Nivolumab is a PD-1 checkpoint inhibitor that showed a clinically meaningful survival benefit, with an improved safety profile, over that seen with the current standard of care in patients with advanced, previously treated squamous-cell NSCLC.…
—Julie Brahmer, MD, and colleagues
In a phase III trial reported in The New England Journal of Medicine, Julie Brahmer, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, and colleagues found that treatment with the programmed cell death protein 1 (PD-1) immune checkpoint inhibitor antibody nivolumab (Opdivo) improved overall and progression-free survival compared with docetaxel in patients with advanced previously treated squamous cell non–small cell lung cancer (NSCLC).
In this open-label international trial, 272 patients with stage IIIB or IV squamous cell NSCLC who had disease recurrence after one prior platinum-containing regimen were randomly assigned between October 2012 and December 2013 to receive nivolumab at 3 mg/kg every 2 weeks (n = 135) or docetaxel at 75 mg/m2 every 3 weeks (n = 137) until disease progression or unacceptable toxicity. Randomization was stratified by prior use of paclitaxel and geographic region (United States or Canada vs Europe vs “rest of the world”—ie, Argentina, Australia, Chile, Mexico, and Peru).
The nivolumab and docetaxel groups were generally balanced for all patient characteristics considered. The primary endpoint was overall survival.
Overall and Progression-Free Survival
Minimum follow-up was approximately 11 months. Median overall survival was 9.2 months (95% confidence interval [CI] = 7.3–13.3 months) in the nivolumab group vs 6.0 months (95% CI = 5.1–7.3 months) in the docetaxel group (hazard ratio [HR] = 0.59, P < .001).
At 1 year, overall survival was 42% (95% CI = 34%–50%) vs 24% (95% CI = 17%–31%). Hazard ratios favored nivolumab across all prespecified subgroups, except for the “rest of the world” geographic subgroup and among the 29 patients aged ≥ 75 years. Median progression-free survival was 3.5 months (95% CI = 2.1–4.9 months) vs 2.8 months (95% CI = 2.1–3.5 months; HR = 0.62, P < .001). The rate of progression-free survival at 1 year was 21% vs 6%.
After discontinuation of treatment, systemic therapy was received by 36% of the nivolumab group (24% received docetaxel) and 30% of the docetaxel group.
PD-1 ligand (PD-L1) expression levels were quantifiable in 83% of patients. PD-L1 expression across the prespecified levels of 1%, 5%, and 10% was not associated with overall or progression-free survival, with outcomes being consistently better with nivolumab and improvements with nivolumab being similar in magnitude to those in the overall population across all expression-level subgroups.
Objective response was observed in 20% vs 9% of patients (P = .008). Similar rates of response were observed in nivolumab patients with PD-L1–negative and PD-L1–positive tumors.
Among 28 nivolumab patients who continued to receive nivolumab after disease progression, a nonconventional pattern of benefit was observed in 9, consisting of appearance of a new lesion followed by decrease from baseline ≥ 10% in the sum of target lesions, initial increase from nadir ≥ 20% in sum of target lesions followed by reduction from baseline ≥ 30%, or initial increase from nadir ≥ 20% in the sum of target lesions followed by at least two tumor assessments showing no further progression (defined as 10% additional increase in the sum of target lesions and new lesions).
Treatment-related adverse events of any grade occurred in 58% of the nivolumab group vs 86% of the docetaxel group, including treatment-related grade 3 or 4 events in 7% vs 55%. The most common treatment-related adverse events of any grade in the nivolumab group were fatigue (16%), decreased appetite (11%), and asthenia (10%), and the most common in the docetaxel group were neutropenia (33%), fatigue (33%, grade 3 or 4 in 30%), alopecia (22%), and nausea (23%). Febrile neutropenia occurred in 10% of the docetaxel group. Among adverse events of special interest, one case each of grade 3 tubulointerstitial nephritis, colitis, and pneumonitis were reported in nivolumab patients
Treatment-related serious adverse events occurred in 7% vs 24% of patients, with the greater frequency in the docetaxel group reflecting primarily hematologic toxicity and infection. Treatment-related adverse events led to treatment discontinuation in 3% of the nivolumab group (pneumonitis in 2%) vs 10% of the docetaxel group (peripheral neuropathy in 3% and fatigue in 2%). Two additional patients in the nivolumab group discontinued treatment due to pneumonitis but were not included in the aforementioned rates (“one for whom the relationship was changed from not treatment-related to treatment-related after database lock, and one who discontinued treatment > 30 days after the most recent dose”).
Treatment-related death occurred in no patients in the nivolumab group and in three patients in the docetaxel group. These deaths were attributed to interstitial lung disease, pulmonary hemorrhage, and sepsis.
The investigators concluded: “Nivolumab is a PD-1 checkpoint inhibitor that showed a clinically meaningful survival benefit, with an improved safety profile, over that seen with the current standard of care in patients with advanced, previously treated squamous-cell NSCLC. The benefit was observed regardless of prestudy PD-L1 expression level. Further research is needed to identify relevant biomarkers that have sufficient sensitivity and specificity to predict which patients are most likely to benefit.” ■
Disclosure: The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.nejm.org.
1. 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.