Efficacy of ipilimumab plus nivolumab with or without chemotherapy according to baseline tumor size: a multicenter retrospective study

Introduction

Lung cancer is the leading cancer-associated cause of death globally (1). Recent phase III clinical trials have demonstrated that treatments containing immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS) and progression-free survival (PFS) in patients with lung cancer compared with conventional platinum-doublet chemotherapy (2-12). Ipilimumab is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor that enhances various immune checkpoints and increases T-cell activation to target tumor cells. Ipilimumab and nivolumab, which are dual immunotherapeutic agents, have received attention for their ability to modify immune responses and provide long-term anticancer effects. The CheckMate227 study demonstrated that ipilimumab plus nivolumab (I-N) improves OS compared with chemotherapy for patients with non-small cell lung cancer (NSCLC) with programmed death-ligand 1 (PD-L1) score ≥1% (13,14). In the CheckMate9LA study, two cycles of I-N plus chemotherapy (I-N-chemo) also improved OS for NSCLC compared with chemotherapy (15,16). These two regimens are primarily distinguished by the inclusion or exclusion of platinum-based agents, and both are approved for use in Japan.

Despite positive findings for these regimens, their optimal application in clinical practice has not been established. Although advanced biomarkers, such as tumor mutational burden or positron emission tomography-computed tomography (PET-CT)-based metabolic tumor volume, can provide valuable insights (13,17-19), they are not always feasible in routine clinical practice due to limited accessibility and procedural complexity. As a result, there remains a need for more pragmatic markers. Uehara et al. reported that chemotherapy combined with ICI yields superior clinical outcomes compared to ICI monotherapy in patients with a large baseline tumor size (BTS) (20), which is a measure that can be easily assessed in daily practice. The relationship between BTS and the efficacy of ICI has been extensively studied in the context of monotherapy, such as pembrolizumab. However, data directly examining the impact of BTS on dual CTLA-4/PD-1 blockade remain limited.

To date, no prospective trials have directly compared these regimens specifically in patients with a PD-L1 tumor proportion score (TPS) of 1–49%. This lack of head-to-head prospective evidence poses a significant clinical challenge for determining the most appropriate treatment strategy, namely whether to prioritize ICI plus chemotherapy or I-N-based therapy. To address this gap, we previously reported the results of the retrospective multicenter TOPGAN2023-01 study, which evaluated whether ICI plus chemotherapy or an I-N-based regimen was more appropriate for patients with a PD-L1 TPS of 1–49% (21). While the I-N-based group included Checkmate227 and Checkmate9LA, the study did not directly compare these two regimens. The key difference between these two regimens is the addition of chemotherapy. To determine if the selection of these regimens should be guided by BTS, the present study investigated the impact of BTS on clinical outcomes in patients treated with I-N-based regimens. We present this article in accordance with the STROBE reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0214/rc).

Methods

Study design and patients

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Hirosaki University (approval No. 2023-037-3). All participating hospitals were informed of and agreed to the study. Individual consent for this retrospective analysis was waived. This study was a multicenter, retrospective, observational study across 19 institutions in Japan. This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (No. UMIN000052228).

Medical records were reviewed for patients who underwent ICI-chemo or I-N-based therapy from January 2018 to March 2022. The present analysis specifically focused on patients treated with I-N-based regimens, who were further categorized into two groups: those receiving I-N alone (I-N) group and those receiving I-N combined with chemotherapy (I-N-chemo) group. Based on previous literature (20), a BTS threshold of 50 mm (≥50 vs. <50 mm) was employed for analysis. BTS is more practical and widely utilized in daily clinical practice than the total sum of all lesion diameters. In this study, BTS was assessed in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST). The inclusion criteria for this study were defined as follows: confirmed NSCLC, clinical stage IIIB or C without indication of definitive thoracic radiotherapy, stage IV, or recurrent disease and NSCLC with PD-L1 TPS 1–49%. We excluded patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene. Collected clinical data included age, gender, smoking status, performance status (PS), cancer stage, tumor histology, PD-L1 TPS, chemotherapy regimen, BTS, tumor response, PFS, OS, and adverse events (AEs) ≥ Grade 3. PD-L1 TPS was assessed by the 22C3 pharmDx assay. The data cut-off date was May 31, 2023.

