Programmed cell death 1 inhibitor alone or combined with chemotherapy for patients with locally advanced or metastatic urothelial carcinoma: a single-center experience

Abstract

Background

Immune checkpoint inhibitors (ICIs) alone or in combination with standard chemotherapy for advanced urothelial carcinoma (UC) have been tested as first-line treatment in clinical trials. This study aimed to evaluate the clinical outcomes of programmed cell death 1 (PD-1) inhibitor alone or combined with chemotherapy for patients with locally advanced or metastatic UC in a real world clinical care setting, and sought to identify prognostic factors for overall survival (OS).

Methods

A retrospective, real-world study involving 35 locally advanced or metastatic UC patients treated with PD-1 inhibitor alone or in combination with chemotherapy was conducted. Kaplan–Meier curves were used to assess progression-free survival (PFS) and OS. A Cox regression analysis was conducted to explore the association of baseline variables with OS.

Results

In our cohort of 35 patients, 7 patients were treated with PD-1 inhibitor alone and 28 with PD-1 inhibitor plus platinum-based chemotherapy. The median OS was 16.0 months (95% CI: 11.9–20.1), and median PFS was 12.0 months (95% CI: 8.6–15.4) for all patients. PD-1 inhibitor combined with chemotherapy was associated with better PFS than PD-1 inhibitor monotherapy (HR: 0.19, p = 0.018). Treatment-related adverse events (AEs) of any grade occurred in 5 (71.4%) patients who received PD-1 inhibitor and 24 (85.7%) patients who received PD-1 inhibitor plus chemotherapy. Eastern Cooperative Oncology Group (ECOG) performance status (PS) and neutrophil-lymphocyte ratio (NLR) were identified as prognostic factors.

Conclusion

This study suggested that patients with locally advanced or metastatic UC could benefit from PD-1 inhibitor alone or combined with chemotherapy in daily clinical practice. ECOG PS and NLR can be used for prognostication of survival.

Introduction

Urothelial carcinoma (UC) is among the most common malignancies worldwide, and can be found across the entire urinary collecting system including the renal pelvis, ureter, bladder, and urethra. UC accounts for 90% of all bladder cancers, which is the 10th most commonly diagnosed cancer worldwide, with an estimated 573,000 new cases and 213,000 deaths in 2020 [1]. Patients with advanced UC have poor prognoses with a 5-year survival rate of less than 5% for those with metastatic, stage IV disease [2]. Platinum-based chemotherapy has become the standard first-line treatment for locally advanced or metastatic UC since 1980s. However, survival outcomes with these regimens remain poor, and almost 50% of patients with advanced UC are ineligible for cisplatin treatment due to poor performance status (PS), comorbidities, or renal insufficiency [3].

Recently, programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been established as a standard treatment for metastatic UC, both for first-line treatment of cisplatin-ineligible patients and for patients with disease progression despite the use of platinum-based chemotherapy [4,5,6,7,8]. In addition, a systematic review and meta-analysis showed that PD-1 inhibitor appeared to exhibit favorable survival outcomes and a comparable safety profile with PD-L1 inhibitor in cancer therapy [9]. Recently, two randomized, phase 3 clinical trials investigated the efficacy and safety of PD-1/PD-L1 inhibitor alone or combined with platinum-based chemotherapy as the first-line treatment for advanced UC. In the IMvigor130 trial, addition of anti-PD-L1 inhibitor atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival (PFS) in patients with advanced UC [10]. In the KEYNOTE-361 trial, however, addition of anti-PD-1 agent pembrolizumab to first-line platinum-based chemotherapy did not significantly improve PFS or overall survival (OS) [11]. Differences in study design, such as masked vs. open label treatment and investigator vs. central review, may have contributed to the conflicting results in the 2 trials. Most recently, Ren et al. [12] revealed that tislelizumab plus chemotherapy as first-line adjuvant treatment provided survivors of locally advanced or metastatic bladder cancer with encouraging antitumor activity. In the present clinical study, we further evaluated the clinical outcomes of PD-1 inhibitor alone or combined with chemotherapy for patients with locally advanced or metastatic UC in a real world clinical care setting.

