediate or poor risk criterion (6) proposed by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) (7, 8). In the subpopulation analysis of Japanese patients in CheckMate 214, the nivolumab plus ipilimumab arm had a numerically higher objective response rate (ORR) and improved safety profile compared with the sunitinib arm (9). On the basis of these data, nivolumab plus ipilimumab combination therapy was approved for patients with unresectable RCC and mRCC in August 2018 in Japan (10). The nivolumab plus ipilimumab combination therapy is currently recommended by the Japanese Urological Association renal cancer guideline as a first-line therapy option for intermediate/poor risk clear cell mRCC (11).
However, CheckMate 214 only included 31 Japanese patients with an IMDC intermediate or poor risk and did not include patients with non-clear cell mRCC (nccRCC) and poor performance status (PS), Karnofsky PS score (KPS) <70 (6, 12). Although a multicentre, retrospective study of nivolumab monotherapy in the Japanese population, including patients with nccRCC or poor PS, has been conducted (13), only a few similar multicentre analyses on nivolumab plus ipilimumab combination therapy in Japanese patients have been published (14-16). Therefore, real-world data of nivolumab plus ipilimumab combination therapy in Japanese patients with mRCC is required.
To evaluate the effectiveness and safety of nivolumab plus ipilimumab combination therapy in actual clinical practice in Japan, we collected and analysed retrospective data of patients with mRCC treated with nivolumab plus ipilimumab combination therapy in nine medical institutions from various areas in Japan. The present study called ‘J-cardinal study’ shows the interim analysis results with 1-year follow-up periods and is continuously following data of enrolled patients.
Patients and Methods
Study design. This is a multicentre, retrospective, observational study conducted at nine hospitals in Japan. Data were retrospectively collected from the patient’s medical records at baseline and approximately 3 months and 1 year after the initiation of nivolumab plus ipilimumab combination therapy. This study was registered with UMIN-CTR Clinical Trial under the title Retrospective Japanese real-world study of metastatic RCC treated with nivolumab plus ipilimumab (J-cardinal study) (ID: UMIN000035974).
Patients. Adult patients (at least 20 years of age) with an IMDC intermediate or poor risk and previously untreated mRCC who received nivolumab plus ipilimumab combination therapy from August 21, 2018 to January 31, 2019, were enrolled in this study.
Ethics. This study was conducted in compliance with Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects (17) and Act on the Protection of Personal Information and approved by the ethics committee of individual institutions: Iwate Medical University (approval number: MH2018-621), Tsukuba University (approval number: R1-047), Chiba University (approval number: 3410), Hirosaki University (approval number: 2018-1159), Tokyo Medical and Dental University (approval number: M2018-309), Niigata University (approval number: 2019-0033), Mie University (approval number: H2019-132), Nagoya City University (approval number: 60-19-0060) and Yokohama City University (approval number: B190404002). All study procedures were conducted according to the principles of World Medical Association Declaration of Helsinki. All patients provided written informed consent and had the opportunity to withhold permission from researchers from using their medical records.
Assessments. The ORR, overall survival (OS), progression-free survival (PFS), disease control rate (DCR), adverse events (AEs), treatment-related AEs, status of the use of nivolumab plus ipilimumab combination therapy, and effectiveness of subsequent treatment after discontinuation of nivolumab plus ipilimumab combination therapy were documented in this study. The swimmer plot provided a visual representation of the treatment duration, BOR, irAE, death and reason for discontinuation. The ORR was calculated as the proportion of patients who achieved complete response (CR) or partial response (PR) as best overall response (BOR) among eligible patients with measurable disease, in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (18). These outcomes were reviewed by the researchers. OS was defined as the period from the first nivolumab plus ipilimumab combination therapy to death. PFS was defined as the period from the first nivolumab plus ipilimumab combination therapy to RECIST-defined progressive disease or death. DCR was defined as the percentage of patients with measurable disease in whom the BOR was CR, PR or stable disease. AEs were collected from the initiation of the treatment to 100 days after the end of the treatment or to the data cut-off day, whichever came first. Treatment-related AEs were collected from the initiation of treatment to the data cut-off day. AEs were coded using the Medical Dictionary for Regulatory Activities version 23.0. Severity was classified based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (19).
Additional evaluations included the analysis of occurrence of immune-related AEs (irAEs) (grade, time of onset). The subgroup analyses based on baseline demographics and treatment history were performed in the outcomes of both effectiveness and safety.
Statistical analysis. All assessments and baseline demographics were reported using descriptive statistics, and categorical variables were reported using number and percentage. The 95% confidence interval (CI) of ORR was calculated. The proportion of patients with AE, treatment-related AE or irAE was calculated using the total number of enrolled patients as the denominator. The aforementioned proportion and that of patients with grade ≥ 3 AE as the worst grade and 95%CI were analysed based on CTCAE version 4.0. OS and PFS rates with their respective 95%CIs at 1 year after the initiation of the nivolumab plus ipilimumab combination therapy were estimated using the Kaplan–Meier method.
