Data from the phase 2 TITAN-TCC trial suggest that early non-responders with metastatic urothelial carcinoma with PD-L1–positive tumors benefit from nivolumab plus nivolumab/ipilimumab boosts.
Treatment consisting of nivolumab (Opdivo) followed by nivolumab and ipilimumab (Yervoy) boosts in early non-responders with metastatic urothelial carcinoma produced improvements in responses compared with findings reported in the phase 2 CheckMate-275 trial (NCT02387996), according to data from the phase 2 TITAN-TCC trial (NCT03219775).
In the intent-to-treat (ITT) population, the objective response rate (ORR) was 33% (90% CI, 24%-42%) with nivolumab induction with or without nivolumab plus ipilimumab boosts. Of those who were treated, 7% achieved complete responses (CRs) and 25% experienced partial responses (PRs). Following nivolumab induction with or without nivolumab plus ipilimumab boosts, the ORR was 46% among patients with PD-L1–positive disease and 24% in the PD-L1–negative population.
Investigators determined that the ORRs reported in the ITT and PD-L1–positive populations of the TITAN-TCC trial were significantly better than the prespecified values of 20% with nivolumab monotherapy in the ITT population and 24% in the PD-L1–positive population of the CheckMate-275 trial.
“Treatment with nivolumab induction therapy and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved [ORR] after previous platinum-based chemotherapy compared with the rate reported for nivolumab as second-line monotherapy in the CheckMate-275 trial,” the study authors stated. “Patients with PD-L1–positive tumors appear to benefit the most from this treatment approach.”
Investigators of the multi-center, single-arm, phase 2 TITAN-TCC trial assessed patients across 19 hospitals and cancer centers in Germany and Austria. Following induction with 4 doses of nivolumab at 240 mg intravenously every 2 weeks, patients with a CR or PR at 8 weeks continued maintenance with nivolumab. Those who had stable or progressive disease at week 8 or progressive disease following nivolumab maintenance received a boost of 2 or 4 doses of intravenous nivolumab at 1 mg/kg plus 3 mg/kg of ipilimumab every 3 weeks.
The primary end point was investigator-assessed ORR in the ITT population. Secondary end points included remission rates, overall survival (OS), progression-free survival (PFS), duration of response (DOR), and safety.
Patients 18 years and older with a histologically confirmed diagnosis of metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible for enrollment on the trial. Additional inclusion criteria included having disease progression during or after first-line platinum-based chemotherapy and up to 1 more second- or third-line treatment, a Karnofsky performance score of at least 70, and measurable disease per RECIST v1.1 criteria.
In the ITT population, patients had a median age of 68 years (interquartile range, 61-76). Additionally, most patients were male (69%), White (99%), had urothelial carcinoma located in the bladder (87%), and a Karnofsky performance status of 100 (51%). Eighty-four percent had received gemcitabine or cisplatin as first-line systemic therapy, and 34% had PD-L1 expression of at least 1%.
For all responders, the median duration of stable disease was 3.2 months (95% CI, 3.0-7.0), and the median DOR was not reached (95% CI, 6.9-not estimable).
The median OS was 7.6 months (95% CI, 5.1-14.9). The 6-month, 12-month, and 18-month OS rates, respectively, were 56% (95% CI, 44%-66%), 39% (95% CI, 28%-50%), and 36% (95% CI, 25%-48%). Additionally, the median PFS was 1.9 months (95% CI, 1.8-3.2). The PFS rates at 6 months, 12 months, and 18 months, respectively, were 28% (95% CI, 19%-38%), 21% (95% CI, 13%-31%), and 18% (95% CI, 10%-27%).
Overall, 98% of patients developed at least 1 any-grade adverse effect (AE), and grade 3/4 AEs occurred in 36% of patients. Additionally, 37% of patients had treatment delays due to treatment-related AEs (TRAEs), and 16% discontinued treatment due to a TRAE. The most common any-grade TRAEs included rash (24%), diarrhea (20%), fatigue or asthenia (18%), colitis (17%), and generalized pruritus (12%).
Investigators indicated that the most common reasons for treatment discontinuation included AEs, intercurrent illness, or rapid disease progression (40%); death (22%); and immune-related AEs (18%). Overall, 13 patients discontinued treatment due to study drug toxicity, including 6 due to immune-mediated enterocolitis and 1 each due to increased alanine and aspartate aminotransferases, colitis, dermatitis, diabetes, diarrhea, immune-mediated hepatitis, and pneumonitis.
Grimm M, 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. Published online February 28, 2023. doi:10.1016/ S1470-2045(23)00053-0