First-line nivolumab plus ipilimumab or chemotherapy versus chemotherapy alone in advanced esophageal squamous cell carcinoma: a Japanese subgroup analysis of open-label, phase 3 trial (CheckMate 648/ONO-4538-50)

Background Programmed cell death 1 (PD-1)-based treatments are approved for several cancers. CheckMate 648, a global, phase 3 trial, showed that first-line nivolumab (anti-PD-1 antibody) plus ipilimumab (NIVO + IPI) or nivolumab plus chemotherapy (NIVO + Chemo) significantly increased survival in advanced esophageal squamous cell carcinoma (ESCC) without new safety signals versus chemotherapy alone (Chemo). Methods We evaluated the Japanese subpopulation of CheckMate 648 (n = 394/970), randomized to receive first-line NIVO + IPI, NIVO + Chemo, or Chemo. Efficacy endpoints included overall survival (OS) and progression-free survival assessed by blinded independent central review in Japanese patients with tumor-cell programmed death-ligand 1 (PD-L1) expression ≥ 1% and in all randomized Japanese patients. Results In the Japanese population, 131, 126, and 137 patients were treated with NIVO + IPI, NIVO + Chemo, and Chemo, and 66, 62, and 65 patients had tumor-cell PD-L1 ≥ 1%, respectively. In patients with tumor-cell PD-L1 ≥ 1%, median OS was numerically longer with NIVO + IPI (20.2 months; hazard ratio [95% CI], 0.46 [0.30–0.71]) and NIVO + Chemo (17.3 months; 0.53 [0.35–0.82]) versus Chemo (9.0 months). In all randomized patients, median OS was numerically longer with NIVO + IPI (17.6 months; 0.68 [0.51–0.92]) and NIVO + Chemo (15.5 months; 0.73 [0.54–0.99]) versus Chemo (11.0 months). Grade 3–4 treatment-related adverse events were reported in 37%, 49%, and 36% of all patients in the NIVO + IPI, NIVO + Chemo, and Chemo arms, respectively. Conclusion Survival benefits with acceptable tolerability observed for NIVO + IPI and NIVO + Chemo treatments strongly support their use as a new standard first-line treatment in Japanese patients with advanced ESCC. ClinicalTrials.gov ID NCT03143153. Supplementary Information The online version contains supplementary material available at 10.1007/s10388-022-00970-1.

A few phase 3 studies provide evidence for advanced ESCC treatments in the Japanese subgroup. Japanese subpopulation data from phase 3 trials for advanced esophageal cancer are limited to KEYNOTE-181 and ATT RAC TION-3 trials that assessed second-line pembrolizumab or nivolumab monotherapy, respectively [13,14]. Survival outcomes of ESCC were different for Japanese population compared with global clinical trial populations, as seen in ATT RAC TION-3, where median OS for nivolumab was numerically longer in the Japanese subpopulation (13.4 months) versus the global intent-to-treat population (10.9 months) [14,15]. Subsequent anticancer treatment rates were also different between the Japanese and global intent-to-treat population in ATT RAC TION-3, suggesting that treatment practices including approval/reimbursement systems may differ between Japan and other countries [3,[14][15][16]. Therefore, analyzing the efficacy and safety data specific to the Japanese subpopulation from the global phase 3 trials for first-line treatment in patients with advanced ESCC is important. Thus, we evaluated the efficacy and safety of nivolumab combination therapies in the Japanese subpopulation of CheckMate 648, and compared these findings with the global population.

Study design and patients
CheckMate 648 is an open-label, phase 3 trial to assess nivolumab-plus-ipilimumab (NIVO + IPI) and nivolumabplus-chemotherapy (NIVO + Chemo) combinations compared with chemotherapy alone (Chemo) as a first-line treatment in patients with advanced ESCC. Detailed methods are published elsewhere [6]. Briefly, patients aged ≥ 18 years who had advanced (unresectable, recurrent, or metastatic), histologically confirmed ESCC or adenosquamous cell carcinoma (predominant squamous differentiation) and measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were enrolled, irrespective of their PD-L1 expression status. Patients had no prior systemic therapy for advanced disease and were not amenable to cancer-directed curative therapies. Patients were stratified according to tumor-cell PD-L1 expression (PD-L1: ≥ 1% vs. < 1%, or indeterminate), region (East Asia [Japan, Korea, Taiwan] vs. rest of Asia vs. rest of the world), Eastern Cooperative Oncology Group performance status (ECOG PS) (0 vs. 1), and number of organs with metastases (≤ 1 vs. ≥ 2). Eligible patients were randomized (1:1:1) to receive nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), nivolumab (240 mg every 2 weeks) plus chemotherapy (4-week cycle of fluorouracil 800 mg/m 2 on days 1-5 and cisplatin 80 mg/m 2 on day 1), or chemotherapy alone (same dose as described above). Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or end of trial. Nivolumab or NIVO + IPI was administered for up to 2 years in the absence of disease progression or unacceptable toxicity. The current analyses focus on the Japanese racial subpopulation enrolled at Japanese sites, with data cutoff identical to that for the global trial population (January 18, 2021).