Several studies have evaluated prognostic factors of survival in patients with metastatic UC treated with platinum-based chemotherapy or PD-1/PD-L1 inhibitors, with Eastern Cooperative Oncology Group (ECOG) PS, hemoglobin level, liver metastasis, platelet count, neutrophil-lymphocyte ratio (NLR), and lactate dehydrogenase (LDH) becoming well-established prognostic factors [13, 14]. However, little is known about the influence of different baseline characteristics on the outcomes of metastatic UC patients treated with first-line PD-1 inhibitor alone or combined with chemotherapy.

Accordingly, we conducted this single-center retrospective study to evaluate the efficacy and safety of PD-1 inhibitor alone or combined with chemotherapy in patients with locally advanced or metastatic UC, and sought to identify prognostic factors for survival.

Methods

Patient population

This retrospective, single-center study of patients with locally advanced or metastatic UC treated with PD-1 inhibitor alone or combined with platinum-based chemotherapy as first-line therapy under regular clinical practice situations between April 2019 and September 2021 was conducted. No patients had previously received any immune checkpoint inhibitors (ICIs) or chemotherapy. Patients received 21-day cycles of gemcitabine on days 1 and 8 of each cycle, plus either cisplatin or nedaplatin on day 1 of each cycle with PD-1 inhibitor (tislelizumab [12, 15] 200 mg or sintilimab [16] 200 mg) administered intravenously. Patients who were ineligible for platinum-based chemotherapy received PD-1 inhibitor (tislelizumab or sintilimab) alone every 21 days until disease progression or unacceptable toxicity.

Study design

Clinical data of patients were extracted from electronic medical records. Demographic, clinical, and tumor related data including age, gender, body mass index (BMI), ECOG PS, histological diagnosis, primary tumor site, metastatic sites, presence or absence of visceral (including liver, lung, bone, brain, and adrenal gland) metastasis, blood test results, as well as treatment regimens were collected. Pretreatment laboratory parameters were dichotomized into categorical variables using the cutoff points of normal vs. abnormal. Follow-ups were performed for all patients every 8 to 12 weeks after initiating the treatment of PD-1 inhibitor or PD-1 inhibitor plus platinum-based chemotherapy.

Efficacy endpoints of PD-1 inhibitor alone or combined with chemotherapy were OS and PFS. Response to treatment was assessed by the investigators according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 including complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Treatment-related adverse events (AEs) were assessed and graded with National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

In order to evaluate the influence of baseline characteristics on therapy efficacy, the following potential prognostic factors were analyzed for their possible association with survival: sex (male vs. female), age, BMI, ECOG (< 2 vs. ≥ 2), smoking history (yes vs. no), visceral metastases (yes vs. no), albumin (< 3.5 vs. ≥ 3.5 g/dl), NLR (< 3 vs. ≥ 3), hemoglobin (< 10 vs. ≥ 10 g/dl), and platelet count (< 400 000 vs. ≥ 400 0000/µl).

Statistical analysis

Continuous variables were summarized using descriptive statistics, and categorical data were tabulated with frequency and percentage. The primary efficacy endpoint was PFS, and OS was a secondary efficacy endpoint. Overall response rate (ORR) was defined as the proportion of patients who achieved CR or PR, and disease control rate (DCR) as the proportion of patients with CR, PR and SD. OS and PFS were estimated using the Kaplan-Meier method. The log rank test was used to compare OS and PFS curves between patients treated with PD-1 inhibitor alone or PD-1 inhibitor plus platinum-based chemotherapy. The Cox proportional hazards model was used to evaluate the statistical significance of the relationship between OS and each of the potential prognostic factors. These factors selected according to their clinical relevance and statistical significance in univariate analysis (p < 0.10) were then included in a multivariate model using the Cox proportional hazards model to identify independent prognostic factors. Two sided p-values were evaluated and a p-value of < 0.05 was considered statistically significant. Analyses were performed with SPSS version 22.0 software (SPSS, Chicago, Illinois), and figures were created by GraphPad version 8.0 software (GraphPad Software, San Diego, CA).

