Neoadjuvant Sintilimab Combined with Gemcitabine and Cisplatin for Muscle-Invasive Bladder Cancer Patients Followed by Selective Bladder Sparing Surgery: A Phase 2 Trial
Article information
Abstract
Purpose
This study aimed to evaluate the safety and efficacy of gemcitabine and cisplatin (GP) regimen in combination with immune checkpoint inhibitor sintilimab as neoadjuvant therapy for muscle-invasive bladder cancer (MIBC) patients and the feasibility of the following selective bladder sparing surgery.
Materials and Methods
Patients with histopathologically confirmed urothelial carcinoma without distant metastases (T2-4a, N ≤ 1, M0, American Joint Committee of Cancer 8th) and with adequate organ function will be enrolled. The therapeutic regimen was sintilimab 200 mg once on day 8, gemcitabine 1,000 mg/m2 and cisplatin 35 mg/m2 once on days 1 and 8, every 21 days for four cycles. The primary endpoint was pathologic complete response (pCR, pT0N0) rate. The secondary end points were ypT < 2 rate, R0 resection rate, event-free survival, and safety.
Results
From May 4, 2020, to May 20, 2023, 55 patients were enrolled. Forty-six patients were evaluated for efficacy. Among the 42 patients who underwent surgery, 16 patients (38.0%) achieved pCR. Thirty-three patients (78.6%) achieved pT < 2. With a median follow-up of 15.7 months, the 1-year event-free survival was 91.3%. Notwithstanding the poor pathological baseline characteristic of a high T3-T4a proportion (39.1%), a promising bladder preservation (including 22 patients transurethral resection of bladder tumor, 5 patients partial cystectomy, and 4 surveillances) rate was achieved (67.4%). The most common grade ≥ 3 treatment-related adverse events was neutropenia (n=15, 27.3%), which was related to chemotherapy. There were no grade 3 immune-related adverse events.
Conclusion
Neoadjuvant GP plus sintilimab is a promising regimen for MIBC patients, with relatively high pT < 2 rate and triggering the emerging roles for the multi-disciplinary team decision-making for bladder sparing surgery.
Introduction
Muscle-invasive bladder cancer (MIBC) portends dismal survival statistics, with a 5-year overall survival (OS) rate of approximately 50% [1,2]. Current guidelines advocate neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) for MIBC. However, RC carries high morbidity with early complications and a perioperative mortality rate of approximately 5% [3]. Furthermore, the necessity of urinary diversion detrimentally affects patient-reported outcomes, including urinary and sexual function [4,5]. In recent years, the role of RC has been questioned by patients who refuse to undergo RC after clinical complete response (cCR) [6]. There is a subset of patients with MIBC who are considered unfit for RC. Bladder-sparing approaches are gaining increasing attention as viable therapeutic options that balance oncological efficacy with quality-of-life (QoL) preservation [7].
The U.S. Food and Drug Administration has sanctioned immune checkpoint blockade therapy for metastatic urothelial cancer based on its efficacy in promising survival benefits [8-11]. Neoadjuvant immune checkpoint inhibitors chemotherapy regimens exhibit robust clinical efficacy, achieving pathologic complete response (pCR) rates between 30% and 43.3% in recent trials [12-16]. In locally advanced rectal cancer with mismatch repair deficiency, 75% of patients achieved a complete response following treatment with sintilimab alone, and 56% of patients chose the watch-and-wait strategy [17]. According to Cercek et al.’s research [18], immunotherapy has shown a 100% clinical complete response, and rectal preservation was achieved for all patients. Owing to the high frequency of pathological complete response, organ-sparing management can be expected [19].
Sintilimab is a humanized IgG4 monoclonal antibody that specifically blockade programmed death-1 (PD-1), showing activity in gastric cancer [20], esophageal squamous cell carcinoma [21], non–small cell lung cancer [22], deficiency in mismatch repair (dMMR) locally advanced rectal cancer [17]. It remains to be further investigated in neoadjuvant settings for MIBC, especially for Chinese populations. Gemcitabine and cisplatin (GC) regimens are commonly used as standard neoadjuvant therapies [23,24]. Based on this rationale, we propose that combining sintilimab with GC as preoperative treatment could improve outcomes in MIBC and permit selective bladder conservation.
