Real‐world sequential treatment patterns and clinical outcomes among patients with advanced urothelial carcinoma in Japan

Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre‐enfortumab vedotin era, many patients could not receive third‐line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real‐world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third‐line treatment.


INTRODUCTION
With immune checkpoint inhibitors 1,2 and antibody-drug conjugates, such as enfortumab vedotin (EV), 3 now clinically available, the treatment of locally advanced and metastatic urothelial carcinoma (la/mUC) has entered a new era of sequential treatment.5][6][7] In multiple large cohort studies, almost half of the patients received no treatment for metastatic disease, while only approximately 15%-20% received second-line therapy.Possible reasons for the lack of optimal receipt of systemic therapies and the high attrition rate include relatively toxic and moderately effective platinum-based chemotherapy regimens, concerns about performance status (PS) and comorbidities in this patient population, communication barriers, lack of social support, and access to affordable healthcare. 8n Japan, where universal health insurance is provided, attrition for economic reasons or barriers to access to medical care is unlikely.An analysis of a Japanese cohort facilitates the identification of medical problems that influence the feasibility of la/mUC treatment.Thus, this unique situation makes it possible to evaluate the feasibility of la/mUC sequential treatment.In this study, we clarified the real-world practice of sequential treatment of la/mUC in Japan while concurrently evaluating the clinical characteristics of patients who died before the opportunity for third-line treatment.

Study design
The clinical data were collected from the Japan Urological Oncology Group nationwide cohort of la/mUC patients.Briefly, this cohort comprised 1023 patients who were diagnosed as having la/mUC from January 2020 to December 2021 at 54 participating institutions.This dataset included information on the patients' clinical backgrounds, sequential treatment details, laboratory data, and treatment outcomes; survival data were collected in May 2023.There were no restrictions on the choice of treatment, which was in accordance with the policies at each institution.The metachronous metastasis group was defined as patients who had recurrence or metastasis after total cystectomy or nephroureterectomy, while the synchronous metastasis group was defined as patients with unresectable or metastatic urothelial carcinoma at diagnosis.This study was approved by the Institutional Review Board at Kyoto University Graduate School of Medicine (approval number R3245) and by the local Institutional Review Board at each participating institute.This study conformed to the provisions of the Declaration of Helsinki.
In Japan, pembrolizumab was approved for patients with failed platinum-based chemotherapy in December 2017, avelumab was approved as maintenance treatment for patients with stable disease or better response to first-line chemotherapy in February 2021, and EV was approved for patients with disease progression after platinum-based chemotherapy and immune checkpoint inhibitors in November 2021.Sacituzumab govitecan and erdafitinib are not currently approved in Japan.Strictly speaking, switch maintenance immunotherapy with avelumab is considered as a part of first-line treatment.In this study, however, avelumab was classified as second-line therapy.This allowed avelumab treatment to be contrasted with second-line pembrolizumab treatment as a post-chemotherapy immunotherapy.Furthermore, EV after avelumab switch maintenance treatment can now be considered as third-line therapy equivalent to EV after second-line pembrolizumab treatment.For similar reasons, perioperative chemotherapy was classified as first-line treatment if the patient received pembrolizumab for recurrence and metastasis within 1 year after radical surgery with perioperative chemotherapy.

Statistical analysis
All statistical analyses were performed using JMP® Pro, Version 15.1.0(SAS Institute Inc., Cary, NC, USA).Overall survival (OS) was defined as the time from the initiation of firstline systemic treatment, excluding perioperative chemotherapy, or the date of the diagnosis in patients without treatment, to death from any cause.OS was estimated using Kaplan-Meier analysis with the log-rank test.Multivariate logistic regression analysis was performed to identify the risk factors in patients who did not reach third-line treatment.The cutoffs for hemoglobin and NLR were in accordance with those in a previous report. 9All tests were two-sided, and p < 0.05 was considered statistically significant.