Results

Patient characteristics

A total of 35 patients in the Zhongnan Hospital of Wuhan University were enrolled in the current study. The average age of the cohort was 64 (range from 56 to 71) and 21 patients (60.0%) were male. The vast majority (30 cases, 85.7%) of the patients had metastatic disease. No patient had previously received any ICIs or chemotherapy. Among the 35 patients, 7 (20.0%) patients received PD-1 inhibitor alone, and the other 28 (80.0%) received PD-1 inhibitor plus platinum-based chemotherapy. At the final analysis, the median follow-up was 12.0 months (range: 4.0–25.0, IQR: 9.0–17.0). The median cycles of PD-1 inhibitor administered were 5 cycles (range: 1–30, IQR: 2–15), and the median cycles of chemotherapy administered were 4 cycles (range: 1–6, IQR: 2–6).

The baseline characteristics of the patients before the first administration of PD-1 inhibitor or in combination with chemotherapy are listed in Table 1. Supplementary Tables 1 and supplementary Fig. 2 summarizes clinical characteristics of the whole series.

Table 1 Baseline demographic and clinical characteristics

Efficacy of PD-1 inhibitor alone or combined with chemotherapy

At the time of data collection, 18 (51.4%) patients out of 35 enrolled patients had died. As assessed by the investigators, 12 (34.3%) patients had confirmed objective responses according to RECIST 1.1, including 5 (14.3%) CR and 7 (20.0%) PR (Table 2). In addition, 4 (11.4%) patients experienced SD, and the DCR was 45.7% (Table 2). The median OS was 16.0 months (95% confidence interval [CI]: 11.9–20.1), and median PFS was 12.0 months (95% CI: 8.6–15.4) of the entire study cohort, and the estimated 12- and 24-month OS rate were 68.5% and 27.4%, respectively (Fig. 1A, B; Table 2).

The median OS, however, in patients treated with PD-1 inhibitor alone or PD-1 inhibitor combined with chemotherapy were 10.0 months (95% CI: 7.4–12.6) and 17.0 months (95% CI: 13.2–20.8), respectively (hazard ratio [HR]: 0.32, 95% CI: 0.09–1.13, p = 0.077) (Fig. 1C). PD-1 inhibitor combined with chemotherapy was associated with better PFS than PD-1 inhibitor monotherapy (12.0 v 6.0 months, HR: 0.19, 95% CI: 0.05–0.75, p = 0.018) (Fig. 1D).

Representative images of responses in lung or liver metastases are shown in supplementary Fig. 1.

Fig. 1

Kaplan-Meier estimates of overall survival and progression-free survival. (A, B) All patients; (C, D) patients according to the treatment group: PD-1 inhibitor versus PD-1 inhibitor plus chemotherapy

Table 2 Response to treatment/efficacy endpoints

Safety

Of the entire study cohort, 29 (82.9%) patients reported any grade of treatment-related AEs, and most AEs were mild to moderate including fatigue (54.3%), nausea (42.9%), constipation (22.9%), vomiting (17.1%), decreased platelet count (17.1%), decreased white blood cell count (17.1%), pruritus (14.3%), rash (5.7%), and anaemia (5.7%) (Fig. 2A). Only 7 (20.0%) patients had grade 3 or 4 AEs, including one patient who suffered from immune-related myocarditis (grade 4 AEs), which required high dose steroid treatment at the intensive care unit (ICU). Four cases in the combination treatment group (14.3%) had grade 4 hematological AEs, decreased blood cell counts. There was no AEs-attributable death. Treatment-related AEs of any grade occurred in 5 (71.4%) patients who received PD-1 inhibitor and 24 (85.7%) patients who received PD-1 plus chemotherapy (Fig. 2B). Supplementary Table 2 summarizes the treatment-related AEs.

Fig. 2

Treatment related adverse events. (A) All patients in the study; (B) Patients treated with PD-1 inhibitor alone and patients with PD-1 inhibitor plus chemotherapy, respectively

Prognostic factors for OS

Ten potential prognostic factors were examined (Cox regression) for their association with OS. Results of the univariate analyses are shown in Fig. 3A. Three variables with univariate significance (p < 0.10), ECOG PS, visceral metastasis, and NLR, were selected to be included in the multivariate analysis using the Cox proportional hazards model, which identified ECOG PS (HR: 4.838, 95% CI: 1.227–19.067, p = 0.024) and NLR (HR: 3.739, 95% CI: 1.248–11.201, p = 0.018) as independent prognostic factors (Fig. 3B).

