Nivolumab (NIV) is a fully human programmed death-1 (PD-1) immune-checkpoint inhibitor antibody in development for a variety of solid tumors, including advanced non-small-cell lung cancer (NSCLC). Like CTLA-4 receptors, PD-1 receptors on tumor cells negatively regulate T-cell activation. However, translational research suggests that CTLA-4 and PD-1 inhibit T-cell activation through distinct and potentially synergistic mechanisms.1
To date, NIV has shown durable clinical activity in a large phase 1 trial of 304 patients with advanced solid tumors.2 Brahmer and colleagues (ASCO 2014; Abstract 8112) updated their analysis of NIV in patients with NSCLC in this phase 1 trial, reporting overall survival (OS) by dose, histology, and PD-L1 tumor status.
A total of 129 patients with relapsed NSCLC received NIV (1, 3, or 10 mg/kg) every 2 weeks for up to 96 weeks in this trial. Over half (54%) of these patients had received 3 or more prior therapies. PD-L1 tumor cell expression was measured in 68 archival specimens using an IHC assay, in which “positive” was defined as ?5% tumor cells.
Across NIV doses and NSCLC histologies, median OS ranged from 9.2 to 14.9 months. One- and 2-year OS rates were 42% and 24% across NIV doses and similar across histologies (squamous: 40% and 24%, respectively; nonsquamous: 43% and 23%, respectively). At the 3-mg/kg NIV dose, median OS was 14.9 months, and 1- and 2-year OS rates were 56% and 45%.
Responses to NIV were observed across a broad array of NSCLC patient populations regardless of histology or KRAS or EGFR mutation status, including heavily pretreated patients and older patients. Among the 129 patients, objective response rate to single-agent NIV was 17% and the median response duration was 17 months. Responses to NIV were observed across all patient subgroups, including those who received <3 prior therapies versus 3 or more, and those with and without EGFR or KRAS mutations, as shown in the Table.
PD-L1 tumor expression was not clearly correlation with OS findings: median OS was 7.8 months in PD-L1-positive patients, and 10.5 months in PD-L1-negative patients.
Table: Clinical Outcomes by NSCLC Subgroup
Abbreviation: NR, not reached. *September 2013 analysis. †One patient had unknown histology.
Grade 3/4 treatment-related adverse events (AEs) were observed in 14% of patients. The most common AEs were fatigue, decreased appetite, and diarrhea.
NIV continues to demonstrate an encouraging survival profile and clinical activity across NSCLC patient subgroups with a manageable safety profile. Ongoing phase 3 trials are evaluating NIV (3 mg/kg) in patients with advanced NSCLC and will further explore the use of PD-L1 expression as a predictor of clinical outcomes.
