Patients with metastatic urothelial carcinoma (mUC) are often administered nivolumab after receiving platinum-based chemotherapy, and studies have suggested that dual checkpoint inhibition paired with high doses of ipilimumab also results in improved outcomes. A recent study published in The Lancet Oncology sought to examine the safety and efficacy of pairing nivolumab induction and high-dose ipilimumab for an immunotherapeutic boost as a second-line treatment for patients with mUC.
The multicenter, single-arm, phase 2 TITAN-TCC trial was conducted in 19 hospitals and cancer centers in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable UC were eligible to take part in the trial. Patients must have experienced disease progression during or after first-line platinum-based chemotherapy and up to 1 more second-line or third-line treatment, had a Karnofsky performance status score of 70 or higher, and had measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1.
Between April 2019 and February 2021, 83 patients with mUC were enrolled in the trial. Each patient received 4 doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks. Patients who had a partial or complete response at week 8 continued maintenance nivolumab, and those with stable or progressive disease at week 8 received a boost of 2 or 4 doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who had progressive disease during nivolumab maintenance were also given a treatment boost using this schedule. A total of 50 (60%) patients received at least 1 booster dose.
The study’s primary end point was the confirmed investigator-assessed objective response rate (ORR) in the intention-to-treat (ITT) population, which had to exceed 20% for the null hypothesis to be rejected (based on the ORR with nivolumab monotherapy in the CheckMate 275 phase 2 trial). A confirmed investigator-assessed objective response was recorded in 27 (33%) patients in the ITT population, including 6 (7%) patients who had a complete response. This ORR was significantly higher than the prespecified threshold of 20% or less (33%; 90% CI, 24-42; P=.0049).
The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis in 9 (11%) patients and diarrhea in 5 (6%) patients. Two treatment-related deaths were reported due to immune-mediated enterocolitis.
The trial found that treatment with nivolumab and nivolumab plus ipilimumab boosts in both early nonresponders and patients who progress late resulted in significantly improved ORR after previous platinum-based chemotherapy compared with the rate reported with nivolumab alone in the CheckMate 275 trial. High-dose ipilimumab can provide additional benefit, and the combination could be utilized as a rescue strategy for platinum-pretreated patients with mUC.