Nivolumab in combination with gemcitabine/cisplatin chemotherapy has demonstrated significant benefits in specific subsets of urothelial carcinoma patients, according to recent data presented at the 2024 ESMO Congress and ASCO Annual Meeting. The CheckMate 901 trial revealed not only improved survival outcomes but also maintained quality of life (QOL) for patients receiving the combination therapy. Additionally, a phase 1/2 trial exploring sacituzumab govitecan with ipilimumab and nivolumab, while halted due to safety concerns, showed promising initial response rates, highlighting the potential of combining antibody-drug conjugates (ADCs) with immune checkpoint inhibitors.
CheckMate 901: Quality of Life and Survival Benefits
The phase 3 CheckMate 901 trial, a randomized study comparing cisplatin/gemcitabine with or without nivolumab, initially presented at the 2023 ESMO Congress, demonstrated an improvement in overall survival (HR 0.78) and progression-free survival (HR 0.72) with the addition of nivolumab. The complete response (CR) rate nearly doubled, from 11.8% with chemotherapy alone to 21.7% with the nivolumab combination, with a median duration of CR of 37.1 months in the nivolumab arm.
An exploratory analysis of QOL outcomes from CheckMate 901, presented at the 2024 ESMO Congress, indicated that the addition of nivolumab to cisplatin/gemcitabine did not negatively impact QOL. Guru Sonpavde, MD, assistant director of the Clinical Research Unit at AdventHealth Cancer Institute, noted, "These results consolidate the role of this regimen by showing that it does not lead to any declining QOL, and it does improve outcomes."
High Response Rates in Lymph Node-Only Metastatic Disease
Further analysis of the CheckMate 901 trial, presented at the 2024 ASCO Annual Meeting, focused on patients with lymph node-only metastatic urothelial carcinoma. This subset experienced a particularly high complete response rate of 63% with the nivolumab/chemotherapy combination, compared to 33.9% with chemotherapy alone. The 12-month complete response rate was also significantly higher in the combination arm (70% vs 32%).
Matthew D. Galsky, MD, of the Tisch Cancer Institute, emphasized the potential implications for treatment strategies, stating, "The objective response rates and complete response rates for the combination of nivolumab with gemcitabine/cisplatin make this an attractive option for such patients in hopes of facilitating curative-intent surgery."
Sacituzumab Govitecan Combination Trial Halted Due to Toxicity
An investigator-initiated phase 1/2 trial explored the combination of sacituzumab govitecan, a TROP-2-targeted ADC, with ipilimumab and nivolumab in cisplatin-ineligible metastatic urothelial carcinoma patients. The recommended phase 2 dose (RP2D) was identified as sacituzumab govitecan 8 mg/kg on days 1 and 8, combined with ipilimumab 3 mg and nivolumab 1 mg. Initial results showed an overall response rate (ORR) of 83.3% in efficacy-evaluable patients, with a median duration of response of 8.04 months at a median follow-up of 21.57 months.
However, the trial was prematurely terminated due to two cases of grade 5 immune myocarditis attributed to the ipilimumab/nivolumab combination. Despite the toxicity, the high response rate suggests the potential of this combination, warranting further investigation into predictive biomarkers for adverse events. Dr. Sonpavde noted the importance of proceeding carefully to prevent associated toxicities and ensure a reasonable therapeutic index.
Correlative studies are underway to investigate potential predictors of immune myocarditis, including the role of UGT1A1 polymorphisms that may increase toxicity from the sacituzumab govitecan payload. These efforts aim to identify patients at higher risk and refine treatment strategies to maximize efficacy while minimizing severe adverse events.
