Table 1.
Overview of clinical trials assessing immune checkpoint inhibitors in bladder cancer.
| Trial reference (ClinicalTrials.gov ID) | Trial title | Therapeutic antibody used | Primary findings | Reference |
|---|---|---|---|---|
| KEYNOTE-045 (NCT02256436) | A Study of Pembrolizumab (MK-3475) Versus Paclitaxel, Docetaxel, or Vinflunine for Participants With Advanced Urothelial Cancer (MK-3475-045/KEYNOTE-045) | Pembrolizumab | Pembrolizumab was associated with significantly longer OS (by approximately 3 months) than chemotherapy as second-line therapy for platinum-refractory mUC. | (23) |
| IMvigor211 (NCT02302807) | A Study of Atezolizumab Compared With Chemotherapy in Participants With Locally Advanced or Metastatic Urothelial Bladder Cancer [IMvigor211] | Atezolizumab | Atezolizumab was not associated with significantly longer OS than chemotherapy in patients with platinum-refractory mUC overexpressing PD-L1 (IC2/3). | (24) |
| KEYNOTE-361 (NCT02853305) |
Study of Pembrolizumab With or Without Platinum-based Combination Chemotherapy Versus Chemotherapy Alone in Urothelial Carcinoma (MK-3475-361/KEYNOTE-361) | Pembrolizumab | The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. | (25) |
| DANUBE (NCT02516241) | Study of MEDI4736 (Durvalumab) With or Without Tremelimumab Versus Standard of Care Chemotherapy in Urothelial Cancer | Durvalumab with or without tremelimumab | This study did not meet either of its coprimary endpoints of OS compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression and between the durvalumab plus tremelimumab versus chemotherapy groups in the ITT population. | (26) |
| IMvigor130 (NCT02807636) | Study of Atezolizumab as Monotherapy and in Combination With Platinum-Based Chemotherapy in Participants With Untreated Locally Advanced or Metastatic Urothelial Carcinoma (IMvigor130) | Atezolizumab | Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged PFS in patients with mUC. The final OS analysis showed a non-statistically significant OS benefit (HR 0.85, p=0.023). OS for atezolizumab monotherapy vs chemotherapy was negative for the ITT population. An exploratory analysis showed a benefit for atezolizumab monotherapy in the PD-L1–high (IC2/3) group. | (27) ASCO-GU 2023 |
| CheckMate-901 (NCT03036098) |
Study of Nivolumab in Combination With Ipilimumab or Standard of Care Chemotherapy Compared to the Standard of Care Chemotherapy Alone in Treatment of Participants With Untreated Inoperable or Metastatic Urothelial Cancer (CheckMate901) | Nivolumab with or without ipilimumab | (2022): Nivolumab plus ipilimumab did not meet the primary endpoint of improved overall survival (OS) in patients with tumors with high PD-L1 expression; (2023): nivolumab in combination with cisplatin-based chemotherapy followed by nivolumab monotherapy demonstrated statistically significant benefits in OS and PFS. | 2022/2023 BMS press release |
| CheckMate-274 (NCT02632409) | An Investigational Immuno-therapy Study of Nivolumab, Compared to Placebo, in Patients With Bladder or Upper Urinary Tract Cancer, Following Surgery to Remove the Cancer (CheckMate 274) | Nivolumab | Disease-free survival was longer with adjuvant nivolumab than with placebo in the ITT population and among patients with a PD-L1 expression level of 1% or more in patients with high-risk muscle-invasive urothelial carcinoma who were treated with radical surgery. | (28) |
| IMvigor010 (NCT02450331) | A Study of Atezolizumab Versus Observation as Adjuvant Therapy in Participants With High-Risk Muscle-Invasive Urothelial Carcinoma (UC) After Surgical Resection (IMvigor010) | Atezolizumab | The trial did not meet its primary endpoint of improved disease-free survival in patients receiving adjuvant atezolizumab over observation. | (29) |
| JAVELIN Bladder 100 (NCT02603432) | A Study Of Avelumab In Patients With Locally Advanced Or Metastatic Urothelial Cancer (JAVELIN Bladder 100) | Avelumab | Maintenance avelumab plus best supportive care significantly prolonged OS, as compared with best supportive care alone, among patients with urothelial cancer who had disease that had not progressed with first-line chemotherapy. | (30) |
| PURE-01 (NCT02736266) | Neoadjuvant Pembrolizumab for Muscle-invasive Urothelial Bladder Carcinoma | Pembrolizumab | Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. | (31) |
| ABACUS (NCT02662309) | Preoperative MPDL3280A in Transitional Cell Carcinoma of the Bladder (ABACUS) | Atezolizumab | The pCR rate was 31% (95% confidence interval: 21–41%), achieving the primary efficacy endpoint. | (32) |
| Preoperative durvalumab and tremelimumab (NCT02812420) | Durvalumab and Tremelimumab in Treating Patients With Muscle-Invasive, High-Risk Urothelial Cancer That Cannot Be Treated With Cisplatin-Based Therapy Before Surgery | Durvalumab with tremelimumab | The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade ≥3 immune-related adverse events. We also observed pathological complete response of 37.5% of patients who completed surgery (n = 24). | (33) |
| NABUCCO (NCT03387761) | Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO) | Nivolumab with ipilimumab | All patients were evaluable for the study endpoints and underwent resection, 23 (96%) within 12 weeks (primary endpoint; feasibility). Grade 3-4 immune-related adverse events occurred in 55% of patients. Eleven patients (46%) had a pCR, meeting the secondary efficacy endpoint. | (34) |
| NABUCCO 2 (NCT03387761) |
Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO) | Nivolumab with ipilimumab | A pCR was observed in six (43%) patients in cohort 2A (ipi 3 mg/kg) and in one (7%) patient in cohort 2B (ipi 1 mg/kg). Absence of plasma ctDNA correlated with pCR. | (35) |
| CheckMate-032 (NCT01928394) | A Study of Nivolumab by Itself or Nivolumab Combined With Ipilimumab in Patients With Advanced or Metastatic Solid Tumors | Nivolumab with or without ipilimumab | Objective response rate was 25.6%, 26.9%, and 38.0% in the NIVO3, NIVO3+IPI1, and NIVO1+IPI3 arms, respectively. Grade 3 or 4 treatment-related adverse events occurred in 21 (26.9%), 32 (30.8%), and 36 (39.1%) patients treated with NIVO3, NIVO3+IPI1, and NIVO1+IPI3, respectively. | (36) |
| EV-101 (NCT02091999) | A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4 | Enfortumab Vedotin | Single-agent EV was generally well tolerated and provided clinically meaningful and durable responses in patients with mUC. | (37) |
| EV-301 (NCT03474107) | A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) | Enfortumab Vedotin | Enfortumab vedotin significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or mUC who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor. | (38) |
| EV-103 (NCT03288545) | A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) | Enfortumab Vedotin and pembrolizumab | Enfortumab vedotin plus pembrolizumab showed a manageable safety profile and promising confirmed objective response rate in cisplatin-ineligible pts with locally advanced or mUC; activity was consistently observed across a range of pre-specified subgroups including those with poor prognosis. | (39, 40) |
| EV-302 (NCT04223856) | Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302) | Enfortumab Vedotin and pembrolizumab | Pending | (41) |