Nivolumab/Ipilimumab Shows Improved Benefit in Urothelial Carcinoma

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Nivolumab plus ipilimumab has shown a response benefit when given at an increased dose for those with metastatic urothelial carcinoma.

"We aimed to improve efficacy compared with nivolumab monotherapy, an approved second-line therapy for patients with [metastatic urothelial carcinoma]. Additionally, we intended to establish a standard to avoid excess toxic effects of dual immune checkpoint inhibition in responders to nivolumab monotherapy," according to the study authors.

"We aimed to improve efficacy compared with nivolumab monotherapy, an approved second-line therapy for patients with [metastatic urothelial carcinoma]. Additionally, we intended to establish a standard to avoid excess toxic effects of dual immune checkpoint inhibition in responders to nivolumab monotherapy," according to the study authors.

Nivolumab (Opdivo) plus high-dose ipilimumab (Yervoy) as second-line treatment was shown to improve benefits in patients with metastatic urothelial carcinoma, according to results from the phase 2 TITAN-TCC trial (NCT03219775).

Two cohorts were analyzed in this trial. Cohort 1 included those who received previous platinum-based chemotherapy, and cohort 2 included patients who received second- or third-line treatment only. Patients were further separated into nivolumab induction in cohort 1 or second- or third-line therapy.

Regarding the TITAN-TCC approach, 48% (Clopper-Pearson exact 90% CI, 0.34-0.61; 1-sided P <.001) of patients in first-line cohort 1 achieved a response, and 7% had a complete response (CR). The disease control rate (DCR) was 57%. A response to treatment was observed in 27% of patients in later-line cohort 1 (Clopper-Pearson exact 90% CI, 0.17-0.40; 1-sided P = .15), 7% had a CR, and the DCR was 45%. In cohort 2, 33% (Clopper-Pearson exact 90% CI, 0.24-0.42; 1-sided P = .005) of patients responded, with 11% achieving a CR. The DCR was 42%.

“In TITAN-TCC, patients with [metastatic urothelial carcinoma] received a tailored approach with nivolumab induction [with or without] nivolumab [plus] ipilimumab as an immunotherapeutic boost with short-term nonresponse or later progression…We aimed to improve efficacy compared with nivolumab monotherapy, an approved second-line therapy for patients with [metastatic urothelial carcinoma]. Additionally, we intended to establish a standard to avoid excess toxic effects of dual immune checkpoint inhibition in responders to nivolumab monotherapy,” the study authors wrote.

A total of 169 patients were enrolled on this study. All patients received 4 doses of 240 mg of intravenous nivolumab every 2 weeks. Those without a response received nivolumab plus ipilimumab boost once every 3 weeks. Those in cohort 1 were given 2 doses of 3 mg/kg of nivolumab plus 1mg/kg of ipilimumab followed by 2 doses of 1 mg/kg of nivolumab plus 3 mg/kg of ipilimumab if no response occurred. In cohort 2, patients were given 2 to 4 doses of 1 of mg/kg nivolumab plus 3 mg/kg of ipilimumab.

Overall, 86 and 83 patients were enrolled in cohort 1 and cohort 2, respectively. Between both cohorts, 69.8% were male, and the median age was 68 years.

In cohort 1, the median time to follow-up was 10.4 months, 7.5 months for second- or third-line treatment, and 6.2 months for cohort 2. For survivors only, the median follow-up times were 14.4 months, 22.0 months, and 27.2 months, respectively. Of the patients receiving first-line therapy in cohort 1, 57% were given an immunotherapy boost, with 40% after week 8, and 17% for progression. In the later-line cohort, 68% of patients were given a dose, with 55% after week 8, and 14% for later progression. In cohort 2, 61% of patients were given an immunotherapy boost, with 53% after week 8, and 8% for later-line therapy.

The study’s planned end was reached by 5% of patients in first-line cohort 1, 2% in later-line cohort 1, and 10% in cohort 2.

In the first-line cohort 1, the median time to first response was 3.3 months (95% CI, 2.5-not estimable [NE]), not reached (95% CI, 4.5-NE) in the later-line cohort, and 19.5 months (95% CI, 4.8-NE) in cohort 2. The median duration of response was 9.1 months (95% CI, 4.1-NE), 18.7 months (95% CI, 4.2-40.0), and 18.0 months (95% CI, 6.9-34.9) in all cohorts, respectively.

In all cohorts, 62%, 77%, and 64% of patients had died. In first-line cohort 1, the median overall survival was 16.4 months (95% CI, 7.3-28.5); in the second- or third-line cohort, it was 8.3 months (95% CI, 5.3-19.3); and in cohort 2, it was 7.6 months (95% CI, 5.0-14.9). The median progression-free survival was 3.0 months (95% CI, 1.8-6.8), 1.9 months (95% CI, 1.7-5.8), and 1.9 months (95% CI, 1.8-3.2), respectively.

Nivolumab induction and responses to nivolumab plus ipilimumab boosts were also evaluated. At week 8 in the first-line cohort, 29% of patients responded to treatment, with 2% having a CR; the DCR was 48%. In the later-line settings for cohort 1, 23% of patients responded to treatment at week 8, and 2% achieved a CR. The DCR was 41%. In cohort 2, 20% of patients responded to treatment, with 2% achieving a CR. The DCR was 34%.

In the first-line setting, of those who received boosted treatment at week 8, 41% had improved their best response vs 8% in the second or third line and 23% in cohort 2. Of those who were given an immunotherapy boost in first-line cohort 1 after week 8 for progressive disease, 29% improved their best response compared with 33% in the later-line settings and 71% in cohort 2.

At least 1 adverse effect (AE) of any grade was observed in 99% of patients. Grade 3/4 treatment-related AEs (TRAEs) occurred in 37% of patients and were slightly more common in the first-line cohort. Treatment was delayed because of TRAEs in 37% of patients, and 27% discontinued.

Reference

Grimm MO, Schostak M, Grün CB, et al. Nivolumab + ipilimumab as immunotherapeutic boost in metastatic urothelial carcinoma: a nonrandomized clinical trial. JAMA Oncol. Published online May 9, 2024. doi:10.1001/jamaoncol.2024.0938

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