Abstract
BACKGROUND
Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse. We evaluated pembrolizumab as adjuvant therapy in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery.
METHODS
The Alliance A031501 AMBASSADOR study is a phase 3 trial where patients were randomized 1:1 to receive pembrolizumab 200 mg every 3 weeks for 1 year or observation. Randomization was stratified by pathologic stage, centrally tested PD-L1 status, and prior neoadjuvant chemotherapy. The co-primary endpoints were disease-free survival and overall survival among the intention-to-treat population. The trial was considered positive if either of the co-primary endpoints showed a significant improvement for the pembrolizumab arm.
RESULTS
A total of 702 patients were randomized,354 to receive pembrolizumab and 348 were assigned to observation. As of July 5, 2024, median follow-up was 44.8 months for disease-free survival. Median disease-free survival was 29.6 months (95% confidence interval (CI) 20.0–40.7) with pembrolizumab and 14.2 months (95% CI 11.0–20.2) with observation (hazard ratio [HR] 0.73; 95% CI 0.59–0.90; 2-sided p=0.0027). Grade 3 or higher adverse events occurred in 50.7% and 31.6% of patients in the pembrolizumab and observation arms, respectively.
CONCLUSIONS
Adjuvant pembrolizumab demonstrated a statistically significant improvement in disease-free survival vs observation for patients with high-risk muscle-invasive urothelial carcinoma after radical surgery. (Funded by the National Cancer Institute of the National Institutes of Health ClinicalTrials.gov Identifier: NCT03244384)
INTRODUCTION
Muscle-invasive urothelial carcinoma is an aggressive disease with high rates of relapse.1,2 The standard of care is radical surgery with neoadjuvant cisplatin-based chemotherapy.2 Although neoadjuvant cisplatin-based chemotherapy has demonstrated an overall survival benefit,3,4 many patients are not eligible or decline therapy. High-risk muscle-invasive urothelial carcinoma patients are those who 1] either were not eligible for or refused neoadjuvant cisplatin-based chemotherapy and have ≥ pathologic (p) T3 or pN+/or microscopic positive surgical margins5 or 2] have persistent muscle-invasive disease (> pT2 or pN+/ or microscopic positive surgical margins) despite neoadjuvant chemotherapy at the time of radical surgery.6,7 While adjuvant cisplatin-based therapy improves disease-free survival after radical cystectomy in patients who did not receive neoadjuvant cisplatin-based chemotherapy, up to a third of patients are not medically fit to receive chemotherapy in the post-operative setting.8,9
Two randomized phase 3 trials reported conflicting results on the efficacy of adjuvant checkpoint inhibitors in patients with high-risk muscle-invasive urothelial carcinoma. The IMvigor010 study which randomized patients with post-operative muscle-invasive urothelial carcinoma to adjuvant atezolizumab vs observation did not report a benefit for the primary endpoint of disease-free survival.10 The median disease-free survival was 19.4 months with atezolizumab and 16.6 months with observation (Hazard Ratio (HR) 0.89, 95% confidence interval (CI) 0.74–1.08). In contrast, the CheckMate 274 study which compared adjuvant nivolumab to placebo did demonstrate benefit for its co-primary endpoints of disease-free survival, with a median disease-free survival of 20.8 months for nivolumab vs 10.8 months for placebo (HR 0.70, 98.22% CI 0.55–0.90) and a more pronounced disease-free survival benefit in the PD-L1 ≥ 1% population (HR 0.55, 98.72% CI 0.35–0.85).11 The overall survival data from CheckMate 274 is immature and has not crossed the prespecified interim efficacy boundaries.12 The positive disease-free survival results from CheckMate 274 led to the approval of adjuvant nivolumab regardless of PD-L1 status in the United States and for patients with tumor expressing PD-L1 ≥ 1% in Europe.
