Abstract
Background/Aim: Immune checkpoint inhibitors (ICI) have become important tools for the treatment of advanced urothelial carcinoma (aUC). However, the clinical strategy using ICIs and chemotherapy is still controversial. The aim of this study was to evaluate the association of clinical parameters in aUC patients with ICI treatment. Patients and Methods: We retrospectively analyzed aUC patients who received atezolizumab and pembrolizumab between January 2015 and October 2020. The associations between baseline demographics and clinical outcomes were evaluated. Results: Of the 74 included patients, the median age was 67 years. Among them, 53 patients received atezolizumab and 21 received pembrolizumab. There were 50 patients receiving first line ICIs therapy and 24 receiving second line monotherapy. Fifty-two (83.87%, 52/62) received cisplatin among all chemotherapy patients. The median progression free survival was 10.94 months, and the overall survival was 28.44 months. Poor chemotherapy response or no chemotherapy, liver metastases, Eastern Cooperative Oncology Group (ECOG) status and higher neutrophil/lymphocyte ratio (NLR) were associated with higher risk of disease progression (HR=5.70, 95% CI=2.04-15.90, p=0.001; HR=6.08, 95% CI=1.79-20.57, p=0.004; HR=5.40, 95% CI=1.76-16.57, p=0.003; HR=6.08, 95% CI=2.56-14.44, p<0.001 and HR=1.02, 95% CI=1.01-1.03, p=0.002, respectively). Liver metastases and WBC before ICI were associated with increased risk of death (HR=11.95, 95% CI=3.22-44.34, p<0.001; HR=1.0001, 95%=CI=1.00001-1.00002, p=0.036 respectively) while ICI response was associated with decreased death (HR=0.22, 95%CI=0.08-0.62, p=0.004). Chemotherapy response was associated with better ICI treatment response (OR=6.52, 95% CI=1.45-29.24, p=0.014) while lymph node metastases and poor ECOG status were associated with poor ICI response (OR=0.31, 95% CI=0.10-0.94, p=0.038; OR=0.32, 95% CI=0.11-0.95, p=0.040). Conclusion: Our real-world data show a predictive role of first-line chemotherapy response to ICI treatment efficacy in aUC patients as well as other prognostic factors, such as ECOG status, serum WBC or NLR and liver metastases.
For decades, chemotherapy has become the standard of treatment for advanced urothelial carcinoma (aUC). Cisplatin-based combination chemotherapy showed a 43.6% to 55.5% response rate with median overall survival ranged from 12.7 months to 15.9 months (1, 2). Despite the high response rate during the first-line chemotherapy, the progression free survival were less than 10 months and patients experience rapid disease deterioration thereafter even with second-line therapies. The progress of immune checkpoint inhibitors (ICI) in metastatic UC opened a new page in this field. From previous experience in the treatment of metastatic solid tumors, ICI showed a long-tail effect as an overall survival signature which was considered beneficial in disease maintenance (3, 4). The rationale came from the observation of phase 2 Imvigor 210 study in which ICI treatment response was escalated after post-chemotherapy higher neo tumor antigens (5). The Javelin bladder 100 study approved this concept by showing the maintenance benefit of avelumab after disease control from chemotherapy (6). However, first-line simultaneously combination of ICI and chemotherapy (phase 3 trial IMvigor 130 and Keynote 361) and second-line ICI monotherapy both showed limited benefit in overall survival (7-13). The diversity of these clinical trial results, both in the biomarker prediction and outcomes confuses the treatment of aUC regarding to mono-, combination or sequential. In addition, recent advances of antibody-drug conjugate (ADC) showed benefit in the second-line and first-line combined with ICI (14, 15). It emphasized the importance of proper chemotherapy in the treatment of aUC. By far, the application of ICI in aUC is still controversial and there is strong unmet needs of more evidence to guide clinical practice (16). Thus, we evaluated metastatic UC patients that underwent ICI treatment and looked for the associations between clinical characteristics and outcomes.
Patients and Methods
Patients. This retrospective study was conducted through chart review and was approved by the institute review board of Taichung Veterans General Hospital, number CE19386B. Metastatic UC patients who received atezolizumab or pembrolizumab with measurable radiographic outcomes between January 2015 and October 2020 were included.
Study assessment. The study end points were progression free survival after ICI treatment, overall survival after treatment start of metastatic diseases and ICI treatment response. Baseline patient characteristics including continuous variables, age, chemotherapy and ICI treatment cycles and duration, blood sample analysis before ICI, such as white blood cell (WBC) count, hemoglobin, neutrophil/lymphocyte ratio (NLR), platelets, lactate dehydrogenase (LDH) and albumin were recorded. The timing of blood samples collected were two weeks before ICI was given. Other categorical parameters, such as sex, primary tumor site, smoking, diabetes mellitus, chronic kidney disease (CKD), end stage renal disease (ESRD), metastatic sites, Eastern Cooperative Oncology Group (ECOG) status, survival status, treatment model, ICI response, chemotherapy duration and ICI duration were recorded as well. CKD was defined as estimated glomerular filtration rate less than 60 mL/minutes but not exceeding ESRD. ESRD was defined as patients who received regular dialysis therapy. Metastatic sites were recorded separately according to radiographic findings. Chemotherapy response and ICI response were recorded according to the Response Evaluation Criteria in Solid Tumor (RECIST) 1.1. The periods of radiographic evaluation were dependent on the clinical demands between 4 and 6 months among each case. However, in the ICI and chemotherapy combination treatment patients, it is difficult to separate the treatment effect. Therefore, the treatment effect would be recorded both for chemotherapy and ICI. The chemotherapy duration or ICI duration were defined as the period between the date of starting treatment and the radiographic progression date or the last dose date.