Subgroup analyses for PFS were conducted to calculate the hazard ratio (HR) of PFS and their 95%CIs. Subgroup analysis for irAE was conducted to calculate the p-value using chi-square test or Fisher’s exact test. Results with p-value of less than 0.05 were regarded as statistically significant. Variables included sex, age, tissue type, Eastern Cooperative Oncology Group (ECOG) PS, IMDC risk, KPS, haemoglobin, calcium, duration from diagnosis to initiation of treatment, neutrophil count, platelet count, number of ipilimumab treatments and irAE. The computer software SAS version 9.1 and above (SAS Institute, Cary, NC, USA) was used for statistical calculations, including Kaplan–Meier method, 95%CI and HR.
Results
Patients. Forty-five patients were enrolled in this study. Table I shows the patient demographics and baseline characteristics at the initiation of nivolumab plus ipilimumab combination therapy. The proportion of male patients was 80%. The median age was 70.0 (range=50-85) years, and the proportion of patients aged ≥75 was 28.9%. Ten patients (22.2%) with nccRCC were enrolled. The details of nccRCC were as follows: five patients with papillary renal carcinoma, three patients with unclassified and two patients with other histological types. The percentage of patients with poor physical condition (ECOG PS ≥2) accounted for 22.2%. Eighteen patients (40%) had previously undergone nephrectomy.
Patient demographics and baseline characteristics.
Treatment patterns. Table II shows the real-world nivolumab plus ipilimumab combination therapy patterns. On the data cut-off day in January 2020, the median observation period was 13.8 (range=0.3-16.6) months. Twenty-nine patients (64.4%) completed the four cycles of nivolumab plus ipilimumab as scheduled. Sixteen patients discontinued nivolumab or ipilimumab during the nivolumab plus ipilimumab combination therapy. Twelve patients discontinued nivolumab, and the discontinuation of nivolumab automatically led to the discontinuation of ipilimumab. Four patients discontinued ipilimumab only. The most common reason for discontinuation of nivolumab or ipilimumab was AE or treatment-related AE. The time to failure and treatment-free interval are shown in Figure 1. Of the responders, eight patients (47.1%) continued nivolumab plus ipilimumab combination therapy. Four patients (100%) of the complete responders continued nivolumab plus ipilimumab combination therapy. Seventeen patients were treated with subsequent therapies, and the most common second-line therapy was axitinib, which was administered in 15 of 17 patients.
Treatment patterns.
Time to failure and treatment-free interval in all patients. The blue, green, and orange bars show the first-line treatment, second-line treatment, and no treatment, respectively. AE: Adverse event: CR: complete response; irAE: immune-related adverse event; PD: progressive disease; PR: partial response; SD: stable disease.
Effectiveness. The ORR, BOR and DCR are presented in Table III. The ORR was 42.5% (95%CI=27.0-59.1) with four patients (10.0%) achieving CR, and the DCR was 87.5% (95%CI=73.2-95.8). The results of the subgroup analyses for ORR based on baseline demographics and treatment history are presented in Figure 2. The ORR and CR rate of the patients who received 0-3 and 4 times treatments of ipilimumab were 36.4% vs. 44.8% and 9.1% vs. 10.3%, respectively. The effectiveness of nivolumab plus ipilimumab combination therapy was confirmed in all patient subgroups for ORR, including patients with older age, nccRCC and poor PS.
Objective response rates by the RECIST (version 1.1)†.
Effectiveness: best overall response by patient background. The black column, dark blue column, and light blue column show complete response (CR), partial response (PR), and stable disease (SD), respectively. Ca: Calcium; DFD: duration from diagnosis to initiation of treatment; ECOG PS: Eastern Cooperative Oncology Group performance status; Hb: haemoglobin; Histo: histological type; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; IPI: ipilimumab; KPS: Karnofsky performance status score; LLN: lower limit of normal; nccRCC: non-clear cell metastatic renal cell carcinoma; Neph: previous nephrectomy; Neu: neutrophil count; No.: number; Plt: platelet count; Sarco: sarcomatoid; ULN: upper limit of normal; y.: years.
The Kaplan–Meier curves of OS and PFS are presented in Figure 3A and B, respectively. The 12-month OS rate was 81.4% (95%CI=66.2-90.2), and the 12-month PFS rate was 56.1% (95%CI=40.0-69.4). The median OS and PFS were not reached (NR) (95%CI=NR-NR, respectively). The results of the subgroup analyses for PFS based on data obtained from baseline demographics and treatment history are presented in Figure 4. Univariate analysis showed that female sex, liver metastasis, bone metastasis and neutrophilia were significant risk factors for PFS, while irAE was a significant favourable factor for PFS (Figure 4A). There were no significant differences in other factors between different subgroups. The five significant factors detected in the univariate analysis were also analysed in the multivariate analysis. In the multivariate analysis, female sex was determined as a significant risk factor and irAE as a significant favourable factor (Figure 4B).