Pre-specified outcomes
The primary endpoints were OS and progression-free survival (PFS) assessed by blinded independent central review (BICR) per RECIST version 1.1 in patients with tumor-cell PD-L1 expression ≥ 1%. Secondary endpoints comprised OS and PFS (BICR) in all randomized patients, and objective response rate (ORR) per BICR in patients with tumorcell PD-L1 expression ≥ 1% and all randomized patients. Key exploratory endpoints included investigator-assessed PFS, subgroup analyses for OS based on demographics and clinical factors for all patients, duration of response (BICR), and safety. Efficacy endpoints were assessed for the global intent-to-treat population. Adverse events (AEs) were assessed in all the patients who had received ≥ 1 dose of the assigned treatment, and were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.0.

Statistical analyses
Descriptive analyses were conducted for the Japanese subpopulation. Hazard ratios (HRs) for OS and PFS were calculated using unstratified Cox proportional hazards model with treatment as the sole covariate. Two-sided 95% confidence intervals (CIs) for the HR were provided. Median OS, PFS, and duration of response for each treatment arms were estimated using the Kaplan-Meier method, and the corresponding 95% CIs were constructed based on a log-log 1 3 transformed CI for the survivor function. OS and PFS rates at fixed time points were derived from the Kaplan-Meier estimate. The 95% CIs for proportions were calculated using the Clopper-Pearson method. Statistical analyses were performed using SAS software v9.2 to v9.4 (SAS Institute, Cary, USA) and R statistical software package.

Characteristics of the Japanese subpopulation
Overall, 394 of 970 patients from CheckMate 648 trial were enrolled in Japan (NIVO + IPI, n = 131; NIVO + Chemo, n = 126; Chemo, n = 137). Baseline patient characteristics were generally balanced between the treatment arms (  (Fig. 1a). The corresponding 12-month OS  Table 2). Objective (complete or partial) responses were also more durable for NIVO + IPI versus Chemo in patients with tumor-cell PD-L1 ≥ 1% and in all randomized patients ( Fig. 1e and f).  Table 2). The duration of response was also longer in the NIVO + Chemo  were calculated using unstratified Cox proportional hazard regression model. DOR was calculated for patients whose best overall response was complete or partial arm than in the Chemo arm for both, tumor-cell PD-L1 ≥ 1% cases and all randomized patients ( Fig. 2e and f).

Subgroup analyses of OS in all randomized Japanese patients
Subgroup analyses were performed for age, sex, ECOG PS, tumor-cell PD-L1 expression status, disease status at study entry, number of organs with metastases, and smoking history using unstratified Cox proportional hazards modeling with treatment as the only covariate (Online Resource 5). OS numerically favored NIVO + IPI or NIVO + Chemo versus Chemo alone across multiple prespecified subgroups in all randomized patients. In both, NIVO + IPI and NIVO + Chemo arms, the OS prolongation effect was numerically larger with the higher tumor-cell PD-L1 expression subgroup, with no further enrichment of efficacy observed in any of the cutoff values higher than 1% (Online Resource 5).