Statistical analysis. The differences between continuous values were analyzed by Mann-Whitney U and Fisher’s exact test for continuous variables. Chi-square test was used for categorical variables. The progression free survival (PFS) and overall survival (OS) curves were plotted by the Kaplan-Meier method. Univariate and multivariate Cox hazard proportional regression was used to estimate the hazard ratio (HR) and 95% confidence interval (CI) for association between variables and PFS, OS and ICI treatment response. The ICI treatment response was defined as complete response or partial response. All the statistical analyses were performed using SAS software version 9.2 (SAS Institute, Inc., Cary, NC, USA).
Results
A total of 85 patients received atezolizumab and pembrolizumab for the treatment of metastatic UC in our database during the study period. Three patients were included in a clinical trial that was not completed and the other eight patients without follow-up radiographic studies were excluded. Therefore, 74 patients were included in this analysis. Among them, 53 patients received atezolizumab and the other 21 received pembrolizumab. Thirty-eight patients received ICI combined chemotherapy as the first line therapy, while 12 patients had ICI as first line monotherapy and the other 24 used chemotherapy followed by ICI. The baseline characteristics and patient demographics are listed in Table I. The median age was 67 years (ranging from 40 to 92), and males were predominant (62.16%, 46/74). Poor general performance patients accounted for only 13.51% (10/74) while ECOG 0 patients were 43.24% (32/74). Thirty-nine patients (52.7%) had upper urinary tract tumors and only 1 patient had concomitant upper and lower tract tumors. Less than a quarter of patients had a history of cigarette smoking, and the prevalence of diabetes and CKD were less than one third. Lymph nodes were the most common sites of metastases (56.76%, 42/74) while 10.81% (8/74) of patients had liver metastases. The median results of blood tests given before ICI were as following: WBC count: 7845/cubic millimeter, hemoglobin: 11.4 g/dl, NLR: 5.9, platelet count: 262.5k, LDH: 195 U/l, albumin: 3.9 g/dl. Sixty-two patients received chemotherapy as first line therapy and 83.87% (52/62) of them took cisplatin. Twenty-nine patients (46.77%, 29/62) reached complete response (CR) or partial response (PR) after chemotherapy while forty-two patients (56.76%, 42/74) had CR/PR after ICI treatment. The median treatment cycles of chemotherapy and ICI were 4 and 6 respectively. The median chemotherapy and ICI duration of treatment were 7.79 and 7.24 months respectively, while the median follow-up duration was 12.7 months.
Baseline characteristics and demographics of metastatic urothelial carcinoma patients.
Figure 1 shows that the median progression free survival after ICI treatment was 10.94 months and the median overall survival since systemic treatment was 28.44 months. In the Cox hazard proportional regression model, no chemotherapy response (PR and SD) or no chemotherapy, liver metastases, ECOG status and higher NLR were associated with higher risk of disease progression [HR=5.70, 95% CI=2.04-15.90, p=0.001; HR=6.08, 95% CI=1.79-20.57, p=0.004; HR=5.40, 95% CI=1.76-16.57, p=0.003; HR=6.08, 95% CI=2.56-14.44, p<0.001 and HR=1.02, 95% CI=1.01-1.03, p=0.002, respectively (Table II)]. Liver metastases and WBC before ICI were associated with increased risk of death (HR=11.95, 95% CI=3.22-44.34, p<0.001; HR=1.0001, 95% CI=1.00001-1.00002, p=0.036, respectively) while ICI response and was associated with decreased death (HR=0.22, 95% CI=0.08-0.62, p=0.004, Table III). Chemotherapy response was associated with better ICI treatment response (OR=6.52, 95% CI=1.45-29.24, p=0.014) while lymph node metastases and poor ECOG status was associated with poor ICI response [OR=0.31, 95% CI=0.10-0.94, p=0.038; OR=0.32, 95% CI=0.11-0.95, p=0.040 respectively, (Table IV)].
Survival analyses among all included advanced urothelial carcinoma patients. Median progression free survival was 10.94 months since immune checkpoint inhibitor treatment and (B) median overall survival was 28.44 months since the start of systemic treatment for advanced urothelial carcinoma patients who received immune checkpoint inhibitors.
Univariate and multivariate analysis for progression free survival after immune checkpoint inhibitors (ICI) treatment.
Univariate and multivariate analysis for overall survival after metastatic urothelial carcinoma systemic treatment.