Kaplan–Meier curves of A) overall survival and B) progression-free survival. CI: Confidence interval; No.: number of patients; NR: not reached; OS: overall survival; PFS: progression-free survival.
Subgroup analyses of progression-free survival (PFS) based on patient demographics and baseline characteristics by A) univariate analysis and B) multivariate analysis. Data were analysed in 44 patients because one patient with an unknown histological type was excluded. Ca: Calcium; CI: confidence interval; ECOG PS: Eastern Cooperative Oncology Group performance status; IMDC: International Metastatic Renal Cell Carcinoma Database Consortium; irAE: immune-related adverse event; KPS: Karnofsky performance status score; No.: number of patients; PFS: progression-free survival.
Safety. AEs and irAEs of all patients are summarised in Table IV. Any grade treatment-related AEs occurred in 35 patients (77.8%), whereas grade ≥3 treatment-related AEs occurred in 17 patients (37.8%). Thirty-three patients (73.3%) and 15 patients (33.3%) showed any and grade ≥3 irAEs, respectively. The most frequent irAEs with any grades were endocrine disorders (33.3%), pulmonary toxicity (20.0%) and skin toxicity (15.6%). The steroid usage rate in patients with irAEs was 50.0% (data not shown).
Adverse events (AEs) and immune-related AEs (irAEs).
The data of the subgroup analyses for irAE based on baseline demographics and treatment history are presented in Table V. No significant difference was observed between patients aged ≥75 and those aged <75 years in patients with any grade irAEs (p=0.136). The subgroup analyses of grade ≥3 irAEs showed no significant difference between patients aged ≥75 and those aged <75 years (p=0.304, data not shown). There was no significant difference between the other subgroups in terms of any grade irAEs. Figure 5 shows the timing of onset of irAEs. Most irAEs occurred within 18 weeks after the initiation of the nivolumab plus ipilimumab combination therapy, after which the incidence rate of irAEs declined.
Subgroup analyses of immune-related adverse events on baseline demographics and treatment history.
Timing of onset of immune-related adverse events (irAEs). The light blue and black columns show grade 1-2 irAEs and grade ≥3 irAEs, respectively.
Discussion
The present study aimed to evaluate the effectiveness and safety of nivolumab plus ipilimumab combination therapy in a real-world setting in Japan and compare its effectiveness and safety with those in the global clinical trial, CheckMate 214. This real-world study can also provide data on patient populations who did not meet the eligibility criteria in the clinical trial, such as patients with nccRCC.
In the present study, the completion rate of ipilimumab administration was 64.4%, which was approximately 15% lower than that reported in the clinical trial (79%) (6). The ORR was 42.5% and the CR rate was 10.0% (Table III). These values are almost comparable with those in the overall population (ORR=42%; CR=9%) and the Japanese population (ORR=39%; CR=6%) in CheckMate 214 (6, 9). The 12-month OS and PFS rates were 81.4% and 56.1%, respectively (Figure 3). In CheckMate 214, the 12-month OS rate was 80%, and the 12-month PFS rate was 41% (20). At 12 months after the initiation of nivolumab plus ipilimumab combination therapy, OS and PFS curves were similar to those in the overall population and Japanese population in CheckMate 214 (6, 9, 20). Recent retrospective studies have also reported that the treatment response to nivolumab plus ipilimumab combination therapy in Japanese patients (ORR=34.3%-52.1%; 12-month PFS rate, 55%-56.2%) is comparable to that of the CheckMate 214 clinical trial (14-16). These real-world studies, including the current study, indicate that nivolumab plus ipilimumab combination therapy in a real-world setting in Japan would have effectiveness similar to that of the CheckMate 214 trial.
The subgroup analyses showed that the effectiveness of nivolumab plus ipilimumab combination therapy was achieved in all patient subgroups for ORR and PFS, such as older age, nccRCC, without previous nephrectomy, poor PS, IMDC poor risk and <4 times treatments of ipilimumab. Ten patients (22.2%) with nccRCC were enrolled in this study (Table I), while patients with nccRCC were excluded in CheckMate 214 (6). TKIs and mTOR inhibitors have lower effectiveness in patients with nccRCC than in those with clear cell RCC (21-23). A recent study has reported the effectiveness of nivolumab plus ipilimumab combination therapy in patients with nccRCC (24). The ORR of the nivolumab plus ipilimumab combination therapy in patients with nccRCC was 33.3% (24), which is comparable to that obtained in this study (33.3%; Figure 2). Additionally, no statistically significant differences in PFS between clear cell mRCC and nccRCC were observed in this study (Figure 4). These findings suggest that nivolumab plus ipilimumab combination therapy may provide clinical benefits in nccRCC as well as clear cell mRCC, unlike TKIs and mTOR inhibitors.
