Second-line tislelizumab versus chemotherapy in Japanese patients with advanced or metastatic esophageal squamous cell carcinoma: subgroup analysis from RATIONALE-302

Background Esophageal squamous cell carcinoma (ESCC) has a poor prognosis, with limited second-line systemic therapy options, and represents an increasing disease burden in Japan. In the phase 3 RATIONALE-302 study, the anti-programmed cell death protein 1 antibody, tislelizumab, significantly improved overall survival (OS) versus chemotherapy as second-line treatment for advanced/metastatic ESCC. Here, we report the Japanese patient subgroup results. Methods Patients with advanced/metastatic ESCC, with disease progression during/after first-line systemic therapy were randomized 1:1 to open-label tislelizumab 200 mg every 3 weeks or investigator’s choice of chemotherapy (paclitaxel/docetaxel). Efficacy and safety were assessed in all randomized Japanese patients. Results The Japanese subgroup comprised 50 patients (n = 25 per arm). Tislelizumab improved OS versus chemotherapy (median: 9.8 vs. 7.6 months; HR 0.59; 95% CI 0.31, 1.12). Among patients with programmed death-ligand 1 score ≥ 10%, median OS was 12.5 months with tislelizumab (n = 10) versus 2.9 months with chemotherapy (n = 6) (HR 0.31; 95% CI 0.09, 1.03). Tislelizumab improved progression-free survival versus chemotherapy (median: 3.6 vs. 1.7 months, respectively; HR 0.50; 95% CI 0.27, 0.95). Objective response rate was greater with tislelizumab (32.0%) versus chemotherapy (20.0%), and responses were more durable (median duration of response: 8.8 vs. 2.6 months, respectively). Fewer patients experienced ≥ grade 3 treatment-related adverse events with tislelizumab (24.0%) versus chemotherapy (47.8%). Tislelizumab demonstrated an improvement in health-related quality of life versus chemotherapy. Conclusions As second-line therapy for advanced/metastatic ESCC, tislelizumab improved OS versus chemotherapy, with a favorable safety profile, in the Japanese patient subgroup, consistent with the overall population. Clinical trial registry ClinicalTrials.gov: NCT03430843. Supplementary Information The online version contains supplementary material available at 10.1007/s10388-023-01040-w.


Introduction
In 2020, esophageal cancer (EC) was ranked the eighth most commonly diagnosed cancer and sixth most common cause of cancer death worldwide [1].The burden of EC is greatest in Eastern Asia, with the highest global incidences reported in this region for both men and women [2,3].In Japan, there were over 26,000 newly diagnosed cases of EC in 2020, along with over 12,000 deaths caused by EC [4].Esophageal squamous cell carcinoma (ESCC) is the predominant histological subtype in Japan, which accounts for over 90% of EC cases [5].
Second-line treatment strategies after initial chemotherapy for advanced ESCC have historically been limited, representing a significant unmet need in this patient population [6].Notably, a real-world study of treatment patterns among a sample of patients with ESCC from Japan in 2018 found that only 54% of patients with advanced disease received active second-line treatment (typically taxane-based chemotherapy), with the remainder receiving best supportive care [6].More recently, trials of drugs targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway have demonstrated prolonged survival with anti-PD-1 antibodies versus chemotherapy in patients with advanced or metastatic ESCC whose disease progressed after first-line systemic therapy [7][8][9].Subgroup analyses of these studies have shown that this survival benefit is also applicable to Japanese patients treated with anti-PD-1 antibodies [10,11].In these studies, second-line therapy with either nivolumab or pembrolizumab demonstrated favorable efficacy compared with chemotherapy (median overall survival 13.4 vs. 9.4 months with nivolumab vs. chemotherapy, HR 0.77; 12.4 vs. 8.2 months with pembrolizumab vs. chemotherapy, HR 0.68) [10,11].Tislelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody with high affinity for PD-1 and has demonstrated antitumor activity in patients with ESCC and gastroesophageal junction adenocarcinoma, either alone or in combination with chemotherapy in clinical trials [12][13][14][15].In the international, randomized, phase 3 RATIONALE-302 study (NCT03430843) that enrolled patients with advanced or metastatic ESCC, tislelizumab monotherapy as second-line treatment demonstrated a statistically significant improvement in overall survival (OS) compared with chemotherapy (median OS: 8.6 vs. 6.3 months, respectively; hazard ratio [HR] 0.70, P = 0.0001) [14].Here, we report the results of a subgroup analysis conducted in Japanese patients from the RATION-ALE-302 study.