Univariate and multivariate analysis for immune checkpoint inhibitors (ICI) treatment response.
Discussion
Our study demonstrated a prognostic and predictive value of first-line chemotherapy response to clinical outcomes in aUC patients which corresponded to the findings in JAVELIN bladder 100 (6). No first-line chemotherapy response or no chemotherapy were associated with poor PFS (HR=5.70, p=0.001, and HR=6.08, p=0.004, respectively). Despite PFS, we also found chemotherapy response CR/PR/SD can predict the ICI treatment response (OR=6.52, p=0.014). This phenomenon corresponds to the rationale that chemotherapy induction in UC can deplete immunosuppressant cells, increasing T-cell infiltration into tumors, increasing antigen presentation, and increasing PD-L1 expression (17, 18). Although chemotherapy response was not associated with OS, ICI treatment responders showed a 78% risk reduction in death and highlighted the importance of the ICI response. In addition, without external validation of our database, the estimated PFS and OS in our study (10.94 and 28.44 months, respectively) showed a comparative outcome with the JAVELIN bladder 100 study (3.7 and 21.4 months, respectively) (6). We suggest that the comparable clinical outcome in our study was the result of the large proportion of lymph node metastases only (41.89%, 31/74) and high cisplatin utility rate (83.87%, 52/62) which also led to a chemotherapy response rate of 46.77% (29/62). The baseline demographics in our series showed a unique UC characteristic in Taiwan. Upper tract UC accounted for the largest proportion (54%, 40/74) and female patients were predominant among this part, which lead to an increase of the female sex percentage (37.84%) (19, 20). These characteristics were different from other reported series while urinary bladder UC and male sex were significantly larger.
In the chemotherapy era, Bajorin et al. determined that a Karnofsky performance status less than 80 and visceral metastases were two independent factors for survival; Bellmunt et al. identified ECOG status more than 0, hemoglobin level less than 10, and the presence of liver metastases as poor prognostic factors to OS (21, 22). In the ICI era, Khaki et al. reported a database analysis on a prognostic model of first-line ICI therapy and found that ECOG ≥2, albumin <3.5 g/dl, NLR >5 and liver metastasis were associated with worse OS (23). Ruiz-Bañobre et al. declared another prognostic model using ECOG, liver metastases, peritoneal metastases, albumin level and proton pump inhibitor use in a mixed first-line and second-line ICI treatment setting (24). Sonpavde et al. collected phase I/II clinical trial database data and found that ECOG-PS (1 vs. 0, HR=1.80), liver metastasis (HR=1.55), platelet count (HR=2.22), NLR (HR=1.94) and LDH (HR=1.60) were five prognostic factors for overall survival (25). Our data not only showed liver metastases as a prognostic factor, but also showed liver metastasis, ECOG status 1 or 2, and high NLR were associated with higher risk of disease progression. This finding corresponded to the pathophysiology study of liver metastases by Yu et al. (26). They found that liver metastases diminished peripheral T cells as well as the diversity and function which may cause increased NLR and reduce the response of ICI treatment. Interestingly, we also found lymph node metastases were associated with poor ICI response. The true reason may not be clarified because of the lack of histological evidence. Currently, PD-L1 stain and new generation sequencing for the genomic profiling are considered as predictive biomarkers for ICI treatment and were approved by USFDA for specific indications (27-29). However, genomic exams and clinical outcomes can vary from a trial to another and have a high cost. Therefore, clinical parameters, such as our results, can provide an alternative aspect on the predictive role using chemotherapy response as an indicator of ICI treatment effect.
Limitations of this study include the small patient population, the retrospective nature, lack of external validation, and confounding of chemotherapy response and ICI response in the first-line combination group. Thirty-eight patients (51.35%, 38/74) received combination chemotherapy and ICI as the first-line therapy and the immune therapy response may be overestimated due to confusion with chemotherapy response. Furthermore, lack of immune signatures such as PD-L1 expression or other comprehensive genomic data can mask some confounding factors in this study.
In conclusion, our real-world experience revealed that first-line chemotherapy response as well as clinical factors including ECOG status, liver metastases, NLR, WBC before ICI could act as prognostic or predictive markers to the ICI related clinical outcomes. Utility of these clinical biomarkers can help in regimen decision making and in avoiding fruitless treatments.
Acknowledgements
This work was supported by the Ministry of Science and Technology, Taiwan, Grant number: MOST 109-2314-B-075A-007-MY3.
Footnotes
Authors’ Contributions
Jian-Ri Li, Cheng-Kuang Yang, Sheng-Chun Hung contributed to study design. Shian-Shiang Wang, Chuan-Shu Chen, Cheng-Kuang Yang, Kun-Yuan Chiu, Shu-Yen Chen contributed to data collection. Statistical analysis was performed by Kevin Lu and Chiann Yi Hsu. The manuscript was written by Jian-Ri Li and revised by Kevin Lu and Chen-Li Cheng.
Conflicts of Interest
None to be declared.
- Received July 14, 2022.
- Revision received September 3, 2022.
- Accepted September 6, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