Details of sequential treatment in the entire cohort
The entire cohort of 1023 la/m UC patients comprised 542 patients in the synchronous metastasis group with unresectable or metastatic UC at diagnosis and 481 in the metachronous group with a history of primary tumor resection (Figure 1).In 118 of these cases, best supportive care (BSC) was selected on the basis of age, comorbidities, and patient preference; 905 received systemic treatment.At the median follow-up of 28.5 months, the median OS from the initiation of first-line treatment for patients with systemic treatment was 19.1 months (95% confidence interval [CI]: 17.6-22.3;Figure 2a).The median OS for patients in the synchronous metastasis group was 17.0 months (95% CI: 15.0-19.0; Figure 2b).Of the 118 patients who were selected for BSC, data on the survival outcome were available in 72 (61%).The median overall survival of the 72 patients was only 5.0 months (95% CI: 4.0-6.0; Figure 2c).
Among the 905 patients with systemic treatment, 730 (81%) received second-line treatment, and 283 (31%) proceeded to third-line treatment (Figures 1 and 3a).Notably, 471 (52%) patients had their treatment terminated before the opportunity for third-line treatment.To address differences in the patients' background data at the start of first-line chemotherapy, we exclusively analyzed the data for the synchronous metastasis group.Among the 455 patients in this subgroup, 346 (76.0%) received second-line treatment, while 142 (31.2%) advanced to third-line treatment (Figures 1 and 3b).This analysis also revealed that 257 (56%) patients discontinued therapy before third-line treatment.Consistent with these data, among patients who died of disease after January 2022, when EV became available, only 40 of 80 (50.0%) patients in the metachronous group and 54 of 106 (50.9%) patients in the synchronous group had received EV.

Characteristics of patients who could not receive third-line treatment in the synchronous metastasis group
The patients' baseline characteristics at the initiation of firstline treatment in the synchronous group are summarized in Table 1.Of the 379 patients without missing data, 196 (51.7%) had died before receiving third-line treatment.Multivariate analysis of the risk factors associated with patients not receiving third-line treatment identified low PS (≥1), low BMI (<21 kg/m 2 ), and high NLR (≥3) as significant risk factors for failure to reach third-line treatment (Table 2).
We assigned the following scores to the three dichotomous or trichotomous variables and incorporated them into predictive models as follows: NLR ≥3  groups (p < 0.0001, chi-square test; Figure 4a).The risk classification of the three-factor model also yielded wide separations of the Kaplan-Meier curves for OS between the groups (p < 0.001, log-rank test; Figure 4b).

