The treatment landscape of advanced urothelial carcinoma has changed considerably in the past few years, with immunotherapy becoming a key component.
In this article, we provide an overview of the published trials of PD-1 pathway and CTLA-4 inhibitors – used as monotherapy, in combination with chemotherapy, or as maintenance – in the first-line treatment of locally advanced or metastatic urothelial cancer. Where a trial includes multiple cohorts (eg, IMvigor210) we focus on the cohorts comprising previously untreated patients.
We have also included a section on ongoing trials that have not reported results yet, and will update the article as and when additional findings are published.
Single-agent immunotherapy
IMvigor210
Phase 2 | |
Patient population: Treatment-naïve, cisplatin-ineligible patients with locally advanced or metastatic urothelial cancer (cohort 1) | Treatment: Atezolizumab 1200 mg every 3 weeks |
Sponsor: Hoffmann-La Roche | |
Atezolizumab had encouraging efficacy in cohort 1, with an objective response rate (ORR) in the total study cohort of 23%, and of 24% and 28% in the subgroups of patients with immune cell PD-L1 levels of at least 1% and 5%, respectively, after a median follow-up of 17.2 months. The investigators noted in their 2016 The Lancet publication, however, that the hierarchical statistical testing plan of the trial precluded a comparison with the historical control at this stage.
KEYNOTE-052: Updated January 2023
Phase 2 | |
Patient population: Cisplatin-ineligible patients who had not received systemic chemotherapy for locally advanced or metastatic urothelial cancer | Treatment: Pembrolizumab 200 mg every 3 weeks for up to 2 years |
Sponsor: Merck Sharp & Dohme Corp | |
Initial analyses from this study, conducted at a median follow-up of 5 months and reported in The Lancet Oncology in 2017, demonstrated an ORR of 24% in the full trial population and 38% in the subgroup of patients with a PD-L1 combined positive score (CPS) of at least 10%.
Subgroup analyses from the trial – published in European Urology Oncology in 2020 – pointed to the benefit of pembrolizumab in patients aged at least 65 years or at least 75 years, and in those with an ECOG performance status of 2.
And longer follow-up, of at least an additional 2 years from the enrolment of the last patient, showed an ORR of 29% and a median duration of response of 30.1 months; the ORR was 47% among patients with a CPS of 10% or more. These results were reported in the Journal of Clinical Oncology in 2020.
The 5-year follow-up data, published in the Annals of Oncology in 2022, demonstrated the continued durable efficacy of pembrolizumab. After a median follow-up of 56.3 months, the ORR was 29.0%, the median duration of response was 33.4 months, and 39.4% of responders had an ongoing response at 48 months.
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Combination immunotherapy and chemotherapy
Hoosier Cancer Research Network GU10-148
Phase 2 | |
Patient population: Treatment-naïve patients with metastatic urothelial cancer | Treatment: Two 21-day cycles of gemcitabine–cisplatin, followed by four 21-day cycles of gemcitabine–cisplatin plus ipilimumab 10 mg/kg given on day 1 of each cycle |
Sponsor: Hoosier Cancer Research Network | |
The study reported a 1-year overall survival (OS) rate of 61%, but as the lower bound of the 90% confidence interval did not exceed the prespecified limit of 60%, the primary endpoint was not met. These findings were published in European Urology in 2017.
IMvigor130
Phase 3 | |
Patient population: Treatment-naïve patients with locally advanced or metastatic urothelial cancer | Treatments: Atezolizumab 1200 mg on day 1 of each 21-day cycle alone or alongside gemcitabine plus carboplatin or cisplatin; or placebo plus chemotherapy |
Sponsor: Hoffmann-La Roche | |
Initial results from this trial were published in The Lancet in 2020, and showed a significant improvement in the co-primary endpoint of progression-free survival (PFS) with the addition of atezolizumab rather than placebo to chemotherapy, at a median of 8.2 versus 6.3 months, and an 18% reduction in the risk for progression or death favoring the PD-L1 inhibitor.
OS, the other primary endpoint, was numerically better in the atezolizumab–chemotherapy than chemotherapy alone arm (median, 16.0 vs 13.4 months), but did not meet the prespecified criteria for statistical significance, which precluded the comparison of atezolizumab alone with chemotherapy.
Related news content:
- PFS boost with atezolizumab–chemotherapy in advanced urothelial carcinoma
- Researcher comment: IMvigor130 trial of atezolizumab in advanced urothelial cancer (video)
- IMvigor130 PROs add support for atezolizumab–chemotherapy use in advanced UC
- Single-agent atezolizumab supported for some cisplatin-ineligible mUC patients (video)
DANUBE
Phase 3 | |
Patient population: Treatment-naïve patients with locally advanced or metastatic urothelial cancer | Treatments: Durvalumab 1500 mg every 4 weeks; four doses of durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks, followed by durvalumab monotherapy; or six cycles of gemcitabine plus cisplatin or carboplatin |
Sponsor: AstraZeneca | |
This trial did not meet either of its co-primary endpoints, showing no significant OS boost with durvalumab versus chemotherapy in the PD-L1-high population (median, 14.4 vs 12.1 months), nor with durvalumab plus tremelimumab versus chemotherapy in the intention-to-treat population (median, 15.1 vs 12.1 months). These findings were published in The Lancet Oncology in 2020.