Pembrolizumab is a PD-1 checkpoint inhibitor approved as monotherapy and in combination with enfortumab vedotin for the treatment of patients with metastatic urothelial carcinoma and as monotherapy for BCG-unresponsive high-risk non-muscle-invasive bladder cancer.13–15 Here we present the results of Alliance for Clinical Trials in Oncology (Alliance) A031501, the AMBASSADOR trial, an investigator-initiated phase 3 study that examined the efficacy of pembrolizumab compared to observation in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery.
METHODS
Patients with confirmed muscle-invasive urothelial carcinoma of the urinary tract or lymph node-positive disease were eligible after radical surgery ≥ 4 weeks but ≤ 16 weeks before trial pre-registration. Patients who received neoadjuvant cisplatin-based chemotherapy must have had a pathologic stage of ≥ ypT2 and/or ypN+ and/or microscopic positive surgical margins. Patients who did not receive neoadjuvant cisplatin-based chemotherapy must have had a pathologic stage of ≥ pT3 and/or pN+ and/or microscopic positive surgical margins. Variant histology (excluding neuroendocrine carcinoma) was allowed if urothelial carcinoma was predominant; any amount of squamous differentiation was allowed. No cap was placed on the enrollment of patients with upper tract or urethral muscle-invasive urothelial carcinoma. Patients must have been free of metastatic disease based on imaging obtained ≤ 42 days before pre-registration with tissue available for PD-L1 analysis and have an Eastern Cooperative Oncology Group performance status of 0–2 (a 5-point scale where higher numbers reflect greater disability. Further details are available in the protocol attached as a supplement available at NEJM.org.
Trial Design and Treatments
This was a randomized, open-label, phase 3, multicenter study of adjuvant pembrolizumab vs observation in patients with high-risk muscle-invasive urothelial carcinoma of the urinary tract. Patients were randomized 1:1 to either pembrolizumab or observation. Randomization was stratified on (1) neoadjuvant chemotherapy (yes, no), (2) pathologic stage (pT2/3N0, pT4N0 or NX, pT any N+ [any], positive surgical margins), and (3) PD-L1 status (positive, negative). PD-L1-positive tumors had a combined positive score (CPS) of ≥ 10% using the Dako PD-L1 IHC 22C3 pharmDx assay. Treatment consisted of either intravenous pembrolizumab 200 mg every 3 weeks or observation for up to 1 year (18 cycles) or until disease progression or unacceptable adverse events occurred. No dose reductions of pembrolizumab were allowed, only dose delays for up to 12 weeks. Treatment modifications are outlined in the protocol.
Endpoints and Assessments
The co-primary endpoints were disease-free survival and overall survival. Disease-free survival was defined as the time from randomization to the first metastatic recurrence or death from any cause. Patients with local recurrent muscle-invasive disease or local high-grade non-muscle-invasive disease needing radical surgery either in the bladder after nephrectomy/ureterectomy or in the upper tract after cystectomy, were considered to have a disease-free survival event. However, patients with local non-muscle invasive urothelial carcinoma recurrence, eligible for local endoscopic therapy (e.g. transurethral resection of bladder tumor) and/or intravesical therapy, were not considered a disease-free survival events.16 Patients who were alive and without a disease-free survival event at the time of analysis were censored at the time of their last disease evaluation. Patients who did not have a disease-free survival event but started an alternative, non-protocol-directed treatment were censored at the last disease evaluation prior to the alternative treatment. A sensitivity analysis was performed where patients who started an alternative treatment prior to a disease-free survival event were deemed to have had a disease-free survival event at the time they started the alternative treatment. Overall survival was defined as the time from randomization until death due to any cause. Patients not known to have died at the time of analysis were censored at the time of their last follow-up. Key secondary objectives were to determine the disease-free survival and overall survival in PD-L1-positive and PD-L1-negative tumors as well as safety. Safety was assessed using the NCI’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Statistical Analysis
The trial was designed to report both disease-free survival and overall survival simultaneously, but a subsequent amendment allowed each endpoint to be reported separately. The study is considered positive if it meets either primary endpoint. A multiplicity strategy was applied to the primary hypotheses (superiority of pembrolizumab on disease-free survival and overall survival in all patients) and the secondary hypotheses (superiority of pembrolizumab on disease-free survival and overall survival in PD-L1-positive (CPS ≥10%) and PD-L1-negative (CPS <10%) tumors). The overall type-I error was strongly controlled at the 0.025 level (one-sided) by the Bonferroni procedure, with 0.01 allocated to disease-free survival in all patients and 0.005 allocated to overall survival in all patients; 0.01 was allocated to the set of secondary hypotheses.
