While treatment with nivolumab (Opdivo) significantly improved overall survival over docetaxel in patients with advanced non–small cell lung cancer in the CheckMate-057 trial, an analysis of deaths occurring within 3 months of initiation of therapy showed numerically more deaths in the nivolumab arm.
Solange Peters, MD, PhD
While treatment with nivolumab (Opdivo) significantly improved overall survival (OS) over docetaxel in patients with advanced non—small cell lung cancer (NSCLC) in the CheckMate-057 trial, an analysis of deaths occurring within 3 months of initiation of therapy showed numerically more deaths in the nivolumab arm, according to findings presented at the IASLC 17th World Conference on Lung Cancer in Vienna.1
The absolute difference in death events between arms within the first 3 months was 15.
“Although nivolumab significantly improved overall survival versus docetaxel in patients with previously treated advanced nonsquamous NSCLC in the CheckMate-057 trial, the Kaplan−Meier overall survival curves for nivolumab and docetaxel crossed at approximately 7 months, suggesting non-proportional hazards between arms,” said Solange Peters, MD, PhD, head of the Thoracic Malignancies Program in the Department of Oncology at the University of Lausanne in Switzerland.
This led Peters and colleagues to investigate the relationship between patient baseline disease characteristics—including PD-L1 expression—and death within the first 3 months of treatment in a post-hoc analysis of data from 582 patients participating in CheckMate-057. All patients had nonsquamous NSCLC and experienced progressive disease (PD) during or after platinum-based doublet chemotherapy; 292 patients were randomly assigned to receive intravenous nivolumab at 3 mg/kg every 2 weeks, and 290 patients were assigned to intravenous docetaxel at 75 mg/m2 every 3 weeks. Nivolumab patients were allowed to continue this treatment beyond PD.
CheckMate-057 met the primary endpoint of OS; median OS was 12.2 months with nivolumab versus 9.5 months in the docetaxel arm (HR, 0.75; 95% CI, 0.83-0.91).2 The 1-year OS rate was 51% versus 39% with nivolumab versus docetaxel, respectively, and the 2-year OS rate continued to favor nivolumab.
However, a numerically higher risk of death was observed with nivolumab compared with docetaxel, with 59 deaths occurring in nivolumab-treated patients versus 44 deaths in the docetaxel arm. At 3 months, 80% of nivolumab-treated patients versus 85% of docetaxel-treated patients were alive, although after this time-point among patients alive longer than 3 months, OS favored nivolumab over docetaxel (HR, 0.59; 95% CI, 0.47−0.74).
The investigators observed that these early deaths were not treatment-related and were attributed to disease progression. Therefore, they evaluated the association between baseline characteristics and early death. Patients were stratified according to prior therapies received, location of disease sites, smoking status, ECOG performance status (PS), PD-L1 expression and the presence of EGFR mutation.
No single baseline factor reliably characterized the OS subgroups. However, by multivariate analysis, factors evaluated in concert were found to associate with higher risk of death during the first 3 months with nivolumab versus docetaxel. The analysis revealed that nivolumab-treated patients with a poorer prognosis (ECOG PS 1, and/or progressive disease) at baseline combined with having lower or no PD-L1 expression may be at higher risk of death within the first 3 months of treatment.
“However, the majority of nivolumab-treated patients with these factors were alive and did not die within the first 3 months, and experienced substantial subsequent benefit,” Peters commented.
She described baseline PD-L1 expression as “a continuum, ranging from 1% to 100%, with increasing expression associated with enhanced overall response and OS benefit from nivolumab; this continuum had no effect on response rates in docetaxel-treated patients.”
“Nivolumab is the standard of care as second-line treatment for advance squamous and nonsquamous NSCLC. While enhanced clinical activity with nivolumab correlates with increasing tumor PD-L1 expression, patients with low or no PD-L1 expression have a comparable probability of response,” she added.
Peters also noted that deep and durable nivolumab responses were observed with nivolumab irrespective of PD-L1 expression levels in the tumor. The favorable safety profile demonstrated with nivolumab was also irrespective of PD-L1 status.
A landmark 3-month evaluation of OS by PD-L1 status in patients alive at 3 months showed that median OS in patients with PD-L1 expression <1% was 14.7 months with nivolumab versus 11.4 months with docetaxel (HR, 0.66; 95 % CI, 0.45-0.97), whereas median OS in patients with PD-L1 expression ≥1% was 17.4 versus 11.3 months with nivolumab versus docetaxel (HR, 0.59; 95 % CI, 0.47-0.74).
“PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pretreated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics,” Peters advised. “Additional biomarker research is ongoing to help identify patients with advanced NSCLC who may derive the most clinical benefit from nivolumab.”