As reported by Carbone et al in The New England Journal of Medicine, the phase III CheckMate 026 trial has shown no progression-free survival benefit for first-line nivolumab (Opdivo) vs platinum-based chemotherapy in patients with recurrent or stage IV non–small cell lung cancer with programmed cell death ligand 1 (PD-L1) expression ≥ 5%.
In the open-label international trial, 541 patients with PD-L1 tumor-expression level ≥ 1% were randomized between March 2014 and April 2015 to receive nivolumab at 3 mg/kg every 2 weeks (n = 271) or investigator’s choice of platinum doublet chemotherapy every 3 weeks for 4 to 6 cycles (n = 270). In the chemotherapy group, treatment consisted of pemetrexed (Alimta)/carboplatin in 44%, pemetrexed/cisplatin in 33%, gemcitabine/carboplatin in 13%, gemcitabine/cisplatin in 5%, and paclitaxel/carboplatin in 6%; 38% of patients received maintenance pemetrexed. Randomization was stratified according to PD-L1 expression level < 5% vs ≥ 5% and tumor histology of squamous vs nonsquamous. PD-L1 expression was determined by a centralized laboratory using anti–PD-L1 antibody (28-8 antibody). The primary endpoint was progression-free survival assessed by blinded independent central review among patients with PD-L1 expression ≥ 5%. Patients in the chemotherapy group with disease progression could cross over to receive nivolumab. The current report is based on the final data analysis with database lock in August 2016.
Among all randomized patients, the percentage of patients who were women (32% vs 45%) and the percentage of patients with PD-L1 expression ≥ 50% (32% vs 47%) were lower in the nivolumab group vs the chemotherapy group; more patients in the nivolumab group had liver metastases (20% vs 13%); and the median tumor burden (sum of target lesions diameter) was greater in the nivolumab group (median = 82 vs 68 mm). Among other baseline characteristics, for the nivolumab vs chemotherapy groups: median age was 63 vs 65 years (11% vs 12% ≥ 75 years); 94% vs 90% had stage IV disease; an Eastern Cooperative Oncology Group performance status was 0 or 1 for 99% in both; smoking status was never for 11% in both, former for 69% vs 67%, and current for 19% vs 20%; 8% vs 9% had received prior adjuvant and 2% vs 1% had prior neoadjuvant therapy; 38% vs 40% had prior radiotherapy; 24% in both had squamous cell carcinoma and 76% in both had nonsquamous cell carcinoma; 12% vs 13% had brain metastases.
In total, 77% of the nivolumab group vs 78% of the chemotherapy group had PD-L1 expression ≥ 5%. Baseline characteristics among patients with PD-L1 expression ≥ 5% were similar to those of the overall population, including a lower proportion of women (32% vs 44%) and patients with PD-L1 expression ≥ 50% (42% vs 59%) and greater tumor burden (median = 83 vs 70 mm) in the nivolumab group.
Progression-Free Survival in Primary Analysis
Median follow-up was 13.5 months, with a median follow-up for overall survival of 13.7 months. Among the 423 patients with PD-L1 expression ≥ 5%, median progression-free survival was 4.2 months in the nivolumab group vs 5.9 months in the chemotherapy group (hazard ratio [HR] = 1.15, P = 0.25). Median overall survival was 14.4 months vs 13.2 months (HR = 1.02, 95% confidence interval [CI] = 0.80–1.30). After disease progression, 128 patients in the chemotherapy group (60%) received nivolumab. Response rates were 26% vs 33%; 27% vs 10% had progressive disease as best response. Median duration of response was 12.1 vs 5.7 months.
For progression-free survival, unstratified hazard ratios were 0.83 (95% CI = 0.54–1.26) among patients with squamous histology and 1.29 (95% CI = 1.02–1.63) among those with nonsquamous histology. For overall survival, the corresponding hazard ratios were 0.82 (95% CI = 0.54–1.24) and 1.17 (95% CI = 0.91–1.52).
Outcomes in Secondary Analyses
Among all randomized patients, median progression-free survival was 4.4 vs 5.8 months (HR = 1.17, 95% CI = 0.95–1.43), and median overall survival was 13.7 vs 13.8 months (HR =1.07, 95% CI = 0.86–1.33). Among the 214 patients with PD-L1 expression ≥ 50%, hazard ratios were 1.07 (95% CI= 0.77–1.49) for progression-free survival and 0.90 (95% CI = 0.63–1.29) for overall survival. Response rates were 34% vs 39%., respectively.
In an exploratory analysis in patients with high tumor mutation burden (30% of nivolumab group and 39% of chemotherapy group), nivolumab treatment was associated with a greater response rate (47% vs 28%) and better progression-free survival (median 9.7 vs 5.8 months, HR = 0.62, 95% CI = 0.38–1.00). Overall survival was similar between treatments groups irrespective of tumor mutation burden. In total, 68% of chemotherapy group patients with high tumor mutation burden received subsequent nivolumab.
Treatment-related adverse events of any grade occurred in 71% of the nivolumab group vs 92% of the chemotherapy group. The most common were fatigue (21%) and diarrhea (14%) in the nivolumab group and nausea (48%) and anemia (43%) in the chemotherapy group. Treatment-related grade 3 or 4 adverse events occurred in 18% vs 51%. No individual adverse event of grade ≥ 3 occurred in > 1% of the nivolumab group; the most common in the chemotherapy group were anemia (17%) and neutropenia (11%). Serious treatment-related adverse events occurred in 17% vs 18%. Treatment-related adverse events led to discontinuation of treatment in 10% vs 13%.
The investigators concluded: “Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals.”
The study was funded by Bristol-Myers Squibb and others.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.