Statistical analysis and assessments

All analyses were performed using JMP 15 software (SAS Institute, Inc., NC, USA). Categorical variables were compared using the Chi-squared test or Fisher’s exact test, as appropriate, while continuous variables were analyzed using the Mann-Whitney U test. Survival outcomes, including PFS and OS, were estimated using the Kaplan-Meier method, with intergroup differences evaluated via the log rank test. Hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) for OS and PFS were calculated using Cox proportional hazard models. All statistical tests were two-sided. Results with a P value <0.05 were considered statistically significant.

AEs severity was determined using the Common Terminology Criteria for Adverse Events (version 5.0) (22). Radiographic responses were evaluated according to the RECIST, version 1.1 (23). We evaluated the objective response rate as the frequency of patients achieving a complete response (CR) or partial response (PR). BTS was based on tumor size assessed by RECIST prior to the initiation of treatment. Radiological evaluations were performed at intervals of 6–12 weeks, in line with standard clinical practice at each institution. Images were reviewed by local clinical teams, rather than through a central review process.

Results

Patient characteristics

A total of 87 patients were treated with I-N-based therapy. Among them, 25 patients (28.7%) were treated with I-N, while 62 (71.3%) received I-N-chemo. Baseline characteristics of the study population are summarized in Table 1. Only 6 (6.9%) patients who had a PS of ≥2 were treated with I-N-based therapy. Twenty-two patients (25.2%) were aged 75 years or older. Patients with BTS ≥50 mm was identified in 62 (71.3%), and BTS <50 mm in 25 (28.7%) patients. Compared with the I-N group, the I-N-chemo group was characterized by a higher proportion of younger patients, those with a favorable PS [0–1], and those with a large tumor burden (BTS ≥50 mm).

Efficacy

PFS and OS in overall result

The follow-up period had a median duration of 20.0 months. The median PFS was 6.0 months (95% CI: 2.7–10.6) in the I-N group and 6.3 months (95% CI: 4.8–9.4) in the I-N-chemo group (Figure 1A). The median OS was 17.3 months (95% CI: 8.4–not reached) in the I-N group and 20.0 months (95% CI: 14.3–not reached) in the I-N-chemo group (Figure 1B). No significant differences were observed in PFS or OS between I-N group and I-N-chemo group.

Figure 1 PFS (A) and OS (B) in the I-N group and I-N-chemo group. Data are presented as median (95% CI). CI, confidence interval; I-N, ipilimumab-nivolumab; NR, not reached; OS, overall survival; PFS, progression-free survival.

PFS and OS in patients with BTS ≥50 mm

Among patients with BTS ≥50 mm, median PFS was 4.0 months (95% CI: 0.7–6.7) in the I-N group and 5.5 months (95% CI: 3.4–8.1) in the I-N-chemo group (P=0.03) (Figure 2A). Median OS was 8.3 months (95% CI: 1.0–10.7) for I-N and 17.7 months (95% CI: 10.9–not reached) for I-N-chemo group (P=0.005) (Figure 2B). One-year PFS rate and OS rate were 0% and 21.6% in the I-N group and 10.5% and 44.2% in the I-N-chemo group, respectively. The Cox proportional hazards model was utilized for univariate analysis to investigate variables linked to PFS and OS in the BTS ≥50 mm group. Among this subgroup, PS 0–1 and the use of I-N-chemo were consistently identified as significant predictors of superior PFS and OS (Table 2). For patients exhibiting a BTS of 50 mm or greater, we applied the Cox proportional hazards model to perform a multivariate analysis and assess how various variables influenced PFS and OS. PS ≥2 was an independent prognostic factor for shorter survival outcomes (Table S1).

