Phase 3 Trial (Checkmate 057) of Nivolumab (NIVO) Versus Docetaxel (DOC) In Advanced Non Squamous Cell (Non-SQ) NSCLC
Options for advanced non squamous (non-SQ) NSCLC patients who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). Docetaxel (DOC) as second line therapy in non-SQ NSCLC has historically resulted in an objective response rate (ORR) of 9-15% and a median overall survival (mOS) of 8-10 months. In a late-breaking presentation, Paz-Ares and coworkers1 reported the results from CheckMate 057, a randomized, global phase 3 study of nivolumab (NIVO), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in patients with advanced non-SQ NSCLC after failure of PT-DC and a tyrosine kinase inhibitor. A total of 582 patients were randomized to NIVO 3 mg/kg every 2 weeks (n=292) or DOC 75 mg/m2 every 3 weeks (n=290) until progression or discontinuation due to toxicity. The primary clinical endpoint was OS, with secondary endpoints that included investigator-assessed objective ORR (per RECIST v1.1), progression-free survival (PFS), efficacy stratified by PD-L1 expression, quality of life, and safety.
NIVO demonstrated statistically significant superiority in OS (Hazard ratio (HR)=0.73; 96% CI: 0.59, 0.89; P=0.00155) and ORR (19.2% vs 12.4%; P=0.0235) compared with DOC in all predefined subgroups, including age gender, smoking status, and EGFR mutation status (see Table). Moreover, the median duration of response (DOR) was significantly higher for the NIVO group (17.2 months) vs. the DOC group (5.6 months). Importantly, PD-L1 expression was associated with benefit from NIVO; in PD-L1+ patients, NIVO demonstrated improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut-points, but mOS nearly doubled with NIVO vs DOC across the PD-L1 continuum, such that no difference in mOS was observed when PD-L1 was not expressed in the tumor and nearly tripled in tumors with ?10% PD-L1 expression. Grade 3–5 drug-related adverse events (AEs) occurred in 10.5% of NIVO-treated and 53.7% of DOC-treated patients. No deaths were related to NIVO, but there was 1 DOC-related death. The authors concluded that NIVO therapy resulted in significantly superior OS and ORR vs DOC treatment in patients with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO was favorable compared with DOC.
Based on this presentation as well as data from other studies, it seems reasonable to consider NIVO as the new standard of care for previously-treated patients with advanced non-SQ NSCLC. It may also be reasonable to consider NIVO as frontline therapy for selected patients, and to explore its activity in patients with NSCLC containing Alk and EGFR mutations. However, questions remain regarding the use of PD-L1 as a biomarker for patient selection for NIVO, technical issues such as marker heterogeneity within a single tumor, and whether the PD-L1 cutpoints used in this study are the most appropriate.
|Efficacy measure||NIVO (n=292)||DOC (n=290)|
|Median OS, months (95% CI)||12.2 (9.7, 15.0)||9.4 (8.0, 10.7)|
|1-yr OS, % (95% CI)||50.5 (44.6, 56.1)||39.0 (33.3, 44.6)|
|Median response duration,
months (95% CI)
|17.1 (8.4–not estimable)||5.6 (4.4–7.0)|
|mPFS, months (95% CI)||2.3 (2.2, 3.3)||4.2 (3.4, 4.9)|
|1-yr PFS, % (95% CI)||18.5 (14.1, 23.4)||8.1 (5.1, 12.0)|
OS=overall survival; PFS=progression-free survival
- Paz-Ares L, et al. ASCO 2015. Abstract LBA109.