Nivolumab Followed by Nivolumab/Ipilimumab Boosting in Nonresponders Among Previously Treated Patients With Advanced Urothelial Carcinoma

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In a German-Austrian phase II study (TITAN-TCC) reported in The Lancet Oncology, Grimm et al found that a strategy of nivolumab monotherapy followed by immunotherapeutic boosting including high-dose ipilimumab in nivolumab nonresponders showed activity in patients with unresectable or metastatic urothelial carcinoma previously treated with platinum-based chemotherapy.

Study Details

A total of 83 patients with urothelial cancer of the bladder, urethra, ureter, or renal pelvis were enrolled in the multicenter trial between April 2019 and February 2021. Patients received four doses of nivolumab at 240 mg every 2 weeks.

Patients with a partial or complete response at week 8 continued maintenance nivolumab until disease progression or the occurrence of immune-related adverse events requiring discontinuation; those with stable or progressive disease at week 8 received a boost of two or four doses of nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg every 3 weeks. Patients with disease progression during nivolumab maintenance also received the boost.

The primary endpoint was confirmed investigator-assessed objective response rate in the intention-to-treat population. The response rate had to be > 20% to reject the null hypothesis, based on the objective response rate observed with nivolumab monotherapy in the phase II CheckMate 275 trial.


A total of 50 patients (60%) received at least one boost dose of nivolumab plus ipilimumab, including 44 (53%) after nonresponse at week 8 and 6 (7%) for disease progression during nivolumab maintenance. Overall, objective response was observed in 27 patients (33%, 90% confidence interval [CI] = 24%–42%), with complete response in 6 (7%); the objective response rate significantly exceeded the prespecified 20% threshold (P = .0049). Median duration of response was not reached (95% CI = 6.9 months to not estimable).


  • Nivolumab monotherapy followed by nivolumab/ipilimumab boosting in nonresponders was associated with objective response in 33% of patients.
  • Of 27 responders, 17 responded to nivolumab monotherapy and 10 to boosting.

After four doses of nivolumab monotherapy, objective response was observed in 17 patients (20%), with complete response in 2 (2%). Among 13 nonresponders to nivolumab who had stable disease at week 8, boosting resulted in objective response in 4 (31%), including complete response in 1. Among 31 nonresponders with progressive disease at week 8, boosting resulted in objective response (all partial responses) in 6 (19%). Among six patients receiving a first boost later than week 8, two (33%) had partial response.

Among patients with available PD-L1 status, objective response after nivolumab induction with or without nivolumab plus ipilimumab boosts was observed in 13 (46%) of 28 PD-L1–positive patients and 12 (24%) of 51 PD-L1–negative patients.

Median progression-free survival was 1.9 months (95% CI = 1.8–3.2 months), with rates at 6, 12, and 18 months of 28%, 21%, and 18%, respectively. Among patients with objective response to nivolumab monotherapy, median progression-free survival was not reached (95% CI = 6.2 months to not estimable). Median overall survival was 7.6 months (95% CI = 5.1–14.9 months), with rates at 6, 12, and 18 months of 56%, 39%, and 36%, respectively.

Adverse Events

Treatment-related grade 3 or 4 adverse events occurred in 36% of patients, most commonly immune-mediated enterocolitis (11%) and diarrhea (6%). Treatment-related adverse events led to treatment discontinuation in 16% of patients. Treatment-related serious adverse events occurred in 28% of patients, most commonly immune-mediated enterocolitis (12%).  Treatment-related death occurred in two patients (2%), due to immune-mediated enterocolitis in both.

The investigators concluded, “Treatment with nivolumab and nivolumab plus ipilimumab boosts in early nonresponders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate 275 trial. Our study provides evidence for the added value of high-dose ipilimumab [at] 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma.”

Marc-Oliver Grimm, MD, of Jena University Hospital, Friedrich-Schiller University Jena, Jena, Germany, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit

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