Materials and Methods
1. Patients
Patients were eligible for enrollment if they were older than 18 years of age, had histopathologically confirmed urothelial carcinoma without distant metastases, and had clinical stage T2-T4a N ≤ 1 M0. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 and adequate organ function. Bladder cancer staging was performed according to the 8th edition of the American Joint Committee of Cancer TNM classification system. The key exclusion criteria included active autoimmune diseases, active infectious disease, tuberculosis, and receipt of immunosuppressive medication.
2. Study procedures
This was a nonrandomized, open-label phase II study (registered on https://www.chictr.org.cn, ChiCTR2000032757). It was planned that patients were to be treated with sintilimab 200 mg once on day 8, gemcitabine 1,000 mg/m2 and cisplatin 35 mg/m2 once on days 1 and 8, every 21 days for four cycles as neoadjuvant therapy. Per the protocol, cisplatin ineligibility was guided by the Galsky criteria [25]. Tumor assessments were performed at baseline and after two cycles and four cycles of therapy. After administration of four cycles of NAC, a multidisciplinary treatment was performed for the surgical plan and the workflow is shown in Fig. 1. If the patient achieved cCR, surgery is recommended, but close observation is also an option. Patients not achieving a cCR were recommended to proceed with surgery. A cCR was defined the absence of a suspicious lesion on cross-sectional imaging, combined with negative urinary cytology and negative malignancy on biopsy. RC and bladder-sparing strategies, including partial cystectomy (PC) and transurethral resection of bladder tumor (TURBT), and surveillance were fully discussed.
The workflow. The workflow of the current multidisciplinary treatment decision flow chart. If the patient achieved clinical complete response (cCR), surgery is recommended, but close observation is also an option. Patients not achieving a cCR were recommended to proceed with surgery. TURBT, transurethral resection of bladder tumor.
3. Endpoints and assessment
The primary end point was pCR, defined as no viable tumor cells in resected tissue (pT0N0). The secondary endpoints included non–muscle-invasive downstaging, defined as the absence of muscle-invasive disease (< pT2), event-free survival (measured from the first day of neoadjuvant treatment to progression, recurrence after cystectomy, or death from any cause), R0 resection rate, safety. QoL was assessed before neoadjuvant therapy, 1 month after surgery and 1 year after surgery using the Functional Assessment of Cancer Therapy- Bladder cancer module (FACT-BL). Tumor regression grade (TRG) was evaluated by a trained pathologist. TRGs were defined as follows: TRG1, complete tumor regression; TRG2, > 50% tumor regression; TRG3, 50% or less tumor regression [26].
4. Statistical considerations
The Z test-based binomial distribution was used to estimate the sample size, and a test level of α=0.05 and of test efficacy of 1–β=0.8 were set for the calculation. As the pCR rate of NAC for bladder cancer was approximately 26% [27], it was expected to reach 46% in our protocol. As the predicted shedding rate was 10%, 45 patients needed to be enrolled. Patients who discontinued neoadjuvant therapy before completing two cycles (either voluntarily or due to unrelated adverse events [AEs]) remained eligible for toxicity assessment, but they were excluded for efficacy evaluation. Kaplan-Meier method was adopted for event-free survival (EFS). p-values of less than 0.05 were considered statistically significant.
Results
1. Patients
From May 4, 2020, to February 20, 2023, 55 patients were enrolled. Nine patients exited the protocol before two cycles of therapy were completed and were evaluated for safety but not for efficacy. Table 1 summarizes the baseline characteristics of the 46 response-evaluable patients. The median age was 62 years (range, 42 to 79 years), and 91.3% were men. Of these 46 patients, 39.1% were clinical stage T3-T4a, and 2.2% had nodal involvement. A total of 73.9% of patients underwent four cycles of neoadjuvant therapy. A total of 97.8% of patients had predominantly histologically pure urothelial carcinoma. A total of 47.8% of patients were current or former smokers.
Demographic and disease characteristics in the response-evaluable population
2. Efficacy
Multidisciplinary treatment was conducted for surgical planning after neoadjuvant therapy for the 46 patients. Bladder preservation was achieved in 31 (67.4%) patients, including 22 patients who underwent TURBT, five patients who underwent PC and four patients who underwent surveillance (4 patients undergoing surveillance after achieving cCR to initial systemic treatment). Sixteen patients ranked as TRG 1, 14 patients ranked as TRG 2, and 12 patients ranked as TRG 3 (Table 2).