Discussion
First-line NIVO + IPI and NIVO + Chemo treatments resulted in a substantial survival advantage over Chemo in Japanese patients with advanced ESCC. The efficacy and safety of NIVO + IPI and NIVO + Chemo were consistent between the CheckMate 648 Japanese subpopulation and the global population (including Japan) [6]. For NIVO + IPI and NIVO + Chemo, the median OS and median PFS (BICR) were numerically longer, with higher ORR for the Japanese subpopulation versus the global population. Specifically, in the chemotherapy-free combination (NIVO + IPI), the  [6]. Baseline patient characteristics of the Japanese subpopulation and the global population were generally similar. However, more patients in the Japanese subpopulation had an ECOG PS of 0 in the NIVO + IPI (71% vs. 46%), NIVO + Chemo (71% vs. 47%), and Chemo (69% vs. 48%) arms versus the global population [6]. It is plausible that a better functional status may have contributed to the survival benefit in the Japanese subpopulation compared with the global population. This hypothesis is supported by findings of NIVO + IPI phase 3 trials for non-small cell lung cancer (NSCLC) suggesting that better performance status was correlated with greater NIVO + IPI efficacy [17,18]. Patients with better clinical condition are generally more likely to receive subsequent treatment. This may explain the higher rates of subsequent anticancer therapies in the current study across all arms in the Japanese subpopulation (63%-75%) versus the global population (51-63%), especially the rate of subsequent systemic anticancer therapies received [6]. Differences in ECOG PS scores and subsequent treatment rates may have affected the OS benefit observed. These findings are concordant with a phase 3 nivolumab monotherapy versus chemotherapy trial (ATT RAC TION-3) in advanced ESCC [14,15]. In ATT RAC TION-3, compared with the global population, the Japanese subpopulation had higher rates of ECOG PS 0 (nivolumab, 61% vs. 48%; Chemo, 64% vs. 51%), subsequent systemic anticancer therapies (nivolumab, 59% vs. 53%; Chemo, 47% vs. 47%), and longer median OS (nivolumab, 13.4 vs. 10.9 months; Chemo, 9.4 vs. 8.4 months) [14,15]. Subsequent chemotherapy after anti-PD-1/PD-L1 therapy improved efficacy outcomes in other types of cancers [19][20][21], which may have contributed to the higher efficacy of the nivolumab combination treatments in the Japanese subpopulation in this study.
Also, the Japanese subpopulation had a relatively higher percentage of smokers than the global population (89% vs. 80%) [6]. The subgroup analyses of CheckMate 648 global population suggested a longer OS in smokers versus nonsmokers in the NIVO + IPI arm [6]. In contrast, nonsmokers tended to have longer OS in the NIVO + Chemo arm, possibly because the concomitant chemotherapy may override any advantage of nivolumab in smokers. Reportedly, immune checkpoint inhibitors are more effective in patients with a smoking history in NSCLC and several other cancers [22,23]. These results suggest that the difference in the proportion of smokers may have enhanced the efficacy of NIVO + IPI in the Japanese population.
In the NIVO + IPI arm, the incidence of serious TRAEs was higher than that in the NIVO + Chemo and Chemo arms, Table 3 Treatment-related adverse events in all treated patients who received ≥ 1 dose of the assigned treatment in the Japanese subpopulation TRAE treatment-related adverse event, Chemo chemotherapy, IPI ipilimumab, NIVO nivolumab Data are presented as number (%) of patients in each arm a Includes events reported between the first dose and 30 days after the last dose of trial therapy. Treatment-relatedness in the NIVO + Chemo arm was attributed to either nivolumab or any of the chemotherapies or both. Treatment-relatedness in the NIVO + IPI arm was attributed to either nivolumab or ipilimumab or both. TRAEs were reported using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, and Medical Dictionary for Regulatory Activities, version 23.1 b Treatment-related deaths were reported regardless of timeframe. Treatment-related death in the NIVO + IPI arm was from pulmonary embolism. Treatment-related deaths in the NIVO + Chemo arm were from pneumatosis intestinalis and pneumonitis whereas the incidence of any TRAEs was lower. Similar trends were observed in the global population [6]. However, in the NIVO + IPI arm, TRAEs with potential immunologic etiology of endocrine, pulmonary, and skin were slightly more common in the Japanese than in the global population [6]. This concurs with reports on renal cell carcinoma or NSCLC treated with NIVO + IPI, where rates of these AE categories were similarly higher in the Japanese or Asian population than in the global population [24][25][26].
The NIVO + IPI and NIVO + Chemo arms were not compared statistically as this study was not designed to compare these 2 arms. It was also not possible to speculate advantage of one or the other nivolumab combination treatment for specific study subgroups. In clinical practice, the choice of cancer treatment regimen is governed by several considerations including disease status, patients' requirements and preferences, and capacity to tolerate specific immunotherapy or chemotherapy. Future studies and exploratory post hoc analyses are warranted to determine prognostic predictors for each of the nivolumab combination regimen.

Conclusion
NIVO + IPI and NIVO + Chemo in the Japanese subpopulation showed efficacy benefits compared with Chemo and had an acceptable safety profile, similar to reports from the global population. This Japanese sub-analysis showed that both NIVO + IPI and NIVO + Chemo treatments can become a new standard first-line treatment option for Japanese patients with advanced ESCC.

Declarations
Ethical Statement All procedures followed in this study were in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines, and were approved by the institutional review board at each study site. All patients provided their informed consent for being included in this study. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.