This article lists the key trial publications on the use of PD-1 pathway and CTLA-4 inhibitors used alone or in combination in the second-line or later treatment of locally advanced and metastatic urothelial carcinoma.
For trials with multiple cohorts and entrance criteria, this article reports only for patients with locally advanced or metastatic urothelial carcinoma receiving second-line or later immunotherapy.
Single-agent immunotherapy
CheckMate 032: Ongoing
Phase ½ | |
Patient population: Locally advanced or metastatic urothelial carcinoma of the renal pelvis, ureter, bladder or urethra that has progressed after platinum-based chemotherapy. | Treatment: Nivolumab 1 mg/kg or 3 mg/kg every 2 or 3 weeks alone or alongside ipilimumab 1 mg/kg or 3 mg/kg every 2 or 3 weeks. |
Sponsor: Bristol-Myers Squibb | |
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Findings for the patients with urothelial carcinoma who received nivolumab monotherapy in this multi-tumor open-label trial were reported in 2016 in The Lancet Oncology, demonstrating an objective response rate (ORR) of 24.4% among given the PD-1 inhibitor at a dose of 3 mg/kg every 2 weeks.
In an update published in the Journal of Clinical Oncology in 2019, the authors reported that the “greatest antitumor activity” in the trial was found in patients given nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks, with an ORR of 38.0%.
In this subgroup, median progression-free survival (PFS) and overall survival (OS) were 4.9 and 15.3 months, respectively, and there were no unexpected safety signals.
KEYNOTE-045: Completed
Phase 3 | |
Patient population: Patients with unresectable locally advanced or metastatic urothelial carcinoma that has progressed or recurred after platinum-based chemotherapy. | Treatment: Pembrolizumab 200 mg every 3 weeks or chemotherapy consisting of paclitaxel 175 mg/m2, docetaxel 75 mg/m2 or vinflunine 320 mg/m2 every 3 weeks. |
Sponsor: Merck Sharp & Dohme | |
Second interim analysis findings published in The New England Journal of Medicine in 2017, after a median 14.1 months of follow-up, showed that OS was significantly better for pembrolizumab-treated patients than those given chemotherapy (median 10.3 vs 7.4 months) and this trend was also true for the subgroup of patients with a tumor PD-L1 combined positive score (CPS) of 10% or higher (median 8.0 vs 5.2 months). There was no difference between the treatment groups with regard to median PFS but pembrolizumab was associated with fewer treatment-related adverse events than chemotherapy.
Pembrolizumab continued to demonstrate an OS advantage after a median 27.7 months of follow-up and median duration of response was still unreached in the PD-1 inhibitor treatment arm at this time, the investigators reported in the Annals of Oncology in 2019.
Pembrolizumab was granted US FDA regular approval for locally advanced or metastatic urothelial carcinoma that has progressed during or within 12 months of platinum-based chemotherapy in 2017.
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JAVELIN Solid Tumor: Completed
Phase 1 | |
Patient population: Patients with locally advanced or metastatic urothelial carcinoma that has progressed after one or more platinum-based chemotherapy regimens. | Treatment: Avelumab 10 mg/kg every 2 weeks. |
Sponsor: EMD Serono Research & Development Institute Inc | |
The multi-tumor, open-label trial of the anti-PD-L1 antibody avelumab included two expansion cohorts of patients with locally advanced or metastatic urothelial carcinoma that had progressed after one or more lines of platinum-based chemotherapy. Pooled analysis of these 161 patients gave an ORR of 17% after a median 9.9 months of follow-up and indicated a manageable safety profile, the investigators reported in The Lancet Oncology in 2017.
An update presented at the 2019 ASCO Genitourinary Cancers Symposium for 249 patients after a median 2.7 years gave an ORR of 16.5%, a median duration of response (DOR) of 20.5 months, and median PFS and OS of 1.6 and 7.0 months, respectively.
Study 1108: Completed
Phase ½ | |
Patient population: Expansion cohort including patients with inoperable or metastatic urothelial carcinoma. | Treatment: Durvalumab 10 mg/kg every 2 weeks. |
Sponsor: MedImmune LCC | |
Overall, 93.4% of 61 patients in this study had received one or more lines of systemic therapy, and 31.1% had received at least three lines, the investigators said in the 2016 interim analysis published in the Journal of Clinical Oncology. The ORR was 31.0% in 42 evaluable participants, rising to 46.4% among the PD-L1-positive subgroup.
An update was reported in 2017 in JAMA Oncology giving an ORR of 17.8%, with median PFS and OS of 1.5 and 18.2 months, respectively. Grade 3–4 treatment-related adverse events occurred in 6.8% of patients.
