Optimal neoadjuvant dose ipilimumab/nivolumab in stage III urothelial cancer

Neoadjuvant high-dose ipilimumab plus low-dose nivolumab is more efficacious than low-dose ipilimumab plus high-dose nivolumab in patients with stage III urothelial cancer, results from the NABUCCO cohort 2 showed.

Standard treatment for patients with stage III (cT3-4aN0M0 or cT1-4aN1-3M0) urothelial cancer is cisplatin-based chemotherapy followed by radical surgery. However, a substantial number of patients is unfit for cisplatin-based chemotherapy. Results from NABUCCO cohort 1 (NCT03387761) showed promising efficacy (46% pathological complete response) of neoadjuvant immunotherapy with ipilimumab/nivolumab [1]. Dosing in this cohort was: ipilimumab 3 mg/kg at day 1 and day 22, and nivolumab 3 mg/kg at day 43. Recent data in pre-operative trials for other cancer types suggests that a lower dose of ipilimumab has equal activity and is better tolerated [2]. NABUCCO cohort 2 compared efficacy and safety of alternative adjuvant dosing regimens. Patients in cohort 2A (n=15) were treated with ipilimumab 3 mg/kg and nivolumab 1 mg/kg at day 1 and day 22, and nivolumab 3 mg/kg at day 43. Patients in cohort 2B (n=15) were treated with ipilimumab 1 mg/kg and nivolumab 3 mg/kg at day 1 and day 22, and nivolumab 3 mg/kg at day 43. Primary endpoint was pathologic complete response (pCR) rate. Secondary endpoints included feasibility (resection within 12 weeks) and grade 3/4 immune-related adverse events. Dr Jeroen van Dorp (Netherlands Cancer Institute, the Netherlands) presented the first results [3].

A total of 26/30 (87%) patients received all 3 treatment cycles; these 26 patients underwent radical surgery, 24 within 12 weeks after start of treatment. Four patients missed one or more cycles of therapy due to immune-related adverse events. Response was evaluable in 28 patients. In cohort 2A, 6/14 (43%) patients had a pCR; 8/14 (57%) had a pCR or ypTisN0. In cohort 2B, 1/14 (7%) had a pCR whereas 3/14 (21%) had a pCR or ypTisN0. Grade 3/4 immune-related adverse events were observed in 5/15 (33%) patients in cohort 2A, and in 3/15 (20%) patients in cohort 2B.

“In contrast to what was observed in other malignancies, neoadjuvant ipilimumab 1 mg/kg and nivolumab 3 mg/kg was less efficacious than ipilimumab 3 mg/kg and nivolumab 1 mg/kg,” concluded Dr van Dorp. Further translational work is currently ongoing.

1. Van Dijk N, et al. Nat Med. 2020;26:1839–1844.
2. Rozeman EA, et al. Lancet Oncol. 2019;20:948–960.
3. Van Dorp J, et al. High- vs low-dose pre-operative ipilimumab and nivolumab in locoregionally advanced urothelial cancer (NABUCCO cohort 2). Abstract LBA31, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 202115 February, 2024