The anticipated 5-year disease-free survival rate for the observation arm was 33.4%.17–19 Assuming a one-sided marginal type-I error rate of 0.01 and an exponential disease-free survival distribution, the log-rank test had at least 96.7% power to detect a hazard ratio (HR) of 0.65. The required number of disease-free survival events for final analysis is 387 in the 2 arms. The anticipated 5-year overall survival rate was approximately 43.5% in the observation arm.17–19 Assuming a one-sided marginal type-I error rate of 0.005 and an exponential overall survival failure distribution, the log-rank test had at least 89% power to detect an HR of 0.65 with a sample size of 739 patients. The required number of overall survival events for final analysis is 320 in the 2 arms.
An intent-to-treat (ITT) approach was used to analyze the disease-free survival and overall survival primary endpoints. The primary analysis comparing disease-free survival and overall survival between the arms used a stratified proportional hazards model with treatment as a covariable and the randomization stratification factors. The proportional hazards assumption was evaluated using a Kolmogorov-type Supremum test. The proportional hazards assumption was not violated for either the disease-free or overall survival endpoints at the 0.05 significance level. The Kaplan-Meier product-limit method was used to estimate the disease-free survival and overall survival distributions for each arm, and they were compared with a stratified log-rank test. There were no missing data in baseline variables and only one patient on the observation arm was lost to follow-up and as such there was no need for missing data analyses. Adverse events were determined using CTCAE v5, and we report the highest grade experienced by the patient. The most common adverse events (occurring in ≥ 10% of patients) by type and grade, regardless of attribution, are summarized for each treatment arm by frequency and relative frequency.
Superiority and futility interim analyses were conducted for the disease-free survival and overall survival endpoints (details can be found in the protocol). The database was frozen on July 5, 2024 for all endpoints other than overall survival. The overall survival data were frozen at the time of the second planned interim analysis, July 13, 2023. No further analysis has been performed for the overall survival data since it has not yet reached the required number of events to trigger a final analysis. The DSMB released the data upon the second interim analysis on 10/18/2023. The second interim analysis for disease-free survival was performed using the first 319 events (82% of the information). The observed HR was 0.69 which was less than the HR efficacy boundary of 0.7448. The second interim analysis for overall survival occurred when 257 deaths (80% of the information) were observed; the interim analysis were reviewed by the DSMB and the data were released on 10/18/2023. The observed HR was not less than the efficacy boundary HR of 0.6933. The statistical team was not blinded, and the interim results were validated by an independent Alliance statistician who was provided the trial data and statistical analysis plan. Statistical analyses were performed with SAS 9.4M8. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Management Center. Data quality was ensured by review of data by the Alliance Statistics and Data Management Center and by the study chairperson following Alliance policies.
Trial Oversight
The trial was funded by the National Cancer Institute (NCI) and was conducted by the Alliance for Clinical Trials in Oncology group and the National Clinical Trials Network. The trial was designed by investigators of the Alliance network and approved by the NCI’s Cancer Therapy Evaluation Program (CTEP) and Merck & Co., Inc., Rahway, NJ, USA. The trial protocol and amendments were approved by a central Institutional Review Board and, if required, by the local board of the participating institution. The trial was conducted in accordance with the Good Clinical Practice guidelines. The Alliance Data and Safety Monitoring Board provided independent monitoring, reviewing the study every 6 months. All patients provided written informed consent before trial enrollment. Pembrolizumab was provided by CTEP through a collaboration with Merck & Co., Inc., Rahway, NJ, USA. The final manuscript was written by the first author with input only from the co-authors. No one who is not an author contributed to writing the manuscript. The authors vouch for the data and adherence to the protocol.
