At a glance: First-line immunotherapy for advanced urothelial carcinoma

Author: Shreeya Nanda

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
https://clinicaltrials.gov/ct2/show/NCT02951767
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

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
https://clinicaltrials.gov/ct2/show/NCT02335424
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 reported in the reported in the Journal of Clinical Oncology in 2020.

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
https://clinicaltrials.gov/ct2/show/NCT01524991
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
https://clinicaltrials.gov/ct2/show/NCT02807636
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.

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
https://clinicaltrials.gov/ct2/show/NCT02516241
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.

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
https://clinicaltrials.gov/ct2/show/NCT02853305
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.

Maintenance immunotherapy

JAVELIN Bladder 100

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
https://clinicaltrials.gov/ct2/show/NCT02603432
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%.

Hoosier Cancer Research Network GU14-182

Phase 3
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
https://clinicaltrials.gov/ct2/show/NCT02500121
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.

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.

CheckMate 901 – Phase 3
Treatments	Primary endpoints	Link
• 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
Treatments	Primary endpoints	Link
• Pembrolizumab plus lenvatinib; or • Pembrolizumab plus placebo	• PFS by blinded independent review; and • OS	https://clinicaltrials.gov/ct2/show/NCT03898180

NILE – Phase 3
Treatments	Primary endpoints	Link
• Durvalumab plus standard-of-care chemotherapy; • Durvalumab and tremelimumab plus chemotherapy; or • Chemotherapy alone	• OS	https://clinicaltrials.gov/ct2/show/NCT03682068

BAYOU – Phase 2 \| Cisplatin-ineligible patients
Treatments	Primary endpoints	Link
• Durvalumab plus olaparib; • Durvalumab plus placebo	• PFS	https://clinicaltrials.gov/ct2/show/NCT03459846

FIGHT-205 – Phase 2 \| Cisplatin-ineligible patients whose tumors carry FGFR3 mutations or rearrangements
Treatments	Primary endpoints	Link
• Pemigatinib plus pembrolizumab; • Pemigatinib alone; or • Standard of care (chemotherapy or pembrolizumab)	• PFS	https://clinicaltrials.gov/ct2/show/NCT04003610

PemCab – Phase 2 \| Cisplatin-ineligible patients with PD-L1 CPS ≥10 or platinum-ineligible
Treatments	Primary endpoints	Link
• Pembrolizumab plus cabozantinib	• ORR	https://clinicaltrials.gov/ct2/show/NCT03534804

NCT04863885 – Phase 1/2 \| Cisplatin-ineligible patients
Treatments	Primary endpoints	Link
• Ipilimumab, nivolumab plus sacituzumab govitecan at various doses	• Maximum tolerated dose; and • ORR	https://clinicaltrials.gov/ct2/show/NCT04863885