Pretreatment predictive factors for primary resistance to nivolumab plus ipilimumab in advanced renal cell carcinoma: a multicenter collaborative study

OBJECTIVE: To identify pretreatment factors associated with developing primary resistance to nivolumab plus ipilimumab therapy in patients with advanced renal cell carcinoma (RCC). METHODS: We retrospectively reviewed the clinical characteristics, laboratory data, and tumor-related factors in patients with advanced RCC who initiated nivolumab plus ipilimumab as first-line therapy between January 2018 and July 2021. Primary resistance was defined as radiographic or clinical progression within 3 months of treatment initiation. Cases with suspected pseudoprogression were excluded. RESULTS: Eighty-nine patients met the inclusion criteria; 23 exhibited primary resistance. Univariate analysis identified the following significant predictive factors: body mass index (P = .006), lymph node metastasis (P = .021), sarcomatoid differentiation (P = .035), solitary metastatic organ (P = .051), liver metastasis (P = .056), and serum lactate dehydrogenase (LDH) (P = .094). Receiver operating characteristic curve analysis determined an LDH cutoff value of 174 U/L, which was significantly associated with primary resistance (P = .029). Considering the number of primary resistance cases, multivariable analysis incorporated three candidate variables (lymph node metastasis, sarcomatoid differentiation, and LDH ≥ 174 U/L) and identified sarcomatoid differentiation (odds ratio, 4.264; 95% confidence interval (CI), 1.299-14.825; P = .017) and LDH ≥ 174 U/L (odds ratio, 3.634; 95% CI, 1.143-13.770; P = .028) as independent predictors of primary resistance. CONCLUSIONS: Sarcomatoid differentiation on pretreatment biopsy or elevated serum LDH before treatment initiation may predict primary resistance to nivolumab plus ipilimumab therapy in patients with advanced RCC. Alternative regimens should be considered in such cases, particularly for patients who are likely to experience rapid disease progression or for whom the occurrence of P-res is not clinically acceptable.