RESULTS
Patients and Treatments
Enrollment began on September 21, 2017, and the study was closed early on August 24, 2021 after the U.S. Food and Drug Administration approved adjuvant nivolumab for patients with high-risk muscle-invasive urothelial carcinoma. A total of 702 patients were enrolled, 96% of the planned 734 patients. Patients were recruited from 246 sites across the United States. Of the 702 patients enrolled, 354 were randomized to pembrolizumab (24 never started treatment) and 348 were randomized to observation (4 never started observation). In the pembrolizumab arm, 185 patients (52.3%) reported disease progression or death; in the observation arm, 194 patients (55.7%) had disease progression or death (Fig. 1: CONSORT diagram, suppl). Of the 169 patients (47.7%) censored for the disease-free survival analysis in the pembrolizumab arm, 123 (72.8 %) were alive and disease-free at follow-up; 46 (27.2%) were censored due to either alternative therapy 3 (1.8%) or withdrawal of consent 43 (25.4%). In the observation arm, of the 154 patients (44.3%) who were censored for the disease-free survival analysis, 96 (62.3%) were alive and disease-free at follow-up; 58 (37.7%) were censored due to either alternative therapy 10 (6.5%), withdrawal of consent 47 (30.5%), or loss to follow-up 1 (0.7%). Patient baseline characteristics, including the stratification variables, were well balanced between the 2 arms (Table 1). Furthermore, a comparison was made of baseline variables between patients censored for disease-free survival between the two treatment arms and no significant differences were found (Supplementary Table 6).
Table 1:
Patient Characteristics
| Pembrolizumab (N=354) | Observation (N=348) | Total (N=702) | |
|---|---|---|---|
| Age, years | |||
| Median (Range) | 69.0 (22.0, 92.0) | 68.0 (34.0, 90.0) | 68.0 (22.0, 92.0) |
| Race, n (%) | |||
| White | 323 (91.2%) | 310 (89.1%) | 633 (90.2%) |
| Black or African American | 14 (4.0%) | 11 (3.2%) | 25 (3.6%) |
| Asian | 5 (1.4%) | 10 (2.9%) | 15 (2.1%) |
| American Indian or Alaska Native | 2 (0.6%) | 2 (0.6%) | 4 (0.6%) |
| Not Reported | 6 (1.7%) | 5 (1.4%) | 11 (1.6%) |
| Unknown | 4 (1.1%) | 10 (2.9%) | 14 (2.0%) |
| Sex, n (%) | |||
| Female | 83 (23.4%) | 95 (27.3%) | 178 (25.4%) |
| Male | 271 (76.6%) | 253 (72.7%) | 524 (74.6%) |
| ECOG performance status, n (%) | |||
| 0 | 184 (52.0%) | 179 (51.4%) | 363 (51.7%) |
| 1 | 151 (42.7%) | 157 (45.1%) | 308 (43.9%) |
| 2 | 19 (5.4%) | 12 (3.4%) | 31 (4.4%) |
| Primary tumor site, n (%) | |||
| Upper tract | 81 (22.9%) | 73 (21.0%) | 154 (21.9%) |
| Upper tract - renal pelvis | 53 (15.0%) | 40 (11.5%) | 93 (13.2%) |
| Upper tract - ureter | 28 (7.9%) | 33 (9.5%) | 61 (8.7%) |
| Lower tract | 273 (77.1%) | 275 (79.0%) | 548 (78.1%) |
| Bladder | 267 (75.4%) | 263 (75.6%) | 530 (75.5%) |
| Urethra | 6 (1.7%) | 12 (3.4%) | 18 (2.6%) |
| Histology, n (%) | |||