Fig. 3

Estimated associations between patient characteristics and overall survival. (A) Results of the univariate analyses; (B) Results of the multivariate Cox proportional hazards model. Abbreviations: HR, hazard ratio; CI, confidence interval; BMI, body mass index; ECOG, Eastern Cooperative Oncology Group; NLR, neutrophil-lymphocyte ratio

Discussion

PD-1 and PD-L1 inhibitors have revolutionized cancer therapy, which shifted clinical investigations toward immunotherapy in advanced UC. In addition, PD-1 inhibitor appears to exhibit favorable survival outcomes and a comparable safety profile with PD-L1 inhibitor in cancer therapy reported in a systematic review and meta-analysis [9]. Therefore, we investigated the efficacy and safety of domestic PD-1 inhibitor (tislelizumab or sintilimab) alone or in combination with platinum-based chemotherapy as first-line treatment for advanced UC in daily clinical practice.

PD-1/PD-L1 are primarily involved in inhibitory immune signaling, and PD-1 or PD-L1 inhibitors can reactivate T cell-mediated antitumor immunity by blocking the PD-1/PD-L1 immune checkpoint pathway [17]. Regimens that combine PD-1/PD-L1 inhibitors and platinum-based chemotherapy are appealing in clinical practice because platinum-based chemotherapy can induce immune-modulatory effects, thereby enhancing concomitant PD-1 and PD-L1 blockade, and this combination might also be beneficial because of the absence of clinical cross-resistance between these different therapeutic classes [18, 19]. PD-1 or PD-L1 inhibitor monotherapy was shown to be an effective treatment option in daily clinical practice for metastatic UC patients, with a median OS of 7.8 months, a median PFS of 2.8 months, and ORR in 24% and DCR in 40% [20]. Pond et al. [21] also reported the clinical outcomes of 79 platinum-ineligible patients with advanced UC treated with first-line PD-1/PD-L1 inhibitors in the real world, and the ORR was 27.9%, the median OS was 45 weeks and the treatment failure-free survival was 16 weeks. Recently, the KEYNOTE-361 trial did not meet the primary endpoints of superior PFS and OS with first-line pembrolizumab (PD-1 inhibitor) plus chemotherapy versus chemotherapy alone in patients with advanced UC, reporting a median PFS of 8.3 months and median OS of 17.0 months for patients treated with pembrolizumab plus chemotherapy [11]. However, Mori et al. [22] conducted a systematic review and meta-analysis that indicated a superior oncologic benefit from first-line ICI combination therapies in patients with chemotherapy-eligible metastatic UC over standard chemotherapy. Moreover, addition of atezolizumab (PD-L1 inhibitor) to platinum-based chemotherapy as first-line treatment prolonged PFS in patients with metastatic UC in the IMvigor130 trial, with a median OS of 16.0 months and median PFS of 8.2 months [10]. In the JAVELIN Bladder 100 trial of 700 patients with advanced UC, maintenance avelumab plus best supportive care significantly prolonged OS after first-line chemotherapy [23]. Most recently, the CheckMate 901 trial reported that nivolumab plus gemcitabine-cisplatin resulted in significant better outcomes in patients with previously untreated advanced UC than gemcitabine-cisplatin alone, whit a median OS of 21.7 months and median PFS of 7.9 months [24]. In addition, enfortumab vedotin plus pembrolizumab significantly prolonged OS (31.5 months) and PFS (12.5 months) than chemotherapy in patients with untreated locally advanced or metastatic UC [25]. In our study, the median OS was 16.0 months and median PFS was 12.0 months for all of the enrolled patients. PD-1 inhibitor combined with chemotherapy achieved better PFS than PD-1 inhibitor monotherapy (12.0 v 6.0 months, HR: 0.19, 95% CI: 0.05–0.75, p = 0.018) and provided a tendency of prolonged OS (17.0 v 10.0 months, HR: 0.32, 95% CI: 0.09–1.13, p = 0.077). However, additional research with multicenter randomized controlled trials and long-term follow-up is needed to further investigate the efficacy of immunotherapy with or without chemotherapy.