Pathologic response at the time of surgery and surgical options
Among the 42 patients who underwent surgery, 16 patients (38.0%) achieved pCR, and 33 patients (78.6%) achieved pT < 2 (16 patients pT0, 4 patients pTa, one patient pTis, 12 patients pT1). All patients achieved R0 resection. The non–muscle-invasive downstaging rate (pT < 2) of patients who received 4 cycles of neoadjuvant therapy was 76.7% (n=23), while it was 57.1% (n=4) for patients who received 2 cycles of neoadjuvant therapy. The pT < 2 rate and pCR rate of clinical T2 disease were 88.9% (n=24) and 37.0% (n=10), respectively (Fig. 2A). The pT < 2 rate and pCR rate of clinical T3-T4a disease were 60.0% (n=9) and 40% (n=6), respectively (Fig. 2B). No patients had clinical or radiographic progression before surgery.
Pathologic response of clinical T2 and clinical T3-T4a disease. (A) The rates of achieving pT < 2 and pathologic complete response (pCR) for clinical T2 disease were 88.9% and 37.0%, respectively. (B) The rates of achieving pT < 2 and pCR in clinical T3-T4a disease were 60.0% and 40.0%, respectively.
With a median follow-up of 25.3 months (range, 11.6 to 45.4 months), the median EFS was not reached (data cutoff January 25, 2024) (Fig. 3A), and the 1-year EFS was 91.3%. Seven patients relapsed. We found that six of the seven patients who relapsed opted for bladder-conserving therapy, and five patients were ranked TRG 3. Although an increased recurrence rate was observed in patients with bladder conservation compared with radical resection, and the EFS curve shows there was a tendency to be more prone to recurrence for the bladder preservation group, there was no significant difference (p=0.337) (Fig. 3B). Patients with a pT < 2 had a trend toward better EFS in comparison to nonresponders. Patients who achieved pCR also had a trend toward better EFS than non-pCR patients, as shown in Fig. 3C and D.
Event-free survival curve. (A) Event-free survival of 46 patients. Event-free survival of 46 patients stratified by bladder preservation and radical cystectomy (RC) (B) whether pT category was less than 2 after neoadjuvant therapy (C) and whether pathologic complete response (pCR) was achieved after neoadjuvant therapy (D). CI, confidence interval; HR, hazard ratio; NR, not reached.
3. Adverse events
Among the 55 patients evaluable for safety, all experienced grade 1 or higher AE, and grade 3 or higher AE were observed in 45.8% of the patients. The most common treatment-related adverse events (TRAEs) of any grade were anemia (n=47, 85.5%), white blood cell (WBC) decrease (n=42, 76.4%), and neutropenia (n=37, 67.3%). The most common grade 3-4 TRAEs was neutropenia (n=15, 27.3%). There were no AEs leading to death. Immune-related AEs (irAEs) were rash (n=6, 10.9%), hyperthyroidism (n=5, 9.1%), fever (n=3, 5.5%), and hypothyroidism (n=2, 3.6%) (Table 3).
Treatment-related AEs occurring in at least 10% of patients and all grade 3-4 AEs
We compared surgery-related parameters, such as the duration of surgery, intraoperative blood loss, hospital stay, and decrease in albumin and hemoglobin values after the operation, between bladder preservation and RC patients. We found that bladder preservation patients had shorter surgery durations, less blood loss, and shorter hospital stays than RC patients (p < 0.001) (S1 Table). One patient developed an intestinal obstruction after RC (Clavien Dindo [15] grade 2). The remaining patients had no surgery-related complications with Clavien Dindo grade greater than 1.
4. Quality of life
The questionnaire completion rates were 100% at baseline (pretreatment), 95.7% at the 1-month postoperative follow-up, and 82.6% at the 1-year follow-up assessment. The questionnaire includes five subscales: physical well-being (PWB), social well-being (SWB), emotional well-being (EWB), functional well-being (FWB) and the bladder cancer subscale (BLCS), with higher scores reflecting better QoL.
No significant differences were observed between RC and bladder preservation patients in PWB, SWB, EWB, FWB, or BLCS scores at baseline (Fig. 4A).