| Pure urothelial carcinoma | 316 (89.3%) | 316 (90.8%) | 632 (90.0%) |
| Variants | 38 (10.7%) | 32 (9.2%) | 70 (10.0%) |
| Squamous cell carcinoma differentiation | 22 (6.2%) | 18 (5.2%) | 40 (5.7%) |
| Multiple mixed variants | 3 (0.8%) | 4 (1.1%) | 7 (1.0%) |
| Plasmacytoid | 4 (1.1%) | 2 (0.6%) | 6 (0.9%) |
| Micropapillary differentiation | 4 (1.1%) | 1 (0.3%) | 5 (0.7%) |
| Sarcomatoid carcinoma | 2 (0.6%) | 3 (0.9%) | 5 (0.7%) |
| Glandular differentiation | 1 (0.3%) | 2 (0.6%) | 3 (0.4%) |
| Mucinous adenocarcinoma | 1 (0.3%) | 1 (0.3%) | 2 (0.3%) |
| Nested features | 1 (0.3%) | 1 (0.3%) | 2 (0.3%) |
| Prior neoadjuvant therapy, n (%) | |||
| Yes | 229 (64.7%) | 218 (62.6%) | 447 (63.7%) |
| No | 125 (35.3%) | 130 (37.4%) | 255 (36.3%) |
| Pathologic stage T and N stage, n (%) | |||
| + Surgical Margins | 9 (2.5%) | 8 (2.3%) | 17 (2.4%) |
| pT-any N+ (any) | 180 (50.8%) | 170 (48.9%) | 350 (49.9%) |
| pT2/3N0 or NX | 146 (41.2%) | 150 (43.1%) | 296 (42.2%) |
| pT4N0 or NX | 19 (5.4%) | 20 (5.7%) | 39 (5.6%) |
| PD-L1 status, n (%) | |||
| Positive, CPS ≥10% | 203 (57.3%) | 201 (57.8%) | 404 (57.5%) |
| Negative, CPS <10% | 151 (42.7%) | 147 (42.2%) | 298 (42.5%) |
CPS, combined positive score
Efficacy
The median follow-up was 44.8 months (range 0.03–70.1 months) for the disease-free survival analysis: 45.7 months for the pembrolizumab arm and 40.5 months for the observation arm. In the ITT population, the median disease-free survival was 29.6 months (95% CI, 20.0–40.7) in the pembrolizumab arm and 14.2 months (95% CI 11.0–20.2) in the observation arm. Pembrolizumab was associated with a statistically significant disease-free survival benefit compared to observation (HR 0.73; 95% CI, 0.59–0.90; 2-sided p=0.0027) (Fig. 1). A sensitivity analysis that assumed patients who started an alternative treatment had a disease-free survival event upon the date they started the treatment also showed a statitsically significant disease-free survival benefit of pembrolizumab compared to observation (HR 0.70; 95% CI, 0.58–0.86) (Fig S2). Among patients with PD-L1-negative tumor expression, the median disease-free survival was 17.3 months (95% CI, 13.2–32.0) in the pembrolizumab arm and 9.0 months (95% CI, 6.9–15.3) in the observation arm (HR 0.71; 95% CI, 0.53–0.95) (Fig. 2a). Among patients with PD-L1-positive tumor expression, the median disease-free survival was 36.9 months (95% CI, 27.2–NE) in the pembrolizumab arm and 21 months (95% CI, 13.6–53.3) in the observation arm (HR for disease recurrence or death, 0.81; 95% CI, 0.61–1.08) (Fig. 2b). Subgroup analysis showed comparable disease-free survival estimates with pembrolizumab compared to observation regardless of nodal status, prior neoadjuvant chemotherapy, and PD-L1 status (Fig. 3).
Figure 1: Disease-Free Survival.
Kaplan-Meier plots for disease-free survival in the intention-to-treat population.