Trial design, treatment, and participants
Full details of the study design and methodology for RATIONALE-302 have been previously described [14].Briefly, this was an open-label, randomized, activecontrolled, global, phase 3 clinical study to compare the efficacy and safety of tislelizumab versus chemotherapy as second-line treatment in patients with advanced or metastatic ESCC, recruiting patients across 11 countries, including Japan.Patients were stratified by region of enrollment (Asia excluding Japan vs. Japan vs. United States of America/Europe), an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and investigator's choice of single-agent chemotherapy (docetaxel, paclitaxel, or irinotecan).Eligible patients had histologically confirmed, locally advanced or metastatic ESCC whose disease progressed during or after first-line systemic therapy, or during or within 6 months after definitive chemoradiotherapy, neo-adjuvant or adjuvant therapy.The study excluded patients who had received ≥ 2 lines of systemic therapy for advanced or metastatic disease or had previously received treatment with a PD-1 or PD-L1 inhibitor.Full inclusion and exclusion criteria are described in the Supplementary Materials.
Eligible patients in the overall study population were randomized (1:1) to receive tislelizumab or investigator's choice of single-agent chemotherapy, which included docetaxel, paclitaxel, or irinotecan.However, as irinotecan is not approved in Japan, investigator's choice of single-agent chemotherapy was restricted to either docetaxel or paclitaxel for the Japanese subgroup.Tislelizumab 200 mg was administered intravenously (IV) every 3 weeks (Q3W).In the chemotherapy arm, paclitaxel 100 mg/m 2 was administered IV once weekly for 6 weeks, followed by 1 week rest; docetaxel 70 mg/m 2 was administered IV Q3W.Cross-over between chemotherapy regimens or between the chemotherapy and tislelizumab treatment arms was not allowed during the study treatment period.

Endpoints and assessments
The primary endpoint was OS in the intent-to-treat (ITT) population, which included all randomized patients.The key secondary endpoint was OS in the PD-L1-positive population, with PD-L1 positivity defined as a PD-L1 score ≥ 10%; details of how PD-L1 score was determined have been previously published [14].Other secondary efficacy endpoints included progression-free survival (PFS), objective response rate (ORR), and duration of response (DoR), all assessed by investigators per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and patient-reported health-related quality of life (HRQoL) outcomes, as previously described for the overall study population [14].
Safety was assessed as a secondary endpoint through monitoring of the incidence and severity of treatment-emergent adverse events (TEAEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.Safety analyses were performed in the safety population, which included all patients who received at least one dose of any study drug.
Further detail on the study endpoints and their assessment is provided in the Supplementary Materials.

Statistical analyses
Sample size calculations and statistical considerations for the primary analyses in the overall study population have been reported previously [14].No formal hypothesis testing was performed for the Japanese patient subgroup analysis and all statistical analyses reported herein are descriptive.
Median OS was estimated by the Kaplan-Meier method with two-sided 95% confidence intervals (CIs) estimated using the method of Brookmeyer and Crowley.HRs for OS analyses were estimated using an unstratified Cox regression model, including only treatment as a covariate, accompanied by two-sided 95% CIs.PFS and DoR were analyzed using similar methodology to OS. ORR was calculated, accompanied by two-sided 95% CIs calculated using the Clopper-Pearson method.In addition, the odds ratio for ORR was calculated, accompanied by two-sided 95% CIs.Changes from baseline to Cycle 4 in patient-reported HRQoL assessments and safety outcomes were analyzed using descriptive statistics.

