Biomarker Analysis of Nivolumab in Previously Treated and Untreated Patients with Metastatic Renal Carcinoma
Nivolumab is a fully human monoclonal antibody that inhibits the programmed death-1 (PD-1) immune checkpoint receptor to restore T-cell antitumor immune responses. Nivolumab demonstrated clinical activity in previously treated patients with metastatic renal-cell carcinoma (mRCC), with an overall response rate (ORR) of 29% and a 1-year overall survival rate of 70%. To establish the optimal dose of nivolumab in patients with mRCC to achieve the best clinical activity, a prospective, open-label, parallel-group, randomized phase 1 trial was conducted in previously treated, as well as treatment-naïve, patients with mRCC (Choueiriri et al. ESMO 2014: Abstract 1051PD).
In addition to assessments of antitumor response and safety, this prospective study was specifically focused on biomarker analysis, with the primary objective of investigating the immunomodulatory activity of tumor-infiltrating T-cells from baseline to posttreatment and serum chemokines in patients with mRCC.
In this study, 91 previously treated patients (1-3 previous therapies; ?1 antiangiogenic agent) were randomized to receive nivolumab 0.3, 2, or 10 mg/kg intravenously, every 3 weeks, whereas the 24 previously untreated patients received nivolumab 10 mg/kg. Across all dose groups, T-cell infiltrates increased from baseline to C2D8 by a median of 78% for CD3+ and by a median of 88% for CD8+. The mean increase from baseline to C4D1 was 180% and 79% for the chemokines CXCL9 and CXCL10, respectively. Tumor-infiltrating lymphocytes increased in the previously treated and the treatment-naïve patients, and this was independent of dose.
Among the 90 evaluable patients included in the overall population, the ORR was 17% and included 12 of 67 (18%) previously treated patients and 3 of 23 (13%) treatment-naïve patients; 6 (43%) of these responses are ongoing. The median duration of response was 64 weeks. The progression-free survival rate was 18% at 48 weeks. Based on an analysis of PD-ligand 1 (PD-L1) expression (n = 56), the ORR was 22% for PD-L1–positive patients and 8% for PD-L1–negative patients.
Grade 3 or 4 adverse events occurred in 15% (n = 14) of the patients, including 2 cases of colitis, 2 cases of elevated AST, 1 case of diarrhea, 1 case of elevated ALT, and 1 case of pneumonitis.
Choueiriri and colleagues concluded that nivolumab demonstrated antitumor activity and a manageable safety level in patients with previously treated or untreated mRCC; no dose-response relationship was observed. The biomarker analysis was consistent with downstream immunomodulatory effects of nivolumab, resulting from PD-1 inhibition.