(UroToday.com)Stage 3 urothelial cancer has a poor prognosis, which can be improved modestly with neoadjuvant cisplatin chemotherapy prior to radical cystectomy. However, options to improve prognosis in patients that are to receive cisplatin are lacking. The NABUCCO trial, cohort 1, involved treating stage 3 urothelial cancer patient with two doses of neoadjuvant ipilimumab (3 mg/kg) with a dose of nivolumab 1 mg/kg followed by a fourth treatment dose with nivolumab 3 mg/kg. This approach resulted in a 46% pathologic complete response rate (pCR) at the time of cystectomy, and 58% of patients had either pCR or non-invasive disease.1
Pharmacokinetics from cohort 1 revealed that the dosing schedule resulted in short duration of exposure to nivolumab relatively late in neoadjuvant therapy. Given the promising efficacy of ipilimumab 1 mg/kg and nivolumab 3 mg/kg as well as its tolerability in other cancer, the investigators of this study opened NABUCCO cohort 2 to explore the optimal dose of neoadjuvant ipilimumab and nivolumab.
The treatment design for cohort 1 and cohort 2 are shown below. The primary endpoint of cohort 2 was also the rate of pCR. A total of 15 patients were enrolled in each dosing arm of cohort 2.
Patient characteristics are illustrated below. A total of four out of 30 patients did not undergo surgery for the reasons indicated in the slide.
With regards to clinical outcome, the rate of pCR in cohort 2A (ipi 3, nivo 1) was consistent with that observed in cohort 1, whereas the pCR rate in cohort 2B (ipi 1, nivo 3) was substantially lower at 21%. This is different than results from melanoma, which showed comparable results between the two regimens.
The two cohort 2 group had comparable amounts of grade 3 or 4 immune-related adverse events.
The presenter concluded by stating that cohort 2 of NABUCCO suggested that ipi 3/nivo 1 is more efficacious with regards to pCR compared to ipi 1/nivo 3 in stage 3 urothelial cancer. Based on this somewhat surprising result, he suggested that testing for the optimal dosing schedule of immunotherapy agents may be warranted in other cancer contexts. Translational studies to explore the underpinnings of this differential response rate are ongoing.
Presented by: Jeroen Van Dorp, Department of Molecular Carcinogenesis, Netherlands Cancer Institute, Amsterdam, the Netherlands
Written by: Alok Tewari, MD, PhD – Genitourinary Medical Oncologist, Instructor in Medicine, Dana-Farber Cancer Institute, Harvard Medical School,
Twitter: @aloktewar during the 2021 European Society for Medical Oncology (ESMO) Annual Congress 2021, Thursday, Sep 16, 2021 – Tuesday, Sep 21, 2021.
References:
- van Dijk N., Gil-Jimenez A., Silina L. et al "Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial." Nature Medicine. 2020. 26, 1839–1844.https://doi.org/10.1038/s41591-020-1085-z