CheckMate 275: Completed
Phase 2 | |
Patient population: Unresectable or metastatic urothelial carcinoma that has progressed or recurred after platinum-based chemotherapy. | Treatment: Nivolumab 3 mg/kg every 2 weeks. |
Sponsor: Bristol-Myers Squibb | |
After a median 7.0 months of follow-up, an ORR was reported in 19.6% of patients given nivolumab monotherapy and response varied by PD-L1 expression, with the highest rate of 23.8% in those with a score of at least 5%, the researchers reported in 2017 in The Lancet Oncology.
An update was presented at the 2019 ASCO Annual Meeting in Chicago, Illinois, USA, after a median 33.7 months of follow-up. At this time, median PFS was 1.9 months, and median OS was 8.6 months, with 22% of patients alive after 3 years.
IMvigor211: Completed
Phase 3 | |
Patient population: Patients with locally advanced or metastatic urothelial bladder cancer who have progressed on or after receiving at least one platinum-based regimen. | Treatment: Atezolizumab 1200 mg every 3 weeks; or docetaxel 75 mg/m2, paclitaxel 175 mg/m2 or vinflunine 320 mg/m2 every 3 weeks. |
Sponsor: Hoffmann-La Roche | |
Initial findings from the open-label, randomized trial were published in The Lancet in 2017 and indicated that OS was comparable between the atezolizumab and chemotherapy arms (median 11.1 vs 10.6 months), although patients given the PD-L1 inhibitor had a numerically longer duration of response than controls and fewer grade 3–4 treatment-related adverse events.
Exploratory OS findings after a median of 33 months of follow-up suggested “long-term durable remission” with atezolizumab versus chemotherapy, the authors reported in 2021 in European Urology, citing a 24-month OS rate of 23% and 13%, respectively.
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SAUL study: Completed
Phase 3b | |
Patient population: Patients with locally advanced or metastatic urothelial or non-urothelial cancer of the urinary tract who have received 1–3 prior lines of treatment | Treatment: Atezolizumab 1200 mg every 3 weeks. |
Sponsor: Hoffmann-La Roche | |
As reported at the 2019 Annual European Association of Urology congress and published later in the year in European Urology, the primary SAUL results confirmed the “tolerability” of atezolizumab in a real-world population that included patients with renal impairment, previously treated central nervous system metastases or stable autoimmune disease. OS was a median 8.7 months in the full cohort, rising to a median 10.0 months among the subgroup of patients who met the IMvigor211 entrance criteria.
Post-hoc analysis in ESMO Open in 2021 pointed to an atezolizumab OS benefit among SAUL participants who had previously received cisplatin or carboplatin, and identified prognostic markers for OS with second-line atezolizumab, including Bellmunt risk and PD-L1 expression.
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JAVELIN Bladder 100: Ongoing
Phase 3 | |
Patient population: Patients with unresectable locally advanced or metastatic transition cell carcinoma of the urothelium who have received 4–6 cycles of gemcitabine plus cisplatin/carboplatin and have an ongoing response to treatment. | Treatment: Avelumab 10 mg/kg every 2 weeks plus best supportive care or best supportive care alone. |
Sponsor: Pfizer | |
Reporting an interim analysis at the 2020 ASCO Annual Meeting, the investigators said that maintenance treatment with the PD-L1 inhibitor avelumab should be considered “a new standard of care” for patients who have not progressed after first-line platinum-based chemotherapy.
Compared with best supportive care alone, the addition of avelumab significantly improved both OS (median 21.4 vs 14.3 months) and PFS (median 3.7 vs 2.0 months), and the PD-L1 inhibitor was described by the researchers as being “well tolerated”.
The findings were subsequently published in The New England Journal of Medicine in 2020 and led to the 2020 US FDA approval of maintenance avelumab in this patient population at a recommended dose of 800 mg every 2 weeks.
In addition, an OS benefit with avelumab maintenance was confirmed for the Japanese patient subgroup – as reported in 2022 in the International Journal of Clinical Oncology.
AVENANCE: Ongoing
Observational | |
Patient population: Patients with locally advanced or metastatic urothelial carcinoma without progression after first-line platinum-based chemotherapy and who received maintenance avelumab in a real-world setting. | Treatment: Avelumab as provided by treating physician. |
Sponsor: Pfizer | |
Preliminary results were presented at the 2022 ESMO Congress for 267 patients who had begun avelumab maintenance at least 6 months before data cutoff. At the time, the median OS was 20.7 months and the median PFS was 5.7 months.
