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Checkmate 214 was the first study that demonstrated the efficacy of combination immunotherapy with ipilimumab/nivolumab compared with standard-of-care single-agent sunitinib in patients with previously untreated, intermediate- or high-risk advanced clear cell renal cell carcinoma (RCC). Based on results from this seminal study, the ipilimumab/nivolumab combination was FDA approved in 2018, thereby establishing the concept of doublet therapy as the new gold standard in this patient population.

Despite the superior efficacy observed with combination immunotherapy in the Checkmate 214 study, grade 3 and 4 treatment-related adverse events (TRAEs) occurred in 46% of immunotherapy-treated patients and led to treatment discontinuation in 22% of patients. This toxicity profile as well as immunotherapy dose modification/de-escalation work from other solid tumors led to the inception of the .

The latter was a randomized, phase II study comparing the "standard" immunotherapy dosing of ipilimumab 1 mg/kg with nivolumab 3 mg/kg every 3 weeks for 4 cycles followed by maintenance nivolumab with the "modified" dosing of ipilimumab/nivolumab given every 12 weeks. The study met its primary endpoint of a statistically significant decrease in incidence of serious (i.e., grade 3-5) TRAEs within the first 12 months of treatment with "modified" versus "standard" immunotherapy dosing of 32.8% and 52.1%, respectively.

The rate of immunotherapy discontinuation was also lower with the "modified" immunotherapy dosing, at 22.7% versus 39.1% with the "standard" dosing. Meanwhile, progression-free survival, overall survival, and overall response rate were similar between the "modified" and "standard" arms, although the study was not powered to compare efficacy differences between the treatment arms.

Overall, the PRISM and Checkmate 214 study populations were similar except that PRISM included patients with low-risk RCC, comprising about one third of each treatment group, as well as less patients who had nephrectomy. Despite some limitations, PRISM highlights the possibility of de-escalating the dose intensity of immunotherapy, with potentially comparable efficacy results to conventional dosing.

Nataliya Mar, MD, is associate clinical professor in the Division of Hematology/Oncology at the Chao Family Comprehensive Cancer Center, UCI Health, in Orange, California.

Read the study here and an interview about it here.