Figure 2 PFS (A) and OS (B) in the I-N group and I-N-chemo group among patients with a BTS ≥50 mm. Data are presented as median (95% CI). BTS, baseline tumor size; CI, confidence interval; I-N, ipilimumab-nivolumab; NR, not reached; OS, overall survival; PFS, progression-free survival.

PFS and OS in patients with BTS <50 mm

In the subgroup with BTS <50 mm, there were no statistically significant differences in PFS (17.4 vs. 10.9 months, log-rank test, P=0.09) (Figure S1A) or OS between the I-N and I-N-chemo groups (not reached vs. 24.1 months, log-rank test, P=0.54) (Figure S1B).

ORR

The objective response rates were 36.0% and 67.7% in the I-N and I-N-chemo groups, respectively (Table S2). Among patients with BTS ≥50 mm, the objective response rates were 23.1% and 65.3% in the I-N and I-N-chemo groups, respectively (Table S3).

Safety

The AEs are showed in Table 3. The incidence of treatment cessation attributed to AEs was 28.0% in the I-N group and 45.1% in the I-N-chemo group. The incidence of any-grade pneumonitis was similar in the two groups (20.0% vs. 17.7%), the rate of Grade 3 or more pneumonitis was observed in 3 patients (4.8%) in I-N-chemo group. Treatment-related deaths occurred in 1 patient (4.0%) and 2 patients (3.2%) treated with I-N and I-N-chemo groups respectively (1 due to Legionella pneumonia, 1 due to cytokine release syndrome, and 1 due to pneumonitis).

More than half of the AEs leading to therapy withdrawal were attributed to pneumonitis, colitis, and liver dysfunction (Table S4). Hematological toxicities were more frequently observed in the I-N-chemo group, which was consistent with the known safety profile of platinum-based chemotherapy.

Discussion

In the present study, the median PFS was 6 months (95% CI: 2.7–10.6) in the I-N group and 6.3 months (95% CI: 4.8–9.4) in the I-N-chemo group. These outcomes are consistent with those of both the CheckMate227 study (median PFS: 5.1 months) (13) and CheckMate9LA study (median PFS: 5.8 months) (15) in patients with PD-L1 TPS ≥1%. In the present cohort, the median OS was 17.3 months (95% CI: 8.4–not reached) in the I-N group and 20.0 months (95% CI: 14.3–not reached) in the I-N-chemo group. Again, these OS outcomes are comparable to those of pivotal trials like the CheckMate227 study (median OS: 17.1 months) (13) and the CheckMate9LA study (median OS: 15.6 months) (15) in patients with TPS ≥1%. As long-term follow-up data indicate that both regimens yield a 5-year survival rate of approximately 20%, the long-term efficacy of I-N and I-N-chemo is considered equivalent (14,16). A recent study by Sumi et al. compared the efficacy of I-N versus I-N-chemo in a cohort of 215 patients, with 104 and 111 patients in each group (24), and found no significant group differences in PFS or OS (median PFS: 5.3 vs. 5.9 months; HR, 1.17; 95% CI: 0.86–1.60); median OS: 22.1 vs. 19.2 months; HR, 1.01; 95% CI: 0.68–1.49). Furthermore, there were no significant differences in OS between the I-N and I-N-chemo groups, regardless of subgroup analysis (PD-L1 TPS, age, or tumor burden). However, they observe a more favorable PFS among patients with a high tumor burden (≥85 mm) in the I-N chemo group compared to the I-N group (4.1 vs. 2.6 months), although this difference was not statically significant.

In the present study, we evaluated the impact of BTS on clinical outcomes in patients receiving I-N or I-N-chemo in a real-world setting. We found that patients with a BTS ≥50 mm achieved a significantly longer PFS and OS with chemotherapy (I-N-chemo) compared to without chemotherapy (I-N); notably, this therapeutic benefit was not observed in patients with a BTS <50 mm. These findings suggest that BTS may serve as a valuable biomarker for treatment selection. However, few studies have investigated the association between BTS and survival outcomes in patients treated with I-N-based regimens in real-world clinical settings. Moreover, no phase III trials have analyzed treatment efficacy stratified by BTS.

