In a German-Austrian phase II study (TITAN-TCC) reported in JAMA Oncology, Grimm et al described outcomes with the use of nivolumab plus ipilimumab as an immunotherapeutic boost in metastatic urothelial carcinoma.
Study Details
In the multicenter trial, 169 patients were enrolled into two cohorts between August 2017 and February 2021. Cohort 1 consisted of 86 patents, with 42 receiving first-line treatment and 44 receiving second-line (89%) or third-line (11%) treatment. Cohort 2 consisted of 83 patients, all of whom received either second-line (n = 78, 94%) or third-line (n = 2, 2%) treatment.
All patients started with four doses of nivolumab at 240 mg every 2 weeks. Patients without an objective response at week 8 received nivolumab plus ipilimumab boosts every 3 weeks: cohort 1 received two doses of nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg followed by two doses of nivolumab plus ipilimumab at 3 mg/kg if no response was achieved. Due to safety concerns, cohort 1 treatment was halted, and no first-line treatment in cohort 2 was pursued. Cohort 2 nonresponders received two to four doses of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg; those with subsequent response continued with nivolumab maintenance but could not receive nivolumab plus ipilimumab for subsequent disease progression. The primary outcome measure of the trial was objective response rate.
Key Findings
Investigator-assessed objective responses to nivolumab induction were observed in 12 (29%) of 42 patients receiving first-line treatment in cohort 1, 10 (23%) of 44 receiving second-line or third-line treatment in cohort 1, and 17 (20%) of 83 patients in cohort 2.
Objective responses using the response-tailored approaches to treatment were observed in 20 patients (48%, 90% confidence interval [CI] = 34%–61%) receiving first-line treatment in cohort 1, 12 patients (27%, 90% CI = 17%–40%) receiving second-line or third-line treatment in cohort 1, and 27 patients (33%, 90% CI = 23%–42%) in cohort 2.
A first progression event before the end of the study occurred in 37 patients (88%) receiving first-line treatment in cohort 1, 39 patients (89%) receiving second-line or third-line treatment in cohort 1, and 71 patients (86%) in cohort 2. Median progression-free survival was 3.0 months (95% CI = 1.8–6.8 months) among patients receiving first-line treatment in cohort 1, 1.9 months (95% CI = 1.7–5.8 months) among patients receiving second-line or third-line treatment in cohort 1, and 1.9 months (95% CI = 1.8–3.2 months) in cohort 2.
On Kaplan-Meier analysis, 3-year overall survival rates were 32% (95% CI = 17%–49%) with first-line treatment in cohort 1, 19% (95% CI = 8%–33%) with second-line or third-line treatment in cohort 1, and 34% (95% CI = 23%–44%) in cohort 2.
The investigators concluded, “In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-line/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with metastatic urothelial carcinoma.”
Marc-Oliver Grimm, MD, of the Department of Urology, Jena University Hospital, Jena, Germany, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by Bristol Myers Squibb. For full disclosures of the study authors, visit ascopubs.org.
