A tailored immunotherapy regimen using nivolumab (Opdivo) induction and “boosts” with nivolumab and high-dose ipilimumab (Yervoy) as second-line treatment for metastatic urothelial cancer was associated with higher response rates compared with historical controls, the phase II TITAN-TCC trial showed.

Among 83 patients in the intention-to-treat (ITT) population, a confirmed investigator-assessed objective response occurred in 33% of patients, including 7% who had a complete response, reported Marc-Oliver Grimm, MD, of Jena University Hospital at Friedrich-Schiller University Jena in Germany, and colleagues.

This objective response rate (ORR) was significantly higher than the prespecified value of 20% (P=0.0049), they noted in Lancet Oncology.

This rate, and the ORR of 46% in the 28 PD-L1-positive patients “compared favorably” with the ORRs observed with nivolumab alone in the pivotal CheckMate 275 trial (20% in the ITT population and 24% in the PD-L1-positive subset), the trial that formed the basis for the approval of nivolumab in locally advanced or metastatic urothelial carcinoma, Grimm and team said.

The results of TITAN-TCC “support the clinical activity of combined PD-1 and CTLA-4 inhibition in patients with metastatic urothelial carcinoma, because the reported objective response rate was higher than that for approved second-line immune checkpoint inhibitor monotherapies, including nivolumab,” they wrote.

“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,” they added.

Grimm and colleagues said that while nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma, the CheckMate 032 trial demonstrated improved outcomes with a combination of nivolumab plus high-dose ipilimumab in these patients. However, this was accompanied by a high incidence of grade 3/4 treatment-related adverse events (39.1%) with the highest ipilimumab dose.

Using the tailored approach in this trial, “we aimed to maintain activity similar to that reported for upfront dual checkpoint inhibition and reduce treatment-related adverse events,” Grimm and colleagues wrote.

TITAN-TCC was a single-arm, phase II trial conducted across 19 hospitals and cancer centers in Germany and Austria, and included 83 patients (median age 68, 57% men) with histologically confirmed metastatic or surgically unresectable urothelial cancer.

Patients had to have progressed during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per RECIST version 1.1 criteria.

Patients received four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, and those with a partial or complete response at week 8 continued maintenance nivolumab. Those with stable or progressive disease (considered non-responders) received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Those who subsequently had progressive disease during nivolumab maintenance also received a boost.

Fifty of the 83 patients received at least one boost of nivolumab plus ipilimumab.

The median follow-up was 5.6 months in the ITT population and 13.9 months for patients alive at data cutoff.

At data cutoff, 58% of patients in the ITT population had died. Median overall survival (OS) was 7.6 months, and the OS rate was 56% at 6 months, 39% at 12 months, and 36% at 18 months.

Median progression-free survival (PFS) was 1.9 months, and the PFS rate was 28% at 6 months, 21% at 12 months, and 18% at 18 months.

“Further follow-up is ongoing to measure long-term outcomes (such as progression-free survival and overall survival), but our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg in patients with metastatic urothelial carcinoma and helps to frame dual checkpoint inhibition in the context of available therapies,” Grimm and colleagues concluded.

There were no new safety signals with nivolumab or nivolumab plus ipilimumab in the study. Treatment-related adverse events of any grade occurred in 76% of patients, while grade 3/4 events occurred in 36%, the most common of which were immune-mediated enterocolitis (11%) and diarrhea (6%). Two treatment-related deaths were reported, both due to immune-mediated enterocolitis.

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