While PD-1 inhibitor in combination with chemotherapy is associated with favorable efficacy outcomes, the safety profile should be considered in daily clinical practice. In fact, there was no statistically significant difference of AEs between ICIs plus chemotherapy and chemotherapy alone [22]. In the KEYNOTE-361 trial, there was no new or unexpected safety signal reported for pembrolizumab plus platinum-based chemotherapy, and this treatment had a similar safety profile to chemotherapy alone [11]. Treatment-related AEs of PD-1 and PD-L1 inhibitors in clinical trials were evaluated in a systemic review and meta-analysis [26]. The most common all-grade AEs were fatigue (18.26%), pruritus (10.61%), and diarrhea (9.47%). The most common grade 3 or higher AEs were fatigue (0.89%), anemia (0.78%), and aspartate aminotransferase increase (0.75%) [26]. In the present study, treatment-related AEs of any grade occurred in 71.4% and 85.7% of patients who received PD-1 inhibitor or PD-1 plus chemotherapy, respectively, and only 7 (20.0%) patients had grade 3 or 4 AEs. The most common AEs were fatigue, gastrointestinal symptoms, and blood system and skin disorders. Most importantly, immune-related myocarditis is a potentially fatal toxicity of ICIs therapy. Myocarditis after ICIs therapy may be more common than appreciated (prevalence of 1.14%), occurs early after starting treatment, has a malignant course, and responds to higher steroid doses [27]. Unfortunately, one patient (2.9%) in our cohort suffered from immune-related myocarditis, while required admission to the ICU and treatment with high dose steroid for recovery.

Prognostic factors help stratify patients for treatment by identifying patients with risks and potential benefits, and are important tools in the management of cancer [28]. Several studies have evaluated prognostic factors of survival in patients with advanced or metastatic UC treated with platinum-based chemotherapy or ICIs, and identified ECOG PS, hemoglobin level, liver metastasis, platelet count, NLR, and LDH as prognostic factors [13, 14]. The impact of ECOG PS on treatment outcomes of advanced UC treated with first line ICIs was evaluated in a real-world study, and patients with a PS of 0 to 1 had longer OS than patients with a PS ≥ 2 [13]. NLR is a simple index of systemic inflammation and a biomarker associated with tumor aggressiveness, and the majority of the studies reported a positive role of a high NLR (≥ 3) in the prediction of worse OS [29]. Ogihara et al. [30] found that elevated pretreatment NLR may be a novel biomarker for identifying poor responders to pembrolizumab among platinum-resistant metastatic UC patients. In our study, three pretreatment variables (ECOG PS, visceral metastases, and NLR) with univariate significance were selected to be included in the multivariate analysis using the Cox proportional hazards model, and ECOG PS and NLR were identified as independent prognostic factors, which are consistent with the previous studies [13, 30]. However, visceral metastases (including liver metastasis) did not show its prognostic value in our study. There were only 2 patients with liver metastasis in our entire cohort, and one of them achieved PR after treatment with PD-1 inhibitor. Therefore, the prognostic value of visceral metastases should be further investigated.

There are some limitations that must be considered in interpreting the results of our study. First of all, it is a retrospective, observational study with limited sample size. As the treatment outcomes of PD-1/PD-L1 inhibitors alone or combined with chemotherapy as first-line therapy for advanced UC are controversial in the well-designed clinical trials [10, 11], the results of our study likely reflect the ‘real-world’ clinical practice and patient care. Secondly, although many important factors that can influence long-term survival were investigated in the present study, our study does not rule out a potential role for other confounding variables. Thirdly, patients were treated with PD-1 inhibitor alone or combined with chemotherapy irrespective of PD-L1 status. PD-L1 expression is associated with improved response rate with PD-1 and PD-L1 inhibitors [31]. Thus, further validation is needed including data based on PD-L1 status and other biomarkers.

Conclusion

In conclusion, the present study suggested that patients with locally advanced or metastatic UC could benefit from PD-1 inhibitor alone or combined with chemotherapy in daily clinical practice. Pretreatment ECOG PS and NLR can be used for prognostication of survival. With the approval of more effective but also more expensive systemic therapies for locally advanced or metastatic UC, further studies are required to address the optimal treatment regimen of ICIs with or without chemotherapy to ensure optimum clinical outcomes for our patients.