Multivariate analyses showed that a favourable outcome of nivolumab plus ipilimumab combination therapy was obtained in male patients and those with irAEs (Figure 4). However, in CheckMate 214, the HR for death in male patients was 0.71, which was numerically higher than that of female patients (0.52) (6). Moreover, to the best of our knowledge, no retrospective studies of nivolumab plus ipilimumab combination therapy in Japan have reported a favourable outcome in male patients (14-16). Thus, this finding needs to be verified by larger-scale studies. The onset of irAEs has also been associated with improvements in PFS and OS in other carcinomas (25). However, the onset of irAE may not be a predictor of effectiveness because there is no clear relationship between the onset of irAE and the onset of response in other carcinomas (26, 27). In the present study, the timing of onset of irAE was also varied and not clearly associated with the timing of onset of response (Figure 1). Therefore, the controversial relationship between the onset of irAEs and effectiveness of immunotherapy needs further evaluation in the future.
No new safety signals for nivolumab plus ipilimumab combination therapy were reported during the period of the real-world study and most irAEs occurred within 18 weeks after the initiation of the nivolumab plus ipilimumab combination therapy (Figure 5). In the overall population of CheckMate 214, the treatment-related select AE incidence rate peaked within the first 6 months of combination therapy with nivolumab plus ipilimumab (28). These results indicate that nivolumab plus ipilimumab combination therapy in a real-world setting in Japan would generate a safety profile and timing of onset of irAEs similar to that of CheckMate 214.
The limitations of this study include the retrospective observational study design, limited sample size, limited observation period, lack of review by a central reviewer and limited number of institutions. Further studies are needed to confirm the results of this study.
The effectiveness and safety of nivolumab plus ipilimumab combination therapy with a 1-year follow-up period in a real-world setting in Japan were comparable with those of CheckMate 214. This combination therapy might be effective in subgroups with various patient backgrounds in real-world clinical practice. No differences in the frequency of irAE between the subgroups were observed. The data for long-term outcomes will be continuously collected in this ongoing study, including follow-up of the enrolled patients.
Acknowledgements
The Authors thank the patients who were involved in the present study, as well as the investigators and study team. The data for this study were collected and analysed by CMIC Co., Ltd., Tokyo, Japan. The Authors also thank Masayuki Asano, PhD of CMIC Co., Ltd., for writing the first draft of the manuscript. Funding for this study and medical writing assistance was provided by ONO Pharmaceutical and Bristol-Myers Squibb (No grant number).
Footnotes
Authors’ Contributions
K. Kabu, H. Murakami and W. Obara contributed towards the conception and design of the study. R. Kato, T. Kojima, T. Sazuka, H. Yamamoto, S. Fukuda, K. Yamana, Y. Sugino, S. Hamamoto, N. Nakaigawa and W. Obara were involved in data acquisition. K. Kabu and H. Murakami contributed to data collection/analysis tools. R. Kato, H. Murakami and W. Obara performed the analysis. R. Kato, H. Murakami and W. Obara wrote the manuscript. All Authors reviewed and provided advice on improving the subsequent drafts of the manuscript. All Authors read and approved the final manuscript. All named Authors meet the International Committee of Medical Journal Editors criteria for authorship of this article, take responsibility for the integrity of the work as a whole and have provided their approval for this version to be published.
This article is freely accessible online.
Conflicts of Interest
R. Kato, T. Kojima, T. Sazuka, H. Yamamoto, S. Fukuda, K. Yamana, Y. Sugino, S. Hamamoto, N. Nakaigawa and W. Obara report research funding from ONO Pharmaceutical. N. Nakaigawa reports grants from ONO Pharmaceutical, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, Novartis, Merck, Astelas, Kissei Pharmaceutical, Chugai Pharmaceutical, Nippon Shinyaku Pharmaceutical, Sanofi and Daiichi-Sankyo Pharmaceutical. T. Kojima reports honoraria from ONO Pharmaceutical and Bristol-Myers Squibb. N. Nakaigawa reports honoraria from ONO Pharmaceutical, Bristol-Myers Squibb, Pfizer, Takeda Pharmaceutical, Novartis, Merck and AstraZeneca. W. Obara reports honoraria from ONO Pharmaceutical, Bristol-Myers Squibb and Merck. N. Nakaigawa reports support for attending meetings and/or travel from ONO Pharmaceutical, Bristol-Myers Squibb and Pfizer. K. Kabu is an employee of Bristol-Myers Squibb. H. Murakami is an employee of ONO Pharmaceutical.
- Received October 1, 2021.
- Revision received October 28, 2021.
- Accepted October 29, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