A previous study by Uehara et al. reported that BTS was a significant predictor of efficacy in patients with advanced NSCLC receiving first-line treatment with ICI monotherapy or ICI plus chemotherapy. In their study, both PFS and OS tended to be superior in ICI plus chemotherapy group patients with a BTS ≥50 mm (median PFS: 3.6 vs. 10.6 months; HR, 0.59; 95% CI: 0.36–0.96; median OS: 15.2 months vs. not reached; HR, 0.56; 95% CI: 0.31–1.04). As patients with high PD-L1 TPS were included in the cohort, a multivariate analysis was conducted for the subgroup with a BTS ≥50 mm. These findings revealed that ICI plus chemotherapy (HR, 0.26; 95% CI: 0.11–0.64) and PD-L1 TPS ≥50% (HR, 0.28; 95% CI: 0.11–0.66) were independent favorable prognostic factors for PFS. Although our study specifically targeted patients with low PD-L1 expression (TPS 1–49%), the findings demonstrate a consistent trend in PFS and OS among patients with a BTS ≥50 mm treated with I-N-based regimens.

In NSCLC, the efficacy of the combination therapy—particularly in patients with a high tumor burden—may be explained by specific immunological and physiological mechanisms. Previous studies have reported associations between a large tumor size and the tumor microenvironment (TME). Large primary lesions and bulky nodal involvement are characterized by an accumulation of myeloid-derived suppressor cells and regulatory T cells (Tregs), both of which are known to correlate with poor prognosis and resistance to PD-1/PD-L1 inhibitors in lung cancer patients (25,26). This immunosuppressive milieu can lead to T-cell exhaustion, and the disproportionately low number of effector T cells relative to the total tumor mass may limit the efficacy of immunotherapy (27). The synergistic effect of chemotherapy likely stems from its ability to modulate this hostile TME. In lung cancer, specific cytotoxic agents, such as platinum-based doublets, have been shown to induce immunogenic cell death. This process triggers the release of tumor antigens and damage-associated molecular patterns, thereby enhancing dendritic cell maturation and antigen presentation within the lung TME (28). The rapid “debulking” effect of chemotherapy is also clinically important in advanced NSCLC. By rapidly reducing the tumor volume, chemotherapy can help prevent early disease progression during the period required for the adaptive immune response to be fully mobilized (29). Although we did not collect biomarkers of TME in the present study, which limits our ability to directly assess these mechanisms, it is plausible that the addition of chemotherapy could enhance the antitumor effect by modulating the immunosuppressive environment in patients with a large BTS.

The safety profile of present study was consistent with that reported in previous study of I-N-based therapy cohort (21). In the present cohort, treatment discontinuation due to AEs was observed in 28.0% of the patients in the I-N group and 45.1% in the I-N-chemo group. Notably, these rates are higher than those calculated from long-term follow-up data for the CheckMate227 and CheckMate9LA studies, which reported discontinuation rates of 18% and 22%, respectively (14,16). Specifically, the treatment discontinuation rate in the I-N-chemo group was higher than that reported in the CheckMate9LA study. This discrepancy may be partly explained by differences in the ethnic backgrounds of the cohorts. John et al. performed a sub-analysis of Asian patients in the CheckMate9LA study, finding a higher incidence of Grade 3–4 AEs in the Asian subgroup compared with the overall population (57% vs. 47%) (30). Specific immune-related AEs, including those affecting the skin, endocrine, hepatic, and pulmonary systems, were more frequent among Asian patients.

Our findings are consistent with real-world data from Japan. Findings from the LIGHT-NING trial, which analyzed 359 patients treated with I-N-based therapy, reported treatment discontinuation rates of 38.2% in the I-N-chemo group and 31.2% in the I-N group (31). The incidence of treatment-related deaths in the LIGHT-NING trial was approximately 3%, which is comparable with our results. Unlike clinical trials, real-world data often include older patients have poor PS, and multiple comorbidities. These factors likely contributed to the elevated rate of AEs leading to treatment discontinuation in our cohort.