Patients and treatment
Of the 512 patients randomized in the RATIONALE-302 study, 50 were enrolled in Japan and evenly randomized to tislelizumab (n = 25) or chemotherapy (n = 25), constituting the Japanese patient subgroup (Fig. S1).
As of final analysis data cutoff on December 1, 2020, the median study follow-up time in the Japanese patient In the Japanese patient subgroup, post-study treatment anti-cancer therapies were received by 68.0% (17/25) of patients in the tislelizumab arm and 48.0%(12/25) in the chemotherapy arm (Table S2).Subsequent anti-cancer therapy included immunotherapy for 16.0% (4/25) and 24.0% (6/25) of patients in the tislelizumab and chemotherapy arms, respectively.

Tumor response
Tislelizumab was associated with higher ORR in the Japanese patient subgroup compared with chemotherapy (32.0%[95% CI 14.9, 53.5] vs. 20.0%[95% CI 6.8, 40.7]) (Table S3).There was one complete response in both arms, more partial responses in the tislelizumab arm than in the chemotherapy arm, and a higher rate of stable disease in the tislelizumab arm than in the chemotherapy arm (Table S3).Responses were more durable with tislelizumab versus chemotherapy, with a median DoR of 8.8 months (95% CI 2.9, NE) vs. 2.6 months (95% CI 1.1, NE) (Table S3).Tumor response results for the overall patient population are shown in Table S3.

Health-related quality of life
Based on changes from baseline to Cycle 4, HRQoL scores in the Japanese patient subgroup tended to be maintained or improved with tislelizumab versus chemotherapy (Fig. S3).Changes in European Organisation for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30), key PRO endpoint scale scores indicated maintenance (i.e., < 5-point change from baseline) in overall global health status/quality of life (GHS/QoL), physical functioning and fatigue scores with tislelizumab, compared with worsening in these scores with chemotherapy.Similarly, changes in the key PRO endpoints (main ESCC symptoms) measured by the EORTC Quality of Life Questionnaire esophageal cancer module (QLQ-EOS18) scores indicated either maintenance or less worsening in dysphagia, eating, reflux, and pain with tislelizumab versus chemotherapy.Changes in EuroQol 5D (EQ-5D-5L) visual analogue scale scores indicated an improvement with tislelizumab that was not clinically meaningful when compared with worsening scores with chemotherapy.Results for the overall patient population are shown in Fig. S3.

Pharmacokinetics
Tislelizumab serum concentrations were similar for the Japanese patient subgroup and the overall patient population, with overlapping concentration ranges (Table S7).