DISCUSSION
Using real-world data, the present study clarified the median OS for la/mUC patients in Japan, showing that more than half of the patients failed to reach third-line treatment despite participation in a universal healthcare system.
The sequential treatment of la/mUC has changed dramatically over the past decade with the introduction of several new agents.Clinical trial data supporting drug approval showed that pembrolizumab prolonged survival by approximately 3 months as second-line therapy after failure of platinum-based chemotherapy, 1 and EV prolonged prognosis by approximately 4 months as third-line treatment after failure of platinum-based chemotherapy and immune checkpoint inhibitors. 3Avelumab has also been shown to prolong prognosis by approximately 7 months as maintenance therapy after platinum-based chemotherapy. 2However, the 17 months of OS from the start of first-line treatment that we identified in this study is not as long as one would expect, compared with the 14-15 months' survival from the era when chemotherapy was the only treatment available. 10ndeed, while OS shown in our previous report for those who received subsequent chemotherapy after second-line pembrolizumab in pre-EV era was 13.3 (95% CI 10.5-19.8)months, 11 OS shown in the present study for those who received subsequent EV in the post-EV era was 12 months (95% CI 10.8-).Of course, it must be mentioned that it is currently difficult to compare these two cohorts due to several crucial biases that are difficult to eliminate using the available data including variations in treatment processes leading up to the initiation of third-line treatment.
Nonetheless, it doesn't seem like there's been any dramatic improvement in patient survival between pre-and post-EV eras from the currently available data so far.This appears to reflect the fact that urothelial carcinoma progresses rapidly, and many patients die before benefiting from secondor third-line treatment.In fact, our data showed that approximately 80% of the patients were eligible to receive immune checkpoint inhibitors as second-line therapy, but less than 50% survived to third-line therapy.This proportion is better than that of the previous report from the United States 8 in which first-line, second-line and third-line systemic anticancer treatment was implemented in only 48, 17, and 6% of patients who were diagnosed la/m UC, respectively.Although this is primarily attributed to the lack of availability of evidence-based treatment, other issues on social healthcare systems including economic reasons and limited access to medical care were also cited as contributing factors.The present study on patients treated in Japan reveals that medical causes make it difficult to carry out sequential treatment for la/mUC to the end, even when the factors of economic reasons and limited access to medical care are excluded.
We identified poor PS, high NLR, and low BMI as risk factors for failure to reach third-line treatment.PS is a prognostic factor both at the start of first-line chemotherapy 12 and at the start of pembrolizumab treatment, 9 while NLR has recently received attention as a marker of systemic inflammatory status and is a prognostic factor for chemotherapy and pembrolizumab treatment. 13,14Therefore, it is reasonable that these risk factors were important in our study, in the execution of sequential treatment.Interestingly, low BMI was also identified as an independent risk factor, whereas high BMI or obesity was not.Low BMI correlates with a patient's frailty status and is included in functional assessment tools for the elderly, such as the G8, which has recently received much attention. 15,16This finding suggests that frailty status remains a negative factor for treatment adherence.Notably, BMI and PS were identified as risk factors rather than liver metastasis, which is often reported as a prognostic factor for chemotherapy and pembrolizumab. 14,17This finding appears to indicate that patient-related factors have a stronger impact on the execution of sequential therapy compared with tumor-related factors.
To improve treatment tolerability and prolong prognosis, nutritional interventions may be useful.However, if the cause of low BMI is inflammatory cytokine-mediated metabolic changes due to cancer, as suggested by high NLR values, the effect of nutritional interventions may be limited.Our proposed risk classification, which combines NLR, PS, and BMI, can easily estimate the likelihood of reaching third-line treatment, and correlates with patient prognosis.For high-risk patients, sequential treatment should be initiated in addition to early preparation for the end stages of cancer.These preparations may include home care and hospice arrangements, which should be considered at the same time as sequential treatment, with consideration of nutritional supportive care.
There is currently no strong evidence for the sequential order of treatment.A major barrier is the lack of wellestablished biomarkers to predict the efficacy of chemotherapy and immune checkpoint inhibitors prior to administration.The order of sequential therapy and novel combination therapies are currently being tested in several clinical trials, and results are anticipated.In particular, it would be interesting to know whether intermediate-or high-risk patients in this study would have benefitted more from early treatment with immune checkpoint inhibitors or EV.In this respect, the Japanese dataset, which, unlike that in the USA, has less variation in sequential treatment because immune checkpoint inhibitors are not available for first-line treatment, is highly valuable for comparisons with other cohorts.
There are several limitations to this study in addition to its retrospective design.First, the number of patients who were selected for BSC without systemic treatment may have been underestimated because the eligible patients were extracted retrospectively from medical record information.Second, the timing and details of sequential treatment changes are based on the judgment of each treating institution and are not standardized.Third, we did not validate our proposed risk classification in an external cohort; therefore, future validation is needed.Fourth, as avelumab and EV became available during the enrollment period of this cohort, the sequential treatment pattern differs between patients who started treatment early in the enrollment period and those started late.Although it is desirable to evaluate frailty using a more specific index such as the frailty index, this study could only use PS and BMI as substitutes.Nonetheless, this study provides important information for sequential treatment of la/mUC in Japan and will serve as control data for future revisions of sequential treatment.

FIGURE 1
FIGURE 1Flowchart of the patients included in this study.AWD, alive with disease; DOC, dead of other causes; DOD, dead of disease; GC, gemcitabine and cisplatin; GCBDCA, gemcitabine and carboplatin; MVAC, methotrexate, vinblastine, doxorubicin and cisplatin; Pts, patients.

FIGURE 2
FIGURE 2 Kaplan-Meier plots displaying overall survival (OS) from initiation of systemic treatment for 898 patients in the entire cohort (a) and 459 patients with synchronous metastasis (b).(c) Kaplan-Meier plots showing OS from the diagnosis of metastatic urothelial carcinoma for 72 patients without systemic treatment.CI, confidence interval; M, months; Pt, patient.

FIGURE 3
FIGURE 3 Sankey diagram of treatment choice for the 1023 patients in the entire cohort (a) and 542 patients with synchronous metastasis (b).AWD, alive with disease; BSC, best supportive care; DOC, dead of other causes; DOD, dead of disease; EV, enfortumab vedotin; GC, gemcitabine and cisplatin; GCBDCA, gemcitabine and carboplatin; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin.

TABLE 2
Multivariate analysis of the factors associated with not receiving third-line treatment.