In the present study, the incidence of pneumonitis was 20.0% in the I-N group and 17.7% in the I-N-chemo group; the rate of Grade ≥3 pneumonitis (Grade ≥3) was 4.8% in the I-N-chemo group. These rates are consistent with previous reports. For example, the JCOG2007 trial reported an incidence of pneumonitis (Grade ≥3) of 5% (32). Notably, the frequency of high-grade pneumonitis in our cohort was higher in the I-N-chemo group than in the I-N group. Overall, these findings emphasize the need for stringent monitoring of pulmonary toxicities in patients receiving I-N-based therapy, particularly when combined with chemotherapy.

This study is subject to several limitations. First, due to its retrospective design, treatment selection bias is present. Patients with more an aggressive disease status, younger age, and better PS were more likely to receive I-N plus chemotherapy (I-N-chemo), whereas patients who were older and had a poor PS were more likely to not have chemotherapy added. Furthermore, radiographic assessments were conducted by the clinical teams at each participating institution, rather than through a blinded independent central review. This approach may have introduced detection bias, potentially influencing the PFS outcomes. Second, the follow-up period for the I-N-based therapy group was short. Because long-term survival has not yet been evaluated, caution is warranted when interpreting the findings. Third, we did not capture detailed information on specific metastatic sites (e.g., brain, bone, and liver) as part of the patient background data. The presence of bone or brain metastasis has been reported to affect prognosis (33,34). Given that bone metastases are often considered unmeasurable lesions by RECIST, further evaluation combining these factors with BTS is warranted. Fourth, the intervals between tumor evaluations varied across the different study sites. Fifth, as the BTS analysis was limited to patients with TPS 1–49%, it remains unclear whether these results are reproducible in patients with high TPS expression or negative expression. Finally, statistical power was limited due to the small sample size of the cohort. As a result, the hazard ratio estimates may be unstable, particularly in the multivariate analysis where the number of confounding variables that could be adjusted for was restricted. These findings should therefore be considered exploratory. Larger multicenter studies are needed to confirm the independent prognostic value of the treatment in this population.

Conclusions

In conclusion, this study supports BTS as a potential predictive marker for the addition of chemotherapy in patients with NSCLC receiving I-N-based therapy. I-N combined with chemotherapy may be more effective than I-N for NSCLC patients with a BTS ≥50 mm. However, given the retrospective nature of this study and the limited subgroup sample sizes, these results should be interpreted with caution. The I-N-chemo regimen is also associated with a higher incidence of hematological toxicities and treatment discontinuation rates. As a result, careful patient selection and stringent monitoring are necessary in clinical practice.

Acknowledgments

This work was presented, in part, at the 2025 ESMO Congress, Berlin (Oct 18, 2025), as a conference abstract. We would like to thank all patients and their families, as well as Yuhei Harutani (Wakayama Medical University) for data collection. The authors would also like to thank Enago (www.enago.jp) for the English language review and thank all members of Department of Respiratory Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Japan; Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan; Department of Pulmonary Medicine, Sendai Kousei Hospital, Sendai, Japan; Department of Respiratory Medicine, Saitama Red Cross Hospital, Saitama, Japan; Department of Thoracic Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan; Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Respiratory Medicine, Kanazawa University Hospital, Kanazawa, Japan; Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Saga, Japan; Department of Respiratory Medicine, Graduate School of Medicine University of Yamanashi, Yamanashi, Japan; Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; Division of Respiratory Disease, Department of Internal Medicine, The Jikei University Daisan Hospital, Tokyo, Japan; Department of Respiratory Medicine, Tohoku University Hospital, Sendai, Japan; Third Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan; Department of Respiratory Medicine, Yamanashi Prefectural Central Hospital, Yamanashi, Japan; Department of Respiratory Medicine, National Hospital Organization Ureshino Medical Center, Nagasaki, Japan; Division of Respiratory Medicine, NTT Medical Center Tokyo, Tokyo, Japan; Department of Medical Oncology and Respiratory Medicine, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan; Department of Respiratory Medicine, Kitakyushu Municipal Medical Center, Kitakyushu, Japan; Department of Respiratory Medicine, Naga Municipal Medical Hospital, Wakayama, Japan.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0214/rc