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Combination immunotherapy
TROPHY-U-01: Ongoing
Phase 2 | |
Patient population: Six cohorts of patients with unresectable or metastatic urothelial cell carcinoma including: Cohort 1 – patients have progression or recurrence after platinum chemotherapy for inoperable or metastatic disease, or experienced recurrence or progression of localized disease within 12 months of platinum chemotherapy. Cohort 2 – patients have progression or recurrence after platinum chemotherapy and PD-1 or PD-L1 inhibitor therapy. Cohort 3 – patients have progression or recurrence following platinum chemotherapy for metastatic disease or within 12 months of neoadjuvant or adjuvant chemotherapy. | Treatment: Cohorts 1 and 2 – Sacituzumab govitecan 10 mg/kg on days 1 and 8 of a 28-day cycle. Cohort 3 – Sacituzumab govitecan 10 mg/kg on days 1 and 8 of a 28-day cycle plus pembrolizumab 200 mg on day 1 of a 21-day cycle. |
Sponsor: Gilead Sciences | |
Interim findings for Cohort 3 of the open-label TROPHY-U-01 trial for the Trop-2-directed antibody–drug conjugate sacituzumab govitecan plus pembrolizumab were presented at the ASCO GU 2022 meeting, showing an “encouraging” ORR and clinical benefit rate for the combination of sacituzumab govitecan and pembrolizumab, at 34% and 44%, respectively.
This was accompanied by a 6-month PFS rate of 47% and a safety profile that was described as “manageable.” Grade 3 and more severe treatment-emergent adverse events (AEs) were reported in 59% of patients, including diarrhea (24%), anemia (20%) and febrile neutropenia (10%).
The results follow findings for cohort 1 – reported at ESMO 2020 and subsequently published in the Journal of Clinical Oncology – who were given sacituzumab govitecan alone, where patients achieved a 27% ORR with a median duration of response of 7.2 months, leading to FDA approval.
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COSMIC-021: Ongoing
Phase 1b | |
Patient population: Patients with locally advanced or metastatic urothelial carcinoma who have progressed during or after platinum-based chemotherapy (cohort 2); or who have had radiographic progression during or after one line of immune checkpoint inhibitor therapy (cohort 5). | Treatment: Atezolizumab 1200 mg every 3 weeks plus cabozantinib 40 mg/day. |
Sponsor: Exelixis, Ipsen, Takeda | |
The initial findings for COSMIC-021 cohort 2 were reported at the 2020 ASCO Annual Meeting where the investigators described “encouraging clinical activity” for the combination approach, with an ORR of 27%, a disease control rate (DCR) of 64% and an unreached median DOR. Median PFS was 5.4 months.
Cohort 5 results presented at the 2022 ASCO Annual Meeting were also positive, with ORR and DCR of 10% and 61%, respectively, and a median DOR of 4.1 months. Median PFS and OS were a respective 3.0 and 8.2 months.
Related news stories:
- More support from COSMIC-021 for cabozantinib–atezolizumab potential in advanced UC
- Cabozantinib–atezolizumab duo shows urothelial cancer potential in COSMIC-021 study
TITAN-TCC: Ongoing
Phase 2 | |
Patient population: Patients with unresectable or metastatic transitional cell carcinoma who have progressed during or after first-line platinum-based chemotherapy and have received up to two further lines of treatment. | Treatment: Four cycles of nivolumab 240 mg every 2 weeks then response-driven option of maintenance nivolumab or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg combination therapy followed by nivolumab maintenance where appropriate. |
Sponsor: AIO-Studien-gGmbH | |
Treatment in this tailored immunotherapy study was guided by each patient’s initial response to four cycles of nivolumab therapy. Patients with a complete or partial response were given maintenance nivolumab while those with stable or progressive disease instead received a boost regimen of nivolumab plus ipilimumab at 3-week intervals.
A 2023 report in The Lancet Oncology indicated that 33% of 83 participants in the intention-to-treat population achieved an object response to treatment, exceeding the prespecified primary endpoint threshold of 20%, and median OS was 7.6 months. Among patients with PD-L1-positive disease, the ORR increased to 46%.
Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma”, the investigators write.
Related news story:
THOR: Ongoing
Phase 3 | |
Patient population: Patients with unresectable or metastatic urothelial carcinoma and select FGFR mutations. Cohort 1: Patients have progressed after one or two lines of prior therapy including a PD-1 or PD-L1 inhibitor. Cohort 2: Patients who have received one line of prior therapy not including a PD-1 or PD-L1 inhibitor. | Treatment: Cohort 1 – erdafitinib 8 mg/day or vinflunine or docetaxel chemotherapy. Cohort 2 – erdafitinib 8 mg/day or pembrolizumab 200 mg every 21 days. |
Sponsor: Janssen Research & Development LLC | |
Cohort 2 of the THOR trial compares the fibroblast growth factor receptor erdafitinib with pembrolizumab for the treatment of patients who have specific pathologic mutations in FGFR3 or FGFR2/3 fusions.
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This independent article was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany