Nivolumab is an established second-line treatment for patients with metastatic urothelial carcinoma. More recently, dual checkpoint inhibition has emerged as a potential strategy to further improve outcomes in this setting. In this context, the phase 2 TITAN TCC trial evaluated the safety and activity of nivolumab and ipilimumab boosts as second-line treatment for these patients. The results of this study, recently published in Lancet Oncology, show that this approach improved objective response in this setting, compared with the rate reported for nivolumab as second-line monotherapy in the CheckMate-275 trial.
PD-(L)1 inhibitors have become an established second-line therapy after platinum-based chemotherapy for patients with locally advanced or metastatic urothelial carcinoma. The PD-1 inhibitor nivolumab was granted approval as a second-line therapy based on the results of the single-arm, phase 2 CheckMate-275 trial, in which the objective response rate of 20.7% was reported, with a median overall survival of 8.6 months. Based on the improved outcomes observed with dual checkpoint inhibition in patients with melanoma and renal cell carcinoma, trials of dual checkpoint inhibitor combinations have also been initiated in the urothelial cancer setting. In this respect, the phase 2 TITAN TCC trial evaluated the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost in the second-line treatment of patients with previously treated metastatic urothelial carcinoma.
The single-arm, phase 2 TITAN-TCC trial was performed at 19 hospitals and cancer centres in Germany and Austria. Eligible patients included adults (≥18 years) with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis. In addition, patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas patients with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed objective response rate and had to exceed 20% for the null hypothesis to be rejected, based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial.
In total, 83 patients with metastatic urothelial carcinoma were enrolled and received nivolumab induction treatment (intention-to-treat [ITT] population). The median number of nivolumab induction doses received was four, with 60% of patients receiving at least one boost dose. After a median follow-up of 5.6 months in the ITT population, a confirmed objective response was reported in 33% of patients, including six (7%) patients with a complete response. Importantly, this objective response rate was significantly higher than the prespecified threshold of 20% (p=0.0049). Patients with PD-L1 positive tumours appeared to benefit most from this treatment strategy, with an objective response rate of 46%. For all responding patients, the median duration of response was not reached, whereas the median duration of stable disease was 3.2 months. At data cut-off, 58% of patients had died. The median overall survival was reported at 7.6 months, with a median progression-free survival of 1.9 months. No new safety signals with nivolumab or nivolumab plus ipilimumab were reported. The most common grade 3/4 treatment-related adverse events were immune-mediated enterocolitis (11% of patients) and diarrhoea (6%). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis.
In conclusion, treatment with nivolumab induction therapy and boosts with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg significantly improved the objective response rate after previous platinum-based chemotherapy in early non-responders and patients who progress late, compared with the rate reported for nivolumab as second-line monotherapy in the CheckMate-275 trial. Patients with PD-L1-positive tumours appear to benefit the most from this treatment approach. Although further follow-up is ongoing to measure long-term outcomes, this 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 M-O, Grün CB, Niegisch G, et al. Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2023;24(4):347-59.