Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab

Abstract

Purpose: Blockade of the programmed death-1 inhibitory cell-surface molecule on immune cells using the fully human immunoglobulin G4 antibody nivolumab mediates tumor regression in a portion of patients with advanced treatment-refractory solid tumors. We report clinical activity, survival, and long-term safety in patients with advanced renal cell carcinoma (RCC) treated with nivolumab in a phase I study with expansion cohorts.

Patients and methods: A total of 34 patients with previously treated advanced RCC, enrolled between 2008 and 2012, received intravenous nivolumab (1 or 10 mg/kg) in an outpatient setting once every two weeks for up to 96 weeks and were observed for survival and duration of response after treatment discontinuation.

Results: Ten patients (29%) achieved objective responses (according to RECIST [version 1.0]), with median response duration of 12.9 months; nine additional patients (27%) demonstrated stable disease lasting > 24 weeks. Three of five patients who stopped treatment while in response continued to respond for ≥ 45 weeks. Median overall survival in all patients (71% with two to five prior systemic therapies) was 22.4 months; 1-, 2-, and 3-year survival rates were 71%, 48%, and 44%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 18% of patients; all were reversible.

Conclusion: Patients with advanced treatment-refractory RCC treated with nivolumab demonstrated durable responses that in some responders persisted after drug discontinuation. Overall survival is encouraging, and toxicities were generally manageable. Ongoing randomized clinical trials will further assess the impact of nivolumab on overall survival in patients with advanced RCC.

Fig 1.

Characteristics of tumor regression in patients with renal cell carcinoma receiving nivolumab therapy. (A) Maximum reduction or minimum increase in sum of target lesion measurements compared with baseline in all treated patients with on-treatment tumor measurements (n = 32). Bar colors indicate nivolumab dose cohorts 1 or 10 mg/kg. Graph shows best individual change during study. Tumors were assessed after each cycle per RECIST (version 1.0) guidelines. Baseline tumor measurements were standardized to zero, and tumor burden was measured as sum of longest diameters of target lesions. Horizontal line at 20% indicates threshold for defining progressive disease according to RECIST; horizontal line at −30% indicates threshold for defining objective response (partial tumor regression) in absence of new lesions or nontarget disease progression according to RECIST. Objective responses were observed at both dose levels (1 and 10 mg/kg). Unconventional response patterns that did not meet RECIST criteria (eg, persistent reduction in target lesions in presence of new lesions, regression after initial progression) were observed in three patients (9%; indicated by asterisks). Response kinetics in patients receiving nivolumab (B) 1 or (C) 10 mg/kg. Baseline tumor measurements were standardized to zero. Tumor burden was measured as sum of longest diameters of target lesions. (B) Asterisk indicates off-scale value of 144%. Gold triangles indicate first occurrence of new lesion. (B, C) Vertical line at 96 weeks demonstrates maximum duration of planned continuous nivolumab therapy; horizontal line at −30% marks threshold for defining objective response (partial tumor regression) according to RECIST, and horizontal line at +20% indicates the threshold for defining progressive disease. Blue curves indicate unconventional immune-related response patterns that did not meet RECIST criteria in (B) one patient at 1-mg/kg dose and (C) two patients at 10-mg/kg dose. Objective responses, unconventional responses, and stable disease persisted after treatment discontinuation in some patients. According to RECIST criteria, 56% of patients (19 of 34) achieved objective response or disease stabilization exceeding 24 weeks (Table 2). (D) Durability of tumor regressions. Ten (29%) of 34 patients had objective tumor regressions, including five (28%) of 18 patients receiving nivolumab 1 mg/kg and five (31%) of 16 patients receiving 10 mg/kg. Blue bars indicate time to and duration of response during treatment; gold bars indicate response duration after treatment discontinuation; open circles indicate first evidence of objective response; arrows indicate ongoing response at time of analysis. Vertical line at 96 weeks indicates maximum duration of planned continuous nivolumab therapy. Reasons for treatment discontinuation with ongoing response included investigator-assessed complete response, attainment of maximum treatment duration, adverse events, investigator discretion, and withdrawal of patient consent.

Fig 2.

Computed tomography scans showing partial response in primary tumor of metastatic renal cell carcinoma in patient treated with nivolumab; 48-year-old patient with low-volume but poorly differentiated disease who developed progressive disease after sunitinib, sorafenib, and thoracic surgery achieved partial response in primary tumor (indicated by arrows) after treatment with nivolumab 1 mg/kg. Treatment was held after three cycles, and response continued for 3 years after therapy.

Fig 3.

Efficacy outcomes in patients with renal cell carcinoma (RCC) receiving nivolumab. Kaplan-Meier curves of (A) overall and (B) progression-free survival in 34 nivolumab-treated patients with RCC. Analysis includes patients from both 1- and 10-mg/kg dose cohorts. (A) Patients with RCC had 1-, 2-, and 3-year overall survival rates of 71%, 48%, and 44%, respectively; median overall survival was 22.4 months. (B) Progression-free survival rates were 35% and 12% at 1 and 2 years, respectively; median was 7.3 months. Open circles indicate censored events, defined for overall survival as time to last known date alive before date of data analysis for patients without death, and defined for progression-free survival as time to last tumor assessment before date of data analysis for patients without disease progression or death. NE, not estimable.