Related news content:
- Durvalumab, alone or with tremelimumab, fails to boost metastatic UC survival
- DANUBE: Durvalumab misses the mark in advanced urothelial cancer (video)
KEYNOTE-361
Phase 3 | |
Patient population: Treatment-naïve patients with locally advanced or metastatic urothelial cancer | Treatments: Pembrolizumab 200 mg every 3 weeks for up to 35 cycles, either as monotherapy or alongside six cycles of gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin AUC 5 or cisplatin 70 mg/m2 on day 1; or chemotherapy alone |
Sponsor: Merck Sharp & Dohme Corp | |
As reported in The Lancet Oncology in 2021, the addition of pembrolizumab to chemotherapy did not significantly improve either co-primary endpoint of PFS or OS.
The trial’s hierarchical statistical testing plan precluded further formal analysis, but OS was comparable between single-agent pembrolizumab and chemotherapy both in the total study population and the subgroup of those with a PD-L1 CPS of at least 10.
Related news content:
- Pembrolizumab no additional benefit for advanced UC
- First-line pembrolizumab combination fails to boost advanced urothelial cancer survival (video)
Maintenance immunotherapy
JAVELIN Bladder 100: Updated January 2023
Phase 3 | |
Patient population: Locally advanced or metastatic urothelial cancer patients without progression after first-line platinum-based chemotherapy | Treatments: Maintenance avelumab 10 mg/kg every 2 weeks plus best supportive care; or best supportive care alone |
Sponsor: Pfizer | |
As reported in The New England Journal of Medicine in 2020, the JAVELIN Bladder 100 trial demonstrated a significant 31% reduction in the risk for death with the addition of maintenance avelumab to best supportive care (BSC) in this patient population. The median OS was 21.4 months in the avelumab plus BSC group and 14.3 months in the BSC alone group, while the respective 1-year OS rates were 71.3% and 58.4%.
A subgroup analysis from the study, focusing on the 73 patients enrolled in Japan, showed that supplementing BSC with maintenance avelumab improved both OS and PFS, albeit not statistically significantly, in these patients. The researchers said in their 2022 International Journal of Clinical Oncology publication that maintenance avelumab has “a favorable benefit-risk balance in Japanese patients.”
May 2022 saw the publication, in European Urology, of the patient-reported outcomes from this trial, which showed that health-related quality of life and time to deterioration of disease-related symptoms were similar for the maintenance avelumab plus BSC and BSC alone groups.
Related news content:
- Maintenance avelumab ‘new standard of care’ for advanced urothelial cancer
- Maintenance avelumab approved for advanced urothelial carcinoma after platinum chemotherapy
- EMA adopts positive opinions for breast, lung, GU cancer indications
- Further JAVELIN Bladder 100 analyses add support for maintenance avelumab
Hoosier Cancer Research Network GU14-182
Phase 2 | |
Patient population: Metastatic urothelial cancer patients without progression after first-line platinum-based chemotherapy | Treatments: Pembrolizumab 200 mg or placebo every 3 weeks for up to 24 months |
Sponsor: Matthew Galsky | |
The investigators reported in the Journal of Clinical Oncology in 2020 that the primary endpoint of PFS was significantly prolonged with maintenance pembrolizumab relative to placebo, at a median of 5.4 versus 3.0 months. But there was no significant difference in OS between the pembrolizumab and placebo groups, with respective median durations of 22.0 and 18.7 months.
Related news story:
BAYOU
Phase 2 | |
Patient population: Treatment-naïve, cisplatin-ineligible patients with metastatic urothelial cancer | Treatments: Durvalumab 1500 mg every 4 weeks plus olaparib 300 mg twice daily or placebo |
Sponsor: AstraZeneca | |
The addition of olaparib to durvalumab did not improve the primary endpoint of PFS in the overall trial population, but subgroup analysis pointed to a benefit of using the PARP inhibitor in patients with homologous recombination repair gene mutations, at a hazard ratio for progression or death of 0.18. These data were published in the Journal of Clinical Oncology in 2022.
Related news story:
Trials in progress
This section includes a brief summary of ongoing trials of first-line immunotherapy regimens. These trials all comprise patients who have not received prior treatment for locally advanced or metastatic disease; any specific characteristics of the trial populations are included where relevant.
Study details | Treatments | Primary endpoints | Link |
CheckMate 901 – Phase 3 | • Nivolumab plus ipilimumab; • Nivolumab plus standard-of-care chemotherapy; or • Chemotherapy alone | • OS in cisplatin-ineligible participants; • OS in participants with ≥1% PD-L1 expression; • PFS by blinded independent review in cisplatin-eligible participants; and • OS in cisplatin-eligible participants | https://clinicaltrials.gov/ct2/show/NCT03036098 |
LEAP-011 – Phase 3 Cisplatin-ineligible patients with PD-L1 CPS ≥10 or platinum-ineligible |
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NILE – Phase 3 |
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FIGHT-205 – Phase 2 Cisplatin-ineligible patients whose tumors carry FGFR3 mutations or rearrangements |
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PemCab – Phase 2 Cisplatin-ineligible patients with PD-L1 CPS ≥10 or platinum-ineligible |
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NCT04863885 – Phase 1/2 Cisplatin-ineligible patients |
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This independent article was supported by an educational grant from Pfizer and Merck Healthcare KGaA, Darmstadt, Germany