HR=hazard ratio. Tick marks indicate patient censored at the last disease evaluation prior to analysis or treatment with alternative therapy prior to a disease-free survival event.
Figure 2: Disease-Free Survival by PD-L1 Status.
Kaplan-Meier plots for disease-free survival based on A] PD-L1 negative tumors and B] PD-L1 positive tumors
HR=hazard ratio. Tick marks indicate patient censored at the last disease evaluation prior to analysis or treatment with alternative therapy prior to a disease-free survival event.
Figure 3: Disease-Free Survival Subgroup Analysis in the Intention-to-Treat Population.
Hazard ratios and two-sided 95% confidence intervals were estimated with the use of a stratified Cox regression model for disease-free survival. Confidence intervals are not adjusted for multiplicity.
At the time of the second interim analysis at a median follow-up of 36.9 months (range 0–63.9 months; 36.9 months for the pembrolizumab arm and 36.9 months for the observation arm), 131 deaths occurred in the pembrolizumab arm compared to 126 deaths in the observation arm. The 3-year survival rate in the ITT population was 60.8% (95% CI 55.3–66.9) in the pembrolizumab arm and 61.9% (95% CI, 56.5–67.9) in the observation arm (HR for death, 0.98; 95% CI, 0.76–1.26) (Fig. 4).
Figure 4: Overall Survival.
Kaplan-Meier plots for preliminary overall survival in the intention-to-treat population.
HR=hazard ratio. Tick marks indicate data censored at the follow-up.
A summary of subsequent treatments after a disease-free survival event found that 94/146 patients (64.4%) in the pembrolizumab arm and 110/159 patients (69.2%) in the observation arm reported subsequent treatments. Of note, 22 patients in the pembrolizumab arm (15.1%) reported subsequent treatment with a checkpoint inhibitor compared with 83 patients (52.2%) in the observation arm (suppl Table 1). Furthermore, 3/354 patients (0.8%) in the pembrolizumab arm received another checkpoint inhibitor before disease progression compared to 12 patients (3.4%) in the observation arm.
Exposure and Safety (data cutoff July 5, 2024)
Safety was assessed for patients receiving at least one dose of pembrolizumab in in the pembrolizumab arm and all patients randomized to observation. The mean number of cycles in the pembrolizumab arm was 11 (range 1–18). The most common reasons for discontinuing pembrolizumab were disease progression (76 patients [21.5%]) and adverse events (65 patients [18.4%], see Supplementary Table 5). There were 167 patients (50.7%) who had a grade ≥ 3 (any cause) adverse event on the pembrolizumab arm compared to 110 patients (31.6%) in the observation arm (suppl Table 2); 87 patients (26.4%) had a treatment-related adverse event on the pembrolizumab arm. The most common treatment-related adverse events of any grade for pembrolizumab were fatigue (156; 47%), pruritus (74; 22%), diarrhea (68; 21%), and hypothyroidism (66; 20%). Five grade 5 adverse events were attributed to pembrolizumab: 1 respiratory failure, 1 multi-organ failure, 1 sepsis, and 2 death of uncertain cause. Fifteen grade 5 adverse events were noted in the observation arm (suppl Tables 2 and 3). The most common adverse events of any grade reported for the observation arm were fatigue (193; 55%), abdominal pain (114; 33%), peripheral sensory neuropathy (86; 25%) and arthralgia (85; 24%). A list of common adverse events on the observation arm and types of grade 5 events are in Suppl Table 4. Of note, the study collected pre-specified solicited adverse events in the observation arm.
DISCUSSION
At this first prespecified interim analysis, adjuvant pembrolizumab demonstrated a statistically significant improvement in disease-free survival compared to observation in patients with high-risk muscle-invasive urothelial carcinoma after radical surgery. The disease-free survival benefit with pembrolizumab was double that seen with observation. A benefit was observed regardless of PD-L1 status, neoadjuvant therapy, pathologic stage, or site of disease. While PD-L1 status was prognostic, it was not predictive of disease-free survival benefit; thus, PD-L1 status should not be used to select patients for treatment with adjuvant pembrolizumab.
