Primary resistance to nivolumab plus ipilimumab therapy in patients with metastatic renal cell carcinoma

Abstract

BackgroundNivolumab plus ipilimumab (NIVO+IPI) is the first‐line treatment for patients with metastatic renal cell carcinoma (mRCC). Approximately 40% of patients achieve a durable response; however, 20% develop primary resistant disease (PRD) to NIVO+IPI, about which little is known in patients with mRCC. Therefore, this investigation aimed to evaluate the clinical implication of PRD in patients with mRCC to select better candidates in whom NIVO+IPI can be initiated as first‐line therapy.MethodsThis multi‐institutional retrospective cohort study used data collected between August 2015 and January 2023. In total, 120 patients with mRCC treated with NIVO+IPI were eligible. Associations between immune‐related adverse events and progression‐free survival, overall survival (OS), and objective response rate were analyzed. The relationship between other clinical factors and outcomes was also evaluated.ResultsThe median observation period was 16 months (interquartile range, 5–27). The median age at NIVO+IPI initiation was 68 years in the male‐dominant population (n = 86, 71.7%), and most patients had clear cell histology (n = 104, 86.7%). PRD was recorded in 26 (23.4%) of 111 investigated patients during NIVO+IPI therapy. Patients who experienced PRD showed worse OS (hazard ratio: 4.525, 95% confidence interval [CI]: 2.315–8.850, p < 0.001). Multivariable analysis showed that lymph node metastasis (LNM) (odds ratio: 4.274, 95% CI: 1.075–16.949, p = 0.039) was an independent risk factor for PRD.ConclusionsPRD was strongly correlated with worse survival rates. LNM was independently associated with PRD in patients with mRCC receiving NIVO+IPI as first‐line therapy and might indicate that a candidate will not benefit from NIVO+IPI.

Combined Administration of Escitalopram Oxalate and Nivolumab Exhibits Synergistic Growth-Inhibitory Effects on Liver Cancer Cells through Inducing Apoptosis

“…Recent clinical trials such as KEYNOTE-240 and CheckMate 459 in HCC treatment did not achieve their predefined goals for overall survival [ 31 ]. Additionally, resistance to ICI treatment, including nivolumab, has been reported in cancers such as ovarian cancer, renal cell carcinoma, and esophageal squamous cell carcinoma [ 32 , 33 , 34 ]. Therefore, the combination of ICIs with other therapies, such as tyrosine kinase inhibitors (TKIs), chemotherapy, or local therapy, is commonly considered and adopted in cancer therapy [ 31 ].…”

The role of RNA-modifying proteins in renal cell carcinoma

“…Although combination therapy showed more effective outcomes, it may induce added toxicity compared to monotherapy [ 19 ]. Primary or acquired treatment resistances remain significant clinical challenges [ 20 , 21 ]. Given these challenges, it is crucial to look for novel therapeutic targets and biomarkers of RCC.…”