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.

Radiologic Heterogeneity in Responses to Anti–PD-1/PD-L1 Therapy in Metastatic Renal Cell Carcinoma

“…Even in this early stage of development, durable responses with PD-1 inhibitors have already been reported in mRCC (2). Conversely, Case 3 illustrates a prolonged time to achieve PR, though the clinical benefits and CT scans continued for more than 2 years.…”

“…The upregulation of the PD-1 pathway and associated complex interactions with the host have been seen in multiple cancers, and the blockade of this pathway has led to remarkable clinical responses in patients with advanced melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), and several other types of cancer (2)(3)(4).…”

Carcinogenesis of renal cell carcinoma reflected in HLA ligands: A novel approach for synergistic peptide vaccination design

“…[11][12][13] However, peptide vaccine design still lacks a sustainable approach to generate individualized vaccination cocktails that consist of several immunogenic tumor-associated antigens (TAAs) which is essential for adequately addressing intra-and intertumoral heterogeneity. 14,15 The most elegant approach to target this goal is the identification of mutated, immunogenic HLA-presented peptides, which have been discovered in mice transgenic for human MHC 16 and are shown to induce tumor rejection in sarcoma-bearing mice 17 but have not yet been identified in any other species.…”

Statistical Challenges in the Design of Late-Stage Cancer Immunotherapy Studies

“…The long-term survival and delayed clinical effect observed in multiple cancer immunotherapy phase III clinical trials with timeto-event endpoints (5,6,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) pose unique statistical challenges in study design. Four basic models summarize how the long-term survival and delayed clinical effects affect the study design with time-to-event endpoints (41).…”

“…11, 12) and the PD-1 ligand, PD-L1 (13), led to the selection of "Cancer Immunotherapy" as the 2013 Breakthrough of the Year by Science (14). Nivolumab, a fully human IgG4 (Immunoglobulin G subclass 4) monoclonal antibody to PD-1, showed promising efficacy in multiple tumor types (15)(16)(17)(18). The significant survival benefit led to decisions by data monitoring committees to discontinue ahead of schedule four randomized phase III nivolumab clinical trials in metastatic melanoma (19), squamous and nonsquamous non-small cell lung cancer (NSCLC; refs.…”