The final analysis of the overall survival data has not been performed since only 80% of the events have been reached and the efficacy boundary was not crossed at the second interim analyses. The overall survival data may be impacted by patients on the observation arm receiving a checkpoint inhibitor, a factor that makes the overall survival data difficult to interpret. The adverse event profile of pembrolizumab was consistent with prior experience, and no new safety concerns were noted.
The approval of adjuvant nivolumab for patients with high-risk muscle-invasive urothelial carcinoma led to early closure of the AMBASSADOR study. While the study was 96% enrolled, this approval may have led to a greater proportion of patients who were censored in the observation arm due to starting an alternative non-protocol treatment or withdrawing from the study completely. Overall survival results may also be diluted by patients who crossed over from the observation arm to receive a checkpoint inhibitor, and the higher withdrawal rates for the observation arm means the remaining patients may no longer be comparable to the treatment group. Black or African American patients were underrepresented of in this study.
Despite these limitations, the results of this trial are in line with the previously reported CheckMate 274 study, which demonstrated a disease-free survival benefit of similar magnitude in patients treated with one year of nivolumab compared to placebo (HR 0.7).11 This contrasts with the IMvigor010 study of atezolizumab vs observation in patients with high-risk muscle-invasive urothelial carcinoma, which failed to meet its primary endpoint of disease-free survival benefit. Notably, in a small exploratory analysis, when stratified by circulating tumor DNA (ctDNA) status post-surgery, treatment with atezolizumab resulted in improved disease-free survival and overall survival for patients with positive ctDNA.20 However, the disease-free survival benefit with atezolizumab patients with positive ctDNA warrants further study, and a select group of patients may need treatment intensification beyond checkpoint inhibitor monotherapy. Although these 3 studies focused on a population of patients with high-risk muscle-invasive urothelial carcinoma, differences in trial design (placebo vs observation), definition of recurrence, therapy choice (anti-PD-1 vs anti-PD-L1), and patient population (e.g., percent of patients with upper tract urothelial carcinoma enrolled) may explain these conflicting results. Ongoing analyses of correlatives from these trials, as well as newly developed clinical trials, are exploring whether further risk stratification can be done to better identify patients who may benefit from adjuvant therapy.20,21 Taking the data in total, adjuvant checkpoint inhibitor therapy improves disease-free survival in certain patients with high-risk muscle-invasive urothelial carcinoma. The AMBASSADOR trial showed a significant benefit of adjuvant pembrolizumab therapy compared with observation in the intent-to-treat population.
Supplementary Material
Funding:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180821 (Alliance for Clinical Trials in Oncology Operations) and U10CA180882 (Statistics and Data Management Center for the Alliance for Clinical Trials in Oncology), UG1CA233180, UG1CA233373, UG1CA239767, UG1CA233290, UG1CA233327, UG1CA233191, UG1CA233160, UG1CA233337, UG1CA233247, UG1CA232760. UG1CA233193, UG1CA233302, UG1CA233196, UG1CA233253, UG1CA233270. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); P30 CA008748; The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Other funding includes Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; National Cancer Institute Intramural Program, Center for Cancer Research, NCI ZIA BC 011351, and the Cancer Therapy Evaluation Program. https://acknowledgments.alliancefound.org
Footnotes
Publisher's Disclaimer: This is an Author Accepted Manuscript, which is the version after external peer review and before publication in the Journal. The publisher’s version of record, which includes all New England Journal of Medicine editing and enhancements, is available at https://www.nejm.org/doi/full/10.1056/NEJMc2408121.