The scores of five dimensions of FACT-BL questionnaire between radical cystectomy and bladder preservation. (A) Baseline (pretreatment). (B) 1-Month postoperative follow-up. (C) 1-Year postoperative follow-up. BLCS, bladder cancer subscale; EWB, emotional well-being; FACT-BL, Functional Assessment of Cancer Therapy- Bladder cancer module; FWB, functional well-being; PWB, physical well-being; SWB, social well-being. *p < 0.05, **p < 0.01, ***p < 0.001.
At 1-month postoperative follow-up, bladder preservation patients demonstrated significantly higher scores than RC patients in SWB (20.33±3.50 vs. 16.86±4.66, p=0.009) and BLCS (32.1±4.89 vs. 28.93±4.14, p=0.04). No significant differences were identified in PWB, EWB, or FWB scores between the two groups (Fig. 4B).
At 1-year postoperative follow-up, bladder preservation patients maintained superior outcomes compared to RC patients across multiple domains: SWB (22.8±3.73 vs. 19.30±4.75, p=0.017), EWB (21.48±2.16 vs. 19.00±3.27, p=0.008), FWB (22.40±2.53 vs. 18.85±5.40, p=0.009), and BLCS (34.52±5.28 vs. 30.85±2.30, p=0.023) (Fig. 4C). These findings collectively indicate QoL advantages in bladder preservation patients.
Discussion
Targeted blockade of the PD-1/programmed death-ligand 1 (PD-L1) represents a novel immunotherapeutic strategy for malignant neoplasms. As a humanized IgG4 monoclonal antibody targeting PD-1, sintilimab has been approved for treating various types of cancer [28-31]. In our trial, the combination of gemcitabine-cisplatin and sintilimab showed promising efficacy in MIBC, as 16 patients (38%) achieved pCR and 33 patients (78.6%) of the surgery patients achieved pT < 2. However, our study did not meet the primary endpoint with pCR less than 46%. We believe this is due to the following reasons: (1) The value we expected to achieve was too high. The pCR rates were 36% in pembrolizumab plus GC [14], 30% in SAKK 06/17 trial [12], 41% in atezolizumab with GC [15], and 43.3% in camrelizumab plus GC [16]. Similarly, other studies have not been able to achieve such high rates of pCR. While it is not a head-to-head comparison, our rate of complete pathological response is similar to that of other studies. (2) The high proportion of patients with stage T3-T4a may be one of the reasons why this study did not meet the study endpoint. In our study, 39.1% of patients were in clinical stage T3-T4a, which is higher than that in a previous study [14,15]. Hermans et al. noted, the pathologic downstaging (≤ T1) rates in cT2 disease were higher than those in more advanced disease [32], which indicates that pathological remission is difficult for tumors in advanced stages.
Notwithstanding the poor pathological situation of a high T3-T4a proportion, the downstaging (pT < 2) rate remains high, which is higher than the previous immunotherapy (IO)-chemotherapy neoadjuvant trials, ranging from 50%-69% [12-16]. We also found that the pT < 2 rate and pCR rate of clinical T3-T4a disease were 60.0% and 40%, respectively. The pT < 2 rate decreased in the 2-cycle neoadjuvant therapy group compared to the 4-cycle therapy group, indicating that adequate neoadjuvant therapy is conducive to tumor downstaging. Previous studies have shown that responders had significantly better recurrence-free survival than nonresponders [14,15]. Achieving a pCR after NAC (ypT0N0) is an independent factor for patients’ long-term survival and 5-year OS [33-35]. Patients with pCR exhibited significantly improved 1-year survival in Han et al.’s study [16]. In our study, an improvement trend in EFS was observed in pT < 2 and pCR patients, but with no significant difference. A longer surveillance might establish clearer associations between pathologic response and prognosis.
Consistent with the established toxicity patterns of immunochemotherapy, the GC-sintilimab regimen in our trial demonstrated a similar safety signature. The most common grade 3-4 treatment-related hematologic AEs were neutropenia (27.3%), thrombocytopenia (14.5%), and WBC decrease (12.7%), which are concordant with existing literature on platinum-combination therapies [14,36]. Grade ≥ 3 thrombocytopenia and neutropenia were observed in ddMVAC and GC, respectively [37]. Among nonhematologic AEs, fatigue was the most common grade 3-4 TRAE, which is consistent with a previous study [15]. Rash represented the most common irAE in this study, and there were no grade ≥ 3 irAEs. To minimize the risk of toxicities of cisplatin, cisplatin was administered in divided doses of 35 mg/m² on days 1 and 8 of each treatment cycle.
