In the phase III CheckMate 057 trial, reported in The New England Journal of Medicine by Hossein Borghaei, DO, of Fox Chase Cancer Center, and colleagues, the programmed cell death protein 1 (PD-1) inhibitor nivolumab (Opdivo) improved overall survival vs docetaxel in patients with advanced nonsquamous non–small cell lung cancer (NSCLC).1 (A phase III trial reported earlier this year by Julie
Renee Brahmer, MD, of Sidney Kimmel Comprehensive Cancer Center, and colleagues showed survival improvement with nivolumab vs docetaxel in advanced squamous NSCLC.2)
Study Details
In this open-label international trial, 582 patients with nonsquamous NSCLC progressing during or after platinum-based doublet chemotherapy were randomly assigned between November 2012 and December 2013 to receive intravenous nivolumab at 3 mg/kg every 2 weeks (n = 292) or intravenous docetaxel at 75 mg/m2 every 3 weeks (n = 290). Nivolumab patients could receive the drug beyond disease progression.
The primary endpoint was overall survival. Formal testing for the primary endpoint was based on a prespecified interim analysis; the current report provided an updated P value based on data from a July 2, 2015, database lock.
The nivolumab and docetaxel groups were generally balanced for all patient characteristics that were assessed.
Overall Survival
Minimum follow-up for overall survival was 13.2 months. Median overall survival was 12.2 months (95% confidence interval [CI] = 9.7–15.0 months) in the nivolumab group vs 9.4 months (95% CI = 8.1–10.7 months) in the docetaxel group (hazard ratio [HR] = 0.73, P = .002). Overall survival rates were 51% (95% CI = 45%–56%) vs 39% (95% CI = 33%–45%) at 1 year. With additional follow-up, median overall survival was 12.2 months (95% CI = 9.7–15.1 months) vs 9.4 months (95% CI = 8.1–10.7 months; HR = 0.72, P < .001), and overall survival at 18 months was 39% (95% CI = 34%–45%) vs 23% (95% CI = 19%–28%).
Subgroup analysis showed that hazard ratios favored nivolumab in most subgroups, except among 66 patients receiving third-line therapy, 98 patients in the “rest of the world” geographic subgroup (South America, Asia, and Australia), 68 patients with central nervous system metastases, 118 never-smokers, and 82 patients with an epidermal growth factor receptor (EGFR)mutation; none of the hazard ratios for these subgroups was significant. Subsequent systemic cancer therapy was received by 42% of the nivolumab group (23% docetaxel, 29% taxanes) and 50% of the docetaxel group (27% antimetabolites, 2% immunotherapy).
Response Rate
The overall response rate was 19% with nivolumab vs 12% with docetaxel (P = .02). Median duration of response was 17.2 vs 5.6 months.
Among 71 patients in the nivolumab group (24%) who continued treatment after initial progression, 16 (23%) exhibited a nonconventional pattern of benefit.
Outcomes by PD-L1 Level
PD-1 ligand (PD-L1) expression was quantifiable in 455 patients (78%). A test for interaction at interim analysis indicated significant associations between treatment effect and PD-L1 expression level. The hazard ratio for overall survival was 0.59 (95% CI = 0.43–0.82) among 123 nivolumab and 123 docetaxel recipients with levels ≥ 1%, 0.43 (95% CI = 0.30–0.63), among 95 nivolumab and 86 docetaxel recipients with levels ≥ 5%, and 0.40 (95% CI = 0.26-0.59) among 86 nivolumab and 79 docetaxel recipients with levels ≥ 10%. The corresponding hazard ratios for progression-free survival were 0.70 (95% CI = 0.53–0.94), 0.54 (95% CI = 0.39–0.76), and 0.52 (95% CI = 0.37–0.75).
Adverse Events
The most common treatment-related adverse events of any grade were fatigue (16%), nausea (12%), decreased appetite (10%), and asthenia (10%) in the nivolumab group and neutropenia (31%), fatigue (29%), nausea (26%), and alopecia (25%) in the docetaxel group. Treatment-related grade 3 or 4 adverse events occurred in 10% (most common = fatigue, nausea, and diarrhea in 1% each) vs 54% (most common = neutropenia in 27%, febrile neutropenia in 10%). Treatment-related serious adverse events occurred in 7% vs 20%.
Treatment-related adverse events led to discontinuation of study drug in 5% vs 15%, with the most common causes being pneumonitis in the nivolumab group (1%) and fatigue in the docetaxel group (3%). Dose delay occurred in 39% of the nivolumab group (45% due to adverse events) and 37% of the docetaxel group (46% due to adverse events). One death in the nivolumab group (due to encephalitis) and one in the docetaxel group (due to febrile neutropenia) were considered related to study treatment.
The most frequently reported treatment-related select adverse events, including immune-related events, of any grade were rash (9% of the nivolumab group vs 3% of the docetaxel group), pruritus (8% vs 1%), erythema (1% vs 4%), diarrhea (8% vs 23%), hypothyroidism (7% vs 0%), increased alanine transaminase (3% vs 1%), increased aspartate transaminase (3% vs 1%), infusion-related reaction (3% vs 3%), and pneumonitis (3% vs < 1%).
The investigators concluded: “Among patients with advanced nonsquamous NSCLC that had progressed during or after platinum-based chemotherapy, overall survival was longer with nivolumab than with docetaxel.” ■
Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.nejm.org.
References
1. Borghaei H, Paz-Ares L, Horn L, et al: Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med 373:1627-1639, 2015.
2. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015.