REFERENCES
- 1.Cancer Facts & Figures 2024. American Cancer Society. Accessed June 2024, https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts-figures.html
- 2.Holzbeierlein J, Bixler BR, Buckley DI, et al. Treatment of Non-Metastatic Muscle-Invasive Bladder Cancer: AUA/ASCO/SUO Guideline (2017; Amended 2020, 2024). J Urol 2024;212:3–10. [DOI] [PubMed] [Google Scholar]
- 3.Meeks JJ, Bellmunt J, Bochner BH, et al. A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur Urol 2012;62:523–33. [DOI] [PubMed] [Google Scholar]
- 4.Pfister C, Gravis G, Fléchon A, et al. Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin or Gemcitabine and Cisplatin as Perioperative Chemotherapy for Patients With Nonmetastatic Muscle-Invasive Bladder Cancer: Results of the GETUG-AFU V05 VESPER Trial. J Clin Oncol 2022;40:2013–22. [DOI] [PubMed] [Google Scholar]
- 5.Hautmann RE, de Petriconi RC, Pfeiffer C, Volkmer BG. Radical cystectomy for urothelial carcinoma of the bladder without neoadjuvant or adjuvant therapy: long-term results in 1100 patients. Eur Urol 2012;61:1039–47. [DOI] [PubMed] [Google Scholar]
- 6.Petrelli F, Coinu A, Cabiddu M, et al. Correlation of pathologic complete response with survival after neoadjuvant chemotherapy in bladder cancer treated with cystectomy: a meta-analysis. Eur Urol 2014;65:350–7. [DOI] [PubMed] [Google Scholar]
- 7.D’Souza AM, Pohar KS, Arif T, et al. Retrospective analysis of survival in muscle-invasive bladder cancer: impact of pT classification, node status, lymphovascular invasion, and neoadjuvant chemotherapy. Virchows Arch 2012;461:467–74. [DOI] [PubMed] [Google Scholar]
- 8.Advanced Bladder Cancer (ABC) Meta-analysis Collaborators Group: Adjuvant Chemotherapy for Muscle-invasive Bladder Cancer: A Systematic Review and Meta-analysis of Individual Participant Data from Randomised Controlled Trials. Eur Urol 2022;81:50–61. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Donat SM, Shabsigh A, Savage C, et al. Potential impact of postoperative early complications on the timing of adjuvant chemotherapy in patients undergoing radical cystectomy: a high-volume tertiary cancer center experience. Eur Urol 2009;55:177–85. [DOI] [PubMed] [Google Scholar]
- 10.Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:525–37. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021;384:2102–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.EAU 2024: Extended Follow-up from CheckMate 274 Including the First Report of Overall Survival Outcomes. UroToday. Accessed July 2024, https://www.urotoday.com/conference-highlights/eau-2024/eau-2024-bladder-cancer/150967-eau-2024-extended-follow-up-from-checkmate-274-including-the-firstreport-of-overall-survival-outcomes.html
- 13.Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 2017;376:1015–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med 2024;390:875–88. [DOI] [PubMed] [Google Scholar]
- 15.Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol 2021;22:919–30. [DOI] [PubMed] [Google Scholar]
- 16.Apolo AB, Milowsky MI, Kim L, et al. Eligibility and Radiologic Assessment in Adjuvant Clinical Trials in Bladder Cancer. JAMA Oncol 2019;5:1790–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol 2001;19:666–75. [DOI] [PubMed] [Google Scholar]
- 18.Griffiths G, Hall R, Sylvester R, et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 2011;29:2171–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Splinter TA, Scher HI, Denis L, et al. The prognostic value of the pathological response to combination chemotherapy before cystectomy in patients with invasive bladder cancer. European Organization for Research on Treatment of Cancer--Genitourinary Group. J Urol 1992;147:606–8. [DOI] [PubMed] [Google Scholar]
- 20.Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595:432–7. [DOI] [PubMed] [Google Scholar]
- 21.Jackson-Spence F, Toms C, O’Mahony LF, et al. IMvigor011: a study of adjuvant atezolizumab in patients with high-risk MIBC who are ctDNA+ post-surgery. Future Oncol 2023;19:509–15. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.