RC is the standard treatment for MIBC. However, the rates of short-term complications, long-term complications, and mortality after RC are high, leading to an increased interest in bladder-sparing strategies, aiming to maintain the health-related QoL of MIBC patients without jeopardizing OS [19,38-47]. Different bladder-preserving protocols, such as unimodal chemotherapy or radiotherapy, maximal TURBT or PC, and multimodal strategies, have been performed in different scenarios [48]. A proportion of MIBC patients undergoing combined TURBT and systemic chemotherapy attain long-term survival [49,50]. In selected patients, PC serves as a viable treatment option, providing comparable cancer control while reducing treatment-related complications [46]. Recently, more trials have adopted bladder-sparing options as an alternative to RC. The phase II HCRN GU 16-257 study (NCT03558087) is investigating the efficacy of preoperative gemcitabine-cisplatin chemotherapy combined with the PD-1 inhibitor nivolumab. Individuals achieving a cCR can choose to continue with either PD-1 inhibition or RC. In the IMMUNOPRESERVE-SOGUG trial (NCT03702179), patients who responded to immunotherapy were candidates for bladder preservation [51]. Many individuals opt against RC after completing TURBT and systemic chemotherapy, especially if there is no evidence of disease [52-55].
In our study, based on the results of the multi-disciplinary team (MDT) combined with the patient’s willingness, bladder-sparing surgery such as TURBT or PC was performed. Our study reported a 67.4% bladder-preserving rate. However, we found that patients who retained their bladder had an increased recurrence rate, although there was no statistically significant difference. Based on this situation and the patients with ypT2 to ypT4a or ypN+ after neoadjuvant cisplatin can benefit from immune-adjuvant therapy according to the Checkmate-274 trial [56], we recommend adjusting the MDT process and perioperative treatment plan based on patients’ response to neoadjuvant therapy. We recommend TURBT for patients who have achieved cT ≤ 1. Observation may be an option if pCR is confirmed. Adjuvant immunotherapy is recommended for patients who do not achieve pCR, particularly those with high-risk factors such as ypT2 and TRG 3. Patients who do not experience downstaging of their clinical T stage after neoadjuvant therapy should be considered for RC. In patients with a single tumor and no carcinoma in situ at baseline who have had a decrease in tumor stage but are not achieving cT ≤ 1, PC may be considered as a treatment option. Intensive surveillance is required for bladder-preserving patients, and salvage RC is recommended in the event of recurrence. Due to the high tumor downstaging rate and pCR rate, the possibility of curing a considerable portion of MIBC patients before RC is improved, making bladder preservation possible. However, follow-up clinical studies are needed to confirm this.
There are several limitations to this study. First, the median follow-up is inadequate, and a longer follow-up is needed to further identify the survival benefit of IO-chemotherapy as neoadjuvant treatment. Second, a biomarker-based approach was lacking in our study, and exploration of the relationship between molecular biomarkers such as PD-L1, DNA damage repair gene mutations and therapeutic effects is warranted. Moreover, some patients may opt for bladder preservation, which could result in incomplete pathological assessments and an overestimation of treatment effectiveness.
Neoadjuvant gemcitabine and cisplatin plus sintilimab is a promising regimen for MIBC patients, with a relatively high pT < 2 rate, triggering emerging roles for MDT decision-making for bladder-sparing surgery.
Electronic Supplementary Material
Supplementary materials are available at Cancer Research and Treatment website (https://www.e-crt.org).
Notes
Ethical Statement
This is an investigator-initiated study. The protocol was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University (approval number: 2020-IIT-158). In accordance with the principles of the Declaration of Helsinki, all the patients were provided with written informed consent before study enrollment.
Author Contributions
Conceived and designed the analysis: Tong Z, Fu G, Zhou F, Zheng Y, Fang W, Zhao P.
Collected the data: Zhu X, Gao Y, Liu L.
Contributed data or analysis tools: Liu X, Zhang H, Wang Y, Bao X.
Performed the analysis: Zhou F, Xue X, Zhang H, Wang Y, Bao X.
Wrote the paper: Tong Z, Fu G, Zhou F.
Revised the manuscript: Zhao P, Jin B.
Conflicts of Interest
Conflict of interest relevant to this article was not reported.
Funding
This work was supported by the National Natural Science Foundation of China (82203186).