Discussion
Consistent with results from the overall population of RATIONALE-302 [16], tislelizumab improved OS compared with chemotherapy as second-line treatment in Japanese patients with advanced or metastatic ESCC.In the Japanese patient subgroup, a favorable improvement in PFS was also seen with tislelizumab compared with All data are presented as number of patients with at least one event (percentage of patients).Data are presented for the Japanese subgroup of the safety population, which comprised all randomized patients who received at least one dose of a study drug, analyzed according to the actual study drug received.TRAEs include TEAEs that were considered by the investigator to be related to study drug or TEAEs with a missing causality.Adverse event grades were based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.Adverse events were coded using Medical Dictionary for Regulatory Activities version 23.0 TEAE treatment-emergent adverse event, TRAE treatment-related treatment-emergent adverse event a Dose modification included dose held, dose interruption and dose reduction for the chemotherapy arm, and dose held and dose interruption for the tislelizumab arm b Deaths caused by disease progression were excluded chemotherapy, together with greater and more durable antitumor responses, and improvements in HRQoL scores, as seen in the overall study patient population [14].Tislelizumab pharmacokinetic profiles in the Japanese patient subgroup were generally consistent with findings in the overall RATIONALE-302 patient population.This corroborates findings from a population PK modeling study, which concluded that race is not a significant covariate of tislelizumab pharmacokinetics [17]; thus, there is no clinically relevant impact of Japanese ethnicity on tislelizumab pharmacokinetic profiles.
The baseline characteristics of the Japanese patient subgroup were generally similar to those of the overall population of RATIONALE-302, except that more patients in the Japanese subpopulation had an ECOG performance status of 0 compared with the overall population in both treatment arms (tislelizumab arm: Japan subgroup 56.0% versus overall population 25.8%; chemotherapy arm: Japan subgroup 56.0% versus overall population 23.4%) [14].This observation of better functional performance status in the Japanese subpopulation compared with the global overall population of RATIONALE-302 is consistent with findings in other studies investigating anti-PD-1 antibodies as monotherapy in second-line treatment of advanced esophageal tumors, or in combination with chemotherapy or other immunotherapies in first-line treatment [10,11,18].In the Japanese subgroup of RATIONALE-302, median OS in both the tislelizumab and chemotherapy arms was numerically longer than in the overall population [14].The observed differences in baseline ECOG performance status between the Japanese subgroup and the overall population may have in part contributed to the numerically better OS outcomes in the Japanese subpopulation.Compared to other randomized trials that assessed the use of immune checkpoint inhibitors as second-line therapy for advanced/metastatic ESCC, treatment with tislelizumab demonstrated an OS improvement over chemotherapy (median OS 9.8 vs. 7.6 months, HR 0.59) that was broadly similar to nivolumab versus chemotherapy (median OS 13.4 vs. 9.4 months, HR 0.77) and pembrolizumab versus chemotherapy (12.4 vs. 8.2 months, HR 0.68) in the Japanese patients [10,11], though caution should be taken when comparing subgroup results across studies.
In the Japanese patient subgroup of RATIONALE-302, the improvements in OS and PFS with tislelizumab versus chemotherapy appeared numerically greater among patients with baseline PD-L1 score ≥ 10% compared with the total Japanese patient subgroup, in line with observations from a similar study of pembrolizumab [11].However, findings based on baseline PD-L1 expression status should be interpreted cautiously because of the very limited sample size of patients with PD-L1 score ≥ 10%, and the imbalance in PD-L1 expression status between treatment arms.
Previous subanalyses of other phase 3 trials have also reported prolonged survival with PD-1 inhibitor monotherapy versus chemotherapy as second-line treatment for advanced ESCC in Japanese patients [10,11].Based on the results of these trials, both nivolumab and pembrolizumab are approved in Japan for the treatment of unresectable, advanced or recurrent ESCC that has progressed following chemotherapy [19], although pembrolizumab use is restricted to patients with PD-L1-positive tumors [17,20].Following these approvals, PD-1 inhibitor monotherapy has become the standard second-line treatment for advanced or metastatic ESCC [20,21].The baseline characteristics of the Japanese patient subgroup in RATION-ALE-302 were comparable with those of the Japanese patient subgroups in the previously reported PD-1 inhibitor trials in this setting [10,11], supporting the relevance and applicability of our findings to Japanese patients with advanced or metastatic ESCC.
The safety profile of tislelizumab was more favorable compared with that of chemotherapy, with no unexpected safety signals identified in the Japanese patient subgroup, similar to observations from analyses of treatment of Japanese patients with nivolumab and pembrolizumab [10,11].Consistent with the results in the overall study patient population [14], fewer patients in the Japanese patient subgroup experienced any TRAEs or ≥ grade 3 TRAEs with tislelizumab compared with chemotherapy.By preferred term, no TRAEs were reported in more than 3 of the 25 patients in the Japanese patient subgroup in the tislelizumab arm, and the spectrum of TEAEs reported was broadly consistent with that seen in the overall study patient population [14].These favorable findings with tislelizumab monotherapy are supported by the HRQoL outcomes indicated via ESCC-specific patient-reported symptoms.
It must be noted that the RATIONALE-302 study and this subgroup analysis are subject to various limitations, including an open-label study design and lack of blinded independent review of tumor responses, which may have impacted response data (ORR, PFS, and DoR).Limitations of the present analysis in this Japanese patient subgroup include the small sample size, and the fact that these exploratory analyses are descriptive only.
In conclusion, among Japanese patients with advanced or metastatic ESCC whose disease progressed during or after first-line systemic therapy, tislelizumab prolonged OS versus chemotherapy, with a manageable safety profile.These results were consistent with the results seen in the overall study population and warrant consideration of tislelizumab as a second-line treatment option for patients with advanced or metastatic ESCC in Japan.

Table 1
Patient demographics and baseline characteristics in the Japanese patient subgroup Data are presented for the Japanese patient subgroup of the intent-totreat population, which comprised all randomized patients, analyzed according to their randomized treatment arm

Table 2
Summary of overall adverse event incidence in the Japanese patient subgroup