Data Sharing Statement: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0214/dss

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0214/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0214/coif). H.T. receives lecture fees from Ono Pharmaceutical Co. Ltd., Bristol Myers Squibb, AstraZeneca, Chugai Pharmaceutical Co., Boehringer-Ingelheim Japan Inc., Pfizer Japan Inc., Takeda, Daiichi Sankyo, MSD K.K and Amgen. T.M. reports receiving lecture fees from Ono Pharmaceutical Co., Ltd., Bristol Myers Squibb, Eli Lilly, Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Novartis Pharma K.K. and Care Net Inc. T.T. reports receiving lecture fees from AstraZeneca and Chugai Pharmaceutical Co. Y.K. reported receiving lecture fees from AstraZeneca K.K, Chugai Pharmaceutical Co, Taiho Pharmaceutical, Eli Lilly, Kyowa Hakko-Kirin, and Life Technologies Japan Ltd. J.K. reports receiving lecture fees from AstraZeneca K.K. and Chugai Pharmaceutical Co. Y.T. reports receiving lecture fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical, MSD K.K, and the Daiichi Sankyo Company. S.O. reports receiving lecture fees from MSD K.K, Bristol-Meyers Squibb, and Chugai Pharmaceutical Co. M.S. reports receiving lecture fees from AstraZeneca K.K, Chugai Pharmaceutical Co., Eli Lilly, and Merck. T.H. reports receiving lecture fees from AstraZeneca K.K, Chugai Pharmaceutical Co., Eli Lilly, and Merck. E.M. reports receiving lecture fees from AstraZeneca, Eli Lilly, Chugai Pharmaceutical Co., Boehringer-Ingelheim Japan, Inc., Taiho Pharmaceutical, Kyowa Hakko-Kirin, Daiichi-Sankyo, MSD, Bristol Myers Squibb, Merck, Amgen, Ono Pharmaceutical Co., Thermo Fisher Scientific, Nippon Kayaku, Takeda Pharmaceutical Co., and Sysmex. He received advisory roles from Boehringer-Ingelheim Japan Inc., Ono Pharmaceutical Co., Daiichi-Sankyo, and Merck outside of the submitted work. R.S. reports receiving lecture fees from AstraZeneca MSD K.K, Merck Biopharma, Taiho Pharmaceutical and Chugai Pharmaceutical Co. Toshio Sakatani reports receiving lecture fees from AstraZeneca, Eli Lilly, MSD K.K, Boehringer-Ingelheim Japan, Inc., Takeda Pharmaceutical Co., Taiho Pharmaceutical, and Bristol Myers Squibb. Y.T.K. reports receiving lecture fees from Bristol Myers Squibb, AstraZeneca, Taiho Pharmaceutical, Chugai Pharmaceutical Co., MSD K.K, Ono Pharmaceutical Co., and Kyowa Hakko-Kirin. M.N. reports receiving lecture fees from AstraZeneca, Amgen, Merck, Merck Sharp & Dohme, Ono Pharmaceutical Tigerise Inc., CMIC Co., Ltd., Daiichi Sankyo Company, Limited, Taiho Pharmaceutical, Takeda Pharmaceutical Company Limited, Chugai Pharmaceutical, Boehringer Ingelheim, Eli Lilly Japan K.K, Nippon Kayaku Co., Ltd., Novartis Pharma K.K, Novocure Co., Ltd., BeOne Medicines Ltd., Pfizer Japan, Bristol-Myers Squibb, Merck Biophama and Johnson & Johnson Innovative Medicine. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Hirosaki University (approval No. 2023-037-3). All participating hospitals were informed of and agreed to the study. The requirement for informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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